Manuel Steiner

Risk factors for diabetes insipidus in langerhans cell histiocytosis

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.

Minimal Residual Disease Values Discriminate Between Low and High Relapse Risk in Children With B-Cell Precursor Acute Lymphoblastic Leukemia and an Intrachromosomal Amplification of Chromosome 21: The Austrian and German Acute Lymphoblastic Leukemia Berlin-Frankfurt- Munster (ALL-BFM) Trials

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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).

Langerhans cell histiocytosis in neonates.

To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH).

Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry.

OBJECTIVE To assess multisystem Langerhans cell histiocytosis reactivation and its impact on morbidity and mortality. STUDY DESIGN Retrospective analysis of 335 patients with MS-LCH and documented complete disease resolution (NAD1). RESULTS 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). CONCLUSIONS 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.

Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis.

Central diabetes insipidus (CDI) is a rare disorder associated with various underlying diseases. Among the systemic diseases that may cause CDI, Langerhans cell histiocytosis (LCH) is the most common. Therefore, in patients with endocrinologically proven CDI, a comprehensive diagnostic evaluation is crucial to identify possible extracranial sites of LCH. The goal of the diagnostic evaluation is to yield histopathological proof of the underlying disease. If possible, this histopathological proof should be provided by a biopsy of extracranial lesions to avoid a potentially hazardous biopsy of the pituitary stalk.

Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis.

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.

Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group.

Children and adolescents with Non‐Hodgkin lymphoma (NHL) and mature B‐cell leukemia (B‐ALL) have an excellent prognosis with contemporary chemotherapy stratified according to the histologic subtype and clinical stage of disease. However, a small subset of patients does not respond to front‐line therapy or suffers from an early relapse.

Mixed lineage leukemia-rearranged childhood pro-B and CD10-negative pre-B acute lymphoblastic leukemia constitute a distinct clinical entity.

Purpose:Mixed lineage leukemia (MLL) abnormalities occur in ∼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. Experimental Design: 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 ≥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. Results: 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. Conclusions: 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.

The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment-related mortality and not an increased relapse rate--a population-based analysis of 25 years of the Austrian ALL-BFM (Berlin-Frankfurt-Münster) Study Group.

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.

Nosocomial rhinovirus infection in preterm infants.

During 11 months, all preterm infants admitted to our neonatal care facility with suspected respiratory tract infection were screened for respiratory viruses by polymerase chain reaction. 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.