[Show abstract][Hide abstract] ABSTRACT: Adolescents aged 15-18 years with acute lymphoblastic leukaemia (ALL) have been historically reported to have a poorer prognosis than younger children. We retrospectively analysed the characteristics and outcome of 67 adolescents included in a population-based series of 1125 non-infant cases that were enrolled into four Austrian ALL-BFM (Berlin-Frankfurt-Münster) multicentre trials at paediatric institutions within a 25-year period. Five-year event-free survival (EFS) and overall survival (OS) were 66 ± 6% and 76 ± 5% respectively, and thus lower than in younger children (83 ± 1%, 91 ± 1%; P < 0·001). This was not due to an increased cumulative incidence of relapse (CIR) (5-year CIR: 19 ± 5% vs. 13 ± 1%; P = 0·284), but due to an increased incidence of treatment-related death [5-year cumulative incidence of death (CID): 15 ± 4% vs. 3 ± 0%; P < 0·001] as a first event. Furthermore, while 44/67 (66%) non-high-risk adolescents had favourable 5-year EFS and OS rates (76 ± 7%, 89 ± 5%), 18/67 (27%) high-risk adolescents had an inferior outcome (5-year EFS: 56 ± 12%, OS 61 ± 11%, P < 0·05). Among the latter patients the CID was significantly higher than in younger high-risk children (22 ± 10% vs. 6 ± 2%; P = 0·020). Given that adolescent age is an independent risk factor for death as a first event, this specific age group may need particular vigilance when receiving intense BFM-type chemotherapy, as relapse-free survival is similar to younger children.
British Journal of Haematology 03/2013; · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During eleven months all preterm infants admitted to our neonatal care facility with suspected respiratory tract infection were screened for respiratory viruses by PCR. Rhinovirus infection was identified in 16 infants, leading to severe respiratory compromise in most cases. Distribution of rhinovirus infections during the year showed a strong clustering trend, suggesting a major role for nosocomial transmission.
The Pediatric Infectious Disease Journal 08/2012; · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A recent study suggested that mesenchymal cells in bone marrow (BM) may counteract l-asparaginase (L-Asp)-containing acute lymphoblastic leukemia (ALL) therapy by secreting asparagine. Herein, we compared asparagine and aspartic acid concentrations in the BM and peripheral blood (PB), in order to determine whether this in vitro observation could be translated into in vivo differences of amino acid levels between both compartments. Asparagine and aspartic acid concentrations in BM (days 15 and 33) and PB (days 12, 15 and 33) were measured during L-Asp-containing Berlin-Frankfurt-Münster (BFM)-based 5-week multi-agent remission induction therapy in 11 children diagnosed with ALL at the St. Anna Children's Hospital in Vienna, Austria. The level of asparagine depletion did not differ significantly between both compartments at any time point measured, but aspartic acid concentrations were significantly higher in BM than PB at days 15 and 33 (p < 0.05). In the context of the reported mesenchymal asparagine production in BM, an increased asparagine production may indeed take place in BM. However, it may be overcome by continuous action of L-Asp, which is mirrored by increased aspartic acid levels but unchanged low asparagine levels in BM, suggesting a higher BM turnover of asparagine generated by L-Asp during induction therapy.
[Show abstract][Hide abstract] ABSTRACT: Cytochemical myeloperoxidase (MPO) positivity represents the gold standard for discrimination between lymphatic and myeloid blasts. Rarely, cytochemical MPO reaction may be positive in >or=3% of blasts with clear lymphoblastic morphology. We present 5 patients with cytochemically MPO-positive acute leukemia classified as lymphoblastic by cytomorphology and lymphoblastic (n=3) or biphenotypic (n=2) by immunophenotyping, who entered first-line treatment for lymphoblastic leukemia. The former 3 are in first remission and both with biphenotypic leukemia relapsed with acute myeloid leukemia. The study primarily shows that cytochemical MPO expression in childhood acute leukemia revealing typical lymphoblastic morphology and phenotype does rarely exist. Although a small number of patients studied, cytochemical MPO expression in acute leukemia does not seem to require myeloid leukemia treatment in case of otherwise lymphoblastic cytomorphology and phenotype.
Journal of Pediatric Hematology/Oncology 11/2009; 32(1):e4-7. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality.
Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1).
The probability of a reactivation within 5 years of NAD1 was 46%. The first reactivation occurred within 2 years after NAD1 in most of the patients. Of 134 events, 35% were confined to skeleton, 24% were single-system nonbony lesions, 24% were multisystem reactivations without risk-organ involvement, and 10% with risk-organ involvement. In 7%, the location was unspecified. Only 3 deaths (2.2%) were documented within the context of a first reactivation. Second disease resolution (NAD2) was achieved in 85% of the cases. The probability of a second reactivation within 5 years of NAD2 was 44%. The risk for permanent consequences in patients with reactivations was higher, compared with patients without reactivation (RHR 2.2, P = .046).
Reactivation is a frequent and early event in MS-LCH, but involvement of risk organs at reactivation is rare and mortality is minimal. However, reactivations increase the risk for permanent consequences by about 2-fold. Prospective trials targeting reduction of acute morbidity and permanent disabilities through nontoxic treatment of the reactivations are warranted.
The Journal of pediatrics 07/2008; 153(5):700-5, 705.e1-2. · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to identify relapse predictors in children with a B-cell precursor acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21), a novel genetic entity associated with poor outcome.
We screened 1,625 patients who were enrolled onto the Austrian and German ALL-Berlin-Frankfurt-Münster (ALL-BFM) trials 86, 90, 95, and 2000 with ETV6/RUNX1-specific fluorescent in situ hybridization probes, and we identified 29 patient cases (2%) who had an iAMP21. Minimal residual disease (MRD) was quantified with clone-specific immunoglobulin and T-cell receptor gene rearrangements.
Twenty-five patients were good responders to prednisone, and all achieved remission after induction therapy. Eleven patients experienced relapse, which included eight who experienced relapse after cessation of front-line therapy. Six-year event-free and overall survival rates were 37% +/- 14% and 66% +/- 11%, respectively. Results of MRD analysis were available in 24 (83%) of 29 patients: nine (37.5%) belonged to the low-risk, 14 (58.5%) to the intermediate-risk, and one (4%) to the high-risk group. MRD results were available in 8 of 11 patients who experienced a relapse. Seven occurred among the 14 intermediate-risk patients, and one occurred in the high-risk patient.
The overall and early relapse rates in the BFM study were lower than that in a previous United Kingdom Medical Research Council/Childhood Leukemia Working Party study (38% v 61% and 27% v 47%, respectively), which might result from more intensive induction and early reintensification therapy in the ALL-BFM protocols. MRD values were the only reliable parameter to discriminate between a low and high risk of relapse (P = .02).
Journal of Clinical Oncology 07/2008; 26(18):3046-50. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The enzyme asparaginase (L-Asp) catalyses the hydrolysis of the non-essential amino acids asparagine and glutamine to aspartic and glutamic acid and ammonia. Ammonia therefore represents a direct metabolite of the biochemical reaction induced by this enzyme. However, data regarding the dynamics and clinical relevance of ammonia levels during L-Asp therapy are lacking.
We prospectively followed the dynamics of ammonia levels during L-Asp containing induction therapy according to the ALL-BFM 2000 protocol in 10 pediatric patients with acute lymphoblastic leukemia (ALL), in order to assess the possible relevance of ammonia levels for clinical practice and its use as a possible surrogate parameter of L-Asp enzyme activity.
We observed a significant elevation of ammonia levels 1 day after intravenous L-Asp administration with ammonia levels reaching up to the seventh fold of normal values, followed by a steep decline to basal values within another 2 days, resulting in an undulating course of ammonia concentrations during L-Asp containing induction treatment.
Although there are potential neurotoxic properties of ammonia, central nervous system (CNS) toxicity has not been observed in our study and is generally not seen as a common side effect of L-Asp therapy. Furthermore, due to the characteristic fluctuation profile, ammonia levels may represent a suitable surrogate parameter of L-Asp enzyme activity and may enable the monitoring of silent inactivation of L-Asp.
Pediatric Blood & Cancer 11/2007; 49(5):640-2. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reduced intensity conditioning followed by allogeneic SCT (RIC-SCT) has recently emerged as promising new salvage option for children suffering from Langerhans cell histiocytosis (LCH) with risk organ involvement and failure to conventional therapy. We report on the posttransplant course of female toddler with high-risk LCH, who achieved complete remission after RIC-SCT, despite a posttransplant chimerism constellation, in which only the T-cell subset proved to be of donor origin in the long-term. We therefore suggest that allogeneic T-cells have played a crucial role in controlling disease activity in this patient and may exert the major curative effect after RIC-SCT for LCH.
[Show abstract][Hide abstract] ABSTRACT: MR imaging signal intensity abnormalities in the cerebellum, the pons, and the basal ganglia, compatible with a neurodegenerative process (ND) were reported in up to 10% of patients with Langerhans cell histiocytosis (LCH). Although the imaging features of ND-LCH have been extensively described, the temporal course of ND-LCH has not been assessed as of yet. The purpose of this study was to describe the long-term course of MR imaging signal intensity abnormalities in ND-LCH on T1- and T2-weighted images.
In this retrospective study, 9 patients with ND-LCH with an observation time of at least 5 years were included. Three or more MR imaging studies per patient, performed in 3-year intervals (+/-11 months), were reviewed. Signal intensity abnormalities on T1- and T2-weighted images in the cerebellum, the pons, and basal ganglia were scored for their signal intensity quality and their extension. In addition, the severity of cerebellar atrophy was scored.
The signal intensity alterations were not resolved in any of the patients. Instead, a progression of the signal intensity alterations either in the cerebellum or basal ganglia was observed in all of the patients but did not correlate with a clinical deterioration. Overt and severe neurologic symptoms were reported in only 2 patients in whom some form of atrophy was noted.
ND-LCH appears to be a slowly progressive process. The increase of signal intensity abnormalities in the cerebellum and basal ganglia does not correlate with neurologic deterioration. MR imaging appears to be a sensitive technique to detect and monitor radiologic ND-LCH.
American Journal of Neuroradiology 01/2007; 28(6):1022-8. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Permanent consequences in Langerhans cell histiocytosis (LCH) are irreversible late sequelae related to the disease that may severely impair the quality of life of survivors. The frequency and pattern of permanent consequences affecting the central nervous system (CNS) remains to be determined.
In this single center study, 25 LCH patients observed for a median time of 10 years 3 months underwent a uniform thorough follow-up program including neuropsychological testing and electrophysiological evaluation.
Overall permanent consequences were seen in 9 of 25 patients. Intracranial abnormalities were the most frequent including diabetes insipidus (DI) in seven patients, anterior pituitary deficiencies in five patients, and neurodegenerative CNS disease in five patients. No patient had overt neurological symptoms upon neurological evaluation, but psychological testing revealed subtle deficits in short-term auditory memory (STAM) in 14 patients. Brain stem evoked potentials showed abnormalities in four of nine tested patients, all of these four had neurodegeneration on MRI.
Psychoneuroendocrine sequelae were found in an unexpectedly high number of patients in this single center study. Long-term follow-up focusing on such sequelae are important in LCH survivors, in order to detect early deficits, to monitor the evolution of the disease, and to provide specific support.
Pediatric Blood & Cancer 01/2007; 48(1):50-6. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Near-tetraploidy (82-94 chromosomes) makes up fewer than 1% of childhood acute lymphoblastic leukemia (ALL) cases and has been reportedly associated with a possibly poorer prognosis compared with other ploidy groups. We analyzed 783 patients enrolled in the ALL-BFM-Austria 86, -90, -95, -99/2000 and Interfant-Austria 99 trials in order to assess its incidence, biological characteristics, and prognostic relevance. Twelve of 783 patients (1.5%) had a near-tetraploid ALL. Fluorescence in situ hybridization revealed that eight of the nine B-cell precursor (BCP) cases and none of the three T-cell ALL cases had an ETV6/RUNX1 rearrangement. After a median follow-up of 11.4 years, none of the patients has relapsed or died. Thus, near-tetraploidy appears to be a specific feature of ETV6/RUNX1+ BCP ALL cases that in turn may explain its excellent outcome.
Genes Chromosomes and Cancer 07/2006; 45(6):608-11. · 3.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mixed lineage leukemia (MLL) abnormalities occur in approximately 50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10- pre-B ALL.
To address this question, we analyzed 29 patients with pro-B ALL, 11 patients with CD10- pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 > or = 80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set.
We found that 15 of 29 pro-B ALL, 7 of 11 CD10- pre-B ALL, and 1 of 2 French-American-British classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10- pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis.
The striking similarities between the two CD10- ALL subsets imply that CD10- pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.
Clinical Cancer Research 05/2006; 12(10):2988-94. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied.
Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI.
Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.
Pediatric Blood & Cancer 03/2006; 46(2):228-33. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Non-Hodgkin lymphoma (NHL) represents one of the most rapidly growing malignancies in childhood and adolescence. About 80% of patients now are cured with adequate treatment. Serious complications at presentation due to tumor lysis syndrome or local tumor effects are commonly observed. Thus, a rapid diagnosis with the least invasive procedure enabling the initiation of early and specific therapy is necessary to diminish early fatality or persistent impairment. In 56 centrally registered patients with NHL, cytomorphologic analyses (FAB criteria) of May-Grünwald-Giemsa-stained touch imprints or malignant effusions and flow cytometric immunophenotyping (EGIL criteria) of fresh cell suspensions with a standardized panel of monoclonal antibodies were performed. The authors identified 23 patients with Burkitt lymphoma by the combination of FAB L3 morphology and a mature B-cell phenotype and 22 patients with lymphoblastic lymphoma by FAB L1/L2 morphology and a T-/B-cell precursor phenotype. They also found 11 patients with large cell lymphomas, 3 of them with anaplastic large cell lymphoma (T-cell phenotype; NPM/ALK-positive). In the remaining 8 patients diffuse large B-cell lymphoma was suspected by the combined use of cytologic and immunophenotypic findings (mature B-cell phenotype). In all cases with available solid tumor material (n = 42/56) the preliminary diagnosis was confirmed by histopathology. Burkitt lymphoma, lymphoblastic lymphoma, and, in a few cases, some large cell lymphomas could be classified reliably by cytomorphology and immunophenotyping of freshly obtained tumor cell material, enabling an early start of specific lymphoma treatment.
Pediatric Hematology and Oncology 01/2006; 23(3):167-76. · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH).
Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry.
The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups.
In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the "wait and see" approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy.
Pediatric Blood & Cancer 12/2005; 45(6):802-7. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Children with multisystem Langerhans cell histiocytosis (LCH) and risk organ involvement who fail to respond to conventional chemotherapy have an extremely poor prognosis. Myeloablative stem cell transplantation (SCT) as a possible salvage approach for these patients has been associated with a high risk of transplant-related mortality. Therefore, allogeneic stem cell transplantation following a reduced-intensity conditioning regimen (RIC-SCT) has recently been performed as an alternative salvage approach. We report on the experience with allogeneic RIC-SCT in nine pediatric high-risk LCH patients. Conditioning regimen included fludarabine in all patients, melphalan in eight patients, total lymphoid irradiation in six patients, total body irradiation in two, antithymocyte globulin in five, and Campath in four patients. RIC-SCT was well tolerated with regard to common procedure-related complications. Two patients died 50 and 69 days after RIC-SCT, respectively. Seven out of the nine patients survived and showed no signs of disease activity (including one with nonengraftment and full autologous hematopoietic recovery) after median follow-up of 390 days post-SCT. Based on this observation, we conclude that RIC-SCT is a feasible procedure with low transplant-related morbidity and mortality and a promising new salvage approach for high-risk LCH patients with resistant risk organ involvement.
Bone Marrow Transplantation 09/2005; 36(3):215-25. · 3.54 Impact Factor