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Anaemia is a common issue in the paediatric age group and it is not uncommon to encounter severe cases of anaemia in the Paediatric Emergency Unit. The correct identification of patients requiring urgent care is of central importance to provide timely interventions. However, considering that most patients are haemodynamically stable, transfusions are not always mandatory. Even in the setting of the Emergency Unit, the differential diagnosis can be narrowed with specific laboratory tests. The paper presents three exemplary cases from the experience of a Paediatric Emergency Unit that will help to provide a summary of the diagnostic and therapeutic approach to severe anaemia in infants and children.

Children with cancer are at high risk for developing short-term and long-term nutritional problems related to their underlying disease and side effects of multimodal treatments. Nutritional status (NS) can influence several clinical outcomes, such as overall survival (OS) and event-free survival (EFS), treatment tolerance, risk of developing infections and quality of life (QoL). However, the importance of nutrition in children with cancer is still underestimated. This review focuses on alterations of NS that occurs in children during cancer treatment. In particular, we reviewed the pathogenesis of undernutrition in oncological children, as well as how NS affects treatment tolerance and response, the immune system and the risk of infections of children with cancer. Thanks to recent advances in all types of supportive therapy and to the progress of knowledge on this topic, it has been realized that NS is a modifiable prognostic factor that can be intervened upon to improve the outcome of these patients. Currently, there is a lack of a systematic approach and standard recommendations for nutritional care in the pediatric cancer population. Literature analysis showed that it is essential to define the NS and treat any alterations in a timely manner ensuring proper growth and development. Nutritional follow-up should become an integral part of the care pathway. Regular nutritional monitoring should be performed at diagnosis, during treatment and during follow-up. A close collaboration and sharing of expertise between pediatric oncologists and nutrition specialists, combined with careful and participatory sharing of the feeding experience with the family and the child (after age 6 years), is strongly required.

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.

The effectiveness of quinolone prophylaxis in high-risk hematological pediatric patients is controversial. A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, including studies that involved children and young adults undergoing chemotherapy for acute leukemia or hematopoietic stem cell transplantation (HSCT) who received quinolone prophylaxis compared with no prophylaxis. A meta-analysis was performed on bloodstream infections and neutropenic fever. Data regarding the impact of prophylaxis on overall survival, antibiotic exposure, antibiotic-related adverse effects, antibiotic resistance, Clostridium difficile infections, fungal infections, length of hospitalization, and costs were reviewed in the descriptive analysis. Sixteen studies were included in the qualitative analysis, and 10 of them met the criteria for quantitative analysis. Quinolone prophylaxis was effective in reducing the rate of bloodstream infections and neutropenic fever in pediatric acute leukemia compared with no prophylaxis, but it had no significant effect in HSCT recipients. Prophylaxis was associated with a higher rate of bacterial resistance to fluoroquinolones and higher antibiotic exposure.

In children affected by malignancies and/or who received hematopoietic stem cell transplantation (HSCT), acute kidney injury (AKI) may occur causing a high mortality rate, despite the implementation of renal replacement therapy (RRT). We performed a nationwide, multicenter, retrospective, observational cohort study including consecutive patients between January 2010 and December 2019. One hundred and fourteen episodes of AKI requiring RRT coming from nine different Italian centers were included. The overall mortality rate was 61.4%. At the 3-month follow-up, the mortality rate was 47.4%. The mortality rate was higher in transplanted patients than those receiving chemotherapy. In particular, HSCT (

Simple Summary Nutritional management is an underestimated issue in treating pediatric cancer, since a systematic approach is currently lacking. In this consensus statement, a cohort of 12 experts selected from four different tertiary pediatric oncology centers formulated 21 clinical questions regarding the identification and treatment of nutritional issues in children with cancer. These questions were discussed, and practical recommendations were provided. With this paper, we aimed to give consensus-based guidance for addressing the nutritional needs of children with cancer, filling a gap in the field. Malnutrition, intended as both overnutrition and undernutrition, is a common problem in children with cancer, impacting quality of life as well as survival. In addition, nutritional imbalances during childhood can significantly affect proper growth. Nevertheless, there is currently a lack of a systematic approach to this issue in the pediatric oncology population. To fill this gap, we aimed to provide practice recommendations for the uniform management of nutritional needs in children with cancer. Twenty-one clinical questions addressing evaluation and treatment of nutritional problems in children with cancer were formulated by selected members from four Italian Association of Pediatric Hematology and Oncology (AIEOP) centers and from the Survivorship Care and Nutritional Support Working Group of Alliance Against Cancer. A literature search in PubMed was performed; during two consensus meetings, all recommendations were discussed and finalized using the nominal group technique. Members representing every institution voted on each recommendation. Finally, recommendations were approved by all authors.

Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06–1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17–1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07–1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.

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.

The intestinal microbiota plays a crucial role in numerous physiological and pathological processes of the developmental age. The development of new investigation methods, such as next generation sequencing, has allowed a more precise characterization of the intestinal microbiota. This allowed us to deepen the complex relationship between the microbial flora and our organism. One of the many functions that emerged is the ability to modulate the host's immune system. The transplantation of hematopoietic stem cells represents a privileged setting for studying this interaction since, after the procedure, we witness the immune reconstruction starting from the donor precursors. The gut microbiota influences the development of major infectious and immune-mediated complications of transplantation and has a significant impact on patient survival. These evidences underline the possible therapeutic implications of the modulation of the intestinal microbiota. An in-depth study of the relationship between the immune system and microbiotic flora could allow us to better understand the role of the latter in other infectious or immune-mediated diseases.

Febrile neutropenia (FN) is a common complication in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Frequently, a precise cause cannot be identified, and many factors can contribute to its genesis. Gut microbiota (GM) has been recently linked to many transplant-related complications, and may also play a role in the pathogenesis of FN. Here, we conducted a longitudinal study in pediatric patients receiving HSCT from three centers in Europe profiling their GM during the transplant course, particularly at FN onset. We found that a more stable GM configuration over time is associated with a shorter duration of fever. Moreover, patients with longer lasting fever exhibited higher pre-HSCT levels of Collinsella, Megasphaera, Prevotella and Roseburia and increased proportions of Eggerthella and Akkermansia at the engraftment. These results suggest a possible association of the GM with the genesis and course of FN. Data seem consistent with previous reports on the relationship of a so-called “healthy” GM and the reduction of transplant complications. To our knowledge, this is the first report in the pediatric HSCT setting. Future studies are warranted to define the underling biological mechanisms and possible clinical implications.

CBL plays a key role in different cell pathways, mainly related to cancer onset and progression, hematopoietic development and T cell receptor regulation. Somatic CBL mutations have been reported in a variety of malignancies, ranging from acute myeloid leukemia to lung cancer. Growing evidence have defined the clinical spectrum of germline CBL mutations configuring the so-called CBL syndrome; a cancer-predisposing condition that also includes multisystemic involvement characterized by variable phenotypic expression and expressivity. This review provides a comprehensive overview of the molecular mechanisms in which CBL exerts its function and describes the clinical manifestation of CBL mutations in humans.

The gut microbiome (GM) has emerged in the last few years as a main character in several diseases. In pediatric oncological patients, GM has a role in promoting the disease, modulating the effectiveness of therapies, and determining the clinical outcomes. The therapeutic course for most pediatric cancer influences the GM due to dietary modifications and several administrated drugs, including chemotherapies, antibiotics and immunosuppressants. Interestingly, increasing evidence is uncovering a role of the GM on drug pharmacokinetics and pharmacodynamics, defining a bidirectional relationship. Indeed, the pediatric setting presents some contrasts with respect to the adult, since the GM undergoes a constant multifactorial evolution during childhood following external stimuli (such as diet modification during weaning). In this review, we aim to summarize the available evidence of pharmacomicrobiomics in pediatric oncology.

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.

The gut microbiome has emerged as a major character in the context of hematopoietic stem cell transplantation. The biology underpinning this relationship is still to be defined. Recently, mounting evidence has suggested a role for microbiome-derived metabolites in mediating crosstalk between intestinal microbial communities and the host. Some of these metabolites, such as fiber-derived short-chain fatty acids or amino acid-derived compounds, were found to have a role also in the transplant setting. New interesting data have been published on this topic, posing a new intriguing perspective on comprehension and treatment. This review provides an updated comprehensive overview of the available evidence in the field of gut microbiome-derived metabolites and hematopoietic stem cell transplantation.

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.

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.

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.

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.

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.