Busulfan/Fludarabine- or Treosulfan/Fludarabine-Based Conditioning Regimen for Patients with Wiskott-Aldrich Syndrome – an EBMT Inborn Errors Working Party and Scetide Study

Introduction Excellent survival rates have been reported after allogeneic haematopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome (WAS) patients. Recipient age >5 years in MUD HSCT as well as MMFD as donor were negative predictors for outcome. However, the vast majority of HSCTs in previously published studies were performed with (oral) busulfan/cyclophosphamide-based conditioning and in the early 2000 years or before. Objectives To compare OS and EFS after HSCT with either busulfan/fludarabine (BuFlu) ± thiotepa (TT) or treosulfan/fludarabine (TreoFlu) ± TT as recommended for primary immunodeficiencies since 2005 by the inborn errors working party (IEWP) of EBMT and ESID. Methods We performed a retrospective analysis via the EBMT and SCETIDE registries of WAS patients transplanted between 20006 and 2016 with these two regimens. At the time of this interim analysis, 174 patients were included, 92 (53%) with BuFlu±TT and 82 (47%) with TreoFlu±TT conditioning, with a median age of 1.6 years (0.2-30) at HSCT and a median follow-up of 32.9 months (1.5-128.9). Donors were MSD in 30, other MRD in 5, MUD (9/10 or 10/10) in 105, MMUD ( Results Two year overall survival (OS) of the entire cohort was 88.6% (95% c.i. 83.5%-93.6%). There was no significant difference in OS between BuFlu±TT or TreoFlu±TT conditioning (2-year OS 88.1% vs. 89.5%; p=0.7). Patients aged >5 years had a worse OS as compared to those 5 years or younger at HSCT (74.9% vs. 90.8%; p=0.005). The type of donor had no influence on OS: 96.4% for MSD/MFD, 86.8% for MUD/MMUD and 87.7% for MMFD (p=0.4). The rate of complete (≥90%) donor chimerism at last follow-up or before a secondary procedure (if a patient had one) was 41/42 (98%) in the BuFlu±TT group and 21/35 (60%) in the TreoFlu±TT group (p=0.0001). Twenty-six patients required a second procedure: stem cell boost in 4, donor lymphocyte infusion in 9, 2nd HSCT in 15 and splenectomy in 1. The 2-year cumulative incidence (CI) of second procedures was higher at 33.9% in the TreoFlu±TT versus 12.8% in the BuFlu±TT group (p=0.017), and 2-year EFS (events: second procedure or death) was 61.4% in the TreoFlu±TT and 75.0% in the BuFlu±TT group (p=0.2). Grade II-IV acute GVHD had the same incidence in both groups (24.4% vs. 26.3%; p=0.849) and chronic GVHD of any grade was borderline more frequent in the TreoFlu±TT group (17.2% vs 6.7%; p=0.054). Conclusion HSCT with either BuFlu±TT or TreoFlu±TT conditioning reliably cures almost 90% of patients with WAS regardless of donor type. Age >5 years at HSCT remains a negative risk factor. More patients were mixed chimeras and required second procedures after TreoFlu±TT than after BuFlu±TT conditioning. These data confirm the feasibility and efficacy of the regimens currently recommended by the IEWP

Middle cerebral arterial thrombosis in a patient with hypofibrinogenemia, 5 days after rFVIIa and FFP infusion

A 13-year-old female patient is presented who had hypofibrinogenemia diagnosed as von Willebrand disease at 5 years of age at another hospital. She was admitted to the department of pediatric hematology with a severe headache, vomiting, and progressive right flaccid hemiplegia and lethargy. Contrast-enhanced computed tomography scan showed subdural hematoma in posterior parietal region of the brain and impending cerebellar herniation. She was given fresh-frozen plasma (FFP) and then activated factor VII (rFVIIa), 80 mu g/kg was infused for replacement of von Willebrand factor. The subdural hematoma was emergently drained. The results of coagulation tests before infusion of FFP and rFVIIa revealed bypofibrinogenemia, and FFP was given every 48 hours. The patient recovered dramatically in a few days. Five days after rFVIIa infusion, a magnetic resonance angiography-proven right middle cerebral arterial thrombosis developed. It is an interesting point of discussion whether the middle cerebral arterial thrombosis was provoked as a consequence of rFVIIa and FFP infusion

Pancytopenia, a rare hematologic manifestation of brucellosis in children

The records of 54 children with brucellosis were evaluated retrospectively. Among them, eight patients (14.8%) with pancytopenia were identified in a 7-year period between 1996 and 2003. Six of the eight patients with pancytopenia had Brucella melitensis isolated from blood cultures, and all eight patients had Brucella agglutination titers of at least 1:320. Agglutination test titers did not correlate with the degree of pancytopenia. Fever was the most common manifestation, followed by malaise, anorexia, sweating, weight loss, and gastrointestinal symptoms. Most patients had hepatosplenomegaly, and bone marrow aspiration specimens showed hyper-cellularity or normocellularity. Hemophagocytosis (3 patients) and histiocytic hyperplasia (4 patients) were observed in bone marrow examinations of eight patients, but bone marrow aplasia and granulomas were not detected. All children recovered completely; the pancytopenia was transient and resolved after the antibiotic treatment of Brucella infection. Brucellosis should be considered as a possible diagnosis among patients with pancytopenia

Correlation of serum coenzyme Q10 and bilirubin levels of jaundiced newborns in intermediate risk zone: Is it an etiopathogenic factor in neonatal jaundice? Orta dereceli risk bölgesinde yer alan sarılıklı yenidoǧanlardaki serum koenzim Q10 ve bilirubin düzeyleri arasındaki ilişki: Koenzim Q10 düzeyi yenidoǧan sarılıǧında bir etyopatojenik faktör olabilir mi?

Aim: Jaundice in newborn is caused by neonatal changes in bilirubin metabolism resulting in increased bilirubin production, decreased bilirubin clearance and increased enterohepatic circulation. Although bilirubin is reported to have antioxidant effects in low concentrations, it is toxic at high levels. At high concentration, bilirubin leads to marked alterations in the membrane content of the several classes of phospholipids and cholesterol, which can render the cells more susceptible to lysis and shorten their lifespan. One of the most important properties of coenzyme Q10 (CoQ10) is its antioxidant activity; it protects cells from free radicals and increases membrane stability of erythrocytes. For that reason in this study, we aimed to investigate any possible relation between serum bilirubin and CoQ10 concentrations in jaundiced newborns in intermediate risk zone. Materials and Methods: Totally, 44 term jaundiced newborns with elevated indirect bilirubin levels were included to the study. Based on the recommendations of American Academy of Pediatrics newborns were divided into two groups according to their day of age and serum bilirubin concentrations: Group I (n:24); newborns in low intermediate risk zone (low-intermediate) and Group II (n:20); newborns in high intermediate risk zone (high-intermediate). Total serum bilirubin levels were obtained at the time of the routine examination in all newborns. Bilirubin concentrations in serum samples were measured spectrophotometrically and total CoQ10 concentration in the same sample of all subjects was measured by HPLC. Results: Mean total serum bilirubin levels of the Group I and Group II were 11.88±2.58 mg/dL and 17.22±1.69 mg/dL, respectively. Mean serum CoQ10 concentration of newborns in Group II was significantly lower according to the newborns in Group I (p<0.001). In addition, a significant negative correlation between serum CoQ10 concentration and bilirubin was found (r=-0.676, p<0.001). Conclusions: The results obtained from 44 fullterm jaundiced newborns indicate that, newborns with higher total serum bilirubin levels in high-intermediate risk group have lower CoQ10 concentrations when compared to low-intermediate risk group. Indeed, increase in bilirubin level is correlated with a decrease in serum CoQ10 concentration. Low serum CoQ10 content in newborns might increase serum bilirubin concentration by leading oxidative stress induced damage to erythrocytes or oxidative and cytotoxic effects of bilirubin might decrease serum CoQ10 concentration. © 2011 TurkJBiochem.com

Intracranial hemorrhage due to late hemorrhagic disease in two siblings

Deficiency of vitamin K predisposes to early, classic or late hemorrhagic disease of the newborn (HDN); late HDN may be associated with serious and life-threatening intracranial hemorrhage. Late HDN is characterized by intracranial bleeding in infants aged 1 week to 6 months due to severe vitamin K deficiency, occurring particularly in exclusively breastfed infants. Late HDN is still an important cause of mortality and morbidity in developing countries where vitamin K prophylaxis is not routinely practiced. In this study, we report on two siblings with intracranial bleeding who were fully breastfed without a routine supplementation of vitamin K. Vitamin K should be given to all newborns as a single, intramuscular dose of 1 mg. (c) 2006 Elsevier Inc

The importance of nucleolar organizer regions in pediatric acute lymphoblastic leukemia

The silver-staining of the nucleolar organizer regions (AgNORs) was performed in patients with acute lymphoblastic leukemia (ALL) to verify the role of cell proliferation in predicting complete remission and survival. Bone-marrow aspiration smears of 20 pediatric cases with ALL were stained with argyrophilic method during the diagnosis, remission, and 3rd, 6th, 9th, and 12th months after remission. The mean NORs count (NORsc) and the mean of (nucleolar organizer regions surface/total nuclear surface x 100) value (NORss/TNs) for each case were calculated. At diagnosis, the NORsc and NORss/TNs value for the whole series were 3.30 +/- 0.86 and 4.77 +/- 1.15, respectively. In complete remission, NORsc and NORss/ TNs values were 1.23 +/- 0.20 and 3.45 +/- 0.87, respectively, and the differences were statistically highly significant (p < .001). The most important parameters of prognostic factors that effect diagnosis NORss/ TNs and NORsc values were found to be FAB morphology and leukocyte count according to the multivariant analysis test. AgNORs analysis is a suitable method to assess cell proliferation in bone marrow aspirate and can predict complete remission, remission duration, and survival in pediatric ALL patients

Harlequin baby with ecthyma gangrenosum

Pseudomonas aeruginosa bacteremia or sepsis often occurs in hospitals, affecting mainly children with underlying disease. Ecthyma gangrenosum is classically considered a pathognomonic sign of sepsis by P. aeruginosa. The harlequin baby, a severe variant of ichthyosis, occurs rarely, and these infants are at high risk of cutaneous infections and sepsis. We herein report a harlequin baby who developed ecthyma gangrenosum

Level and Effect of Adrenomedullin on Endotoxin Induced Disseminated Intravascular Coagulation Model in Rabbits

Adrenomedullin (ADM) is a regulatory peptide having a variety of pharmacological properties secreted from vascular endothelial cells and adrenal medulla. There are only a few studies about the effects of ADM on coagulation and platelets which is secreted from endothelial cells. The aim of this study is to assay ADM levels in rabbits with endotoxin induced disseminated intravascular coagulation (DIC) model and to investigate the probable effects of ADM on coagulation parameters in this model. Four groups (Control, DIC, Heparin, ADM) each consisting of eight New Zeland rabbits were formed randomly. A DIC model was developed by infusion of endotoxin from Escherichia coli. Then the effect of standard dose heparin and 0.05 mu g/kg/min ADM infusion were evaluated. Administration of endotoxin resulted in severe changes of coagulation parameters as shown by the significant prolongation of the prothrombin time and activated partial thromboplastin time, decrease in platelet count, plasma fibrinogen level, antithrombin, and protein C activity. These results were in accordance with DIC findings and were significantly different from baseline and control group. In DIC group, the baseline, second, and sixth hour mean ADM levels were 7.09+/-1.63, 8.10+/-1.55, 9.35+/-0.76 ng/dl, respectively. ADM levels on sixth hour were significantly higher than baseline and control group. Heparin and ADM were used in the DIC model but both of them were not effective. In conclusion, ADM levels were found elevated during the progress of endotoxin induced DIC model. ADM were not effective in overt DIC model but it might be useful in the early phase of the DIC

Serum leptin levels in patients with childhood immune thrombocytopenic purpura

Acute immune thrombocytopenic purpura (ITP) induces thrombocytopenia by means of an autoimmune mechanism. Recent studies suggested that T helper immune response is responsible for the pathogenesis of chronic ITP. Despite several studies that were carried out, we do not have a clue as to what triggers the autoimmunity. Leptin is a 16-kd protein secreted from the adipose tissue. Leptin is structurally similar to interleukin (IL)-2, IL-6, and IL-15. The structural similarities between leptin receptor and hernatopoietic cytokine receptors suggested that leptin could play a role in hematopoiesis and immune function. Recent studies suggested that leptin could play an important role in autoimmunity. We made a prospective analysis of a series of 39 newly diagnosed acute childhood ITP in a year period. Serum leptin levels were obtained after diagnosis and before treatment and all patients were followed up at least 6 months to designate acute or chronic event. We conclude that in childhood acute ITP, leptin did not play a role in the pathophysiology of the disease. Further investigations are needed to examine what triggers T cells and how the autoimmune disease became