Search

Background To depict ecthyma gangrenosum (EG) clinical presentation and evolution in a large multicenter pediatric retrospective collection of children with malignancies or bone marrow failure syndromes, to facilitate early diagnosis. Methods EG episodes diagnosed in the period 2009-2019 were identified by a retrospective review of clinical charts at centers belonging to the Italian Pediatric Hematology Oncology Association. Results Thirty-eight cases of EG occurring in children (male/female 16/22; median age 5.2 years) with hematologic malignancy (29), allogeneic stem cell transplantation (2) or relapsed/refractory solid tumor (3) were collected. The involved sites were: perineal region (19), limbs (10), trunk (6), head and the iliac crest (3). Bacteremia was present in 22 patients. Overall, the germs isolated were Pseudomonas aeruginosa (30), Stenotrophomonas maltophilia (3) and Escherichia coli (1); 31% of them were multidrug-resistant. All patients received antibacterial treatment, while surgery was performed in 24 patients (63.1%). Predisposing underlying conditions for EG were severe neutropenia (97.3%), corticosteroid treatment (71%) and iatrogenic diabetes (23.7%). All patients recovered, but EG recurred in 5 patients. Nine patients (24%) showed sequelae (deep scars, with muscle atrophy in 2). Four patients (10.5%) died, 1 due to relapse of EG with Carbapenem-resistant Enterobacteriaceae co-infection and 3 due to the progression of the underlying disease. Conclusions EG requires early recognition and a proper and timely treatment to obtain the recovery and to avoid larger necrotic lesions, eventually evolving in scarring sequelae.

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: 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 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.

Background: In patients with relapsed/refractory acute myeloid leukaemia (R/R AML) who received salvage chemotherapy, limited and not updated studies explored the incidence of invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP). The aims of this multicentre retrospective 'SEIFEM 2016-B' study were as follows: (1) to evaluate the current rate and the outcome of proven/probable IA and (2) to assess the efficacy of AP, in a large 'real life' series of patient with R/R AML submitted to salvage chemotherapy. Results: Of 2250 R/R AML patients, a total of 74 cases of IA (5.1%) were recorded as follows: 10 (0.7%) proven and 64 (4.3%) probable. Information about AP were available in 73/74 (99%) patients. Fifty-eight (79%) breakthrough infections occurred, mainly during AP with posaconazole [25 (43%)]. The patients who received AP during salvage chemotherapy showed a benefit from antifungal therapy (AT) than patients who did not received AP [43 (86%) vs 7 (14%); p&nbsp

Purpose Jacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited. Methods Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR, and lymphocyte functional testing were collected. Results Recurrent infections were registered in 6/12 patients (50%), while bleeding episodes in 2/12 (16.7%). White blood cell and absolute lymphocyte counts were reduced in 8/12 (66.7%) and 7/12 (58.3%) patients, respectively. Absolute numbers of CD3+ and CD4+ T cells were reduced in 8/12 (66.7%) and 7/12 (58.3%), respectively. Of note, recent thymic emigrants (RTE) were reduced in all tested patients (9/9), with T-cell receptor excision circle analysis (TRECs) showing a similar trend in 8/9 patients; naive CD4+ T cells were low only in 5/11 patients (45.4%). Interestingly, B-cell counts, IgM memory B cells, and IgM serum levels were reduced in 10/12 (83.3%) patients. Natural killer (NK) cell counts were mostly normal but the percentages of CD16+CD56low/- cells were expanded in 7/7 patients tested. The observed immunological alterations did not correlate with patients' age. Finally, responses to proliferative stimuli were normal at presentation for all patients, although they may deteriorate over time. Conclusions Our data suggest that patients affected with JS may display important numeric and maturational alterations in the T-, B-, and NK-cell compartments. These findings suggest that JS patients should be regularly monitored from an immunological point of view.

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

Prophylaxis of Pneumocystis jiroveci pneumonia (PJP) with trimethoprim/sulfamethoxazole is a standard of care for children with hematologic malignancies, while its use in solid tumor patients is still debated. A retrospective study focusing on the use of PJP prophylaxis in patients with solid tumors was performed among 16 AIEOP centers: 1046/2863 patients did not receive prophylaxis and no cases of PJP were reported.

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.

Splenomegaly in children is really common and its main cause is infectious disease. The aetiology in newborns and older children is well established, while it is less defined in suckling infants. The paper describes three cases of splenomegaly in infants hospitalized in Oncohaematology Department of Sant’Orsola Malpighi Hospital. These infants presented with splenomegaly associated with other signs and symptoms that should prompt further investigations to exclude severe diseases. The aim of this paper is to offer paediatricians some indications for the diagnostic approach in infants with enlarged spleen. In particular, it reports the first level exams, the differential diagnosis and the red flags, the signs and symptoms that require special attention in infants with splenomegaly.

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (

Hepatic sinusoidal obstruction syndrome (SOS/VOD) represents a dramatic complication of hematopoietic stem cell transplantation (HSCT), particularly in children. Recent evidence has suggested a role for the gut microbiome (GM) in the context of HSCT and its related complications, but no data are available on the relationship between GM and SOS/VOD. Here, we conducted a retrospective case–control study in allo-HSCT pediatric patients developing or not SOS/VOD and profiled their GM over time, from before the transplant up to 72 days after. A rich and diverse GM before HSCT was found to be associated with a reduced likelihood of developing SOS/VOD. Furthermore, prior to transplant, patients not developing SOS/VOD showed an enrichment in some typically health-associated commensals, such as Bacteroides, Ruminococcaceae and Lachnospiraceae. Their levels remained overall higher until post-transplant. This high-diversity configuration resembles that described in other studies for other HSCT-related complications, including graft-versus-host disease, potentially representing a common protective GM feature against HSCT complications.

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.

The scenario of pediatric acute leukemia has changed extremely rapidly over these last decade and the pediatric hematologists are now facing new challenges related to the biology of the disease, the prognostic classifications of patients, and the consequent risk-based targeted approach. Acute lymphoblastic leukemia (ALL) in children has always represented a paradigm of success, and the recent advent of large-scale genomic studies and novel immunotherapy-based approaches have further revolutionized the perspective on this disease. Pediatric acute myeloid leukemia (AML) still suffers from a lower cure rate if compared to ALL, due to a still high incidence of recurrence and of severe and dose-limiting short- and long-term toxicities. Nevertheless, much has been learned about the biology of the disease through studies of specific recurrent genetic lesions and the outcomes for these children are progressively improving thanks to the great collaborative efforts of the main pediatric AML groups worldwide.

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 Identification of predictive factors of IEI in immune cytopenic children is an important objective for a prompt immunological diagnosis and appropriate management. Aim of this study is to detect clinical and laboratory signs of IEI, in particular the latter by an extensive lymphocyte immunophenotyping. 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 2 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 (9/19), Autoimmune lymphoproliferative syndrome (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+ the extended lymphocyte immunophenotyping identified the presence of statistically significant (p-value

Nutritional support for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely debated. Enteral nutrition (EN) is recommended as first-line nutritional support by the main international guidelines. However, these recommendations are based on weak evidence, and there is wide variability in the types of nutritional support among transplantation centers, with the majority providing parenteral nutrition (PN) instead of EN. Here we provide an up-to-date systematic review and meta-analysis of studies comparing EN and PN for nutritional support during the neutropenic period after allo-HSCT. The literature search strategy identified 13 papers, of which 10 compared clinical transplantation outcomes, 2 compared gut microbiota (GM) compositions, and 1 compared systemic metabolic profiles. For the meta-analysis, among the 10 clinical studies, 8 studies in which 2 groups were compared were selected: in 1 group, EN was provided as primary nutritional support in the neutropenic phase after allo-HSCT with or without the addition of PN (EN group), whereas in the other group, only PN was provided as nutritional support. The incidence rates of acute graft-versus-host disease (aGVHD) (relative risk [RR], 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = .0007), aGVHD grade III-IV (RR, 0.44; 95% CI, 0.30 to 0.64; P < .0001), and gut aGVHD (RR, 0.44; 95% CI, 0.30 to 0.66; P < .0001) were lower in the EN group than in the PN group. No differences were found between the 2 groups with regard to the incidence of severe oral mucositis (RR, 0.95; 95% CI, 0.83 to 1.09; P = .46) or overall survival at day +100 (RR, 1.07; 95% CI, 0.95 to 1.21; P = .29). Other variables were too heterogeneous to perform quantitative analyses. The results of the meta-analysis showed that EN reduced the incidence of aGVHD, specifically grade III-IV and gut aGVHD. This result should prompt improved efforts to implement EN as first-line nutritional support in patients undergoing allo-HSCT. Considering the emerging evidence regarding the association between GM dysbiosis and aGVHD onset, we speculate that this protective effect could be attributed to the improved gut eubiosis observed in enterally fed patients. Further studies are warranted to better address the relationship between the GM composition, aGVHD, and the nutritional administration route during HSCT.

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.

Background Little is known as yet about the outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children being treated for cancer. Methods We collected information on the clinical characteristics and outcomes of a cohort of 29 children (16 female and 13 male; median age, 7 years [range, 0–16 years]) diagnosed with SARS-CoV-2 infection while on chemotherapy/immunotherapy (n = 26), or after stem cell transplantation (n = 3) during the peak of the epidemic in Italy. These patients suffered from leukemia (n = 16), lymphoma (n = 3), solid tumors (n = 10), and Langerhans cell histiocytosis (n = 1). Results The course of the disease was mild in all cases, with only 12 children developing symptoms (pneumonia in 3 cases), and none needing intensive care. Fifteen patients were hospitalized, including 7 asymptomatic patients. Nine patients (including 5 with no symptoms) were given hydroxychloroquine, and 3 of them were also given lopinavir/ritonavir. Among the 26 patients on chemotherapy/immunotherapy, the treatment was suspended in 16 cases for a median of 26 days (range, 15–68 days), whereas 8 patients continued their chemotherapy and 2 had minor modifications to their treatment regimen. Conclusions SARS-CoV-2 infection seems to take a milder clinical course in children than in adults with cancer. Specific SARS-CoV-2 treatment seems unnecessary for most children. In light of our findings, and albeit with the necessary caution, we suggest avoiding major changes to planned anticancer treatments in pediatric patients acquiring COVID-19., We describe clinical characteristics and outcomes of 29 SARS-CoV-2–infected children with cancer. In comparison to adult oncology patients, children presented a milder clinical course. A substantial number of them continued their anticancer treatment without major modifications.

SARS-COV-2 infection can be asymptomatic or mildly symptomatic. The effect of chemotherapy on an asymptomatic infected patient is unknown. Three hundred-thirty-four and 56 NFS were performed as screening for SARS-CoV-2 infection in 247 and 34 pediatric patients undergoing chemotherapy and stem cell transplantation, respectively. NFS was positive in 10 patients. All positive patients withdrew from chemotherapy. Nine patients became negative. One patient is still positive after 38 days.The identification of asymptomatic SARS-COV-2 infection is important to reduce the hospital spread of infection. Further studies are needed to define the least risky management of chemotherapy in asymptomatic SARS-CoV-2 patients.

NA

Aim: The aim of this study was to describe the characteristics of Posterior Reversible Encephalopathy Syndrome (PRES) in infants and young children (

Enteral Nutrition (EN) is recommended as first line nutritional support for patients undergoing Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT), but only few studies exist in the literature which compare EN to Parenteral Nutrition (PN) in the paediatric population.Forty-two consecutive paediatric patients undergoing allo-HSCT at our referral centre between January 2016 and July 2019 were evaluated. Post-transplant and nutritional outcomes of patients receiving EN for more than 7 days (EN group, n = 14) were compared with those of patients receiving EN for fewer than 7 days or receiving only PN (PN group, n = 28). In the EN group, a reduced incidence of Blood Stream Infections (BSI) was observed (p = 0.02) (n = 2 vs. n = 15; 14.3% vs. 53.6%). The type of nutritional support was also the only variable independently associated with BSI in the multivariate analysis (p = 0.03). Platelet engraftment was shorter in the PN group than in the EN group for a threshold of > 20*109/L (p = 0.04) (23.1 vs 35.7 days), but this correlation was not confirmed with a threshold of > 50*109/L. The Body Mass Index (BMI) and the BMI Z-score were no different in the two groups from admission to discharge.Our results highlight that EN is a feasible and nutritionally adequate method of nutritional support for children undergoing allo-HSCT in line with the present literature. Future functional studies are needed to better address the hypothesis that greater intestinal eubyosis maintained with EN may explain the observed reduction in BSI.

Although recurrent infections in Rubinstein–Taybi syndrome (RSTS) are common, and probably multifactorial, immunological abnormalities have not been extensively described with only isolated cases or small case series of immune deficiency and dysregulation having been reported. The objective of this study was to investigate primary immunodeficiency (PID) and immune dysregulation in an international cohort of patients with RSTS. All published cases of RSTS were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Ninety-seven RSTS patients were identified. For 45 patients, we retrieved data from the published reports while for 52 patients, a clinical update was provided. Recurrent or severe infections, autoimmune/autoinflammatory complications, and lymphoproliferation were observed in 72.1%, 12.3%, and 8.2% of patients. Syndromic immunodeficiency was diagnosed in 46.4% of individuals. Despite the broad heterogeneity of immunodeficiency disorders, antibody defects were observed in 11.3% of subjects. In particular, these patients presented hypogammaglobulinemia associated with low B cell counts and reduction of switched memory B cell numbers. Immunoglobulin replacement therapy, antibiotic prophylaxis, and immunosuppressive treatment were employed in 16.4%, 8.2%, and 9.8% of patients, respectively. Manifestations of immune dysfunctions, affecting mostly B cells, are more common than previously recognized in patients with RSTS. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment. [Figure not available: see fulltext.]

The gut microbiota (GM) is able to modulate the human immune system. The development of novel investigation methods has provided better characterization of the GM, increasing our knowledge of the role of GM in the context of hematopoietic stem-cell transplantation (HSCT). In particular, the GM influences the development of the major complications seen after HSCT, having an impact on overall survival. In fact, this evidence highlights the possible therapeutic implications of modulation of the GM during HSCT. Insights into the complex mechanisms and functions of the GM are essential for the rational design of these therapeutics. To date, preemptive and curative approaches have been tested. The current state of understanding of the impact of the GM on HSCT, and therapies targeting the GM balance is reviewed herein.

Hematopoietic stem cell transplantation (HSCT) is the first-line immunotherapy to treat several hematologic disorders, although it can be associated with many complications reducing the survival rate, such as acute graft-versus-host disease (aGvHD) and infections. Given the fundamental role of the gut microbiome (GM) for host health, it is not surprising that a suboptimal path of GM recovery following HSCT may compromise immune homeostasis and/or increase the risk of opportunistic infections, with an ultimate impact in terms of aGvHD onset. Traditionally, the first nutritional approach in post-HSCT patients is parenteral nutrition (PN), which is associated with several clinical adverse effects, supporting enteral nutrition (EN) as a preferential alternative. The aim of the study was to evaluate the impact of EN vs. PN on the trajectory of compositional and functional GM recovery in pediatric patients undergoing HSCT. The GM structure and short-chain fatty acid (SCFA) production profiles were analyzed longitudinally in twenty pediatric patients receiving HSCT&mdash, of which, ten were fed post-transplant with EN and ten with total PN. According to our findings, we observed the prompt recovery of a structural and functional eubiotic GM layout post-HSCT only in EN subjects, thus possibly reducing the risk of systemic infections and GvHD onset.

Evans syndrome (ES) is a rare but challenging condition, characterized by recurrent and refractory cytopenia episodes. Recent discoveries highlighted that an appropriate diagnostic workup is fundamental to identify an underlying immune dysregulation such as primary immunodeficiencies or a rheumatological disease. We hereby describe clinical features and laboratory results of 12 pediatric patients affected by ES referred to the Pediatric Onco-Hematology Unit of Bologna. Patients experienced a median of four acute episodes of cytopenia with 9 years as median age at the onset of symptoms. In 8/12 (67%) patients an underlying etiology, primary immunodeficiencies, or rheumatological disease was identified. In 4/12 children, other immune manifestations were associated (Thyroiditis, Celiac disease, Psoriasis, Vitiligo, Myositis, Membranoproliferative Glomerulonephritis). ES remained the primary diagnosis in four patients (33%). At a median follow-up time of 4 years, 5/12 (42%) patients revealed a chronic ITP, partially responsive to second line therapy. Immunoglobulin Replacement Therapy (IRT) was effective with a good hematological values control in three patients with a secondary ES (ALPS, CVID, and a patient with Rubinstein Taybi Syndrome and a progressive severe B cell deficiency with hypogammaglobulinemia). Our experience highlights that, in pediatric patients, ES is often only the first manifestation of an immunological or rheumatological disease, especially when cytopenias are persistent or resistant to therapy, with an early-onset or when are associated with lymphadenopathy.

Liver stiffness measurement by transient elastography is a non-invasive ultrasound-based technique used mainly for the evaluation of liver fibrosis in patients with chronic liver diseases. Some authors have suggested that it could be useful in the assessment of hepatic complications during hematopoietic stem cell transplant (HSCT), especially veno-occlusive disease (VOD) or sinusoidal obstructive syndrome (SOS). Here, we present the evaluation of liver stiffness in three patients who developed severe hepatic VOD/SOS after HSCT. Liver stiffness measurement values were normal before transplant and afterward until the diagnosis of VOD/SOS when a dramatic increase was observed. After the VOD/SOS specific treatment, the values of stiffness showed a similar pattern of progressive reduction in all the three patients, with normalization after two weeks. In this report, we discuss the role of LSM in the management of patients after the diagnosis of VOD/SOS.

The gut microbiome of pediatric patients undergoing allo-hematopoietic stem cell transplantation (HSCT) has recently been considered as a potential reservoir of antimicrobial resistance, with important implications in terms of patient mortality rate. By means of shotgun metagenomics, here we explored the dynamics of the gut resistome – i.e. the pattern of antibiotic resistance genes provided by the gut microbiome – in eight pediatric patients undergoing HSCT, half of whom developed acute Graft-versus-Host Disease (aGvHD). According to our findings, the patients developing aGvHD are characterized by post-HSCT expansion of their gut resistome, involving the acquisition of new resistances, as well as the consolidation of those already present before HSCT. Interestingly, the aGvHD-associated bloom in resistome diversity is not limited to genes coding for resistance to the antibiotics administered along the therapeutic course, but rather involves a broad pattern of different resistance classes, including multidrug resistance, as well as resistance to macrolides, aminoglycosides, tetracyclines and beta-lactams. Our data stress the relevance of mapping the gut resistome in HSCT pediatric patients to define the most appropriate anti-infective treatment post HSCT.

Background The onset of acute Graft-versus-Host Disease (aGvHD) has been correlated with the gut microbiota (GM) composition, but experimental observations are still few, mainly involving cohorts of adult patients. In the current scenario where fecal microbiota transplantation has been used as a pioneer therapeutic approach to treat steroid-refractory aGvHD, there is an urgent need to expand existing observational studies of the GM dynamics in Hematopoietic Stem Cell Transplantation (HSCT). Aim of the present study is to explore the GM trajectory in 36 pediatric HSCT recipients in relation to aGvHD onset. Methods Thirty-six pediatric patients, from four transplantation centers, undergoing HSCT were enrolled in the study. Stools were collected at three time points: before HSCT, at time of engraftment and > 30 days following HSCT. Changes in the GM phylogenetic structure were studied by 16S rRNA gene Illumina sequencing and phylogenetic assignation. Results Children developing gut aGvHD had a dysbiotic GM layout before HSCT occurred. This putative aGvHD-predisposing ecosystem state was characterized by (i) reduced diversity, (ii) lower Blautia content, (iii) increase in Fusobacterium abundance. At time of engraftment, the GM structure underwent a deep rearrangement in all patients but, regardless of the occurrence of aGvHD and its treatment, it reacquired a eubiotic configuration from day 30. Conclusions We found a specific GM signature before HSCT predictive of subsequent gut aGvHD occurrence. Our data may open the way to a GM-based stratification of the risk of developing aGvHD in children undergoing HSCT, potentially useful also to identify patients benefiting from prophylactic fecal transplantation. Electronic supplementary material The online version of this article (10.1186/s12920-019-0494-7) contains supplementary material, which is available to authorized users.

[Background] Immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal disease caused by mutations in a transcription factor critical for the function of thymus-derived regulatory T (Treg) cells (ie, FOXP3), resulting in impaired Treg function and autoimmunity. At present, hematopoietic stem cell transplantation is the therapy of choice for patients with IPEX syndrome. If not available, multiple immunosuppressive regimens have been used with poor disease-free survival at long-term follow-up. Rapamycin has been shown to suppress peripheral T cells while sparing Treg cells expressing wild-type FOXP3, thereby proving beneficial in the clinical setting of immune dysregulation. However, the mechanisms of immunosuppression selective to Treg cells in patients with IPEX syndrome are unclear., [Objective] We sought to determine the cellular and molecular basis of the clinical benefit observed under rapamycin treatment in 6 patients with IPEX syndrome with different FOXP3 mutations., [Methods] Phenotype and function of FOXP3-mutated Treg cells from rapamycin-treated patients with IPEX syndrome were tested by flow cytometry and in vitro suppression assays, and the gene expression profile of rapamycin-conditioned Treg cells by droplet-digital PCR., [Results] Clinical and histologic improvements in patients correlated with partially restored Treg function, independent of FOXP3 expression or Treg frequency. Expression of TNF-receptor-superfamily-member 18 (TNFRSF18, glucocorticoid-induced TNF-receptor–related) and EBV-induced-3 (EBI3, an IL-35 subunit) in patients’ Treg cells increased during treatment as compared with that of Treg cells from untreated healthy subjects. Furthermore inhibition of glucocorticoid-induced TNF-receptor–related and Ebi3 partially reverted in vitro suppression by in vivo rapamycin-conditioned Treg cells., [Conclusions] Rapamycin is able to affect Treg suppressive function via a FOXP3-independent mechanism, thus sustaining the clinical improvement observed in patients with IPEX syndrome under rapamycin treatment.

To evaluate cystic dynamics in two pediatric low grade gliomas during proton beam therapy (PBT) by weekly MRI and in the follow up (FU) time. Early late toxicity was also reported. Both solid and cystic tumor’s components were drown in weekly MRI performed during proton radiation and in the FU phase. P1 case was a multiple partially resected 5 yo girl with hypothalamic pylocitic Astrocytoma no-responding after second line of chemotherapy, who acutely lost visual acuity due to cystic tumor’s progression. P2 case was a 13 yo boy with progressive mesencephalic pylocitic Astrocytoma previously treated with multi-agents chemotherapy and several surgeries. After cystic drainage both were treated with PBT at 54 Gy GCE. During proton therapy # 7 MRI for P1 and # 6 MRI for P2 patient were performed and didn’t shown cyst growth which required intervention; P1 developed two episodes of severe acute headache and both developed partial alopecia. In P1 patient both cystic and solid component progressively reduced (cyst/solid-1w +2/-15%, cyst/solid-2w -9/-22%, cyst/solid-3w -17/-28%, cyst/solid-4w -18/-38%, cyst/solid-5w -30/-43%, cyst/solid-6w -34/-44%, cyst/solid-1FU -43/-50%, cyst/solid-2FU -51/-63%). In P2 patient only cyst part progressively increased (cyst/solid-2w +7/-4%, cyst/solid-3w +36/-10%, cyst/solid-4w +58/-12%, cyst/solid-5w +73/-15%, cyst/solid-6w +90/-15%, cyst/solid-7w +94/-16%, cyst/solid-1FU +126/-37%, cyst/solid-2FU -18/-45%). P2 had transient cyst growth after PT with significant volume reduction on the second FU. After 10 months of median FU, no late side effects were noted however P1 improved visual acuity.

PURPOSE: Epileptic seizures are frequent manifestations after hematopoietic stem cell transplantation (HSCT). In this retrospective single-center study we evaluated electroclinical features and analyzed etiologies and outcome of seizures after pediatric HSCT. METHODS: Of 261 children transplanted between 2000 and 2010, we identified and analyzed data of 28 patients with seizures within a year from HSCT. RESULTS: Most frequent etiologies were posterior reversible encephalopathy syndrome (PRES, 14 patients) and central nervous system (CNS) infections (4 patients). Seizures were the presentation of the underlying complications in 22 patients. Sixteen episodes of status epilepticus were identified. Seizures secondary to PRES were usually longer and associated with non-convulsive signs. Early neuroimaging and EEG monitoring proved to be crucial to diagnose and treat seizures and their causes. No patients developed epilepsy suggesting that chronic antiepileptic therapy is not necessary in these patients. Overall survival was 32.3% over 5 years in patients with seizures and 45.8% in patients without seizures (p

Posterior reversible encephalopathy syndrome (PRES) is a clinical neuroradiologic entity that is becoming increasingly well known and documented in pediatrics. It is characterized by a variable association of seizures, headache, vomiting, altered mental status, visual disturbances, and seizures, as well as imaging suggesting white-gray matter edema involving the posterior regions of the central nervous system in most cases. The pathophysiology of PRES remains unclear. Although PRES has been associated with a widespread range of clinical conditions, namely infections, adverse drug events, autoimmune diseases, and many others, its onset after hematopoietic stem cell and solid organ transplantation remains the most commonly reported. Historically, PRES has proved to be generally reversible and associated with good clinical outcomes; however, severe complications, sometimes life-threatening, can also occur. Most reported cases of childhood PRES after hematopoietic stem cell or solid organ transplantation have been case reports or series across a broad spectrum of different transplant settings, and no clear consensus exists regarding how best to manage the syndrome. Thus, in this article, we provide a comprehensive review of the pathophysiological, clinical, and diagnostic aspects of PRES in children, with a specific focus on the transplant scenario. Differential diagnoses with other neurologic complications after pediatric transplantation are reviewed, and crucial issues in the management of PRES and the development of future research are ultimately addressed.

Therapy-related neurotoxicity greatly affects possibility of survival and quality of life of pediatric patients treated for cancer. Central nervous system involvement is heterogeneous, varying from very mild and transient symptoms to extremely severe and debilitating, or even lethal syndromes. In this review, we will discuss the broad scenario of central nervous system complications and toxicities occurring during the treatment of pediatric patients receiving both chemotherapies and hematopoietic stem cell transplantation. Different types of complications are reviewed ranging from therapy related to cerebrovascular with a specific focus on neuroradiologic and clinical features.

Oral chronic graft versus host disease (cGVHD) is often refractory to systemic therapies. Additional topical treatment is commonly required. The potency of the agent, the vehicle and formulation in which it is delivered are all critical factors in determining the effectiveness of topical therapies. High potency of budesonide, combined with its very low bioavailability when absorbed through mucosal surfaces, increased the potential role in topical application for oral cGVHD. Viscous formulation increases mucosal contact time resulting in a greater decrease in mucosal inflammation. This short communication suggests that oral viscous budesonide should be considered as a potential new therapy in the management of oral cGVHD.

The cure of children with severe AD, especially patients with severe, progressive, and therapy-resistant autoimmunity, represents a challenge for current medical practice. The idea of HSCT as a promising therapeutic opportunity was borne accidentally from finding patients who, after undergoing HSCT for a hematological indication, were cured of a concomitant AD. Thus, over the last two decades, HSCT has been extensively investigated, and it has become an appealing therapy for rheumatological (juvenile rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis) and hematological diseases (immune cytopenias). Recently, interesting results have been also described in type 1 diabetes mellitus and Crohn's disease. Although the use of HSCT has been steadily rising in the last few years, many questions are still open, especially after the discoveries of many new biological agents. Given the low incidence of ADs in children, most of the data about the use of the HSCT for these diseases are taken from a mixed cohort of adults and children. The aim of this review is to summarize the published studies and to try to answer the question as to whether this procedure can be considered a promising approach.

Background Apnoea of prematurity (AOP) frequently recurs in preterm infants. We have previously shown that a significant but variable proportion of AOP is induced by gastro-oesophageal reflux (GOR). Aim The aim of this study is to evaluate the efficacy of sodium alginate in reducing the frequency of GOR-related AOP. Subjects Twenty-eight preterm infants with AOP were studied by a six-hour recording of combined multichannel intraluminal impedance and pH monitoring and polysomnography, including two three-hour postprandial periods: sodium alginate was given after one single meal named as drug-given (DG) meal, while the other as drug-free (DF). Results During 165 h of registration, 715 apnoeas were recorded, 368 after-DG and 347 after-DF (p = .99); furthermore, 851 GOR episodes were detected, 315 after-DG and 536 after-DF (p = .001). No differences in the number of AOP were found between DG and DF. A significant reduction in the number of acid GORs and in acid exposure was found during DG, while the administration of sodium alginate didn't influence non-acid GOR indexes. The frequency of GOR-related apnoeas didn't differ between DG and DF. Discussion Sodium alginate doesn't reduce the total number of AOP nor GOR-related apnoeas. On the other hand, it reduces acid GOR features, while it had no effect on non-acid GOR indexes.

Objective: To document the existence of a relationship between apnoea of prematurity (AOP) and gastro-oesophageal reflux (GER) in preterm infants. Setting: Neonatal intensive care unit. Patients: Twenty-six preterm infants (gestational age ⩽32 weeks) with recurrent apnoeas. Intervention: Simultaneous and synchronised recording of polysomnography and pH-impedance monitoring (pH-MII). Polysomnography detects and characterises apnoeas, by recording of breathing movement, nasal airflow, electrocardiogram and pulse oximeter saturation. pH-MII is the state-of-the-art methodology for GER detection in preterm newborns. Main outcome measures: Relationship between AOP and GER, which were considered temporally related if both started within 30 seconds of each other. Results: One hundred and fifty-four apnoeas out of 1136 were temporally related to GER. The frequency of apnoea during the 1-minute time around the onset of GER was significantly higher than the frequency detected in the GER-free period (p = 0.03). Furthermore, the frequency of apnoea in the 30 seconds after GER (GER-triggered apnoeas) was greater than that detected in the 30 seconds before (p = 0.01). A great inter-individual variability was documented in the proportion of GER-triggered apnoeas. A strong correlation between total number of apnoeas and the difference between apnoeas detected 30 seconds after and before GER was found (p = 0.034). Conclusions: Our data show that a variable rate of apnoeas can be triggered by GER in very preterm infants. Further studies are needed to recognise clinical features that identify those patients who are more susceptible to GER-triggered apnoeas.

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.

Acute GvHD (aGvHD) is the main complication of hematopoietic SCT (HSCT) during the treatment of hematological disorders. We carried out the first longitudinal study to follow the gut microbiota trajectory, from both the phylogenetic and functional points of view, in pediatric patients undergoing HSCT. Gut microbiota trajectories and short-chain fatty acid production profiles were followed starting from before HSCT and through the 3–4 months after transplant in children developing and not developing aGvHD. According to our findings, HSCT procedures temporarily cause a structural and functional disruption of the gut microbial ecosystem, describing a trajectory of recovery during the following 100 days. The onset of aGvHD is associated with specific gut microbiota signatures both along the course of gut microbiota reconstruction immediately after transplant and, most interestingly, prior to HSCT. Indeed, in pre-HSCT samples, non-aGvHD patients showed higher abundances of propionate-producing Bacteroidetes, highly adaptable microbiome mutualists that showed to persist during the HSCT-induced ecosystem disruption. Our data indicate that structure and temporal dynamics of the gut microbial ecosystem can be a relevant factor for the success of HSCT and opens the perspective to the manipulation of the pre-HSCT gut microbiota configuration to favor mutualistic persisters with immunomodulatory properties in the gut.

Risk factor analysis of posterior reversible encephalopathy syndrome after allogeneic hematopoietic SCT in children

The mediastinum is the most common site of chest masses in children. Mediastinal masses are placed in one of three mediastinal compartments (anterior, middle, posterior) on the basis of a lateral chest radiograph [1] They comprise a wide spectrum of disease, and around 40% occur in children aged

Chest wall tumors (CWTs) in children comprise a wide range of benign and malignant neoplasms. These tumors are rare in infants, children and young adults, accounting for 1.8% of solid tumors [1]. However, high proportions of CWTs are malignant, and represent a diagnostic and therapeutic challenge to pediatric thoracic surgeons. The chest wall can be affected by: primary malignant neoplasms arising from different structures; secondary tumors which can invade the chest wall from the adjacent structures (e.g., breast, pleura, mediastinum, lung); metastatic tumors [2].

Background: Benign nodular hepatic regenerating lesions such as focal nodular hyperplasia (FNH) have been reported as rare complications of the antineoplastic therapy received during infancy. Little is known about the risk factors associated with the onset of these lesions and their diagnostic management. Methods: We have analyzed a series of benign hepatic nodular lesions occurring in children previously treated for malignant tumors in our institution in a period of 11 years. An extensive description of the imaging presentation of the lesions has been provided to facilitate the differential diagnosis, and a risk factor analysis has been conducted. Results: A total of 14 diagnoses (10 FNH and 4 hemangiomas) of benign nodular hepatic lesions have been found. Hematopoietic stem cell transplantation is the most important statistically independent risk factor associated with the development of these lesions, especially for FNH. No malignant transformation of nodules has been recorded during a median follow-up time of 4 years. Conclusions: In our experience, FNH is the most frequent benign nodular hepatic lesions occurring after treatment for childhood cancer. Hematopoietic stem cell transplantation is the most important risk factor to be taken in account. After a secure diagnosis of these benign lesions, only a close imaging follow-up is recommended.

HC is a possible cause of morbidity and extended hospitalization after HSCT. Recent studies have reported the efficiency of HOT in adult patients who underwent allogeneic HSCT, but data in children are scarce. We report our single center experience with HOT in late-onset HC after HSCT. Treatment with HOT consisted of daily sessions of breathing 100% O(2) for a total of 75 min in the hyperbaric chamber with a minimum of eight sessions. HOT had been associated with a concomitant treatment with oral oxybutynin, hyperhydration and/or irrigation of the bladder through the catheter. Cidofovir had been administered based on the demonstration of viral infection. Between 2004 and 2011, 10 patients developed severe HC after a median of 26 days after HSCT. HOT was started after a median of six days since the clinical diagnosis of HC. After a median of 10 sessions of HOT, seven of 10 patients were in complete remission. HOT is a well-tolerated procedure also in the pediatric setting. The early start of HOT might be effective in the treatment of HC offering advantages in terms of duration of symptoms and hospitalization.

Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among 'Nordic' origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-alpha gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90-95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL.

Introduction and aim: Childhood cytogenetically normal acute myeloid leukemia (CN-AML) is a subgroup of pediatric AML lacking any known cytogenetic and abnormality. CN-AML accounts for 20% of pediatric AML and exhibits a very heterogeneous response to treatment and, consequently, variable outcome. With the aim of providing new insights into the molecular lesions of this subset of AML, we analyzed, through RNA-seq, 13 cases of pediatric CN-AML, corroborating our findings in an independent cohort of 152 AML patients enrolled in the AIEOP AML 2002/01 clinical trial. Methods: Paired-end RNA-seq (75×2) was performed on PoliA(+) RNA extracted from blasts at diagnosis. ChimeraScan, deFuse and FusionMap algorithms were used for chimeric transcript detection. Results: An alteration that was present in 2 out 13 cases was a chimeric transcript involving the genes nucleoporin 98kDa (NUP98) and PHD finger protein 23 (PHF23), resulting from a cryptic translocation t(11;17)(p15;p13). Both patients showed an in-frame fusion between exon 13 of NUP98 and exon 4 of PHF23 that was confirmed by RT-PCR analysis and Sanger sequencing. To date, the cryptic translocation t(11;17)(p15;p13) was never described before in pediatric AML and has been reported only once in an adult AML patient (Reader, et al. Leukemia 2007). In both our patients the same breakpoint in PHF23 gene at the beginning of exon 4 was present, which was different from that present in the adult patient. To assess the incidence of NUP98-PHF23 fusion in pediatric CN-AML, then we studied by RT-PCR and Sanger sequencing a validation cohort of 152 CN-AML children negative for the most common recurrent cytogenetic and molecular lesions, i.e. those involving MLL, CBFB, NPM1 and FLT3. Overall, 2 out of the 152 CN-AML cases were found positive for NUP98-PHF23, demonstrating that this genomic aberrancy is not rare in pediatric CN-AML (tentative frequency 2.4%). Fluorescence in situ hybridization analysis confirmed the cryptic chromosomal translocation t(7;11)(p15;p13) leading to the fusion between NUP98 and PHF23 in all cases. Conclusions: Lately, genome-wide approaches have been widely used to investigate the mutational landscape of CN-AML in adults. However, the genetic profile of childhood CN-AML still needs to be defined. Here, for the first time, we report the identification of a NUP98-PHF23 chimeric transcript in pediatric CN-AML. Together with recently published data demonstrating that NUP98-PHF23 promoted leukemogenesis and the observation that treatment with inhibitors of PHD-domain-mediated H3K4me3 binding, such as disulfiram (an FDA-approved drug), could selectively killed cells expressing NUP98-PHF23 (Gough, et al Cancer Discovery 2014), our findings enforce the role of epigenetic regulators in pediatric AML and suggest screening for this fusion gene at diagnosis in CN-AML pediatric patients. Citation Format: Marco Togni, Riccardo Masetti, Martina Pigazzi, Annalisa Astolfi, Daniele Zama, Valentina Indio, Salvatore Serravalle, Elena Manara, Valeria Bisio, Sergio Rutella, Franca Fagioli, Giuseppe Basso, Andrea Pession, Franco Locatelli. NUP98-PHF23 is a novel fusion gene in pediatric cytogenetically normal acute myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-211. doi:10.1158/1538-7445.AM2015-LB-211