Nicola Santoro

• University of Bari Aldo Moro

BACKGROUND This study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR. METHODS Thirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-...

Background Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae. Methods Eight hundred seventy-seven youth (6–21 years) with overweight/obesity, recruited fro...

Obesity is one of the leading causes of the development of insulin resistance, diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) in children. With the progression of insulin resistance, both glucose and free fatty acid (FFA) plasma levels are elevated, leading to cardiometabolic complications such as impaired glucose tol...

Background: Serum albumin is crucial for critically ill patients. To date, several reports have focused on the influence of lower albumin levels on poorer prognosis and disease outcome in different subsets of critical clinical conditions varying from sepsis, to cirrhosis, renal failure, and cancer. In the last few years, investigators reported the...

RMS is a malignant tumor of soft tissues affecting primarily children and adolescents. Around 6% to 23% RMS patients present bone marrow infiltration but leukemia-like involvement is very rare; in these patients cytomorphology on bone marrow smears can lead to misdiagnosis. Differential diagnosis with alveolar RMS should be kept in mind in every pe...

Background Lactate is not considered just a “waste product” of anaerobic glycolysis anymore. It has been proved to play a key role in several metabolic diseases, such as in the metabolic dysfunction–associated steatotic liver disease, obesity, and diabetes. The capability of simulating glucose-insulin-lactate interaction would be useful to design a...

Hodgkin lymphoma (HL) is among the most commonly occurring malignancies in adolescents. For relapsed/refractory disease, many regimens have been proposed. Novel agents are increasingly used, like brentuximab vedotin (BV), an antiCD30 antibody-drug conjugate, used as a single agent or in combination with classic regimens mainly in adults, while limi...

Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the success...

Aim In this study, we investigated glucose and lactate kinetics during a 75 g oral glucose tolerance test (OGTT) in 23 overweight and obese adolescents and assessed putative differences among participants with and without metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods We enrolled 23 young people (six girls) with obesity...

Background In Italy, there is a network of centres headed by the Italian Association of Pediatric Hematology and Oncology (AIEOP) for the diagnosis and treatment of paediatric cancers on almost the entire national territory. Nevertheless, migration of patients in a hospital located in a region different from that of residence is a widespread habit,...

Background: Treatment of children with newly diagnosed AML is based on induction therapy, followed by consolidation approaches which differ according to the group of risk patients (pts) are allocated to. In this respect, most treatment protocols stratify pts into 3 risk groups, namely standard (SR), intermediate (IR) and high-risk (HR), mainly base...

Background. Advances in genomic techniques have recently shed light on leukemia biology, recognizing that pediatric acute myeloid leukemia (AML) is a highly genetically heterogeneous disease. In the last two decades, genetic and cytogenetic abnormalities contributed to the stratification of patients in different classes of risk, where children rece...

Background In Italy, there is a network of centres headed by the Italian Association of Pediatric Hematology and Oncology (AIEOP) for the diagnosis and treatment of paediatric cancers on almost the entire national territory. Nevertheless, migration of patients in a hospital located in a region different from that of residence is a widespread habit...

In youth with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on beta cell function and insulin sensitivity. Youths with obesity and 2-h glucose≥120mg/dL underwent a 3-h OGTT and an isoglycemic intravenous glucose inf...

Objective Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity wh...

NUT carcinoma (NC) is an exceedingly rare and poorly differentiated carcinoma characterised by BDR4:NUTM1 gene translocation. It typically affects young adults, and due to its dismal clinical course, standardized therapeutic recommendations are lacking. In this study, we present a successful multimodal treatment approach for a 13-year-old boy diagn...

Hodgkin Lymphoma (HL) is a common malignancy in adolescents. For relapsed/refractory disease many regimens have been proposed and novel agents are increasingly used. Brentuximab Vedotin (BV) is an antiCD30 antibody-drug conjugate used as single agent or in combination with classical regimens mainly in adults, while limited is the experience in paed...

Background Gaucher disease (GD) diagnosis can be delayed due to non-specific symptoms and lack of awareness, leading to unnecessary procedures and irreversible complications. GAU-PED study aims to assess GD prevalence in a high-risk pediatric population and the presence, if any, of novel clinical or biochemical markers associated with GD. Material...

Primary Central Nervous System Lymphoma is a rare extranodal non-Hodgkin lymphoma, primarily arising in brain and spinal cord tissue, leptomeninges and vitreoretinal eye. Pediatric PCNSLs are even rarer. We describe the case of a boy presenting with seizures and a suspected brain meningioma, but a final diagnosis of ALK+ Anaplastic Large Cell Lymph...

Importance: Pediatric obesity is a growing health care burden. Understanding how the metabolic phenotype of youth with obesity may modify the effect of intestinal fermentation on human metabolism is key to designing early intervention. Objective: To assess whether adiposity and insulin resistance in youth may be associated with colonic fermentat...

Purpose: to investigate the effects of intensive chemotherapy and glucocorticoid (GC) treatment on bone remodeling markers in children with acute lymphoblastic leukemia (ALL). Methods: A cross-sectional study was carried out in 39 ALL children (aged 7.64 ± 4.47) and 49 controls (aged 8.7 ± 4.7 years). Osteoprotegerin (OPG), receptor activator of...

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading liver disorder among U.S. children and is most prevalent among Hispanic children with obesity. Previous research has shown that reducing the consumption of free sugars (added sugars + naturally occurring sugars in fruit juice) can reverse liver steatosis in adolescents with NAFLD...

Pediatric obesity has become in the last forty years the most common metabolic disease in children and adolescents affecting about 25% of the pediatric population in the western world. As obesity worsens, a whole-body insulin resistance (IR) occurs. This phenomenon is more pronounced during adolescence, when youth experience a high degree of insuli...

Unlabelled: Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in...

Childhood acute lymphoblastic leukemia (ALL) survivors who underwent chemotherapy with anthracyclines have an increased cardiovascular risk. The aim of the study was to evaluate left and right cardiac chamber performances and vascular endothelial function in childhood ALL survivors. Fifty-four ALL survivors and 37 healthy controls were enrolled. Al...

Background: Music therapy (MT) is a complementary therapy offered to children, young adults and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in t...

Objective To develop and validate a weighted score, named ONCOREUM Score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA). Study design Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed to compare children with cancer and arthropathy with thos...

Aims/hypothesis IgM is the primary antibody produced by B cells and we hypothesise that IgM antibodies to gut microbiota may play a role in immunometabolism in obesity and type 2 diabetes. To test our hypothesis, we used B6 mice deficient in activation-induced cytidine deaminase (Aid−/− [also known as Aicda−/−]) which secrete only IgM antibodies, a...

Objective: In a large, multiethnic cohort of youths with obesity, we analyzed pathophysiological and genetic mechanisms underlying variations in plasma glucose responses to a 180 min oral glucose tolerance test (OGTT). Research design and methods: Latent class trajectory analysis was used to identify various glucose response profiles to a nine-p...

Melanocortin 4 receptor gene (MC4R) mutations result in early-onset obesity, but it is unclear how they affect abdominal fat distribution, intrahepatic fat, and related metabolic sequelae. 484 overweight/obese (BMI >85th percentile for age, sex, and height) youth (6-21 years) were screened for functionally damaging, rare variants (minor allele freq...

Background: We assessed the longitudinal trajectory of beta-cell function with respect to baseline incretin effect in youth with obesity. Methods: At baseline and two years, youth with obesity and 2-h glucose ≥ 120mg/dL underwent a 3-hour OGTT and isoglycemic intravenous glucose infusion (to quantify the incretin effect) . Participants were stratif...

Aim To examine the determinants and metabolic impact of the reduction in fasting and postload insulin levels after a low n‐6 to n‐3 polyunsaturated fatty acid (PUFA) ratio diet in obese youth. Materials and Methods Insulin secretion and clearance were assessed by measuring and modelling plasma insulin and C‐peptide in 17 obese youth who underwent...

Purpose. To describe ecthyma gangrenosum (EG) characteristics and complications in a large multicenter pediatric retrospective collection of children with malignancies or bone marrow failure syndromes. Methods. EG episodes diagnosed in the period 2009-2019 were identified by a retrospective review of clinical charts at centers belonging to the Ital...

Purpose Childhood acute lymphoblastic leukemia (ALL) survivors who underwent chemotherapy with anthracyclines have an increased cardiovascular risk. Few are data about right ventricle function (RV) in these patients. The aim of the study was to evaluate left and right cardiac chambers and vascular endothelial function in ALL survivors. Methods We...

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in children. The mechanisms that drive NAFLD disease progression in this specific patient population remain poorly defined. In this study, we obtained liver biopsy samples from a multiethnic cohort of pediatric patients with NAFLD (n = 52, mean age = 13.6 year...

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease and is often the precursor for more serious liver conditions such as nonalcoholic steatohepatitis and cirrhosis. Although the gut microbiome has been implicated in the development of NAFLD, the strong association of obesity with NAFLD and its effect on microbiome stru...

Objective Growth differentiation factor 15 (GDF15) has been associated with food intake and weight regulation in response to metabolic stress. In animal models, it has been noted that it may play a role in the progression of non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease in children. Design In the current stu...

Background and Aims NAFLD is the most common form of liver disease and is often the precursor for more serious liver conditions such as NASH and cirrhosis. The gut microbiome has been implicated in the development of NAFLD, but studies have often compared healthy individuals to those with the disease. In this study, we aimed to examine the taxonomi...

Objective: Pediatric obesity predisposes children and adolescents to early onset insulin resistance and dysglycemia. In the last 20 years this has led to a rise in the prevalence of prediabetes, diabetes and fatty liver in youngsters, due to the high degree of insulin resistance experienced by these patients and the consequent high availability of...

Background: Owing to the increasing rate of pediatric obesity, its complications such as non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) have become prevalent already in childhood. We aimed to assess the relationship between these two diseases in a cohort of children with obesity. Methods: We enrolled 153 children with o...

Central precocious puberty (CPP) is a condition that causes early gonadotropin-dependent sexual development; CPP is idiopathic in girls in most cases, whereas more than 50% of boys have an identifiable etiology. We conducted a qualitative systematic review following the ENTREQ (enhancing transparency in reporting the synthesis of qualitative resear...

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 ch...

Background In the last few years, there has been a growing interest in the role of gut microbiota in the development of obesity and its complications. Objectives In this study, we tested the following hypotheses: 1) lean youth and youth with obesity experience a different capability of their gut microbiota to ferment carbohydrates and produce acet...

Context Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. Objective To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study (GWAS). Design, participants and main outcome measures We geno...

Free-download https://authors.elsevier.com/a/1dU%7EqivMu9WwG During COVID-19 pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures to minimize the risk of in-hospital infections in frail patients and staff members. Access to the wards was significantly reduced and music therapy (MT) activities were suspended. T...

Background Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The metabolic phenotypes of beta-cell function and insulin sensitivity and clearance were explored in normoglycemic youth with Stage 1 T1D and compared to healt...

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...

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Researc...

The presence of CBFA2T3‐GLIS2 fusion gene has been identified in childhood Acute Myeloid Leukemia (AML). In view of the genomic studies indicating a distinct gene expression profile, we evaluated the role of immunophenotyping in characterizing a rare subtype of AML‐CBFA2T3‐GLIS2 rearranged. Immunophenotypic data were obtained by studying a cohort o...

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common liver disease in pediatrics. NAFLD is a chronic condition that predisposes to the development of cirrhosis and hepatocellular carcinoma. There is a strong link between NAFLD and type 2 diabetes in adults and adolescents, while some studies suggest that subjects with type 1 diab...

Preliminary evidence suggests that the glutamate–serine–glycine (GSG) index, which combines three amino acids involved in glutathione synthesis, may be used as a potential biomarker of non-alcoholic fatty liver disease (NAFLD). We investigated whether the GSG index is associated with NAFLD in youth, independent of other risk factors. Intrahepatic f...

Children with onco-hematological diseases are at increased risk of infection. However, this risk can in part be controlled or reduced using currently available vaccines. Despite available evidence, in patients diagnosed with a hematological or oncological disease the vaccination schedule is often inappropriately discontinued. In this study we evalu...

Objective: The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146...

Background & Aims A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of N...

Background: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth. Objectives: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase...

Introduction Body fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat...

Context Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, affecting approximately 3 in 10 obese children worldwide. Objective We aimed to investigate the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a strong genetic contributor to NAFLD. De...

Growth differentiation factor 15 (GDF15) has been associated with many important biological functions, such as food intake and weight regulation in response to metabolic stress. In animal models, it has also been noted that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease...

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease. Since gut microbiota has been associated with pediatric obesity, we explored the potential relationship between gut microbiota and NAFLD in obese youth, while considering the role of PNPLA3 rs738409, a genetic contributor to NAFLD. Seventy-three obese youth (BMI > 9...

Prediabetes and type 2 diabetes in obese youths are associated with a reduced incretin effect. Herein, we investigated the metabolic and genetic determinants of incretin effect in obese youths with normal and impaired glucose tolerance. We studied 35 obese youth (15.8±2.4y, BMI 39.9±6.1kg/m2, NGT/IGT 18/17, F/M 18/17). All participants were genotyp...

Aim To evaluate whether intrahepatic fat accumulation contributes to impaired insulin clearance and hepatic insulin resistance across different ethnic groups. Methods The intrahepatic fat content (HFF%) was quantified by magnetic resonance imaging in a multi‐ethnic cohort of 632 obese youths aged 7‐18 years at baseline and after a 2‐year follow‐up...

Background: Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiomet...

Childhood obesity is one of the most serious global public-health challenges of the twenty-first century. Over the past four decades, the number of children and adolescents with obesity has risen more than tenfold. Worldwide, an increasing number of youth are facing greater exposure to obesity throughout their lives, and this increase will contribu...

Context The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak. Methods We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 63...

Background & Aims A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of N...

Childhood acute lymphoblastic leukemia (ALL) peaks around age 2–4, and in utero genetic epigenetic mother-fetus crosstalk might tune ALL onset during childhood life. Folate genes variably interact with vitamin status on ALL risk and prognosis. We investigated DHFR and MTHFR gene variants in 235 ALL children and their mothers to disclose their role...

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children, but diagnosis is challenging due to limited availability of noninvasive biomarkers. Machine learning applied to high-resolution metabolomics and clinical phenotype data offers a novel framework for developing a NAFLD screening panel in youth. Here, untarg...

Background: Beta-cell function can be dissected into a dynamic component, estimating the immediate secretion after glucose change, and a static component representing the insulin secreted at any given glucose level. We evaluated their clinical and genetic determinants as well as their effect on glucose time to peak in obese youths. Methods: A 3hOGT...

Type 2 diabetes (T2D) in youth is associated with a pro-atherogenic lipid profile characterized by high triglycerides (TG), high low-density lipoprotein cholesterol (LDL-c), and low high-density lipoprotein cholesterol (HDL-c). Genome wide association studies (GWAS) in adults have discovered more than 100 variants associated with lipid traits, but...

Hepatic fat accumulation is often associated with cardiometabolic disease (CMD) risk factors in children, but the mechanism is unclear. We measured untargeted metabolomics in plasma from 219 obese children/adolescents with (37%) and without (63%) fatty liver assessed by magnetic resonance imaging. An integrative network analysis, which involved sev...

Background: Hyperinsulinemia results from β-cell ompensatory adaptation to insulin resistance and reduced insulin clearance. We examined the relationship between hepatic/peripheral insulin clearance and β-cell function in lean and obese insulin sensitive (IS) and insulin resistant (IR) adolescents. Methods: A 2-step euglycemic hyperinsulinemic clam...

Recent literature suggests that the dietary imbalance between high omega-6 (n6) and low omega-3 (n3) polyunsaturated fatty acids (PUFA) intake, characteristic of the Western diet (average ratio 15:1), leads to development of fatty liver disease. We aimed to determine whether 12 weeks of a low n6/n3 PUFA ratio (4:1) normo-caloric diet might impact f...

Background Vitamin D (25-OHD) has a role in bone health after treatment for cancer. 25-OHD deficiency has been associated with risk factors for cardiovascular disease, but no data focusing on this topic in childhood cancer survivors have been published. We investigated the 25-OHD status in children treated for acute lymphoblastic leukemia (ALL), an...

Objective of the study: In this study we aimed to retrospectively evaluate how centers, belonging to the Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP), manage severe acquired hypofibrinogenemia in children with acute lymphoblastic leukemia, particularly evaluating the therapeutic role of human fibrinogen concentrate (HFC) and fre...

Invasive aspergillosis in hematologic pediatric patients is an opportunistic infection that is difficult to treat, with a high mortality rate when localized in the central nervous system. We are describing a 3-year-old girl who was affected by acute lymphoblastic leukemia who developed cerebral and pulmonary aspergillosis during induction chemother...

Background: The relative proportion of visceral fat (VAT) to subcutaneous fat (SAT) has been described as a major determinant of insulin resistance (IR). Our study sought to evaluate the effect of body fat distribution on glucose metabolism and intrahepatic fat content over time in a multiethnic cohort of obese adolescents. Subjects/methods: We...

Patterns of abdominal fat distribution (for example, a high vs. low visceral adipose tissue [VAT]/[VAT + subcutaneous adipose tissue (SAT)] ratio), independent of obesity, during adolescence carry a high risk for insulin resistance and type 2 diabetes. Longitudinal follow-up of a cohort of obese adolescents has recently revealed that a high ratio (...

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. Materia...

AIMS One‐hour post‐load hyperglycaemia has been proposed as an independent predictor of type 2 diabetes in adults. We examined whether 1‐hour plasma glucose (1hPG) during an oral glucose tolerance test (OGTT) can predict changes in the glucose tolerance status of a multi‐ethnic cohort of youths with normal glucose tolerance (NGT). Materials and me...

Aims In this study, we investigated whether adipose tissue insulin resistance (IR) is affected by the degree of obesity during the fasting and post-prandial state, independent of glucose tolerance among obese children and adolescents. We also tested whether systemic subclinical inflammation is associated with adipose tissue IR. Methods Subjects we...