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.

Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK).

Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases.

Hemiplegic-Migraine-like Attacks as First Manifestation of Diffuse Leptomeningeal Glioneuronal Tumor: A Case Report.

BACKGROUND: Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a low-grade tumor characterized by diffuse leptomeningeal infiltrates. Symptoms are usually secondary to hydrocephalus. Hemiplegic migraine (HM)-like episodes have never been associated with DLGNT, but they have been reported with different inflammatory and tumoral entities involving leptomeninges. OBSERVATIONS: We report the case of a 10-year-old boy with recurrent episodes of right hyposthenia, aphasia, and headache lasting hours to days with complete remission. The electroencephalogram during the attack showed diffuse slower activity on the left hemisphere, which improved together with the symptoms. DLGNT was discovered during a follow-up magnetic resonance imaging and confirmed by biopsy. CONCLUSIONS: This is the first report of HM-like attacks in DLGNT. We discuss the pathogenetic hypotheses of our case and previously reported cases of "symptomatic" HM with leptomeningeal involvement.

Proton therapy: A therapeutic opportunity for aggressive pediatric meningioma.

Meningiomas are an extremely rare histology among pediatric brain tumors, and there is a shortage of literature on their management. Proton therapy is currently used safely and effectively for many types of both pediatric and adult cancer, and its main advantage is the sparing of healthy tissues from radiation, which could translate in the reduction of late side effects. We review the literature on radiotherapy and proton therapy for pediatric meningiomas and report clinical outcomes for two aggressive pediatric meningiomas we treated with protons. Proton therapy might be a safe and effective therapeutic option for this rare subgroup of tumors.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

PROCEDURE: The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. METHODS: We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. RESULTS: Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. CONCLUSION: Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Defining the impact of prognostic factors at the time of relapse for nonmetastatic rhabdomyosarcoma.

BACKGROUND: The prognosis for patients with relapsed rhabdomyosarcoma (RMS) depends on a number of variables, including tumor characteristics, type of relapse, and treatment received. All published studies have considered tumor characteristics at initial diagnosis, but not at the time of recurrence. In this study, we compared tumor characteristics at diagnosis and at the moment of local relapse to better define the chance of cure in this group of patients. METHODS: We first analyzed 92 children with localized RMS treated according to the RMS96 and RMS2005 protocols who developed relapse after achieving complete remission at the end of treatment. Then we restricted our analysis to 51 patients with local recurrence to compare their initial tumor characteristics with those at relapse. All characteristics were studied using univariate and multivariate analyses. RESULTS: The 10-year progression-free survival (PFS) and overall survival (OS) rates for the whole group were 23.5% (15.4-32.6) and 34.4% (24.8-44.1), respectively. On multivariate analysis, only primary tumor site appeared to have a strong impact on prognosis (P = .0010). The 10-year PFS and OS rates of patients with locoregional recurrences were 22.7% (12.3-35.0) and 34.9% (22.1-47.9), respectively. Multivariate analysis showed that tumors at unfavorable sites (P = .0044), and tumor size > 5 cm at recurrence (P = .0088) were associated with the poorest prognosis. CONCLUSION: Our study demonstrates that to estimate the chance of cure in patients with relapsed RMS, we should also consider tumor characteristics at the time of relapse, and tumor size in particular.

Prognostic role of pleural effusion or ascites in localized rhabdomyosarcoma.

PURPOSE: The presence of pleural effusion or ascites at the time of diagnosis is generally considered a poor prognostic factor for children with rhabdomyosarcoma (RMS), and treatment is usually intensified despite the fact that there are no published studies to support this decision. We investigated the prognostic role of the presence of pleural effusion or ascites at diagnosis in patients with localized RMS consecutively enrolled in the Italian Soft Tissue Sarcoma Committee protocols over a 30-year period. METHODS: We reviewed the radiological reports at diagnosis of 150 children with supradiaphragmatic and infradiaphragmatic RMS, noting any presence of effusion and its extent (minimal, moderate, or massive). All patients received intensive chemotherapy, surgery, and standard or hyperfractionated radiotherapy. RESULTS: Effusion was identified in 32 children (21.3%), 14 with pleural effusion and 18 with ascites. As for its extent, 13 children presented with minimal, 12 with moderate, and 7 with massive effusion. The 5-year progression-free survival (PFS) rate was 49.8% (confidence interval [CI] 31.7-65.5) and 49.5% (CI 40-58.2) for patients with and without effusion, respectively (P = .5). When only patients with moderate or massive effusion were considered, however, their PFS was 36.8% (CI 16.5-57.5) versus 51.2% (CI 42.2-59.5) in patients with minimal or no effusion (P = .01). On the whole, patients with pleural effusion had a very poor outcome with a 5-year PFS of 35.7% (CI 13-59.4). CONCLUSIONS: The presence of moderate or massive effusion seems to be an unfavorable prognostic factor in children with RMS, and justifies their inclusion in experimental studies.

A survey on hematology-oncology pediatric AIEOP centres: The challenge of posterior reversible encephalopathy syndrome.

OBJECTIVES: Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurological complications in hematology-oncology pediatric patients. Despite an increasingly recognized occurrence, no clear consensus exists regarding how best to manage the syndrome, because most cases of PRES have reported in single-case reports or small series. Aim of this paper is to identify incidence, clinical features, management, and outcome of PRES in a large series of hematology-oncology pediatric patients. METHODS: The cases of PRES occurred in twelve centers of the Italian Association of Pediatric Hematology and Oncology were reported. RESULTS: One hundred and twenty-four cases of PRES in 112 pediatric patients were recorded with an incidence of 2.1% and 4.7%, respectively, in acute lymphoblastic leukemia in first complete remission and hematopoietic stem cell transplantation (HSCT). The majority of cases occurred after a cycle of chemotherapy rather than after stem cell transplant. PRES after chemotherapy significantly differs from that after HSCT for diagnosis, time of presentation, risk factors, management, and outcome. CONCLUSIONS: This study demonstrates that PRES is a common neurological complication and occurring preferentially in course of induction treatment of some hematologic malignancies, as ALL and after HSCT. It also highlights great clinical differences in the management and outcome in patients with PRES occurring after chemotherapy or after HSCT.

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT.

OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.

Factors possibly affecting prognosis in children with Wilms' tumor diagnosed before 24 months of age: A report from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) Wilms Tumor Working Group.

BACKGROUND: Children with Wilms' tumor (WT) aged under 24 months (infants) have a better prognosis than older patients. Our aim was to study the epidemiology of this age group, with focus on the modality of diagnosis, tumor size, and association with malformations/syndromes, seeking to understand if any of these factors might be related to prognosis. PATIENTS AND METHODS: Infants diagnosed with WT between 2003 and February 2010 were evaluated. A query form was used to collect data on the modality of WT diagnosis (symptomatic or incidental), tumor volume, maximum diameter, site, and stage. RESULTS: Data were collected for 117 of 124 WT infants registered. Twenty-four cases had an incidental diagnosis (ID) of renal mass, usually arising from an abdominal ultrasound performed for other reasons, and 93 had been diagnosed based on clinical signs/symptoms. The incidental cohort displayed unifocal disease, mean tumor diameter 5.52 cm, mean tumor volume 84.30 ml, and 14 patients showed associated malformations. Symptomatic patients had mean maximum tumor diameter of 10.18 cm, mean tumor volume of 451.18 ml, and six had associated malformations. CONCLUSIONS: Our study showed that 20% of the infants had an ID of WT; they had a relatively smaller nonmetastatic tumor and a higher rate of malformations than infants of the symptomatically diagnosed group, but we did not detect any difference in age at diagnosis between the two groups. Conversely, we found a significant difference in the 5-year event-free survival rate (P = 0.018) between infants under 1 year (96%), more frequently associated with congenital malformations, and infants 1-2 years (80%).

Pediatric nonrhabdomyosarcoma soft tissue sarcomas arising at visceral sites.

BACKGROUND: Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. METHODS: Inclusion criteria for the study were as follows: a pathological diagnosis of "adult-type NRSTS," arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. RESULTS: Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). CONCLUSIONS: This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors.

Single-day trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis pneumonia in children with cancer.

OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.

Spleen nodules: a potential hallmark of Visceral Leishmaniasis in young children.

BACKGROUND: Visceral leishmaniasis (VL) is a severe disease caused by Leishmania infantum in the Mediterranean basin, and is associated with considerable morbidity and mortality. Infantile VL may begin suddenly, with high fever and vomiting, or insidiously, with irregular daily fever, anorexia, and marked splenomegaly. Delays in diagnosis of VL are common, highlighting the need for increased awareness of clinicians for VL in endemic European countries. CASE PRESENTATION: We report 4 cases of young children in northern Italy presenting with persistent fever of unknown origin and diagnosed with VL by serological and molecular methods. At the time of diagnosis, these patients showed an unusual echographic pattern characterized by multiple iso-hypoechoic nodules associated with splenomegaly. CONCLUSION: We suggest that detection of spleen nodules represents a signature of VL in infants, thus helping to diagnose systemic Leishmania infantum infection in children.

Pediatric non-Hodgkin lymphoma as a rare cause of spinal cord injury: When lymphoma hides in the canal.

Key Clinical Message: Spinal cord compression from non-Hodgkin lymphoma (NHL) should be considered as a potential diagnosis in cases of acute signs of myelopathy in pediatric patients. Abstract: Spinal cord compression in pediatric non-Hodgkin lymphoma (NHL) is a rare presentation with potential diagnostic challenges. We report on two pediatric patients with NHL who exhibited myelopathy signs as initial presentation. Considering NHL as a differential diagnosis in pediatric patients presenting with spinal cord compression is crucial for optimizing the outcome of these patients.

A 10-Year Retrospective Study on Pediatric Visceral Leishmaniasis in a European Endemic Area: Diagnostic and Short-Course Therapeutic Strategies.

BACKGROUND: Visceral leishmaniasis (VL) is a potentially fatal disease, with an increasing occurrence in northern Italy, affecting children and both immunocompetent and immunocompromised adults. METHODS: This retrospective study conducted at the St. Orsola University Hospital of Bologna, Italy, evaluates the characteristics of 16 children (with a median age of 14.3 months) who were hospitalized between 2013 and 2022 for VL. RESULTS: Seventy-five percent of patients presented with a triad of fever, cytopenia, and splenomegaly. An abdominal ultrasound examination revealed splenomegaly and hypoechoic spleen abnormalities in 93.8% and 73.3% of cases, respectively. Five VL cases were complicated by secondary hemophagocytic lymphohistiocytosis. Eleven patients were treated with a single 10 mg/kg dose of Liposomal Amphotericin B (L-AmB), while five received two doses (total of 20 mg/kg); one of the former groups experienced a recurrence. The fever generally decreased 48 h after the first L-AmB dose, and hemoglobin levels normalized within a month. The splenomegaly resolved in approximately 4.5 months. CONCLUSIONS: Pediatricians should consider VL in children with fever of an unknown origin, anemia, cytopenia, and splenomegaly. In our experience, abdominal ultrasounds and molecular tests on peripheral blood contributed to diagnosis without the need for bone marrow aspiration. The short-course therapy with two 10 mg/kg doses of L-AmB is safe and effective.

A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children.

Given that the rationale for empirical antifungal therapy in neutropenic children is limited and based on adult patient data, we performed a prospective, randomized, controlled trial that evaluated 110 neutropenic children with persistent fever. Those at high risk for invasive fungal infections (IFI) received caspofungin (Arm C) or liposomal amphotericinB (Arm B); those with a lower risk were randomized to receive Arm B, C, or no antifungal treatment (Arm A). Complete response to empirical antifungal therapy was achieved in 90/104 patients (86·5%): 48/56 at high risk (85·7%) [88·0% in Arm B; 83·9% in Arm C (P = 0·72)], and 42/48 at low risk (87·5%) [87·5% in control Arm A, 80·0% Arm B, 94·1% Arm C; (P = 0·41)]. None of the variables tested by multiple logistic regression analysis showed a significant effect on the probability to achieve complete response. IFI was diagnosed in nine patients (8·2%, 95% confidence interval, 3·8-15·0). This randomized controlled study showed that empirical antifungal therapy was of no advantage in terms of survival without fever and IFI in patients aged <18 years and defined with low risk of IFI. Higher risk patients, including those with relapsed cancer, appear to be the target for empirical antifungal therapy during protracted febrile neutropenia.

Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics.

Visceral Leishmaniasis (VL) is a vector-borne disease caused by an intracellular protozoa of the genus Leishmania that can be lethal if not treated. VL is caused by Leishmania donovani in Asia and in Eastern Africa, where the pathogens' reservoir is represented by humans, and by Leishmania infantum in Latin America and in the Mediterranean area, where VL is a zoonotic disease and dog is the main reservoir. A part of the infected individuals become symptomatic, with irregular fever, splenomegaly, anemia or pancytopenia, and weakness, whereas others are asymptomatic. VL treatment has made progress in the last decades with the use of new drugs such as liposomal amphotericin B, and with new therapeutic regimens including monotherapy or a combination of drugs, aiming at shorter treatment duration and avoiding the development of resistance. However, the same treatment protocol may not be effective all over the world, due to differences in the infecting Leishmania species, so depending on the geographical area. This narrative review presents a comprehensive description of the clinical picture of VL, especially in children, the diagnostic approach, and some insight into the most used pharmacological therapies available worldwide.

Mutational analysis of ribosomal proteins in a cohort of pediatric patients with T-cell acute lymphoblastic leukemia reveals Q123R, a novel mutation in RPL10.

T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL involving the malignant expansion of T-cell progenitors. It is driven by a number of different possible genetic lesions, including mutations in genes encoding for ribosomal proteins (RPs). These are structural constituents of ribosomes, ubiquitous effectors of protein synthesis. Albeit the R98S mutation in RPL10, recurring with a higher frequency among RP mutations, has been extensively studied, less is known about the contribution of mutations occurring in other RPs. Alterations affecting translational machinery may not be well tolerated by cells, and there may be a selective pressure that determines the emergence of mutations with a compensatory effect. To explore this hypothesis, we sequenced the exomes of a cohort of 37 pediatric patients affected by T-ALL, and analyzed them to explore the co-occurrence of mutations in genes involved in ribosome biogenesis (including RPs) and translational control, and in known T-ALL driver genes. We found that some of the mutations in these sub-classes of genes tend to cluster together in different patients, indicating that their co-occurrence may confer some kind of advantage to leukemia cells. In addition, our sequencing highlighted the presence of a novel mutation in RPL10, namely the Q123R, which we found associated with a defect in protein synthesis. Our findings indicate that genetic alterations involving ribosome biogenesis and translational control should be carefully considered in the context of precision medicine in T-ALL.

Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study.

Medulloblastoma is the most common malignant brain tumor in children. Even if current treatment dramatically improves the prognosis, survivors often develop long-term treatment-related sequelae. The current radiotherapy standard for medulloblastoma is craniospinal irradiation with a boost to the primary tumor site and to any metastatic sites. Proton therapy (PT) has similar efficacy compared to traditional photon-based radiotherapy but might achieve lower toxicity rates. We report on our multi-centric experience with 43 children with medulloblastoma (median age at diagnosis 8.7 years, IQR 6.6, M/F 23/20; 26 high-risk, 14 standard-risk, 3 ex-infant), who received active scanning PT between 2015 and 2021, with a focus on PT-related acute-subacute toxicity, as well as some preliminary data on late toxicity. Most acute toxicities were mild and manageable with supportive therapy. Hematological toxicity was limited, even among HR patients who underwent hematopoietic stem-cell transplantation before PT. Preliminary data on late sequelae were also encouraging, although a longer follow-up is needed.

High Grade of Amplification of Six Regions on Chromosome 2p in a Neuroblastoma Patient with Very Poor Outcome: The Putative New Oncogene TSSC1.

We observed a case of high-risk neuroblastoma (NB) carried by a 28-month-old girl, displaying metastatic disease and a rapid decline of clinical conditions. By array-CGH analysis of the tumor tissue and of the metastatic bone marrow aspirate cells, we found a high-grade amplification of six regions besides MYCN on bands 2p25.3-p24.3. The genes involved in these amplifications were MYT1L, TSSC1, CMPK2, RSAD2, RNF144A, GREB1, NTSR2, LPIN1, NBAS, and the two intergenic non-protein coding RNAs LOC730811 and LOC339788. We investigated if these DNA co-amplifications may have an effect on enhancing tumor aggressiveness. We evaluated the association between the high expression of the amplified genes and NB patient's outcome using the integration of gene expression data of 786 NB samples profiled with different public platforms from patients with at least five-year follow-up. NB patients with high expression of the TSSC1 gene were associated with a reduced survival rate. Immunofluorescence staining on primary tumor tissues confirmed that the TSSC1 protein expression was high in the relapsed or dead stage 4 cases, but it was generally low in NB patients in complete remission. TSSC1 appears as a putative new oncogene in NB.