Intravenous ferric carboxymaltose for iron deficiency anemia or iron deficiency without anemia after poor response to oral iron treatment: Benefits and risks in a cohort of 144 children and adolescents.

OBJECTIVE: The objective of this single-center observational study was to determine the clinical and hematologic responses to intravenous ferric carboxymaltose (FCM) in a cohort of pediatric patients with poor response to oral iron therapy. The occurrence of adverse events was systematically recorded for up to 96 hours after infusion. STUDY DESIGN: A retrospective cohort of 144 consecutive patients aged 18 months to < 18 years with iron deficiency anemia (IDA) or iron deficiency (ID) without anemia was investigated. All patients had failed oral iron therapy. The assessments before and after FCM treatment followed a predefined protocol. RESULTS: One hundred of 117 (85 %) of patients with complete data achieved the target ferritin level ≥ 30 µg/L after a single FCM dose. Of 77 patients with IDA and complete data, 38 (49%) showed a complete hematological response within 6-12 weeks; a complete or partial response was achieved by 83%. Clinical symptoms improved in 85% of all patients. In 92% of patients (n = 133 /144), FCM infusion was uneventful. During the 96-hour follow-up, five patients reported potentially related symptoms. No serious adverse events occurred. CONCLUSION: The study confirms the safety and efficacy of FCM in children (aged 18 months and older) and adolescents unresponsive to oral therapy, in real-world experience. Single-dose FCM treatment was followed by clinical improvement with advantages of safety, compliance, and lower cost compared with previous generation parenteral iron preparations that had to be administered in fractionated sessions.

Neutropenia in Barth syndrome: characteristics, risks, and management.

PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 µg/kg/day (mean 1.16 µg/kg/day, median 1.16 µg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ±â€Šprophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ±â€Šantibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.

Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.

BACKGROUND: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting. METHODS: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948. FINDINGS: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. INTERPRETATION: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. FUNDING: Gentium SpA, European Group for Blood and Marrow Transplantation.

Is acute fibrinous and organizing pneumonia the expression of immune dysregulation?

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a recently described histologic pattern of diffuse pulmonary disease. In children, all cases reported to date have been fatal. In this study, we describe the first nonfatal AFOP in a child and review the literature. DESCRIPTION: A 10-year-old boy developed very severe aplastic anemia (VSAA) after being admitted to our hospital with a fulminant hepatic failure of unknown origin. A chest computed tomography scan revealed multiple lung nodules and a biopsy of a pulmonary lesion showed all the signs of AFOP. Infectious workup remained negative. We started immunosuppressive therapy with antithymocyte globulin and cyclosporine to treat VSAA. Subsequent chest computed tomography scans showed a considerable diminution of the lung lesions but the VSAA did not improve until we performed hematopoietic stem cell transplantation 5 months later. CONCLUSIONS: Aplastic anemia is associated with a variety of autoimmune syndromes. The sequence of events in our patient suggests that the hepatic failure, AFOP, and the VSAA may all have been part of an autoimmune syndrome. AFOP could be the result of immune dysregulation in this pediatric case with favorable outcome after immunosuppressive therapy and hematopoietic stem cell transplantation.

GSTP1 hypermethylation is associated with reduced protein expression, aggressive disease and prognosis in neuroblastoma.

Epigenetic modifications such as methylation of CpG islands in tumor-suppressor gene promoter regions have been associated with tumor development in many human cancers. Using methylation specific multiplex ligation-dependent probe amplification method, we analyzed the methylation status of 35 different genes in 16 neuroblastoma (NB) cell lines and 50 NB tumor samples (NBs), and investigated whether specific hypermethylation was associated with biological and/or clinical parameters. Among the genes found hypermethylated, the effect of GSTP1 hypermethylation on mRNA and protein expression was also explored. The median number of hypermethylated genes was higher in cell lines compared to NBs (5.5 vs. 2). For eight genes, aberrant methylation of CpG-islands in NB was not (ESR1, PAX5, WT1, CADM1, MSH6, and CDKN2B) or very rarely (CDH13 and GSTP1) reported in literature. GSTP1 was found hypermethylated in 44% of the NB cell lines and in 33% of the stage 4-11qLOH -non MYCN-amplified high risk NBs. Hypermethylation was correlated with reduced mRNA and protein expression. In the whole NBs cohort, GSTP1 hypermethylation was less frequently detected (8%), but found to be associated with lower event-free (EFS) and overall survival. Hypermethylation of GSTP1 showed also association with lower EFS in high risk subgroups as stage 4 and older patients (≥547 days). Our results suggest that, as in several adult cancers, aberrant methylation of GSTP1 may contribute to the carcinogenetic process in NB and could be potentially used as a new marker leading to define an ultra-high risk subgroup.

A simplified method for busulfan monitoring using dried blood spot in combination with liquid chromatography/tandem mass spectrometry.

RATIONALE: Busulfan (Bu) is an important component of the myeloablative conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) especially in children. Intravenously administered Bu exhibits a therapeutic window phenomenon requiring therapeutic drug monitoring. Analytical methods developed for Bu routine monitoring were aimed at using low volumes of biological fluids and development of simple procedures to facilitate the dosage adjustment. In this report, we describe a simple, rapid method for Bu measurement using dried blood spots (DBS) from only 5 µL of whole blood. METHODS: Bu extracted from DBS with methanol was measured by high-performance liquid chromatography with electrospray ionization and tandem mass spectrometry in multiple reaction monitoring mode using D8-Bu as an internal standard. The method was in-house validated evaluating trueness, repeatability, within-laboratory reproducibility, specificity and the lower limit of quantification (LLOQ). RESULTS: The method was linear in the calibration range of 100-2000 ng mL(-1) (r(2)>0.99) encompassing the therapeutic concentrations of Bu. A good trueness (<14%), precision (<10%), and recovery (100%) were observed during validation of the method with quality controls of 300, 600 and 1400 ng mL(-1). The LLOQ was determined as 50 ng mL(-1) and no matrix or carryover effects were observed. The validated method was applied to measure Bu levels in four children receiving infusion of Bu prior to HSCT. A good correlation was observed between the Bu levels measured by DBS and dried plasma spot (DPS) (r(2) =0.96) and between DPS and the GC/MS method (r(2) =0.92). Bu was found to be stable in DBS up to 6 h at room temperature and for 24 h at 4 °C. CONCLUSIONS: The new DBS method facilitates earlier dosage adjustment during Bu therapy by its specific and simple procedure using 5 µL of whole blood.

Secondary pulmonary alveolar proteinosis after unrelated cord blood hematopoietic cell transplantation.

PAP is a rare alveolointerstitial lung disorder characterized histologically by the intra-alveolar accumulation of eosinophilic and PAS-positive material. We observed two cases of PAP after unrelated CB hematopoietic progenitor cell transplantation in children with ALL. No antagonist activity toward GM-CSF was identified in the patient tested. The putative multifactorial PAP etiology is discussed. This potentially curable condition should be considered in a CB allograft recipient with alveolointerstial lung disorder.

Third-party mesenchymal stromal cell infusion is associated with a decrease in thrombotic microangiopathy symptoms observed post-hematopoietic stem cell transplantation.

TA-TMA is a pathology that occurs after allogenic HSC transplantation with an incidence of 4-13%, and represents one of the most severe vascular damage related with this therapy. We report here the case of a nine-yr-old girl suffering from a severe refractory aplastic anemia who received an unrelated, 9/10 HLA-matched HSC. Soon after transplantation, the patient developed a graft-versus-host disease (GvHD), a TA-TMA, and renal insufficiency. These pathologies remained refractory to the various treatments undertaken and required several hospitalizations in the intensive care unit. On day 106 post-HSC transfusion, after several episodes of intensive care, the patient was infused with mismatched, third-party MSCs. Schizocyte levels rapidly decreased after MSC infusion, and two wk later, most biological parameters returned to normal. Erythrocyte and thrombocyte transfusions were discontinued, and the patient remained stable for 10 wk. Thereafter, TA-TMA symptoms, viral reactivation, pleural and cardiac effusions reappeared and lead to the death of the patient. Our observations suggest that allogenic MSC infusion may decrease the symptoms of TA-TMA, but further investigation is required to determine how and when MSC should be infused to develop a long-lasting protective effect.

Outcome and risk factors for late-onset complications 24 months beyond allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: The aim of this retrospective study was to assess the incidence of late complications occurring ≥2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy. METHODS: Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T-cell depletion in 84%. RESULTS: Non-relapse mortality (NRM) was 3% (95% CI 0-11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft-versus-host disease (cGvHD) was 30% (95% CI 23-40), and that of infectious complications was 17% (95% CI 11-23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2-3.2, P=0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1-3.3, P=0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2-143, P=0.03), as well as those receiving steroids for >3 months (HR 40.3, 95% CI 2.3-718, P=0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8-68, P=0.024). CONCLUSIONS: A significant proportion of long-term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T-cell depletion resulting in immunosuppression and infectious complications.

Prognosis in pediatric hematologic malignancies is associated with serum concentration of mannose-binding lectin-associated serine protease-2 (MASP-2).

BACKGROUND: Mannose-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) are key components of the lectin pathway of complement activation. Their serum concentrations show a wide interindividual variability. This study investigated whether the concentration of MBL and MASP-2 is associated with prognosis in pediatric patients with cancer. METHODS: In this retrospective multicenter study, MBL and MASP-2 were measured by commercially available ELISA in frozen remnants of serum taken at diagnosis. Associations of overall survival (OS) and event-free survival (EFS) with MBL and MASP-2 were assessed by multivariate Cox regression accounting for prognostically relevant clinical variables. RESULTS: In the 372 patients studied, median serum concentration of MBL was 2,808 microg/L (range, 2-10,060) and 391 microg/L (46-2,771) for MASP-2. The estimated 4-year EFS was 0.60 (OS, 0.78). In the entire, heterogeneous sample, MBL and MASP-2 were not significantly associated with OS or EFS. In patients with hematologic malignancies, however, higher MASP-2 was associated with better EFS in a significant and clinically relevant way (hazard ratio per tenfold increase (HR), 0.22; 95% CI, 0.09-0.54; P = 0.001). This was due to patients with lymphoma (HR, 0.11; 95% CI, 0.03-0.47; P = 0.003), but less for those with acute leukemia (HR, 0.35; 95% CI, 0.11-1.15; P = 0.083). CONCLUSION: In this study, higher MASP-2 was associated with better EFS in pediatric patients with hematologic malignancies, especially lymphoma. Whether MASP-2 is an independent prognostic factor affecting risk stratification and anticancer therapy needs to be assessed in prospective, disease-specific studies.

Spontaneous thrombosis of hepatic aneurysms in an infant with Wiskott-Aldrich syndrome.

Vasculitides and aneurysm formation are well-known complications in Wiskott-Aldrich syndrome (WAS), most often appearing later in life, usually in second decade. The authors report the case of a 5-month-old boy with a genetically and phenotypically severe Wiskott-Aldrich syndrome and sequential formation and spontaneous thrombosis of hepatic aneurysms. This case demonstrates that aneurysm formation may develop early in the course of severe WAS phenotypes. Because of the progressive nature of these manifestations, surgical or interventional procedures are not advisable. Early allogeneic hematopoietic stem cell transplantation (HSCT) should be considered before the manifestation of irreversible organ damage.

Detection of ATM gene deletion/duplication by multiplex ligation-dependant probe amplification in childhood lymphoid malignancies: a report from the Children's Oncology Group.

ATM gene alterations have been described in various lymphoproliferative malignancies suggesting that ATM contributes to lymphomagenesis. Using multiplex ligation-dependant probe amplification (MLPA), we screened 61 childhood lymphoid malignancies for ATM genomic deletion/duplication. Five samples were found to have a complete deletion or duplication. All the three deletions were found in B-precursor ALL (15%), two were submicroscopic, not detected by standard cytogenetic studies. These observations indicate that as in adult ALL, complete ATM submicroscopic deletion is frequent in childhood B-precursor ALL. As previously hypothesized, these results suggest that ATM may act as a tumor suppressor gene in the pathogenesis of childhood B-precursor ALL.

Adrenocortical oncocytoma in a child.

Adrenocortical oncocytoma is a rare epithelial tumor only described in adults. We report the case of a 12-year-old female who presented a left adrenal mass with abdominal pain, fatigue, acne vulgaris, and elevation of the androstenedione and total testosterone. She had an adrenalectomy. A diagnosis of adrenocortical oncocytoma was made after detailed histological, immunohistochemical, and ultrastructural studies.

Severe autoimmune hemolytic anemia in a liver transplanted child.

AIHA can complicate solid organ and bone marrow transplantation early after transplant. We describe the first case report of a 16-month-old boy with mixed type warm-acting IgM and warm IgG autoantibodies AIHA, occurring eight months after liver transplantation. This case describes the complexity of this very rare form of AIHA. It also illustrates the efficacy of rituximab in this indication, as well as the transfusion support with extremely rare blood, along with the importance of international collaboration to provide it. In this report, the etiologies of HA occurring in post-transplant pediatric patients are reviewed and the different treatment strategies are discussed.

Tissue plasminogen activator for a left atrial thrombus after Senning repair.

OBJECTIVE: To avoid the surgical removal of an obstructive thrombus in a Senning baffle by the administration of recombinant tissue-type plasminogen activator. SETTING: A pediatric intensive care unit in a children's university hospital. PATIENTS: A 3-yr-old male was diagnosed with a large left atrial thrombus 2 wks after Senning repair for D-transposition of the great arteries. The child presented with massive chylous pleural, pericardial effusions, and cardiac tamponade, secondary to partial obstruction of the pulmonary venous channel. INTERVENTION: Thrombolysis with recombinant tissue-type plasminogen activator was instituted. RESULTS: We observed a resolution of the thrombus in <48 hrs. Minor local bleeding was the only noted side effect. No signs of systemic thromboembolization were detected. CONCLUSION: Early thrombolysis with recombinant tissue-type plasminogen activator could be considered a possible alternative to surgical thrombectomy in selected postoperative pediatric cases, although there may be a potential risk of serious bleeding.

Haematopoietic stem cell transplantation: activity in Switzerland compared with surrounding European countries.

Haematopoietic stem cell transplantation (HSCT) is a highly specialised procedure used to treat malignancies of the lymphohaematopoietic system as well as some acquired and inherited disorders of the blood. This analysis by the Swiss Blood Stem Cell Transplantation Group, based on data from 2008-2011, describes, treatment rates in Switzerland for specific indications and compares this with data from Germany, France, Italy and the Netherlands, corrected for the size of the population. Differences in transplant rates, in rates for particular indications, and in the use of specific transplant technologies such as use of unrelated donors, use of cord blood or mismatched family donors are described. These data are put in correlation with donor availability from international registries and with number of transplant teams and number of procedures per team all corrected for population size.

Natural history of Barth syndrome: a national cohort study of 22 patients.

BACKGROUND: This study describes the natural history of Barth syndrome (BTHS). METHODS: The medical records of all patients with BTHS living in France were identified in multiple sources and reviewed. RESULTS: We identified 16 BTHS pedigrees that included 22 patients. TAZ mutations were observed in 15 pedigrees. The estimated incidence of BTHS was 1.5 cases per million births (95%CI: 0.2-2.3). The median age at presentation was 3.1 weeks (range, 0-1.4 years), and the median age at last follow-up was 4.75 years (range, 3-15 years). Eleven patients died at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths were observed in patients ≥3 years. Fourteen patients presented with cardiomyopathy, and cardiomyopathy was documented in 20 during follow-up. Left ventricular systolic function was very poor during the first year of life and tended to normalize over time. Nineteen patients had neutropenia. Metabolic investigations revealed inconstant moderate 3-methylglutaconic aciduria and plasma arginine levels that were reduced or in the low-normal range. Survival correlated with two prognostic factors: severe neutropenia at diagnosis (<0.5 × 109/L) and birth year. Specifically, the survival rate was 70% for patients born after 2000 and 20% for those born before 2000. CONCLUSIONS: This survey found that BTHS outcome was affected by cardiac events and by a risk of infection that was related to neutropenia. Modern management of heart failure and prevention of infection in infancy may improve the survival of patients with BTHS without the need for heart transplantation.

Mannan-binding lectin (MBL) and MBL-associated serine protease-2 in children with cancer.

QUESTIONS UNDER STUDY: Mannan-binding lectin (MBL) and MBL-associated serine protease-2 (MASP-2) are two key components of the lectin-pathway of complement-activation. Information on the potential role of lectin-pathway components in carcinogenesis versus immune surveillance of cancer is scarce. This study aimed to determine if serum concentrations of MBL and MASP-2 differ between children with cancer and healthy age-matched controls. METHODS: In this retrospective multicentre study, MBL and MASP-2 were measured by commercially available ELISA in frozen remnants of serum taken at diagnosis in paediatric patients with cancer. For six diagnostic groups, these concentrations were compared with serum concentrations of age-matched healthy controls using exact Wilcoxon signed-rank tests. RESULTS: MBL and MASP-2 were measured in serum of 372 patients. MBL was significantly higher in patients with solid tumours vs. controls (median, 2,799 vs. 1,917 µg/L; P = 0.008), and MASP-2 was significantly higher in patients with acute lymphoblastic leukaemia (406 vs. 317 µg/L; P = 0.009), Non-Hodgkin lymphoma (361 vs. 293 µg/L; P = 0.037) and CNS tumors (463 vs. 296 µg/L; P = 0.002). CONCLUSIONS: These results may indicate a role of MBL and MASP-2 in the initiation or progression of specific paediatric cancers, while other mechanisms remain possible as well. Larger, disease-specific studies are warranted for confirmation and for elucidation of the underlying mechanisms.

Predicting bacteremia in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study.

STUDY AIM: To develop a score predicting the risk of bacteremia in cancer patients with fever and neutropenia (FN), and to evaluate its performance. METHODS: Pediatric patients with cancer presenting with FN induced by nonmyeloablative chemotherapy were observed in a prospective multicenter study. A score predicting the risk of bacteremia was developed from a multivariate mixed logistic regression model. Its cross-validated predictive performance was compared with that of published risk prediction rules. RESULTS: Bacteremia was reported in 67 (16%) of 423 FN episodes. In 34 episodes (8%), bacteremia became known only after reassessment after 8 to 24 hours of inpatient management. Predicting bacteremia at reassessment was better than prediction at presentation with FN. A differential leukocyte count did not increase the predictive performance. The reassessment score predicting future bacteremia in 390 episodes without known bacteremia used the following 4 variables: hemoglobin ≥ 90 g/L at presentation (weight 3), platelet count <50 G/L (3), shaking chills (5), and other need for inpatient treatment or observation according to the treating physician (3). Applying a threshold ≥ 3, the score--simplified into a low-risk checklist--predicted bacteremia with 100% sensitivity, with 54 episodes (13%) classified as low-risk, and a specificity of 15%. CONCLUSIONS: This reassessment score, simplified into a low-risk checklist of 4 routinely accessible characteristics, identifies pediatric patients with FN at risk for bacteremia. It has the potential to contribute to the reduction of use of antimicrobials in, and to shorten the length of hospital stays of pediatric patients with cancer and FN.