Autoimmune Complications after Hematopoietic Stem Cell Transplantation in Children with Nonmalignant Disorders

Background. Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for many nonmalignant disorders, such as autoimmune disorders, inborn metabolic disorders, hemoglobinopathies, and immunodeficiency disorders. Autoimmune complications (AICs) after HSCT, such as autoimmune cytopenias, autoimmune hepatitis, primary biliary cirrhosis, and autoimmune cutaneous manifestations, are still neither well defined nor characterized. Patients. Between 2000 and 2012, 92 patients (47 males, 45 females) were treated with HSCT in our hospital, 51 with congenital hemoglobinopathies, 19 with primary immunodeficiency disease, 10 with metabolic disorders, five with Fanconi anemia, three with aplastic anemia, and four with familial hemophagocytic lymphohistiocytosis. Results. Mean age at HSCT was 6.4 years (range, 0.2–32 years) and mean duration of followup after HSCT was 6.81 years (range, 1–11 years). Sixteen (17.4%) patients developed chronic GVHD and five (5.4%) showed sclerodermatous features. Five (5.4%) patients were diagnosed with scleroderma manifestations, six (6.5%) with vitiligo, six (6.5%) with autoimmune hemolytic anemia (AIHA), six (6.5%) with idiopathic thrombocytopenia, three (3.3%) with mild leucopenia, two (2.2%) with aplastic anemia, two (2.2%) (one boy, one girl) with autoimmune thyroid disease, and one (1.1%) with autoimmune hepatitis. Conclusions. It was concluded that AICs are clinically significant complications after HSCT that contribute to morbidity but not to mortality. AICs are more frequent after HSCT for metabolic disorders, and sclerodermatous GVHD is more significant in children who underwent allogeneic HSCT for hemoglobinopathies. The potential to identify risk factors for AICs could lead to less morbidity and mortality and to maintain the patient’s quality of life

Cardiac Function in Long-Term Survivors of Childhood Lymphoma

Objectives. We studied long-term effects of therapy for childhood lymphoma on cardiac function. Design and patients. We prospectively evaluated 45 survivors of childhood lymphoma, using clinical parameters, electrocardiography and echocardiography. Further comparisons were made between lymphoma subgroups and between males and females. Results. Mean age at diagnosis was 9.1 years. Mean followup duration was 10.9 years. The NYHA functional class was I in 43 patients and II in 2 patients. A prolonged QTc interval (>0.44 msec) was found in 8 patients. Left ventricular (LV) systolic function and compliance were normal (LV shortening fraction 40 ± 5.6%; cardiac index 2.84 ± 1.13 L/min/m(2); E/A wave ratio 2.5 ± 1.3; mean ± S.D.), LV mass was normal (97 ± 40 grams/m(2), mean ± S.D.). Mitral regurgitation was observed in 7/45 patients (16%). Asymptomatic pericardial effusions were found in 3/45 (7%) patients. Conclusions. Long-term follow-up shows that most parameters of cardiac function are normal in survivors of childhood lymphoma. This is likely due to relatively low doses of anthracyclines in modern protocol modalities. Abnormalities in mitral valve flow, QTc prolongation and in a small proportion of survivors, and functional capacity necessitate long-term cardiac follow-up of these patients

Precision Medicine in Relapsed and Refractory Childhood Cancers: Single-center Experience, Literature Review, and Meta-analysis

Objective: To date, the understanding of pediatric tumor genomics and how these genetic aberrations correlate with clinical outcome is lacking. Here, we report our experience with the next-generation sequencing (NGS) test program and discuss implications for the inclusion of molecular profiling into clinical pediatric oncology trials. We also aimed to explore studies on NGS in pediatric cancers and to quantify the variability of finding actionable mutations and the clinical implications. Methods: We present a retrospective case series of all patients whose tumor tissue underwent NGS tests during treatment in our department. We also reviewed the literature and carried out a meta-analysis to explore studies on NGS in pediatric cancers. Results: In 35/37 (94%) patients, we found at least one genomic alteration (GA); mean number of GAs per patient was 2 (range, 0–67), while 164 GAs were detected. Only 3 (8%) patients received precision medicine due to their GAs for a mean of 9 months (range, 5–14 months). Four studies were included in the meta-analysis. The pooled positive actionable mutation rate was 52% (95% CI 39%–66%), and the pooled rate of children who received precision medicine was 10% (95% CI 3%–20%). Conclusions: In children and young adults with high-risk, recurrent, or refractory malignancies, tumor profiling results have clinical implications, despite barriers to the use of matched precision therapy

Heparanase Levels Are Elevated in the Plasma of Pediatric Cancer Patients and Correlate with Response to Anticancer Treatment1

Heparanase is an endoglycosidase that specifically cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans, the major proteoglycan in the extracellular matrix (ECM) and cell surfaces. Heparanase upregulation was documented in an increasing number of primary human tumors, correlating with reduced postoperative survival rate and enhanced tumor angiogenesis. The purpose of the current study was to determine heparanase levels in blood samples collected from pediatric cancer patients using an ELISA method. Heparanase levels were elevated four-fold in the plasma of cancer patients compared with healthy controls (664 ± 143 vs 163 ± 18 pg/ml, respectively). Evaluating plasma samples following anticancer therapy revealed reduced heparanase levels (664 ± 143 vs 429 ± 82 pg/ml), differences that are statistically highly significant (P = .0048). Of the 55 patients with complete remission (CR) or very good partial remission (VGPR) at restaging, 41 (74.5%) had lower heparanase amounts, whereas 14 patients (25.5%) had similar or higher amounts of plasma heparanase. All nine patients with stable or advancing disease had similar or elevated levels of heparanase on restaging. The results show that heparanase levels are elevated in the plasma of pediatric cancer patients and closely correlate with treatment responsiveness, indicating that heparanase levels can be used to diagnose and monitor patient's response to anticancer treatment