An Asymptomatic, Ectopic Mass as a Presentation of Adrenocortical Carcinoma Due to a Novel Germline TP53 p.Phe338Leu Tetramerisation Domain Variant.

Adrenocortical carcinoma (ACC) is a rare cancer in childhood. ACC is frequently associated with germline TP53 variants, with founder effects especially due to the p.Arg337His mutation. ACC leads to the secretion of adrenocortical hormones, resulting in endocrine syndromes, which is the usual trigger for establishing the diagnosis. We present a surprising ACC pathology in a non-secreting, ectopic retroperitoneal tumour in a 4-year-old boy, successfully controlled with chemotherapy and mitotane after microscopically incomplete tumour resection with spillage. Genomic analysis (gene panel sequencing and copy-number microarray) demonstrated a novel p.Phe338Leu tetramerisation domain (TD) TP53 variant in the proband and his cancer-free mother and a monoallelic deletion encompassing the TP53 locus in cancer tissue, consistent with cancer-predisposition syndrome. While the recurrent p.Arg337His variant translates into high ACC risk, residue 338 and, in general, TD domain variants drive heterogeneous clinical scenarios, despite generally being considered less disruptive than TP53 DNA-binding domain mutations.

One Hundred Consecutive Neutropenic Febrile Episodes Demonstrate That CXCR3 Ligands Have Predictive Value in Discriminating the Severity of Infection in Children with Cancer.

This study assesses the value of the CXCR3 ligands CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC when used to supplement the standard infection markers C-reactive protein (CRP) and procalcitonin (PCT) in the diagnostic algorithm of neutropenic fever in children with cancer. The concentration of CRP, PCT and chemokines was determined during the first hour of fever and 12-24 h afterwards in pediatric oncology patients with neutropenia. Among 100 consecutive febrile episodes in neutropenic patients, 34 cases demonstrated fever of unknown origin (FUO) (group A), 47 demonstrated mild clinically or microbiologically proven infection (Group B) and 19 severe infection (Group C). Significantly higher PCT-1 levels were found in group C (0.24 ng/mL) vs. group A (0.16 ng/mL), and PCT-2 in group C (1.2 ng/mL) vs. A (0.17 ng/mL), and in C vs. B (0.2 ng/mL). Chemokine concentrations (I-TAC-1, IP-10-1, IP-10-2) were significantly lower in Group A vs. B+C; I-TAC 1: 48.64 vs. 70.99 pg/mL, p = 0.03; IP-10 1: 59.95 vs. 96.84 pg/mL, p = 0.04; and IP-10 2: 102.40 vs. 149.39 pg/mL, p = 0.05. The selected pro-inflammatory chemokines I-TAC and IP10 might help to distinguish cancer patients with febrile neutropenia with the highest risk of infection. Although procalcitonin could serve as a marker of a high risk of infection, its delayed response diminishes its usefulness.

Pulmonary Exacerbation of Undiagnosed Toxocariasis in Intensively-Treated High-Risk Neuroblastoma Patients.

Toxocariasis is one of the most common zoonoses, with high seroprevalence in apparently healthy individuals. Neuroblastoma is an aggressive childhood cancer. The cure rates are improving due to dose-dense chemotherapy, progress in surgical practice, myeloablative therapy with autologous stem cell transplantation, and recently, anti-GD2 immunotherapy. This is associated with a burden of complications, some of which are relatively specific for neuroblastoma treatment. Based on previous reports of Toxocara canis infection in high-risk neuroblastoma patients and cases of pulmonary exacerbation from our center in this disease, we propose that toxocariasis is a specific complication of intensive pediatric cancer treatment and advocate for active surveillance.

Dynamic changes in specific anti-L-asparaginase antibodies generation during acute lymphoblastic leukemia treatment.

BACKGROUND: L-asparaginase (L-asp) remains one of the key components of acute lymphoblastic leukemia therapy. Immune reactions to the drug are associated with its diminished activity. The aim of the study was to determine the level of IgM, IgG and IgE-class anti-L-asp antibodies during the induction and reinduction phases of acute lymphoblastic leukemia therapy and their influence on L-asp activity. METHODS: The study group comprised 65 patients treated for acute lymphoblastic leukemia in one pediatric oncology center. L-asp antibodies were assessed using ELISA at the end of the induction and reinduction phases. L-asp activity was assessed prior to each drug administration by colorimetry. RESULTS: At the end of the first exposure to L-asp antibodies were detected in 35 patients (54%). In the reinduction phase of the treatment anti-L-asp antibodies were found in 38/55 patients (69%). In the induction phase patients with inadequate L-asp activity had higher IgM concentrations (median 5.88 versus 2.81 µg/mL, p = 0.03). In the reinduction phase IgG and IgM levels correlated inversely with L-asp activity. Patients with L-asp allergy had higher levels of IgG (median 61.6 versus 18.36 µg/mL, p = 0.01), whereas higher IgE levels were noted in the group of patients with inadequate drug activity (median 0.91 versus 0.64 µg/mL, p = 0.03). CONCLUSIONS: Subsequent exposure to L-asp in the treatment of acute lymphoblastic leukemia was associated with the increase of anti-L-asp antibodies in all studied classes. However, the changes observed in specific classes of antibodies were not distinctive for L-asp hypersensitivity or inactivation, suggesting that the mechanism is more complex.

Asparagine synthetase (ASNS) gene polymorphism is associated with the outcome of childhood acute lymphoblastic leukemia by affecting early response to treatment.

The polymorphism of 14-bp tandem repeat sequence located in the ASNS gene probably acts as a transcriptional enhancer element and leads to higher expression of the gene in carriers of more than 2 repeats (>R2). We searched for an association with disease outcome in 264 children with ALL. A multivariate proportional hazard regression model adjusted for age at diagnosis (HR (95%CI)=1.05 (1.04-1.09)) and high-risk group (HR(95%CI)=3.47 (1.74-6.88)) revealed that R3 carriers with a poor response at day 15 had an increased risk of events, HR (95%CI)=2.72 (1.06-6.96). These results suggest a conditional interaction between the ASNS polymorphism and an early response to chemotherapy among pediatric patients with ALL.

Higher glycemic variability in very low birth weight newborns is associated with greater early neonatal mortality.

OBJECTIVE: To determine the association between mean glycemia and its variability with perinatal mortality in preterm newborns hospitalized in an intensive care unit (ICU). METHODS: Patients admitted to the ICU within the first 12 hours of life, with birth weight <1500 g, at least three blood glucose measurements/day and lack of insulin treatment were evaluated. Association of mean glycemia and its standard deviation (SD) with death during initial 7 days of life was evaluated. Multivariate logistic regression analysis was performed twice, using continuous glucose concentrations and by means of a quintile-based approach correcting for nonnormal distribution and nonlinear effects. RESULTS: A total of 95 newborns were enrolled. Eleven patients (11.5%) died during the initial 7 days of life, overall mortality equaled 22%. Multivariate analysis showed that 5 minute Apgar score and SD of glucose concentrations were significantly associated with increased mortality in both models. Odds ratios (ORs) equaled 0.44; 95% confidence interval (95% CI) 0.27-0.74 and OR 1.34; 95% CI 1.03-2.03 for the continuous model and 0.50 95% CI 0.34-0.75 and OR 1.82 95% CI 1.07-3.11 for the quintile-based model. In both cases, mean glycemia was removed during the stepwise model-building procedure. CONCLUSIONS: Higher glycemic variability may be associated with greater odds of perinatal mortality.