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Background: Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma. Methods: In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). Results: A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×106 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×106 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively. Conclusions: The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others

Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or displaying profound lymphopenia and/or rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T cells transduced with a second-generation (4.1BB) CD19-directed CAR for treatment of patients with BCP-ALL in a hospital-exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR–Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy-based manufacturing process (CD19-CAR–Lenti_ALLO). Thirteen children/young adults received ALLO–CAR-T cells between March 2021 and October 2022. Doses ranged between 1.0 × 106 and 3.0 × 106 CAR-T cells per kg. The toxicity profile was comparable with that of autologous CAR-T cells, characterized mainly by cytopenia, cytokine release syndrome (maximum grade 1), and grade 2 immune-effector cell–associated neurotoxicity syndrome. One case of acute graft-versus-host disease (GVHD) occurred and was rapidly controlled with steroids and ruxolitinib. None of the other patients, including 3 given ALLO–CAR-T cells from an HLA-haploidentical donor, experienced GVHD. Two patients received ALLO–CAR-T cells before HSCT and showed a significant expansion of CAR-T cells without any sign of GVHD. All patients obtained complete remission (CR) with absence of minimal residual disease in the bone marrow. With a median follow-up of 12 months (range, 5-21), 8 of 13 patients maintained CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly refractory BCP-ALL relapsing after allo-HSCT without showing increased toxicity as compared with autologous CAR-T cells.

BACKGROUND: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. METHODS: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. RESULTS: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. CONCLUSION: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

Owing to an increasing number of infections in adults, Lactococcus (L.) garvieae has gained recognition as an emerging human pathogen, causing bacteraemia and septicaemia. In September 2020, four paediatric onco-hematologic patients received a platelet concentrate from the same adult donor at Bambino Gesù Children’s Hospital IRCCS, Rome. Three of four patients experienced L. garvieae sepsis one day after transfusion. The L. garvieae pediatric isolates and the donor’s platelet concentrates were retrospectively collected for whole-genome sequencing and shot-gun metagenomics, respectively (Illumina HiSeq). By de novo assembly of the L. garvieae genomes, we found that all three pediatric isolates shared a 99.9% identity and were characterized by 440 common SNPs. Plasmid pUC11C (conferring virulence properties) and the temperate prophage Plg-Tb25 were detected in all three strains. Core SNP genome-based maximum likelihood and Bayesian trees confirmed their phylogenetic common origin and revealed their relationship with L. garvieae strains affecting cows and humans (bootstrap values >100 and posterior probabilities = 1.00). Bacterial reads obtained by the donor’s platelet concentrate have been profiled with MetaPhlAn2 (v.2.7.5); among these, 29.9% belonged to Firmicutes, and 5.16% to Streptococcaceae (>97% identity with L. garvieae), confirming the presence of L. garvieae in the platelet concentrate transfusion. These data showed three episodes of sepsis for the first time due to a transfusion-associated transmission of L. garvieae in three pediatric hospitalized hematology patients. This highlights the importance to implement the screening of platelet components with new human-defined pathogens for ensuring the safety of blood supply, and more broadly, for the surveillance of emerging pathogens.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal disease with a median overall survival (OS) of less than 12 months after diagnosis. Radiotherapy (RT) still remains the mainstay treatment. Several other therapeutic strategies have been attempted in the last years without a significant effect on OS. Although radiological imaging is the gold standard for DIPG diagnosis, the urgent need to improve the survival has led to the reconsideration of biopsy with the aim to better understand the molecular profile of DIPG and support personalized treatment. Methods: In this study, we present a single-center experience in treating DIPG patients at disease progression combining targeted therapies with standard of care. Biopsy was proposed to all patients at diagnosis or disease progression. First-line treatment included RT and nimotuzumab/vinorelbine or temozolomide. Immunohistochemistry-targeted research included study of mTOR/p-mTOR pathway and BRAFv600E. Molecular analyses included polymerase chain reaction, followed by Sanger sequences and/or next-generation sequencing. Results: Based on the molecular profile, targeted therapy was administered in 9 out of 25 patients, while the remaining 16 patients were treated with standard of care. Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (5/9), PI3K/AKT/mTOR pathway and BRAFv600E (1/9), ACVR1 (2/9) and PDGFRA (1/9); no severe side effects were reported during treatment. Response to treatment was evaluated according to Response Assessment in Pediatric Neuro-Oncology criteria, and the overall response rate within the cohort was 66%. Patients treated with targeted therapies were compared with the control cohort of 16 patients. Clinical and pathological characteristics of the two cohorts were homogeneous. Median OS in the personalized treatment and control cohort was 20.26 and 14.18 months, respectively (p = 0.032). In our experience, the treatment associated with the best OS was everolimus. Conclu

Rhabdoid tumors are rare aggressive malignancies in infants and young children with a poor prognosis. The most common anatomic localizations are the central nervous system, the kidneys, and other soft tissues. Rhabdoid tumors share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, members of the SWI/SNF chromatin-remodeling complex. Rhabdoid tumor predisposition syndrome (RTPS) is a condition characterized by a high risk of developing rhabdoid tumors, among other features. RTPS1 is characterized by pathogenic variants in the SMARCB1 gene, while RTPS2 has variants in SMARCA4. Interestingly, germline variants of SMARCB1 and SMARCA4 have been identified also in patients with Coffin-Siris syndrome. Children with RTPS typically present with tumors before 1 year of age and in a high percentage of cases develop synchronous or multifocal tumors with aggressive clinical features. The diagnosis of RTPS should be considered in patients with rhabdoid tumors, especially if they have multiple primary tumors and/or in individuals with a family history. Because germline mutations result in an increased risk of carriers developing rhabdoid tumors, genetic counseling, and surveillance for all family members with this condition is recommended.

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumor in children. Adjuvant treatment, consisting in chemotherapy and radiotherapy, is often necessary if a complete surgical resection cannot be obtained. Traditional treatment approaches result in a significant long-term morbidity, with a detrimental impact on quality of life. Dysregulation of the mitogen-activated protein kinase (MAPK) pathway is the molecular hallmark of pLGGs and hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway is frequently observed. We report clinical and radiological results of front-line treatment with everolimus in 10 consecutive patients diagnosed with m-TOR positive pLGGs at the Bambino Gesù Children's Hospital in Rome, Italy. Median duration of treatment was 19 months (range from 13-60). Brain magnetic resonance imaging showed stable disease in 7 patients, partial response in 1 and disease progression in 2. Therapy-related adverse events were always reversible after dose reduction or temporary treatment interruption. To the best of our knowledge, this is the first report of everolimus treatment for chemo- and radiotherapy-naïve children with pLGG. Our results provide preliminary support, despite low sample size, for the use of everolimus as target therapy in pLGG showing lack of progression with a manageable toxicity profile.

Medulloblastoma is the most common malignant brain tumor in children. In addition to sporadic cases, medulloblastoma may occur in association with cancer predisposition syndromes. This review aims to provide a complete description of inherited cancer syndromes associated with medulloblastoma. We examine their epidemiological, clinical, genetic, and diagnostic features and therapeutic approaches, including their correlation with medulloblastoma. Furthermore, according to the most recent molecular advances, we describe the association between the various molecular subgroups of medulloblastoma and each cancer predisposition syndrome. Knowledge of the aforementioned conditions can guide pediatric oncologists in performing adequate cancer surveillance. This will allow clinicians to promptly diagnose and treat medulloblastoma in syndromic children, forming a team with all specialists necessary for the correct management of the other various manifestations/symptoms related to the inherited cancer syndromes.

Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B-and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines.

Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.

Il contributo offre un’analisi dettagliata della lettera di Petrarca a Livio, che è posta al centro del libro XXIV delle Familiari rivolte Antiquis illustrioribus. Vengono riconosciute le fonti in essa sottese, in particolare il prologo agli Ab urbe condita, e si chiarisce il rapporto che intrattiene con i manoscritti liviani e degli storici antichi posseduti e postillati dal poeta, come il Par. lat. 5690. L’anno di datazione della lettera coincide addirittura con l’anno di acquisto di quest’ultimo codice.

Il contributo offre una panoramica della fortuna di Livio nel Trecento e della sua importanza nella nascita del cosiddetto pre-umanesimo, rintracciando la presenza degli Ab urbe condita nelle opere di alcuni dei più importanti intellettuali del tempo. Tra di essi, una posizione di rilievo è occupata da Petrarca, il cui interesse per Livio è innegabile ma merita ulteriore approfondimento, in particolar modo per quanto riguarda il suo ruolo nella tradizione manoscritta di Livio.