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Worldwide, the coronavirus 19 disease pandemic caused a worse chance of a timely diagnosis for cancer patients. We conducted a retrospective analysis of new diagnoses registered in the national pediatric oncology database, comparing the first lockdown period (March-May 2020) with the same period of 2015-2019. The total number of cases (0-19 years) dropped by 20.8% (from 441 between 2015 and 2019 to 349 in 2020). A major reduction was observed for adolescents (15-19 years) (-32.9%) and for adolescents with solid tumors (-56.4%, p = 0.03). Our data suggest that the enforced lockdown reduced the possibility for these already vulnerable patients to access the referral centers.

The gut microbiome (GM) has emerged as a key factor in the genesis and progression of many diseases. The intestinal bacterial composition also influences treatment-related side effects and even the efficacy of oncological therapies. Acute leukemia (AL) is the most common cancer among children and the most frequent cause of cancer-related death during childhood. Outcomes have improved considerably over the past 4 decades, with the current long-term survival for acute lymphoblastic leukemia being ∼90%. However, several acute toxicities and long-term sequelae are associated with the multimodal therapy protocols applied in these patients. Specific GM configurations could contribute to the multistep developmental hypothesis for leukemogenesis. Moreover, GM alterations occur during the AL therapeutic course and are associated with treatment-related complications, especially during hematopoietic stem cell transplantation. The GM perturbation could last even after the removal of microbiome-modifying factors, like antibiotics, chemotherapeutic drugs, or alloimmune reactions, contributing to several health-related issues in AL survivors. The purpose of this article is to provide a comprehensive review of the chronological changes of GM in children with AL, from predisposition to cure. The underpinning biological processes and the potential interventions to modulate the GM toward a potentially health-promoting configuration are also highlighted.

Background Dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by hereditary hemolytic anemia. Case presentation We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. Conclusions This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.

Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these “inconclusive” specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.

Background: Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. Objective: Aim of this study is to provide clinical-immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. Methods: We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0–18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into two groups (IEI+ and IEI−), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). Results: IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. Conclusion: The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI-related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted-gene variants responsible for IEI phenotype.

Background 5–10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60–70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients. Methods We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients. Results Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for “pure” ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism). Conclusions Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.

Rationale & Objective: The objective of this study is to evaluate the effect of body mass index (BMI) on estimated glomerular filtration rate (eGFR) levels in children with congenital solitary kidney (CSK). Moreover, we evaluated if other factors could influence this relationship. Study Design: Multicenter cross-sectional study. Setting & Participants: University hospital pediatrics departments. Subjects: Two hundred eighty-one patients with CSK. Predictors: Weight, height, BMI-SDS (standard deviation score), duration of overweight/obesity, pubertal stage, systolic (SBP) and diastolic (DBP) blood pressure, eGFR, and renal ultrasound were obtained at the last follow-up visit. The population was classified on the basis of nutritional status and divided in tertiles for duration of overweight/obesity. We compared eGFR levels among these categories. A simple regression was used to correlate eGFR with BMI-SDS. To evaluate if other factors could influence the relationship between eGFR and BMI-SDS, a general linear model was performed, including gender, birth weight

Contains fulltext : 249078.pdf (Publisher’s version ) (Open Access) OBJECTIVES: To assess the effect of migrant status on treatment outcomes among children living with HIV in Europe. METHODS: Children aged

Lockdown due to COVID-19 pandemic has forced a decrease in physical activity (PA), an increase in sedentary behavior (SB) and a possibly worsening of fat accumulation in already obese subjects. The aim of this study was to investigate how social restriction may have contributed to weight changes in adolescents with obesity. Secondary aim was to evaluate possible parameters influencing weight changes.Parameters of 51 obese adolescents were compared between two visits: within 2 months before 8 March, start of lockdown, and within 40 days after the end of it.Mean weight gain during lockdown was 2.8 ± 3.7 kg (p 0.001). Weight increase was higher in males than in females (3.8 ± 3.4 kg vs 1.2 ± 3.7 kg, p = 0.02). The hours dedicated to SB increased (+2.9 ± 2.8 h/day; p 0.001) while the hours of PA decreased (-1.0 ± 1.6 h/week; p 0.001). Males spent more hours in SB than females (+3.8 ± 2.7 h/day vs +1.5 ± 2.5 h/day; p = 0.003). There were minor changes in diet during lockdown. The most significant variables influencing both delta BMI and waist/height ratio increase were hours devoted to SB during lockdown and differences in mild and moderate PA before and after lockdown.Obese adolescents showed a worsening of obesity during lockdown, with males mainly affected, mainly due to a reduced mild PA and increased hours spent in SB.

Summary Background Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2–4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89–408·12]), followed by weight loss (59·88 [6·34–565·53]), thrombocytopenia (12·67 [2·40–66·92]), monoarticular involvement (11·30 [4·09–31·19]), hip involvement (3·30 [1·13–9·61]), and male sex (2·40 [1·03–5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01–0·20]), joint swelling (0·03 [0·01–0·09]), and involvement of the small hand joints (0·02 [0–1·05]). Interpretation Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. Funding Associazione Lorenzo Risolo.

This article reviews the primary goals and achievements of the Italian Association for Pediatric Hematology-Oncology (Associazione Italiana Ematologia Oncologia Pediatrica [AIEOP]), a national cooperative group that has been working for children and adolescents with cancer in Italy since 1975.

AimsIn metastatic colorectal carcinomas (mCRC), RAS/RAF genes mutations are first tested to determine the eligibility for anti-EGFR (Epidermal Growth Factor Receptor) therapy in combination with conventional cytotoxic agents. Recent advancements in next-generation sequencing (NGS) have highlighted the potential of multi-gene panels. This multi-gene analysis may provide useful information for the molecular characterisation of mCRC, other than the status of RAS/RAF genes. Aim of this study was to evaluate the feasibility of two NGS custom multi-gene panels in the characterisation of CRC cases and evaluating the relevance of PIK3CA mutation in a routine cohort of consecutive CRC cases.MethodsA total of 961 formalin-fixed and paraffin-embedded specimens from two medical centres (Bologna and Naples) were analysed using two lab-developed NGS multi-gene panels.ResultsKRAS mutations (56.2%) were the more frequent alterations observed in our cohort. Intriguingly, PIK3CA mutations were more frequent (16.8%) than variants observed in the other two genes nowadays analysed in CRC clinical practice (NRAS and BRAF, 4.2% and 9.6%, respectively). Moreover, in more than 10% of samples, coexistent mutations were detected in our cohort of CRC.ConclusionsOur study demonstrates the feasibility and efficacy of lab-developed targeted multi-gene NGS panels in the clinical practice of CRC. Moreover, the data lead to hypothesise that PIK3CA mutations, together with those of RAS/BRAF, worth to be further investigated in clinical CRC specimens.

Purpose The short-stitch technique for midline laparotomy closure has been shown to reduce hernia rates, but long stitches remain the standard of care and the effect of the short-stitch technique on short-term results is not well known. The aim of this study was to compare the two techniques, using an ultra-long-term absorbable elastic suture material. Methods Following elective midline laparotomy, 425 patients in 9 centres were randomised to receive wound closure using the short-stitch (USP 2-0 single thread, n = 215) or long-stitch (USP 1 double loop, n = 210) technique with a poly-4-hydroxybutyrate-based suture material (Monomax®). Here, we report short-term surgical outcomes. Results At 30 (+10) days postoperatively, 3 (1.40%) of 215 patients in the short-stitch group and 10 (4.76%) of 210 patients in the long-stitch group had developed burst abdomen [OR 0.2830 (0.0768–1.0433), p = 0.0513]. Ruptured suture, seroma and hematoma and other wound healing disorders occurred in small numbers without differences between groups. In a planned Cox proportional hazard model for burst abdomen, the short-stitch group had a significantly lower risk [HR 0.1783 (0.0379–0.6617), p = 0.0115]. Conclusions Although this trial revealed no significant difference in short-term results between the short-stitch and long-stitch techniques for closure of midline laparotomy, a trend towards a lower rate of burst abdomen in the short-stitch group suggests a possible advantage of the short-stitch technique. Trial registry NCT01965249, registered October 18, 2013.

Febrile neutropenia (FN) is a common complication of chemotherapy in oncological children and one of the most important causes of morbidity and mortality in these patients. The early detection of a bacteremia and the rapid therapeutic intervention are crucial to improve the outcome. We analyzed the literature in order to clarify the epidemiology of FN in children undergoing chemotherapy, the specific factors associated with a negative outcome, the most common etiology, and the value of biological markers as a tool to make an early diagnosis or to monitor the evolution of the infection. Several studies have tried to identify specific factors that could help the clinician in the detection of an infection and in its microbiological identification. However, due to the heterogenicity of the available studies, sufficient evidence is lacking to establish the role of these risk factors in clinical practice and future research on this topic appear mandatory. Determinations of risk factors, etiology, and markers of febrile episodes in these patients are complicated by the characteristics of the underlying illness and the effects of treatments received. Although some studies have tried to develop an evidence-based guideline for the empiric management of FN in pediatrics, validated predictive scores and algorithms are still lacking and urgently needed.

Pediatric 2019 novel coronavirus disease (COVID-19) is characterized by a wide clinical spectrum, including hematological manifestations.1 Anemia and thrombocytopenia occur mainly in severe forms of the disease and in multisystem inflammatory syndrome2 but are rare in asymptomatic and mildly symptomatic patients. Only few reports of autoimmune hemolytic anemia (AIHA), rarely associated with immune thrombocytopenia (ITP), have been described in children with COVID-19.3–5 Here, we present two pediatric cases of severe cold agglutinin disease and a brief review of the literature

In the field of medical care, successful transition from pediatric-centered to adult-oriented healthcare can provide a sense of continuity in the development of youth, and prepare them to accept responsibility for and manage their own chronic kidney condition in complete autonomy. The so-called transition process requires the presence of some basic aspects: a multidisciplinary team, which acts as a bridge between child and adult services; a comprehensive clinical, cognitive, psychological, and social change for the young people; the involvement of family and caregivers. Within the framework of transition and chronicity during the developmental age, we selected international papers explaining models which agreed on some important steps in the transition process, although many differences can be observed between different countries. In fact, in Europe, the situation appears to be heterogeneous as regards certain aspects: the written transition plan, the educational programmes, the timing of transfer to adult services, the presence of a transition coordinator, a dedicated off-site transition clinic. We then analyzed some studies focusing on patients with renal diseases, including the first to contain a standardized protocol for transition which was launched recently in the USA, and which seems to have already achieved important positive, although limited, results. In Italy, the issue of transition is still in its infancy, however important efforts in the management of chronic kidney disease have already been initiated in some regions, including Emila Romagna, which gives us hope for the future of many young people.

Medical advances have dramatically improved the long-term prognosis of children and adolescents with inborn errors of immunity (IEIs). Transfer of the medical care of individuals with pediatric IEIs to adult facilities is also a complex task because of the large number of distinct disorders, which requires involvement of patients and both pediatric and adult care providers. To date, there is no consensus on the optimal pathway of the transitional care process and no specific data are available in the literature regarding patients with IEIs. We aimed to develop a consensus statement on the transition process to adult health care services for patients with IEIs. Physicians from major Italian Primary Immunodeficiency Network centers formulated and answered questions after examining the currently published literature on the transition from childhood to adulthood. The authors voted on each recommendation. The most frequent IEIs sharing common main clinical problems requiring full attention during the transitional phase were categorized into different groups of clinically related disorders. For each group of clinically related disorders, physicians from major Italian Primary Immunodeficiency Network institutions focused on selected clinical issues representing the clinical hallmark during early adulthood.

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.

Background: In the medical complexity of a children with cerebral palsy, impaired airway clearance represents a major problem, leading to significative respiratory morbidity and mortality. Its management is difficult because of limited cooperation and poor tolerance to invasive treatments. Free Aspire(®) (FA) is a device designed to remove bronchial secretions noninvasively, without generating cough. Methods: The aim of our pilot prospective study is to assess the efficacy and acceptability of FA in removing airway obstruction in subjects with cerebral palsy and ineffective cough. We enrolled 11 subjects. At enrollment and after 3, 6, and 12 months, we collected data regarding health care resources use for respiratory exacerbations, perceived efficacy, and acceptability of treatment. Results: We observed a reduction in emergency room (ER) accesses, home pharmacological treatment, hospitalizations number, and hospital stay length. In particular after 12 months we observed a reduction of 74% in ER accesses and home pharmacological treatment, 38% in hospitalizations number, and 17% in hospital stay length for respiratory exacerbations. The 100% of caregivers considered the treatment effective and simple to use and noted an improvement in subjects' general condition. They also reported good treatment tolerance of subjects, with an overall good compliance. Conclusion: The study demonstrates that FA is an effective device for the removal of bronchial secretions, with a positive caregivers' perception, that favored a good long-term compliance.

Type 1 diabetes (T1D) and obesity are strongly associated with cardiovascular (CV) risk and can start in the paediatric age. The CV risk profile of two groups of adolescents was compared through the evaluation of sAGE, IMT and known variables associated with CV risk. The first group was affected by T1D with duration of disease of at least 5 years or 3 years since puberty onset, and the second by severe obesity for more than 3 years. A total of 116 patients were prospectively enrolled in the study (71 T1D, 33 males and 38 females; 45 obese, 18 males and 27 females), and their sAGE, IMT, waist/height ratio, LDL cholesterol, triglycerides/cholesterol HDL ratio, BMI, HbA1c and blood pressure were measured. An IMT value > 0.7 mm, cut-off value to define CV risk, was present in 28% of the obese patients and in no T1D patients. Age-adjusted sAGE and HbA1c levels were higher T1D patients, whereas a higher percentage of pathological values was present in most of the remaining studied variables. In T1D patients, there was a higher percentage of females with waist/height ratio > 0.5, LDL cholesterol > 100 mg/dL, triglycerides/HDL cholesterol ratio > 2 and BMI > 99° centile and a higher percentage of males with HbA1c > 7%. On the contrary, in obese patients there were no differences between males and females. Multiple analysis is identified BMI SDS as the only variable with a significant influence on IMT in both groups. Furthermore, it showed that HbA1c and gender affected sAGE in T1D patients, whereas only age and gender in the obese patients. Our study demonstrates that our adolescents with severe obesity carry a much higher CV risk than adolescents with T1D unless in bad metabolic control. Apart from lower sAGE levels, most of the variables considered to define CV risk were higher in the obese group than in the T1D group. Gender seems to have a significant impact on sAGE levels but not on IMT.

Background Recurrent pericarditis (RP) is a complication (15–30%) of acute pericarditis with an unknown etiology. Treatment regimen consists of a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, with the addition of corticosteroids in resistant or intolerant cases. In the last decade anakinra was shown as an effective treatment in patients with colchicine resistant and steroid-dependent RP, initially in anecdotal reports in children and more recently in a randomized trial. Canakinumab is a monoclonal antibody selectively blocking IL-1β and its use is only anecdotally reported to treat pericarditis. We report two pediatric patients with refractory recurrent pericarditis, who presented an optimal response to anakinra treatment but prompt relapse after switch to canakinumab. Case presentation The first patient is a girl with Recurrent Pericarditis started in April 2015, after heart surgery. NSAIDs and oral steroids were started, with prompt relapse after steroid suspension. The child showed a steroid-dependent RP; anakinra was therefore started with excellent response, but discontinued after 2 weeks for local reactions. In July 2016 therapy with canakinumab was started. She experienced four relapses during canakinumab therapy despite dosage increase and steroid treatment. In January 2018 a procedure of desensitization from anakinra was performed, successfully. Anakinra as monotherapy is currently ongoing, without any sign of flare. The second patient is a girl with an idiopathic RP, who showed an initial benefit from NSAIDs and colchicine. However, 10 days after the first episode a relapse occurred and therapy with anakinra was established. Two months later, while being in complete remission, anakinra was replaced with canakinumab due to patient’s poor compliance to daily injections. She experienced a relapse requiring steroids 10 days after the first canakinumab injection. Anakinra was subsequently re-started with complete remission, persisting after 24 months follow-up. Conclusions We describe two cases of failure of the treatment with anti-IL-1β monoclonal antibodies in steroid- dependent idiopathic RP. This anecdotal and preliminary observation suggests a different efficacy of the two IL-1 blockers in the management of RP and support a possible pivotal role of IL-1α in the pathogenesis of this condition.

Purpose: To describe how the provision of services for adolescents with cancer has evolved in Italy, the study evaluated access to pediatric oncology centers affiliated to the national cooperative ...

Das Cholangio- und Gallenblasenkarzinom (CCA) stellt eine seltene Krebserkrankung mit schlechter Prognose dar. Zur Optimierung der onkologischen Versorgungsstruktur werden interdisziplinare Tumorboards (TuB) unter Beteiligung von Experten verschiedener Fachdisziplinen abgehalten. Die vorliegende Untersuchung beschaftigt sich mit der Frage, ob Patienten mit einem CCA hinsichtlich ihrer Lebenserwartung und -qualitat von der Einfuhrung von TuBs profitieren. In dieser retrospektiven Studie wurden 161 Patienten untersucht, die sich in der Behandlung eines CCA befanden. Das Patientenkollektiv wurde in zwei Gruppen (TuB+ vs. TuB−) eingeteilt und mithilfe des Propensity-Scores gematcht. In Patientengruppe TuB+ befinden sich 109 Patienten (67,7 %), in der Kontrollgruppe (TuB−) 52 Patienten (32,3 %). 84 TuB+-Patienten wurden mit 50 TuB−-Patienten gematcht. Die Uberlebensraten der gematchten Patienten zeigen in TuB+-Gruppe (1-JUR: 61,9 %, 5‑JUR: 23,6 %, 10-JUR: 18,0 %) einen Vorteil gegenuber der TuB−-Gruppe (1-JUR: 32,0 %, 5‑JUR: 8,0 %, 10-JUR:−) mit p

In many autoimmune rheumatic diseases, there is an increased risk of cancer compared to the general population. The link between autoimmunity and cancer is dynamic and bidirectional. Recent advances in terms of knowledge of biology, epidemiology, and long-term outcomes for the autoimmune rheumatic diseases have revealed several new connections between these two entities. Data suggest that chronic inflammation from the rheumatic diseases or their therapies may contribute to the onset and promotion of cancer. Conversely, antitumor immune responses may become cross-reactive with self-tissues resulting in the development of autoimmunity. In this review, we discuss about the potential mechanisms that link autoimmune rheumatic diseases and cancer and the association of malignancies with common autoimmune disorders. The increased incidence of malignancy in autoimmune rheumatic diseases has been largely described, although the biology underpinning this relationship should be further investigated. The development of evidence-based cancer screening recommendations in patients with autoimmune rheumatic diseases is complex due to the heterogeneity of clinical rheumatic phenotypes, cancer sites at risk and exposure to anti-neoplastic and anti-rheumatic treatment. In order to lay the foundation of risk stratification and targeted cancer screening, larger longitudinal cohort studies that provide a more detailed framework of the links between cancer and autoimmunity are urgently needed.

Cow’s milk allergy (CMA) is one of the most common food allergies in infants, and its prevalence has increased over recent years. In the present paper, we focus on CMA as a model of food allergies in children. Understanding the diagnostic features of CMA is essential in order to manage patients with this disorder, guide the use of an elimination diet, and find the best moment to start an oral food challenge (OFC) and liberalize the diet. To date, no shared tolerance markers for the diagnosis of food allergy have been identified, and OFC remains the gold standard. Recently, oral immunotherapy (OIT) has emerged as a new therapeutic strategy and has changed the natural history of CMA. Before this, patients had to strictly avoid the food allergen, resulting in a decline in quality of life and subsequent nutritional, social, and psychological impairments. Thanks to the introduction of OIT, the passive approach involving rigid exclusion has changed to a proactive one. Both the heterogeneity in the diagnostic process among the studies and the variability of OIT data limit the comprehension of the real epidemiology of CMA, and, consequentially, its natural history. Therefore, well-planned randomized controlled trials are needed to standardize CMA diagnosis, prevention, and treatment strategies.

Simple Summary Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. Immunologists and oncologists should interact to monitor and promptly diagnose the potential development of cancer in known IEI patients, as well as an underlying IEI in newly diagnosed cancers with suggestive medical history or high rate of therapy-related toxicity. The creation of an international registry of IEI cases with detailed information on the occurrence of cancer is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the aim of improving prognosis and reducing comorbidities. Abstract Inborn Errors of Immunity (IEI) are a heterogeneous group of disorders characterized by a defect in the function of at least one, and often more, components of the immune system. The aim of this narrative review is to discuss the epidemiology, the pathogenesis and the correct management of tumours in patients with IEI. PubMed was used to search for all of the studies published over the last 20 years using the keywords: “inborn errors of immunity” or “primary immunodeficiency” and “cancer” or “tumour” or “malignancy”. Literature analysis showed that the overall risk for cancer in children with IEI ranges from 4 to 25%. Several factors, namely, age of the patient, viral infection status and IEI type can influence the development of different cancer types. The knowledge of a specific tumour risk in the presence of IEI highlights the importance of a synergistic effort by immunologists and oncologists in tracking down the potential development of cancer in known IEI patients, as well as an underlying IEI in patients with newly diagnosed cancers. In the current genomic era, the creation of an international registry of IEI cases integrated with malignancies occurrence information is fundamental to optimizing the diagnostic process and to evaluating the outcomes of new therapeutic options, with the hope to obtain a better prognosis for these patients.

A wide range of malignancies presents MYCN amplification (MNA) or dysregulation. MYCN is associated with poor prognosis and its over-expression leads to several dysregulations including metabolic reprogramming, mitochondria alteration, and cancer stem cell phenotype. Some hints suggest that MYCN overexpression leads to cancer immune-escape. However, this relationship presents various open questions. Our work investigated in details the relationship of MYCN with the immune system, finding a correlated immune-suppressive phenotype in neuroblastoma (NB) and different cancers where MYCN is up-regulated. We found a downregulated Th1-lymphocytes/M1-Macrophages axis and upregulated Th2-lymphocytes/M2-macrophages in MNA NB patients. Moreover, we unveiled a complex immune network orchestrated by N-Myc and we identified 16 genes modules associated to MNA NB. We also identified a MYCN-associated immune signature that has a prognostic value in NB and recapitulates clinical features. Our signature also discriminates patients with poor survival in non-MNA NB patients where MYCN expression is not discriminative. Finally, we showed that targeted inhibition of MYCN by BGA002 (anti-MYCN antigene PNA) is able to restore NK sensibility in MYCN-expressing NB cells. Overall, our study unveils a MYCN-driven immune network in NB and shows a therapeutic option to restore sensibility to immune cells.

Background: Non-canonical mutations of the isocitrate dehydrogenase (IDH) genes have been described in about 20–25% and 5–12% of patients with WHO grade II and III gliomas, respectively. To date, the prognostic value of these rare mutations is still a topic of debate. Methods: We selected patients with WHO grade II and III gliomas and IDH1 mutations with available tissue samples for next-generation sequencing. The clinical outcomes and baseline behaviors of patients with canonical IDH1 R132H and non-canonical IDH1 mutations were compared. Results: We evaluated 433 patients harboring IDH1 mutations. Three hundred and ninety patients (90.1%) had a canonical IDH1 R132H mutation while 43 patients (9.9%) had a non-canonical IDH1 mutation. Compared to those with the IDH1 canonical mutation, patients with non-canonical mutations were younger (p &lt, 0.001) and less frequently presented the 1p19q codeletion (p = 0.017). Multivariate analysis confirmed that the extension of surgery (p = 0.003), the presence of the 1p19q codeletion (p = 0.001), and the presence of a non-canonical mutation (p = 0.041) were variables correlated with improved overall survival. Conclusion: the presence of non-canonical IDH1 mutations could be associated with improved survival among patients with IDH1 mutated grade II–III glioma.

The disruption of gut microbiota eubiosis has been linked to major complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Various strategies have been developed to reduce dysbiosis and related complications. Fecal microbiota transplantation (FMT) consists of the infusion of fecal matter from a healthy donor to restore impaired intestinal homeostasis, and could be applied in the allo-HSCT setting. We conducted a systematic review of studies addressing the use of FMT in allo-HSCT patients. In the 23 papers included in the qualitative synthesis, FMT was used for the treatment of recurrent Clostridioides difficile infections or as a therapeutic strategy for steroid-resistant gut aGvHD. FMT was also performed with a preventive aim (e.g., to decolonize from antibiotic-resistant bacteria). Additional knowledge on the biological mechanisms underlying clinical findings is needed in order to employ FMT in clinical practice. There is also concern regarding the administration of microbial consortia in immune-compromised patients with altered gut permeability. Therefore, the safety profile and efficacy of the procedure must be determined to better assess the role of FMT in allo-HSCT recipients.

Pediatric type 1 narcolepsy (NT1) is often associated with overweight and obesity. Sodium oxybate (SO), approved for the treatment of narcolepsy with cataplexy from the age of 7 years old in the United States, has been associated with weight loss, although longitudinal pediatric studies are lacking. We report a retrospective cohort of 129 consecutive patients with a 4-year follow-up, to analyze the impact of different pharmacological treatments on body mass index (BMI) z-score. At baseline, the prevalence of obesity and overweight was 26.4% (34/129) and 29.5% (38/129), respectively. Patients were divided into three groups: children treated with SO alone (group 1), with SO-combined therapy (group 2), and without SO (group 3). At the end of the first year of follow-up, group 1 and group 2 showed a significant BMI z-score reduction compared to baseline: from 1.2 ± 1.1 to 0.4 ± 1.4 for group 1 (p < 0.001), and from 1.4 ± 1.1 to 1 ± 1.3 for group 2 (p = 0.002), independently from baseline clinical features. In the second year, only group 2 experienced a further and significant BMI z-score decrease (from 1.0 ± 1.2 to 0.6 ± 1.2, p = 0.037). No further significant BMI z-score changes were observed in SO-treated patients in the following years. Instead, children treated without SO developed a significant weight increase between the second and third year of therapy (BMI z-score from 0.3 ± 0.9 to 0.5 ± 0.9). In conclusion, SO treatment in pediatric NT1 is associated with a favorable weight reduction in the first year of treatment.

SARS-CoV-2 pandemic restrictions have deeply altered the common respiratory illnesses burden. The aim of this paper was to clarify how these measures may have influenced bronchiolitis epidemiology, exploring possible explanations. We studied 342 infants hospitalized for bronchiolitis at our center from four different epidemic seasons (October–April 2017–2018, 2018–2019, 2019–2020 and 2020–2021). March–April hospitalization rate, RSV (respiratory syncytial virus) infection, pediatric intensive care unit (PICU) admission and oxygen therapy administration data were compared among different seasons to outline any changes during the SARS-CoV-2 outbreak. In March–April, 30 (23.1%), 28 (24.6%) and 5 (5.1%) infants were hospitalized for bronchiolitis, respectively, in 2017–2018, 2018–2019 and 2019–2020, with a lower rate in March–April 2020 (p < 0.001). No hospitalizations for bronchiolitis occurred during the epidemic season of 2020–2021. No significant differences in RSV infections, oxygen therapy administration and PICU admissions across seasons were outlined. In conclusion, we report a severe decrease in hospitalizations for bronchiolitis at our center throughout the entire SARS-CoV-2 outbreak rather than only during the lockdown periods. This seems to suggest a pivotal role for the systematic implementation of cost-effective non-pharmaceutical interventions (NPIs) such as compulsory face masks and hand hygiene, which were deployed for the entire pandemic, in reducing the circulation of infectious agents.

(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, several different methods have been used for detecting HPV infection. The aim of the present study was to compare three different methods for the diagnosis of the presence of the HPV genome. (2) Methods: A total of 50 samples were analyzed. Twenty-five of them were tested using both next generation sequencing (NGS) and VisionArray® technology, the other 25 were tested using Hybrid Capture (HC) II assay and VisionArray® technology. (3) Results: A substantial agreement was obtained using NGS and VisionArray® (κ = 0.802), as well as between HC II and VisionArray® (κ = 0.606). In both analyses, the concordance increased if only high risk HPVs I(HR-HPVs) were considered as “positive”. (4) Conclusions: Our data highlighted the importance of technical choice in HPV characterization, which should be guided by the clinical aims, costs, starting material, and turnaround time for results.

Ovarian carcinomas represent a heterogeneous group of neoplasms consisting of separate entities with distinct risk factors, precursor lesions, pathogenesis, patterns of spread, molecular profiles, clinical course, response to chemotherapy, and outcomes. The histologic subtype and the related molecular features are essential for individualized clinical decision-making. The fifth edition of the World Health Organization classification of tumors of the female genital tract divides ovarian carcinomas into at least five main and distinct types of ovarian carcinomas: high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma. Molecular pathology has improved the knowledge of genomic landscape of ovarian carcinomas identifying peculiar alterations for every histologic subtype. It is well-known that high-grade and low-grade serous carcinomas are separate entities with entirely different morphologic and molecular characteristics. TP53 and BRCA mutations are typical of high-grade serous carcinoma, whereas BRAF and KRAS mutations frequently occur in low-grade serous carcinoma. Endometrioid and clear cell carcinomas are frequently associated with endometriosis. Endometrioid tumors are characterized by β-catenin alterations, microsatellite instability, and PTEN and POLE mutations, while ARID1A mutations occur in both endometrioid and clear cell carcinomas. Mucinous carcinomas are uncommon tumors associated with copy-number loss of CDKN2A and KRAS alterations and metastasis from other sites should always be considered in the differential diagnosis.

Background A synonymous single nucleotide polymorphism (SNP) is a substitution of a single base that does not modify the primary amino acid sequence but could influence protein function. In patients with brain tumors, the incidence of the silent SNP IDH 1 105GGT (rs11554137) is three times higher than the normal population. Methods Our aim was to investigate the prognostic role of the IDH 1 105GGT SNP. We selected only patients with diagnosis of IDH grade II or III mutated glioma. Additional inclusion criteria were: complete clinical data and adequate tumor samples for IDH 1 or 2 sequencing. Results 71 patients with grade II and III IDH-mutated glioma have been evaluated. Nine of 71 patients (12.7 %) presented the SNP 105GGT. Patients with SNP 105GGT had a longer Progression Free Survival (PFS - 47.3 months vs Not reached; p = 0.015). The SNP 105GGT (HR 0.240; 95 %CI 0.074−0.784, p = 0.018) was confirmed as an independent prognostic factors in multivariate analysis. Conclusions Patients with IDH1 or 2 mutated grade II and III glioma presenting the SNP105GGT had longer PFS regardless adjuvant treatment received and extension of primary surgery. A validation is warranted to confirm our preliminary results.

Atopic dermatitis is frequently associated with the onset of other allergic conditions, such as asthma, rhino-conjunctivitis and food allergy. The etiology of atopic dermatitis is marginally understood in spite of the number of predisposing factors, above all, mutations in the Filaggrin gene (FLG). In this study, the association between loss-of-function variants in the FLG gene and other allergic manifestations, in particular food allergy, was evaluated in an Italian pediatric population affected by atopic dermatitis. The 10 more frequently mutated loci in the FLG gene were genotyped in 238 children affected by atopic dermatitis and tested for association with clinical features of allergic disorders by a multivariate logistic regression model. R501X and 2282del4 were the only two mutations identified, 12.2% of children carry one of these variants, corresponding to an allelic frequency of 6.5%. According to multivariate statistical analysis, loss-of-function variants in the FLG gene represent a risk factor for the onset of severe manifestations of food allergy (OR = 8.9, CI: 3.1&ndash, 28.3). Peanut and hazelnut were identified as high-risk foods in patients with FLG mutations. This study demonstrates that atopic children carrying FLG mutations represent a high-risk population due to their predisposition to develop severe food allergy reactions, such as anaphylaxis.

We retrospectively checked patients who underwent chemotherapy and/or hematopoietic stem cell transplantation from 2007 to 2016, in order to evaluate whether early computed tomography is useful in children treated for cancer with acute central nervous system complications. Out of a total sample of 443 patients, 52 children (11.7%) presented these complications. In the end, 31 patients were included, with a total of 33 events of central nervous system complications. The computed tomography was abnormal in 22 events (67%) and diagnostic for a specific complication in 20 events (61%), whereas it directly influenced the treatment in 16 events (48%). Computed tomography should be still considered a relevant diagnostic tool in the management of acute central nervous system complications in the emergency setting.

Hereditary alpha tryptasemia (HαT) is a recently described autosomal dominant genetic trait caused by an increased copy number of the TPSAB1 gene. It commonly leads to elevated basal serum tryptase levels, and it is associated with heterogeneous clinical manifestations. Some individuals report few to no symptoms, while others present with a spectrum of debilitating features. Most symptoms related to HαT may be explained by mast cell activation and mediator release, namely multiple allergies, anaphylaxis, and skin rash. However, the genotype-phenotype correlation has not yet been clearly understood. In particular, the characterization of the clinical spectrum lacks in children, where differential diagnosis could be challenging. Systemic mastocytosis, HαT, and mast cell activation syndrome are all associated with overlapping pathophysiology and symptoms, making the distinction between these conditions a difficult task. We herein describe two pediatric cases of HαT and their respective families at our tertiary care teaching hospital, highlighting the diagnostic workup and differential diagnosis. We also provide a brief review of the literature to underline the peculiar features of this condition in children.

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.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype&ndash, genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G&gt, A, p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD&mdash, both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7R&alpha, expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

The gut microbiome (GM) has been associated with different clinical outcomes in the context of allogeneic hematopoietic stem cell transplantation (HSCT). Large multicenter cohort studies in adults have found significant correlations with overall survival, relapse, and incidence of complications. Moreover, GM is already a promising target for therapeutic interventions. However, few data are available in children, a population presenting unique features and challenges. During childhood, the GM evolves rapidly with large structural fluctuations, alongside with the maturation of the immune system. Furthermore, the HSCT procedure presents significant differences in children. These considerations underline the importance of a specific focus on the pediatric setting, and the role of GM and its age-dependent trajectory in influencing the immunity reconstitution and clinical outcomes. This review provides a comprehensive overview of the available evidence in the field of GM and pediatric HSCT, highlighting age-specific issues and discussing GM-based therapeutic approaches.

Introduction Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. Materials and methods CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). Results Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86–88) and at 45 years was 81% (95% CI: 77–84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7–12), corresponding to an AER of 48 (95% CI: 45–51). Mortality decreased by 60% for survivors treated most recently (1990–1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. Conclusions This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

Next generation sequencing (NGS) allows parallel sequencing of multiple genes at a very high depth of coverage. The need to analyze a variety of targets for diagnostic/prognostic/predictive purposes requires multi-gene characterization. Multi-gene panels are becoming standard approaches for the molecular analysis of solid lesions. We report a custom-designed 128 multi-gene panel engineered to cover the relevant targets in 22 oncogene/oncosuppressor genes for the analysis of the solid tumors most frequently subjected to routine genotyping. A total of 1695 solid tumors were analyzed for panel validation. The analytical sensitivity is 5%. Analytical validation: (i) Accuracy: sequencing results obtained using the multi-gene panel are concordant using two different NGS platforms and single-gene approach sequencing (100% of 83 cases), (ii) Precision: consistent results are obtained in the samples analyzed twice with the same platform (100% of 20 cases). Clinical validation: the frequency of mutations identified in different tumor types is consistent with the published literature. This custom-designed multi-gene panel allows to analyze with high sensitivity and throughput 22 oncogenes/oncosuppressor genes involved in diagnostic/prognostic/predictive characterization of central nervous system tumors, non-small-cell lung carcinomas, colorectal carcinomas, thyroid nodules, pancreatic lesions, melanoma, oral squamous carcinomas and gastrointestinal stromal tumors.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Pediatric acute myeloid leukemia (AML) is an aggressive malignancy with poor prognosis for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting the proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been observed. Recent studies have reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here, we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulates the expression of genes with relevant roles in cancer development. Such modifications in the transcriptional program increase the apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. Through ChIP-seq analysis, we identified the genes regulated by DOT1L irrespective of MLL-r, including the Sorafenib target BRAF, providing mechanistic insights into the drug combination activity. Our results highlight a novel therapeutic strategy for pediatric AML patients.

Background How to address the counseling of lifetime risk of developing Parkinson’s disease in patients with Gaucher disease and their family members carrying a single variant of the GBA1 gene is not yet clearly defined. In addition, there is no set way of managing Gaucher disease patients, taking into account the possibility that they may show features of Parkinson’s disease. Methods Starting from an overview on what has recently changed in our knowledge on this issue and grouping the experiences of healthcare providers of Gaucher disease patients, we outline a path of counseling and management of Parkinson’s disease risk in Gaucher disease patients and their relatives. Conclusion The approach proposed here will help healthcare providers to communicate Parkinson’s disease risk to their patients and will reduce the possibility of patients receiving inaccurate information from inadequate sources. Furthermore, this resource will help to empower healthcare providers to identify early signs and/or symptoms of Parkinson’s disease and decide when to refer these patients to the neurologist for appropriate specific therapy and follow-up.

Background X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce. Objective Our aim was to describe the natural history of XLA. Methods A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base. Results Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease. Conclusions This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.

We report for the first time the occurrence of a filamentous fungus, Albifimbria verrucaria, in the blood of a pediatric neuroblastoma patient. The Albifimbria genus comprises common soil-inhabiting and saprophytic fungi and has been isolated as a plant pathogen in Northern and Southern Italy. As a human pathogen, A. verrucaria has been implicated in keratitis and can produce trichothecene toxins, which are weakly cytotoxic for mammalian cell lines. A. verrucaria was isolated from blood during the follow-up of a previous coagulase-negative Staphylococcus catheter-related infection. Lung nodules, compatible with fungal infection, had been observed on a CT scan 6 months earlier; they still persist. Possible routes of transmission were considered to be airborne, catheter related, or transfusion dependent, as the patient had undergone platelet and red blood cell transfusions during rescue chemotherapy. No filamentous fungi were isolated from sputum or CVCs. In conclusion, we describe an unprecedented fungemia caused by A. verrucaria and show how an unexpected pathogen may be acquired from the environment by patients at high risk due to immunosuppression. The route of transmission remains unknown.

Nowadays, thanks to extensive studies and progress in precision medicine, pediatric leukemia has reached an extremely high overall survival rate. Nonetheless, a fraction of relapses and refractory cases is still present, which are frequently correlated with poor prognosis. Although several molecular features of these diseases are known, still the field of energy metabolism, which is widely studied in adult, has not been frequently explored in childhood leukemias. Metabolic reprogramming is a hallmark of cancer and is deeply connected with other genetic and signaling aberrations generally known to be key features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This review aims to clear the current knowledge on metabolic rewiring in pediatric ALL and AML, also highlighting the influence of the main signaling pathways and suggesting potential ideas to further exploit this field to discover new prognostic biomarkers and, above all, beneficial therapeutic options.

Pancreatic adenocarcinoma (PDAC) is the most frequent histological type of malignancy in the pancreas. Extracellular matrix (ECM), plays a critical role during the process of human carcinogenesis and the possible diversity in matricellular proteins composition of ECM may have a significant impact on the clinical course of PDAC. Aim of this paper was to evaluate the expression of three matricellular proteins, including Periostin (POSTN), Tenascin (TNS) and Osteopontin (OPN), in PDAC from long-survival (LS) and non-long survival (NLS) patients. A total of 30 PDAC were analyzed, 15 from patients that survived more than 60 months after surgery (LS) and 15 that died from the disease within 24 (NLS). RNA was extracted and OPN, TNS and POSTN mRNA levels were evaluated by qRT-PCR.LS and NLS samples showed the same type of POSTN and TN isoforms. On the contrary, OPN seems to be preferentially expressed in NLS PDAC. Moreover, OPNb and OPNc isoforms were expressed exclusively in NLS samples. In conclusion, Our data led to hypothesize a possible relationship between the expression of different isoforms of each of these proteins and the clinical outcome of patients with PDAC.