Modelling and assessment of glucose-lactate kinetics in youth with overweight, obesity and metabolic dysfunction-associated steatotic liver disease: A pilot study.

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 [body mass index 33 (29-37)]. Glucose-lactate kinetics parameters (disposal glucose insulin sensitivity, SID; fraction of glucose converted into lactate, fr; fractional lactate clearance rate, kL) and lactate production rate (LPR) were estimated using the oral glucose-lactate minimal model. MASLD presence was assessed using the proton density fat fraction. We analysed glucose, lactate and LPR time to peak, peak values and area under the curve and evaluated differences using the Wilcoxon test. MASLD and no-MASLD participants were compared using the Mann-Whitney test. Correlations between parameters were assessed using the Spearman correlation coefficient (ρ). We also tested the performance of two (4 or 3 h OGTT) protocols in estimating oral glucose-lactate minimal model and LPR parameters. RESULTS: Glucose peaks 30 min earlier than lactate (p = .0019). This pattern was present in the no-MASLD group (p < .001). LPR peaks 30 min later in the MASLD group (p = .02). LPR and kL were higher in MASLD, suggesting higher glycolysis and lactate utilization. SID and fr correlate significantly (ρ = -0.55, p = .008). SID and fr were also correlated with the body mass index, (ρ = -0.45, p = .04; and ρ = 0.45; p = .03). The protocol duration did not influence the estimates of the parameters. DISCUSSION: Youth with MASLD showed a delayed glucose metabolism, possibly because of greater utilization of the underlying substrates. A 3-h OGTT may be used to assess lactate metabolism effectively.

Combining Brentuximab Vedotin With Dexamethasone, High-dose Cytarabine, and Cisplatin as Salvage Treatment in Pediatric Relapsed or Refractory Classic Hodgkin Lymphoma: Two Case Reports.

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 limited is the experience in pediatrics. We report here on 2 boys with aggressive and high-risk relapsed HL, successfully treated with the BV plus dexamethasone, high-dose cytarabine, cisplatin regimen as induction salvage treatment. Our experience provides real-world evidence on the use of BV-dexamethasone, high-dose cytarabine, cisplatin as first-line salvage therapy for relapsed/refractory HL and expands the current therapeutic choices.

A Novel NUTM1-NSMCE2 Fusion Gene in a Pediatric Chest NUT Carcinoma.

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 successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.

Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate a weighted score, the 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 at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The ß coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively). RESULTS: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively. CONCLUSIONS: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

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 this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

Orbital Extenteration Defects: Ablative and Reconstructive Flowchart Proposal.

ABSTRACT: Orbital exenteration is a radical and disfiguring operation. It is still under debate the absence of correlation between the term describing the resulting orbital defect and the type of reconstruction. Authors' goal was to propose a consistent and uniform terminology for Orbital Exenteration surgery in anticipation of patients' tailored management. Twenty-five patients who underwent orbital exenteration between 2014 and 2020 were reviewed. A parallel comprehensive literature review was carried on. Five different types of orbital exenteration where outlined. Multiple reconstructive procedures were enclosed. An algorithm for orbital reconstruction was proposed based on anatomic boundaries restoration. Eyelid removal was first considered as an independent reconstructive factor, and both orbital roof and floor were indicated as independent reconstructive goals, which deserve different defect classification. In our opinion, this algorithm could be a useful tool for patient counseling and treatment selection, which might allow a more tailored patient care protocol. LEVEL OF EVIDENCE: Level III.

IgM-associated gut bacteria in obesity and type 2 diabetes in C57BL/6 mice and humans.

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, and human faecal samples. METHODS: We studied the immunometabolic effects and gut microbial changes in high-fat-diet-induced obesity (HFDIO) in Aid-/- B6 mice compared with wild-type mice. To determine similarities between mice and humans, human stool samples were collected from children and adolescents who were obese with normal glucose tolerance (NGT), obese with glucose intolerance (IGT), or obese and newly diagnosed with type 2 diabetes, for faecal microbiota transplant (FMT) into germ-free (GF) B6 mice and we assessed IgM-bound bacteria and immune responses. RESULTS: Compared with wild-type mice, Aid-/- B6 mice developed exacerbated HFDIO due to abundant levels of IgM. FMT from Aid-/- B6 to GF B6 mice promoted greater weight gain in recipient mice compared with FMT using wild-type mouse faecal microbiota. Obese youth with type 2 diabetes had more IgM-bound gut bacteria. Using the stools from the obese youth with type 2 diabetes for FMT to GF B6 mice, we observed that the gut microbiota promoted body weight gain and impaired glucose tolerance in the recipient GF B6 mice. Importantly, some clinical features of these obese young individuals were mirrored in the GF B6 mice following FMT. CONCLUSIONS/INTERPRETATION: Our results suggest that IgM-bound gut microbiota may play an important role in the immuno-pathogenesis of obesity and type 2 diabetes, and provide a novel link between IgM in obesity and type 2 diabetes in both mice and humans. DATA AVAILABILITY: The 16s rRNA sequencing datasets supporting the current study have been deposited in the NCBI SRA public repository ( https://www.ncbi.nlm.nih.gov/sra ; accession no. SAMN18796639).

A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth.

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 a nine-point, 180-minute oral glucose tolerance test (OGTT) before and after a 12-week, eucaloric low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio diet. Hepatic fat content was assessed by repeated abdominal magnetic resonance imaging. RESULTS: Insulin clearance at fasting and during the OGTT was significantly increased after the diet, while body weight, glucose levels, absolute and glucose-dependent insulin secretion, and model-derived variables of ß-cell function were not affected. Dietary-induced changes in insulin clearance positively correlated with changes in whole-body insulin sensitivity and ß-cell glucose sensitivity, but not with changes in hepatic fat. Subjects with greater increases in insulin clearance showed a worse metabolic profile at enrolment, characterized by impaired insulin clearance, ß-cell glucose sensitivity, and glucose tolerance, and benefitted the most from the diet, achieving greater improvements in glucose-stimulated hyperinsulinaemia, insulin resistance, and ß-cell function. CONCLUSIONS: We showed that a 12-week low n-6:n-3 PUFA ratio diet improves hyperinsulinaemia by increasing fasting and postload insulin clearance in obese youth, independently of weight loss, glucose concentrations, and insulin secretion.

CD56, HLA-DR, and CD45 recognize a subtype of childhood AML harboring CBFA2T3-GLIS2 fusion transcript.

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 of 20 pediatric CBFA2T3-GLIS2-AML and 77 AML patients not carrying the fusion transcript. Enrolled cases were included in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) AML trials and immunophenotypes were compared using different statistical approaches. By multiple computational procedures, we identified two main core antigens responsible for the identification of the CBFA2T3-GLIS2-AML. CD56 showed the highest performance in single marker evaluation (AUC = 0.89) and granted the most accurate prediction when used in combination with HLA-DR (AUC = 0.97) displaying a 93% sensitivity and 99% specificity. We also observed a weak-to-negative CD45 expression, being exceptional in AML. We here provide evidence that the combination of HLA-DR negativity and intense bright CD56 expression detects a rare and aggressive pediatric AML genetic lesion improving the diagnosis performance.

Colonic Fermentation and Acetate Production in Youth with and without Obesity.

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 acetate; and 2) colonic acetate may serve as a substrate for hepatic de novo lipogenesis (DNL). METHODS: Nineteen lean youth [mean ± SE BMI (in kg/m2): 21.8 ± 0.521] and 19 youth with obesity (BMI: 35.7 ± 1.66), ages 15-21 y, frequency-matched by age and sex, underwent a fasting 10-h sodium [d3]-acetate intravenous infusion to determine the rate of appearance of acetate (Raacet) into the peripheral circulation before and after an oral dose of 20 g of lactulose. Pre- and post-lactulose Raacet values were determined at a quasi-steady state and changes between groups were compared using a quantile regression model. Acetate-derived hepatic DNL was measured in 11 subjects (6 youth with obesity) and its association with Raacet was assessed using Spearman correlation. RESULTS: Mean ± SE Raacet was not different before lactulose ingestion between the 2 groups (7.69 ± 1.02 µmol · kg-1 · min-1 in lean youth and 7.40 ± 1.73 µmol · kg-1 · min-1 in youth with obesity, P = 0.343). The increase in mean ± SE Raacet after lactulose ingestion was greater in lean youth than in youth with obesity (14.7 ± 2.33 µmol · kg-1 · min-1 and 9.29 ± 1.44 µmol · kg-1 · min-1, respectively, P = 0.001). DNL correlated with Raacet, calculated as changes from the pre- to the post-lactulose steady state (ρ = 0.621; P = 0.046). CONCLUSIONS: These data suggest that youth with obesity ferment lactulose to a lesser degree than youth without obesity and that colonic acetate serves as a substrate for hepatic DNL.This trial was registered at clinicaltrials.gov as NCT03454828.

A Low ω-6 to ω-3 PUFA Ratio (n-6:n-3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth.

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 3 (PNPLA3) rs738409 variant affects the response. METHODS: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used. RESULTS: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time. CONCLUSIONS: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

Intrahepatic fat, irrespective of ethnicity, is associated with reduced endogenous insulin clearance and hepatic insulin resistance in obese youths: A cross-sectional and longitudinal study from the Yale Pediatric NAFLD cohort.

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. Insulin secretion rate (ISR), endogenous insulin clearance (EIC) and hepatic insulin resistance index (HIRI) were estimated by modelling glucose, insulin and C-peptide data during 3-hour, 9-point oral glucose tolerance tests. RESULTS: African American youths exhibited the lowest HFF% and a prevalence of non-alcoholic fatty liver disease (NAFLD) less than half of that shown by Caucasians and Hispanics. Furthermore, African Americans had lower EIC and glucose-stimulated ISR, despite similar HIRI and plasma insulin levels, compared with Caucasians and Hispanics. EIC and HIRI were markedly reduced in individuals with NAFLD and declined across group-specific HFF% tertiles in all ethnic groups. Consistently, the HFF% correlated with EIC and HIRI, irrespective of the ethnic background, after adjustment for age, sex, ethnicity, adiposity, waist-hip ratio, pubertal status and plasma glucose levels. An increased HFF% at follow-up was associated with decreased EIC and increased HIRI across all groups. CONCLUSIONS: Intrahepatic lipid accumulation is associated with reduced insulin clearance and hepatic insulin sensitivity in obese youths, irrespective of their ethnic background.

Cardiometabolic risk factor clustering in patients with deficient branched-chain amino acid catabolism: A case-control study.

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 cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.

Isavuconazole Treatment of Cerebral and Pulmonary Aspergillosis in a Pediatric Patient With Acute Lymphoblastic Leukemia: Case Report and Review of Literature.

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 chemotherapy. The patient failed first-line voriconazole treatment because of being a CYP2C19 ultrarapid metabolizer and received effective isavuconazole therapy with no notable side effects.

Designing a Streaming Algorithm for Outlier Detection in Data Mining-An Incrementa Approach.

To design an algorithm for detecting outliers over streaming data has become an important task in many common applications, arising in areas such as fraud detections, network analysis, environment monitoring and so forth. Due to the fact that real-time data may arrive in the form of streams rather than batches, properties such as concept drift, temporal context, transiency, and uncertainty need to be considered. In addition, data processing needs to be incremental with limited memory resource, and scalable. These facts create big challenges for existing outlier detection algorithms in terms of their accuracies when they are implemented in an incremental fashion, especially in the streaming environment. To address these problems, we first propose C_KDE_WR, which uses sliding window and kernel function to process the streaming data online, and reports its results demonstrating high throughput on handling real-time streaming data, implemented in a CUDA framework on Graphics Processing Unit (GPU). We also present another algorithm, C_LOF, based on a very popular and effective outlier detection algorithm called Local Outlier Factor (LOF) which unfortunately works only on batched data. Using a novel incremental approach that compensates the drawback of high complexity in LOF, we show how to implement it in a streaming context and to obtain results in a timely manner. Like C_KDE_WR, C_LOF also employs sliding-window and statistical-summary to help making decision based on the data in the current window. It also addresses all those challenges of streaming data as addressed in C_KDE_WR. In addition, we report the comparative evaluation on the accuracy of C_KDE_WR with the state-of-the-art SOD_GPU using Precision, Recall and F-score metrics. Furthermore, a t-test is also performed to demonstrate the significance of the improvement. We further report the testing results of C_LOF on different parameter settings and drew ROC and PR curve with their area under the curve (AUC) and Average Precision (AP) values calculated respectively. Experimental results show that C_LOF can overcome the masquerading problem, which often exists in outlier detection on streaming data. We provide complexity analysis and report experiment results on the accuracy of both C_KDE_WR and C_LOF algorithms in order to evaluate their effectiveness as well as their efficiencies.

A low visceral fat proportion, independent of total body fat mass, protects obese adolescent girls against fatty liver and glucose dysregulation: a longitudinal study.

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 examined markers of glucose metabolism by oral glucose tolerance test, and body fat distribution by abdominal MRI at baseline and after 19.2 ± 11.4 months in a cohort of 151 obese adolescents (88 girls, 63 boys; mean age 13.3 ± 3.4 years; mean BMI z-score 2.15 ± 0.70). Hepatic fat content was assessed by fast-gradient MRI in a subset of 93 subjects. We used the median value of VAT/(VAT + SAT) ratio within each gender at baseline to stratify our sample into high and low ratio groups (median value 0.0972 in girls and 0.118 in boys). RESULTS: Female subjects tended to remain in their VAT/(VAT + SAT) category over time (change over follow-up P = 0.14 among girls, and P = 0.04 among boys). Baseline VAT/(VAT + SAT) strongly predicted the hepatic fat content, fasting insulin, 2-h glucose, and whole-body insulin sensitivity index at follow-up among girls, but not in boys. CONCLUSIONS: The VAT/(VAT + SAT) ratio is a major determinant of impaired glucose metabolism and hepatic fat accumulation over time, and its effects are more pronounced in girls than in boys.

Metabolic Features of Nonalcoholic Fatty Liver (NAFL) in Obese Adolescents: Findings From a Multiethnic Cohort.

We conducted a prospective study in a large, multiethnic cohort of obese adolescents to characterize clinical and genetic features associated with pediatric nonalcoholic fatty liver (NAFL), the most common cause of chronic liver disease in youth. A total of 503 obese adolescents were enrolled, including 191 (38.0%) whites, 134 (26.6%) blacks, and 178 (35.4%) Hispanics. Participants underwent abdominal magnetic resonance imaging (MRI) to quantify hepatic fat fraction (HFF), an oral glucose tolerance test (OGTT) to assess glucose tolerance and insulin sensitivity, and the genotyping of three single-nucleotide polymorphisms (SNPs) associated with nonalcoholic fatty liver disease (NAFLD) (patatin-like phospholipase domain-containing protein 3 [PNPLA3] rs738409, glucokinase regulatory protein [GCKR] rs1260326, and transmembrane 6 superfamily member 2 [TM6SF2] rs58542926). Assessments were repeated in 133 subjects after a 2-year follow-up. Prevalence of nonalcoholic fatty liver (NAFL) was 41.6% (209 patients) and ranged widely among ethnicities, being 42.9% in whites, 15.7% in blacks, and 59.6% in Hispanics (P < 0.0001). Among adolescents with NAFL, blacks showed the highest prevalence of altered glucose homeostasis (66%; P = 0.0003). Risk factors for NAFL incidence were white or Hispanic ethnicity (P = 0.021), high fasting C-peptide levels (P = 0.0006), and weight gain (P = 0.0006), whereas baseline HFF (P = 0.004) and weight loss (P = 0.032) predicted resolution of NAFL at follow-up. Adding either gene variant to these variables improved significantly the model predictive performance. CONCLUSION: Black obese adolescents are relatively protected from liver steatosis, but are more susceptible to the deleterious effects of NAFL on glucose metabolism. The combination of ethnicity/race with markers of insulin resistance and genetic factors might help identify obese youth at risk for developing NAFL.

One-hour post-load plasma glucose predicts progression to prediabetes in a multi-ethnic cohort of obese youths.

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 METHODS: A total of 202 obese youths with NGT (33.7% Caucasian, 31.1% Hispanic, 32.2% African American) underwent a 3-hour OGTT at baseline and after a 2-year follow-up period. Whole-body insulin sensitivity, insulin secretion, ß-cell function and insulin clearance were estimated by modeling plasma glucose, insulin and C-peptide levels. RESULTS: Obese youths with 1hPG ≥7.4 mmol/L (or 133 mg/dL; n = 83) exhibited higher body mass index (BMI), plasma triglycerides and fasting and post-load glucose concentrations than individuals with 1hPG <7.4 mmol/L. Also, 1hPG ≥7.4 mmol/L was associated with a lower disposition index (DI) (P < 0.0001) and with alterations in whole-body insulin sensitivity, ß-cell function and insulin clearance. Adolescents with 1hPG ≥7.4 mmol/L were approximately three times more likely to develop prediabetes (ie, impaired glucose tolerance and/or impaired fasting glucose) over time (OR, 2.92 [1.22-6.98]; P = 0.02), independent of age, sex, race/ethnicity, BMI, insulin sensitivity, DI and plasma glucose concentrations. No differences emerged in the risk of prediabetes related to 1-hour hyperglycaemia among different ethnic groups. CONCLUSIONS: A plasma glucose concentration ≥ 7.4 mmol/L at 1 hour during an OGTT is associated with a worse clinical and metabolic phenotype and may be an independent predictor of progression to prediabetes in obese youths with NGT.

Human Fibrinogen Concentrate and Fresh Frozen Plasma in the Management of Severe Acquired Hypofibrinogenemia in Children With Acute Lymphoblastic Leukemia: Results of a Retrospective Survey.

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 fresh frozen plasma (FFP). METHODS: We conducted a survey among AIEOP centers; thereafter, we collected and analyzed data with regard to the treatment of episodes of severe acquired hypofibrinogenemia occurring during the induction and reinduction phases of the AIEOP-BFM ALL 2009 protocol. RESULTS: In total, 15 of the 37 AIEOP centers invited to join the survey agreed to collect the data, with 10 and 5 centers declaring to react to severe acquired hypofibrinogenemia (<70 mg/dL) by administering HFC or FFP, respectively. Of the 150 episodes of severe hypofibrinogenemia occurring in 101 patients, 47.3% were treated with HFC and 52.7% with FFP, with a normalization of fibrinogen levels achieved in greater proportion and in a shorter amount of time in the HFC group as compared with the FFP group. None of the patients presented with bleeding or thrombosis during the observation period. CONCLUSIONS: Even with the limitations of the retrospective nature of this study, HFC seems to be a safe and effective alternative to FFP for replacement therapy in case of severe hypofibrinogenemia in children with acute lymphoblastic leukemia.

Invasive mucormycosis in children with cancer: A retrospective study from the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. OBJECTIVES: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. PATIENTS: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. RESULTS: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months. CONCLUSIONS: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high.