Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000.

Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.

Allogeneic stem cell transplantation for pediatric and adolescent patients with CML: results from the prospective trial CML-paed I.

PURPOSE: Stem cell transplantation (SCT) can definitely cure chronic myeloid leukemia (CML), a rare disease in childhood. We prospectively evaluated the results of early SCT in pediatric CML after standardized pretreatment with hydroxyurea+/-interferon. PATIENTS AND METHODS: Between 1995 and 2004, 200 children (median age: 12.4 years) were enrolled and stratified: given the availability of an HLA-matched related donor (MRD), SCT was scheduled within 6 months and otherwise from an unrelated donor (UD) within 12 months following diagnosis. RESULTS: 176 patients underwent SCT; from MRD within median 4 months and from UD within median 11 months after diagnosis. At SCT, 158 patients were in chronic phase (CP1 or CP2), 9 patients were in accelerated phase and 9 patients were in blast crisis (BC). The conditioning regimen - total body irradiation or busulfan - exerted no different impact on overall survival (OS). Probability of OS at 5 years was 87+/-11% if grafted from a sibling (n=41), 52+/-9% from matched UD (MUD, n=71), and 45+/-16% from mismatched donors (MMD, n=55), respectively. A trend for better OS in CP1 was observed if SCT was performed within 6 months (n=49; 74+/-9%), compared to 7-12 months (n=52; 62+/-15%), and >12 months (n=43; 62+/-17%) after diagnosis, respectively (p=0.157). Probability of relapse at 5 years was 20+/-12%. Transplant-related mortality and graft-versus-host disease mainly contributed to the inferior outcome in UD and HLA-mismatched SCT. CONCLUSION: These data from the first prospective trial on CML restricted to children and adolescents might be considered for decision making when balancing the risks of SCT against the increasing use of imatinib as upfront treatment for CML.

[MRI screening before stem cell transplantation--necessary?]. / MRT-Untersuchung des Neurokraniums vor Stammzelltransplantation--notwendig oder überflüssig?

PURPOSE: In the context of stem cell transplantation (SCT), we often observe neurological complications as a consequence of immune system suppression, conditioning therapy or prophylaxis and treatment of graft-versus-host disease. Furthermore, cerebral lesions in existence prior to transplantation can be found. The aim of this study was to evaluate the benefit of cerebral magnetic resonance imaging (MRI) prior to stem cell transplantation. PATIENTS AND METHOD: Cerebral MR examinations of 116 children and adolescents were performed before SCT. Patients ranged in age from 1.1 to 21.4 years (mean 12.6 years). All MR images were obtained by a 1.5 T system. The predefined short protocol included an axial T 1-weighted SE sequence and a coronary T 2-weighted TSE sequence. We evaluated existing cerebral lesions, the diameter of the ventricular system, and the paranasal sinuses. In the case of pathological findings, the short examination protocol was expanded. RESULTS: In 5 of 116 children (4.3 %) we observed prior to SCT findings requiring immediate treatment although the patients did not show any clinical symptoms (1 x aspergilloma, 1 x hemorrhage of vascular anomaly). An increased risk of bleeding caused by cavernoma or another vascular anomaly without hemorrhage also had to be taken into account. 32 of 116 patients (37.1 %) showed atrophic lesions. In 42 children (36.2 %), we observed affections of the paranasal sinuses. CONCLUSION: The imaging findings requiring immediate treatment even though the children did not show any clinical signs, justify cerebral MR examinations prior to stem cell transplantation.

Relapse, not regimen-related toxicity, was the major cause of treatment failure in 11 children with Down syndrome undergoing haematopoietic stem cell transplantation for acute leukaemia.

We report a retrospective analysis of 11 children with Down syndrome (DS) treated by SCT in eight German/Austrian SCT centres. Indications for transplantation were acute lymphoblastic leukaemia (N=8) and acute myeloid leukaemia (N=3). A reduced intensity conditioning (RIC) containing 2 Gy TBI was given to two patients, another five received a myeloablative regimen with 12 Gy TBI. Treosulphan or busulphan was used in the remaining four children. Four of eleven (36%) patients are alive. All of them were treated with a myeloablative regimen. One of the four surviving children relapsed 9 months after SCT and is currently receiving palliative outpatient treatment. The main cause of death was relapse (5/11). Two children died of regimen-related toxicity (RRT), one from severe exfoliative dermatitis and multiorgan failure after a treosulphan-containing regimen, the other from GvHD-related infections after RIC. Acute GvHD of the skin was observed in 10 of 10 evaluable patients, and chronic GvHD in 4 of 8. Our data show that DS patients can tolerate commonly used, fully myeloablative preparative regimens. The major cause of death is relapse rather than RRT resulting in an event-free survival of 18% and over all survival of 36%.

Reduced intensity conditioning in unrelated donor transplantation for refractory cytopenia in childhood.

Myelodysplastic syndromes (MDS) are a heterogenous group of acquired hematopoietic stem cell disorders. Refractory cytopenia (RC) is the most common subtype of childhood MDS and hematopoietic stem cell transplantation (HSCT) is the only curative treatment. HSCT following a myeloablative preparative regimen is associated with a low probability of relapse and considerable transplant-related mortality. In the present European Working Groups of MDS pilot study, we investigated whether a reduced intensity conditioning regimen (RIC) is able to offer reduced toxicity without increased rates of graft failure or relapse. Nineteen children with RC were transplanted from an unrelated donor following RIC consisting of fludarabine, thiotepa and anti-thymocyte globulin. Three patients experienced graft failure. Neutrophil and platelet engraftment occurred at a median time of 23 and 30 days, respectively. Cumulative incidence of grade II-IV and grade III and IV acute graft-versus-host disease (GVHD) was 0.48 and 0.13, respectively; three patients developed extensive chronic GVHD. Although infections were the predominant complications, only one patient with extensive chronic GVHD died from infectious complications. Overall and event-free survival at 3 years were 0.84 and 0.74, respectively. In conclusion, our results were comparable to those of patients treated with myeloablative HSCT. Long-term follow-up is needed to demonstrate the expected reduction in long-term sequelae.

Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties.

This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.

Cystic fibrosis in 65- and 67-year-old siblings. Clinical feature and nasal potential difference measurement in patients with genotypes F508del and 2789+5G-->A.

Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G-->A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CFTR function and alternate chloride channel function were detected during superfusion of the nasal epithelium with isoproterenol and ATP. Long-term survival with CF is basically influenced by the CFTR genotype. The patients' genotype was discussed as a mild one with remaining CFTR function. We demonstrated this residual CFTR function in both siblings using NPD. Additionally the siblings' continuous healthy lifestyle and their engagement in a remarkably high level of exercise activities from early childhood to the present possibly have an important effect on the long-term outcome of CF as disease-modifying factors. In this regard this report can encourage CF patients to maintain a high level of physical activity in their daily lives.

Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML.

Insulin-like growth factor binding protein (IGFBP)-2 has mitogenic effects in normal and neoplastic cells. The purpose of this study is to examine the diagnostic and prognostic significance of elevated IGFBP-2 levels in children with AML after hematopoietic stem cell transplantation (HSCT) at relapse and continuous complete remission (CCR). In 27 children with AML (mean age 13.6+/-5.3 years; patients in remission n=15 with relapse n=12) serum parameters of IGFBP-2, IGFBP-3, IGF-I and IGF-II were analyzed up to 18 months after HSCT by RIA. AML-patients with evidence of relapse demonstrated a continuous increase of IGFBP-2 levels during the follow-up. At day 100 after HSCT, IGFBP-2 concentrations were significantly higher in patients with relapse than in children without relapse (7.4+/-4.0 standard deviation score (SDS) vs 3.9+/-1.7 SDS; P=0.01). Serum IGFBP-2 was identified as an independent factor for the prediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 >4.5 SDS at day 100 after HSCT was 31% compared to patients with IGFBP-2 <4.5 SDS was 72% (P=0.004). Patients with IGFBP-2 concentration up to 4.5 SDS more likely developed a relapse and had a poorer outcome. Identification of these patients allows a more individualized and aggressive adjuvant treatment and follow-up.

T-cell independent production of salivary secretory IgA after hematopoietic stem cell transplantation in children.

This study examined the recovery of secretory IgA (S-IgA) in saliva after hematopoietic stem cell transplantation (HSCT) in 35 children and young people between the ages of 3 and 27 years (mean=13.6), and compared this recovery with that of serum immunologic constituents. Reference values for human salivary S-IgA in saliva were obtained from 77 healthy control subjects between the ages of 7 and 25 years (mean=11.4). In the 35 patients, a nadir of secretory IgA concentrations in saliva (S-IgA) was observed between the 3rd and the 4th month, and a return to normal values 1 year after HSCT. Serum IgA concentrations reached their nadir in the 6th month, and normalized in the 18 months after HSCT. The recovery of T-helper cells (CD4+/3+) was also delayed to beyond 18 months. We found a significant correlation between the reconstitution pattern of S-IgA and that of T-helper lymphocytes, but no correlation was found between the post-transplant evolutions of S-IgA and serum IgA, or between S-IgA and T-helper cells. The recovery of S-IgA was more rapid than that of serum IgA and appeared to be T-helper cell independent.

Donor leukocyte infusion after hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative disorder of early childhood. In all, 21 patients with JMML who received donor leukocyte infusion (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT) for either mixed chimerism (MC, n=7) or relapse (n=14) were studied. Six patients had been transplanted from an HLA-matched sibling and 15 from other donors. Six of the 21 patients (MC: 3/7 patients; relapse: 3/14 patients) responded to DLI. Response rate was significantly higher in patients receiving a higher total T-cell dose (> or =1 x 10(7)/kg) and in patients with an abnormal karyotype. None of the six patients receiving DLI from a matched sibling responded. Response was observed in five of six patients who did and in one of 15 children who did not develop acute graft-versus-host disease following DLI (P=0.01). The overall outcome was poor even for the responders. Only one of the responders is alive in remission, two relapsed, and three died of complications. In conclusion, this study shows that some cases of JMML may be sensitive to DLI, this providing evidence for a graft-versus-leukemia effect in JMML. Infusion of a high number of T cells, strategies to reduce toxicity, and cytoreduction prior to DLI may improve the results.

Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity.

OBJECTIVE: To evaluate the safety and efficacy of autologous stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA). DESIGN: Retrospective analysis of follow up data on 34 children with JIA who were treated with ASCT in nine different European transplant centres. Rheumatological evaluation employed a modified set of core criteria. Immunological reconstitution and infectious complications were monitored at three month intervals after transplantation. RESULTS: Clinical follow up ranged from 12 to 60 months. Eighteen of the 34 patients (53%) with a follow up of 12 to 60 months achieved complete drug-free remission. Seven of these patients had previously failed treatment with anti-TNF. Six of the 34 patients (18%) showed a partial response (ranging from 30% to 70% improvement) and seven (21%) were resistant to ASCT. Infectious complications were common. There were three cases of transplant related mortality (9%) and two of disease related mortality (6%). CONCLUSIONS: ASCT in severely ill patients with JIA induces a drug-free remission of the disease and a profound increase in general wellbeing in a substantial proportion of patients, but the procedure carries a significant mortality risk. The following adjustments are proposed for future protocols: (1) elimination of total body irradiation from the conditioning regimen; (2) prophylactic administration of antiviral drugs and intravenous immunoglobulins until there is a normal CD4+ T cell count.

Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions.

The study was performed to compare whole-body short time inversion recovery (STIR) MR imaging and (99m)Tc-methylene diphosphonate planar scintigraphy in the examination of children with suspected multifocal skeletal malignant lesions. Sixteen patients with known or suspected malignant skeletal disease underwent both whole-body STIR MR imaging and bone scintigraphy. The lesions were described and numbered according to scintigraphic evaluation criteria. Thus, 16 regions were analyzed in each patient for the comparison between the two modalities. Histology was proven in the primary malignant regions. Follow-up MRIs were registered. Scintigraphy and MRI follow-up were evaluated as gold standard. A total of 139 different lesions was observed by both modalities. Baseline whole-body MRI revealed 119 bone lesions in 256 possible sites (46.5%); scintigraphy revealed only 58 lesions (22.6%). Congruence was observed in only four patients (25%). According to the location of the lesion, correlation was observed in 39/139 lesions (28%). In all, 57.5% of the lesions were detected only by MRI and 14.5% of the lesions were detected only by scintigraphy. Whole-body MRI was more sensitive (P<0.001). Of all lesions numbered which could be separated in the initial MRI, whole-body MRI detected 178 lesions in the patients. The results suggest that whole-body MRI using a STIR sequence is an effective radiation free method for examination of children with suspected multifocal bone lesions. MRI showed more lesions than conventional (99m)Tc-methylene diphosphonate scintigraphy. Therefore, whole-body MRI may be feasible as a screening modality for metastatic and skip lesions in osteosarcoma, PNET, Ewing sarcoma and Langerhans cell histiocytosis in children.

Haematopoetic stem cell transplantation for refractory autoimmune cytopenia.

This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity.

[Parvovirus B 19 associated hemophagocytic syndrome in a patient with hereditary sperocytosis]. / Parvovirus-B-19-assoziiertes hämophagozytisches Syndrom bei einer Patientin mit hereditärer Sphärozytose.

Infections with parvovirus B 19 can cause aplastic crises with a rapid decline of hemoglobin levels in patients with hereditary spherocytosis. Usually, the symptoms and signs of the actual infection are mild. We here report on an eight year old girl with hereditary spherocytosis who was admitted to hospital with high temperature, headache, impaired consciousness and a profound anemia (Hb 2.9 mmol/l). Since she also developed low leukocyte and platelet counts a hematological malignancy was suspected. The bone marrow aspirate showed only 1 % erythroblasts and macrophages with active hemophagocytosis. The serum ferritin was 1381,4 ng/ml. Both, serology and PCR revealed an active infection with parvovirus B 19. Coagulation analysis suggested a low degree of disseminated intravasal coagulation (low fibrinogen, high D-dimers). We diagnosed a parvovirus B 19 associated hemophagocytic syndrome. With only symptomatic treatment the patient's condition and laboratory findings improved during the course of a few days. In accordance with other reported cases, the prognosis of parvovirus B 19 associated hemophagocytic syndrome seems to be better than in hemophagocytic syndrome of other origin.

Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis.

Since 1997, autologous stem cell transplantation (ASCT) had been applied to more than 40 children with polyarticular or systemic juvenile idiopathic arthritis (JIA). For this review, results of the follow-up are available from 25 children with systemic JIA and six with polyarticular JIA that were reported in detail from eight different pediatric European transplant centers. Before ASCT all children had progressive disease despite the use of corticosteroids, methotrexate (MTX) up to 1 mg/kg/week, cyclosporin (2.5 mg/kg/day) and/or anti-TNFalpha therapy. The clinical follow-up of these children ranges from 8 to 60 months (median 33 months).

Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia.

SUMMARY: Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) may play an important role in tumor proliferation. This study aimed to investigate the IGF system in children with acute leukemia prior to and after hematological stem cell transplantation (HSCT). In 51 patients (AML n=27; ALL n=24; mean age 11.2+/-4.8 years), serum parameters (IGF-I,-II, IGFBP-2,-3) were investigated up to 18 months after HSCT by RIA. Patients with AML showed a significant increase of IGFBP-2 up to 100 days after HSCT (mean +/-s.d. prior to HSCT: 3.2+/-3.6 SDS vs 100 days after HSCT: 5.3 degrees +/-3.4 SDS, P=0.005). Furthermore, IGF-I and IGFBP-3 were significantly decreased (IGF-I: -0.3+/-1.5 vs -0.7 +/-1.2 SDS, P=0.001; IGFBP-3: -0.3+/-1.1 vs -1.0+/-1.1 SDS, P=0.02). Children with AML showed significantly higher IGFBP-2 (P=0.04) and significantly lower IGF-I (P=0.03) and IGFBP-3 (P=0.05) levels than children with ALL at day 100 after HSCT. We conclude that children with acute leukemia show important changes in the IGF system after HSCT. In particular, IGFBP-2 was significantly elevated at day 100 after HSCT. Increased IGFBP-2 and decreased IGF-I and IGFBP-3 may be associated with the increased proliferation rate of transplanted bone marrow.

Recurrent vomiting and ethylmalonic aciduria associated with rare mutations of the short-chain acyl-CoA dehydrogenase gene.

We report identification of short-chain acyl-CoA dehydrogenase (SCAD) deficiency in a 12-year-old boy who suffered from recurrent attacks of vomiting once or twice a year from infancy. Growth and development were normal and there were no muscular symptoms. Metabolic screening was performed during a hospitalization at 8 years of age and revealed an increased excretion of ethylmalonic acid (EMA; 45-80 mmol/mol creatinine, normal 0.2-6.6), suggesting a degradation defect of short-chain fatty acids. An increased n-butyrylcarnitine was found in freshly collected serum (0.9 micromol/L; normal <0.4) but not in dry blood spots. Neither of the frequent SCAD gene variants 625G>A and 511C>T was present, but direct sequencing of the promoter and coding regions of the SCAD gene revealed that the patient had mutations on both alleles: 417G>C (Trpl15Cys) and 1095G>T (Gln341His). Neither mutation has been described before in compound heterozygosity or homozygosity. Enzymatic investigations subsequently confirmed a defect of SCAD in both fibroblasts and muscle extracts. Furthermore, expression studies of both mutations demonstrated impaired enzyme function or structure. To our knowledge, this case is the first description of a patient with proven SCAD deficiency presenting with recurrent emesis but without other symptoms, and emphasizes the wide clinical phenotype of this disorder.

Procalcitonin, C-reactive protein, and endotoxin after bone marrow transplantation: identification of children at high risk of morbidity and mortality from sepsis.

We prospectively evaluated the capacity of serum procalcitonin (PCT), compared with serum levels of C-reactive protein (CRP) and endotoxin, to identify children at high risk for mortality from sepsis after BMT. Of 47 pediatric bone marrow transplantation patients studied, 22 had an uneventful course post-transplant (Group 1), 17 survived at least one septic event (Group 2), and eight died from multiorgan failure (MOF) following septic shock (Group 3). Median concentrations of PCT over the course of the study were 1.3, 15.2, and 102.8 ng/ml, respectively, in each of the three groups (P<0.002 for each comparison). Median concentrations of CRP were 91, 213, and 260 mg/l, respectively (P<0.001 for Group 1 vs Group 2 and Group 3; P=NS for Group 2 vs Group 3). Median concentrations of endotoxin were 0.21, 0.30, and 0.93 U/l, respectively (P=NS for each comparison). Median concentrations of PCT, in contrast to serum CRP and endotoxin, correlated with the severity of sepsis (8.2 ng/ml in 'sepsis' and 22.3 ng/ml in 'severe sepsis', P=0.028) and provided useful prognostic information during septic episodes.

Pre-emptive therapy with rituximab for prevention of Epstein-Barr virus-associated lymphoproliferative disease after hematopoietic stem cell transplantation.

Epstein-Barr virus (EBV)-associated lymphoproliferative disease (LPD) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Therefore, early diagnosis of EBV reactivation and pre-emptive therapy may be clinically useful. We report three patients who presented with an extremely high EBV load in peripheral blood mononuclear cells and plasma without evidence of EBV disease. Following pre-emptive therapy with a single dose of rituximab, a concordant decrease of EBV-genome copies and B lymphocytes was observed. In all three patients, no EBV-associated LPD occurred. We conclude that pre-emptive therapy with rituximab appears to be effective for prevention of EBV-associated LPD after HSCT.

[Early results of ultrasound based calculation of broadband ultrasound attenuation and speed of sound in children and adolescents suffering from asthma]. / Erste Ergebnisse der ultraschallbasierten Bestimmung der Schallabsorption und Schallgeschwindigkeit bei Kindern mit Asthma bronchiale.

PURPOSE: To determine broadband ultrasound attenuation (BUA) and speed of sound (SOS) on the os caicis in asthmatic children. To correlate these findings with sex, age, weight and height, topical steroid intake, and asthma severity grade (ASG). PATIENTS AND METHODS: 178 children (ASG 1 - 3)/(98 m, 80 f; mean age 11.9 +/- 3.1 y) were consecutively chosen from 4/00 to 9/01. Children with any other chronic disease were excluded. BUA and SOS were measured using SAHARA (Hologic lnc. Waltham, USA). Regional normative BUA and SOS data of 3 299 children (obtained with the same system), were used to calculate age-, weight- and height-matched standard-deviation-scores (SDS) for both sexes. Asthma severity grade and steroidal intake were determined. The highest topical steroid dosage was 500 micro g Fluticasone or 800 micro g Budesonide per day. RESULTS: 10/178 children were small and 7/178 tall per age (5.6 %/3.9 %), 11/178 children were light (6.2 %) and 9 heavy per age (5.0 %). 19 and 45 children had reduced BUA and SOS values, respectively. The following rates of reduced values were observed: girls: BUA 15.0 % (12/80), SOS 25.0 % (20/80); boys: BUA 7.1 %, SOS 25.5 % (7/98 and 25/98). Sexual differences were not significant. Reduced SOS-values were associated with higher severity and occurred significantly more frequent at children under steroidal intake (0.09 vs. 0.25 [BUA] and - 0.37 vs. - 0.07 [SOS]). CONCLUSION: Following our results an increase incidence of reduced speed of sound occurs in asthmatic children which is attributed to asthma severity and seems to be negatively influenced even by topically applied low dose steroids. This could be attributed to a steroid induced collagen synthesis deficiency followed by a reduced bone elasticity. Further studies, especially using a longitudinal study design are required to verify these findings.