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Ubereinstimmend werden ausgepragte Defizite in Diagnostik und Therapie bei seltenen Erkrankungen in der westlichen Welt festgestellt. In drei von vier Fallen treten die ersten Symptome im Kindesalter auf. Dies stellt die Kindermedizin vor besondere Herausforderungen. In den letzten vier Jahrzehnten wurde eine betrachtliche Zahl an Arbeiten veroffentlicht, die belegen, dass viele chirurgische, nichtchirurgische und kindermedizinische Handlungen mit zunehmender Wiederholung erfolgreicher werden. Weiters zeigen sie sowohl fur individuelle Therapeuten als auch fur betreuende Abteilungen eine Lernkurve mit zu Beginn geringem Erfolg und spater guter Kompetenz. „Volume matters“ ist wohl der Sukkus dieser Untersuchungen. Diese Erkenntnis hat in zahlreichen Landern zur Bildung von Expertisezentren („Centres of Expertise“) gefuhrt, wo in erster Linie fur bestimmte seltene, komplexe und aufwendige Erkrankungen eine spezifische Diagnostik und Therapie angeboten werden. Zur umfassenden Betreuung – besonders wenn es sich um schwere chronische Erkrankungen handelt – mussen die lokalen Therapeuten verlasslich vernetzt sein. In Europa wird die Umsetzung der dargestellten Erkenntnisse v. a. von der Europaischen Union vorangetrieben. Osterreich hat sich mit der Erlassung des Nationalen Aktionsplans fur Seltene Erkrankungen (NAP.se) am 28.2.2015 gut positioniert. Die Umsetzung wird hoffentlich bald folgen.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

Background Since the early 1990s, three consecutive pediatric acute myeloid leukemia (AML) trials have been performed in Austria (AML-Berlin-Frankfurt-Münster (BFM) 93, AML-BFM 98, and AML-BFM 2004) in close cooperation with the international BFM study center. Herein, we review the pertinent patient characteristics, therapy, and outcome data. Patients and methods From January 1993 to April 2013, 249 children and adolescents (193 protocol patients) diagnosed with AML were enrolled in the three BFM studies. Patients were mainly treated in one of five pediatric hematology/oncology centers distributed over Austria. Results Many characteristics and outcome parameters were not statistically different between the three trials. Almost similar proportions of patients were stratified into two risk groups: standard risk (SR) (approximately 37 % overall) and high-risk (HR) (61 %). MLL rearrangements were found in 23 % of patients overall as the most frequent genetic aberration subtype. Complete remission (CR) was achieved by 84–95 % of patients. The most important type of event was leukemic relapse (5-year cumulative incidence 40 ± 8 %, 21 ± 5 %, and 39 ± 6 %; p = 0.058), with a trend to a higher rate specifically in SR patients of study AML-BFM 2004 compared with AML-BFM 98. Importantly, the frequency of death from causes other than relapse sequelae declined over the years (AML-BFM 93: 5/42 12 %, AML-BFM 98: 5/57 9 %, and AML-BFM 2004: 5/94 5 %). Altogether, event-free survival at 5 years varied insignificantly (48 ± 8 %, 61 ± 7 %, and 50 ± 6 %; p = 0.406). Nevertheless, survival (pSU) apparently improved from BFM 93 to subsequent studies, both overall (57 ± 8 %, 75 ± 6 %, and 62 ± 6 %; p = 0.046) and regarding the HR group (5-year-probability of survival (pSU) 40 ± 10 %, 66 ± 8 %, and 52 ± 8 %; p = 0.039). Conclusion Treatment of pediatric AML in Austria renders survival rates in the range of international best practice. However, unambiguous statistical comparison of treatment periods is eventually hampered by small numbers and inequalities of recruitment. Hence, only internationally collaborative trials will allow developing treatment further to achieve higher cure rates with fewer events.

Durch Kommunikation, Koordination und Kooperation ist bei der padiatrischen akuten lymphoblastischen Leukamie eine hohe Heilungsrate erreicht worden. Weitere Zusammenarbeit ist notwendig, um durch eine moglichst an die individuellen Gegebenheiten der Patienten und deren Erkrankungen angepasste Behandlung resistente Erkrankungen anzugehen und bei Patienten mit bereits erkennbar guter Heilungschance die Therapietoxizitat zu vermindern.

We analyzed outcome of a population-based cohort of 74 children with second and third acute lymphoblastic leukemia (ALL) relapse and aimed to identify prognostic factors. Duration of previous remission and site of relapse appeared of prognostic relevance as patients with a second remission duration >1.5 years and isolated extramedullary relapse did better. Neither patient with a second bone marrow relapse who underwent previous allogeneic transplantation nor patients with T-cell ALL survived. Overall, 7 of 74 (9%) patients are in long-term remission. Stem cell transplantation seemed to be the only curative option for systemic relapse of B-cell precursor ALL as all 4 surviving patients with a second/third relapse involving the bone marrow received a transplant. Conclusively, patients with a second ALL relapse are ideal candidates for phase I/II trials exploring new innovative drugs.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from 80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

Between 1981 and 2000, 6 609 children (

Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs). In the present study, we demonstrate that LCH cells exhibit a unique transcription profile that separates them not only from plasmacytoid and myeloid DCs, but also from epidermal Langerhans cells, indicating a distinct DC entity. Molecular analysis revealed that isolated and tissue-bound LCH cells selectively express the Notch ligand Jagged 2 (JAG2) and are the only DCs that express both Notch ligand and its receptor. We further show that JAG2 signaling induces key LCH-cell markers in monocyte-derived DCs, suggesting a functional role of Notch signaling in LCH ontogenesis. JAG2 also induced matrix-metalloproteinases 1 and 12, which are highly expressed in LCH and may account for tissue destruction in LCH lesions. This induction was selective for DCs and was not recapitulated in monocytes. The results of the present study suggest that JAG2-mediated Notch activation confers phenotypic and functional aspects of LCH to DCs; therefore, interference with Notch signaling may be an attractive strategy to combat this disease.

The overall outcome for children with nephroblastomas is excellent when treated according to protocols that include surgery, chemotherapy, and, in selected cases, radiotherapy. This study was conducted to provide population-based data on Austrian children who had been treated in neoadjuvant nephroblastoma trials between October 1988 and July 2001. One hundred and forty-eight children with newly diagnosed untreated renal tumors were registered in the Austrian–Hungarian Wilms Tumor Study (AHWTS) 1989 (N = 63) and the SIOP 93-01/GPOH Study (N = 85). After a median follow-up of 11.8 years from diagnosis, 130 patients have been reported to be alive; 18 patients have died. Three patients had carcinoma and three had nephroblastomatosis; the 5-year event-free survival (EFS) and overall survival (OS) rates for the remaining 142 patients were 83 ± 3 % and 91 ± 2 %, respectively (SIOP 93-01/GPOH trial, 5-year EFS 85 ± 4 %, OS 95 ± 2 %; AHWTS 1989 trial, 5-year EFS 79 ± 5 %, OS 86 ± 5 %). Outcome was better for low-risk pathology (N = 14; 5-year EFS 92 ± 8 %, OS 100 %) than for intermediate-risk (N = 106; 5-year EFS 89 ± 3 %, OS 94 ± 2 %) and high-risk pathology (N = 22; 5-year EFS 50 ± 11 %, OS 68 ± 10 %; P

Background Hypothalamic-pituitary (HP) disease is the most common CNS manifestation of Langerhans cell histiocytosis (LCH) frequently leading to diabetes insipidus (DI) and anterior pituitary hormone deficiencies (APD). On MRI, loss of the normal posterior pituitary signal and thickening of the pituitary stalk have been described, as well as neurodegenerative signal changes associated with neuropsychological disabilities in some patients. The influence of therapy on the long-term course of HP tumors and neurodegeneration (ND) is not well-understood. Procedure In this retrospective survey we focused on patients with LCH and HP disease with clinical and MRI data available at diagnosis of HP disease and at least three follow up investigations. We collected clinical and MRI follow-up information for central review and analysis. Results We identified 22 patients with HP tumors (HPT) registered at the LCH study center. Many different treatment regimens were applied for variable periods, with more than one regimen in most patients. Regression of the tumor was seen in the majority, but all patients had APD or ND on MRI at last follow up. In none of the patients APD and ND regressed or resolved. A deterioration of radiological ND was noted in 17 patients leading to overt clinical neuropsychological impairment in five. Conclusions Patients with HPT appear to be at high risk to develop permanent neuroendocrine consequences. Coordinated studies for patients with LCH and HP disease including thorough MRI monitoring and neuropsychological tests are needed. Pediatr Blood Cancer 2012; 58: 606–610. © 2011 Wiley Periodicals, Inc.

Background & Aims This study was undertaken in a pediatric gastroenterology clinic to retrospectively evaluate a real-time polymerase chain reaction (PCR) for the detection and clarithromycin susceptibility testing of Helicobacter pylori using stool specimens. Methods All consecutive children who underwent a gastroscopy between March 2006 and February 2009 and also having been examined by stool PCR were enrolled. Rapid urease test, histology, and culture were the reference methods for the detection of H pylori and E-test for susceptibility testing, respectively. Results A total of 143 children (mean age, 10.8 y; range, 2.8–17.9; males:females, 1:1.5) were evaluable. Sensitivity, specificity, and test accuracy for the detection of H pylori were 83.8%, 98.4%, and 90.2%, respectively. Sensitivity, specificity, and accuracy for the detection of clarithromycin resistance were 89.2%, 100%, and 94.0%, respectively. Conclusions Stool PCR was a reliable and useful noninvasive tool for detection and clarithromycin susceptibility testing of H pylori in a pediatric population with a high prevalence of clarithromycin-resistant strains.

Cytochemical myeloperoxidase (MPO) positivity represents the gold standard for discrimination between lymphatic and myeloid blasts. Rarely, cytochemical MPO reaction may be positive inor=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.

Remarkable advances in paediatric cancer research and treatment were achieved during the last decades: In industrialised nations, overall cure rates were raised from below 20% to over 75% during the last forty years. Randomised investigator-driven clinical trials have been the backbone of this progress so far. The EU Clinical Trial Directive was introduced to improve the quality and safety of drug development; however, it has created considerable administrative “extra” workload as well as financial constraints for trials aiming at cancer treatment optimisation in children. It failed to provide harmonisation for clinical trials throughout Europe because translation into national law was highly divergent. To address the resulting challenges for future advances in European paediatric oncology including the promotion of new drug development, improved communication between all stakeholders is warranted. Supported by the EC-funded FP7 science-communication project “DIRECT”, a meeting of European paediatric oncologists, representatives of patients’ and parents’ associations, survivors, and competent authorities was organised to investigate past successes and future challenges in paediatric oncology in Europe. The DIRECT-Symposium contributed to assess what is required in the future to advance the care and closer approach to “total cure” of European children and adolescents with cancer in all medical, psychological and social aspects. Various strategies were discussed and are summarised in this article. EC-funded science-communication projects such as DIRECT are successful means to foster the public awareness of the necessities in caring for and curing paediatric cancer patients in the future. Amongst these, appreciation of the specific conditions and a need of continual funding by the EU are imperative.

Although cure rates for childhood cancer have improved from below 20% to more than 75% during the last 40 years, childhood cancer is still the number one killer amongst paediatric diseases. European paediatric cancer research also faces new challenges by the increasing number of childhood cancer survivors, some of whom experience significantly altered life-quality due to serious psychosocial and medical long-term side-effects of the intensive cancer treatment. Hence, to achieve even higher quantity and quality of cure for Europe’s children and adolescents with cancer, development of new treatment options is now required, as are intensified epidemiological investigations into health and psycho-social issues of paediatric cancer survivors on the EU-level. Based on presentations and discussions at a recent meeting of leading European paediatric oncologists supported by the EC-funded science-communication project “DIRECT", this article discusses the situation of European paediatric cancer research under the EU-Framework Programmes (FPs). Single, partially interlinking paediatric oncological research projects received EU-funding during the last three FPs. However, given the increased budgets for health research under the FP6 and FP7 together with their goal to improve the European Research Area (ERA), relatively few of the current challenges in European paediatric oncology have been covered so far when compared to the spending for adult cancer. Although still fragmented, current EC-funded projects in paediatric oncology would be amenable to a higher level of integration. In order to achieve a closer approach to “total cure” including all medical, psychological and social aspects, paediatric cancer should become a horizontal priority of European research funding.

Purpose To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. Patients and Methods Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. Results At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% ± 4% and 73% ± 4%, respectively (all survival rates in this abstract are calculated and displayed with ±95% CI). EFS/OS rates by histology were 60% ± 5%/72% ± 5% in rhabdomyosarcoma, 62% ± 10%/69% ± 10% for Ewing tumors of soft tissues, 84% ± 12%/90% ± 10% for synovial sarcoma, and 67% ± 38%/83% ± 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% ± 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% ± 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. Conclusion Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for a fatal outcome in paediatric oncology. Although initial ALL cure rates have improved up to 80%, the prognosis of recurrent ALL remains dismal with event-free-survival (EFS) rates about 35%. In order to analyse a population-based cohort with uniform treatment of initial disease, we examined the outcome of children suffering from relapsed ALL in Austria for the past 20 years and the validity of the currently used prognostic factors (e.g. time to and site of relapse, immunophenotype). Furthermore, we compared survival rates after chemotherapy alone with those after allogeneic stem cell transplantation (SCT). All 896 patients who suffered from ALL in Austria between 1981 and 1999 were registered in a prospectively designed database and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%) suffered from recurrent disease. One-hundred-and-seventy-two patients (85%) achieved second complete remission. The probability of 10-year EFS for the total group was 34 +/- 3%. Clinical prognostic markers that independently influenced survival were time to relapse, site of relapse and the immunophenotype. Additionally, a Cox regression model demonstrated that allogeneic SCT after first relapse was associated with a superior EFS compared with chemo/radiotherapy only (hazard ratio = 0.254; P = 0.0017).

Objective To explore the frequency and course of neurodegenerative central nervous system (CNS) disease in Langerhans cell histiocytosis (ND-LCH). Study design We studied 83 patients with LCH in whom magnetic resonance imaging (MRI) of the brain was performed at least twice for various clinical indications. We defined radiologic ND-LCH as an MRI pattern comprising bilateral symmetric lesions in the dentate nucleus of the cerebellum or basal ganglia. Results Forty-seven of 83 patients (57%) had radiologic ND-LCH, at a median of 34 months (range 0-16 years) from the diagnosis of LCH. The MRI findings deteriorated in 31/47 (66%) patients over a median of 3 years (range 2 months to 12 years 6 months) and did not reverse in any patient. In 12 patients with radiologic ND-LCH (25%), clinical ND-LCH with overt symptoms were found 3 to 15 years (median 6 years) after initial LCH diagnosis. These symptoms included intention tremor, cerebellar ataxia, dysarthria, dysdiadochokinesis, concentration deficits, psychomotor retardation, severe headaches, and psychosis. Conclusion We conclude that radiologic ND-LCH is serious, not uncommon in patients studied by MRI, irreversible, and may be followed by severe clinical ND-LCH many years after the initial diagnosis of LCH.

Purpose We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS). Patients and Methods Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m2) plus cyclophosphamide (4,500 mg/m2) and melphalan (120 mg/m2) plus etoposide (1,800 mg/m2). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 × 75 mg/m2/day) plus etoposide (10 days 2 × 25 mg/m2/day), and 4 cycles trofosfamide (10 days 2 × 75 mg/m2/day) plus idarubicin (10 days 4 × 5 mg/m2). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy. Results From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan–Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or “RMS-like” tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome. Conclusion Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors. Pediatr Blood Cancer 2008;50:739–745. © 2008 Wiley-Liss, Inc.

The aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults.Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5-10 mg/kg body weight intravenously every 2-3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months.Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively.Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.

Multisystem Langerhans cell histiocytosis (MS-LCH) is associated with high mortality when patients have risk organ involvement (RO+) or are younger than 2 years. In an international randomized trial, LCH-II, we intensified their treatment: arm A consisted of 6 weeks of daily prednisone and weekly vinblastine followed by 18 weeks of daily 6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm B. Considering all 193 randomized risk patients, there were similar outcomes: rapid (6 weeks) response (arm A vs arm B: 63%/71%), 5-year survival probability (74%/79%), disease reactivation frequency (46%/46%), and permanent consequences (43%/37%). However, (1) patients younger than 2 years without RO involvement (RO−) had 100% survival and uniformly high (> 80%) rapid response, (2) RO+ patients not responding within 6 weeks had highest mortality, and (3) importantly, the more intensive arm B reduced mortality in RO+ patients (relative hazard rate, accounting for differences in risk organ involvement, of 0.54; 95% CI = 0.29-1.00). Finally, comparison of RO+ patients in LCH-I and LCH-II confirmed that increasing treatment intensity increased rapid responses (from 43% in arm A LCH-I to 68% in arm B LCH-II; P = .027) and reduced mortality (from 44% in arm A LCH-I to 27% in arm B LCH-II; P = .042). We conclude that intensified treatment significantly increases rapid response and reduces mortality in risk MS-LCH. This trial was registered at http://www.controlled-trials.com as no. ISRCTN57679341.

Health-related quality of life (HRQL) is a concept being increasingly used in paediatric health care. Since health professionals have to rely on both child and adult reports of the child’s condition, more information as to which factors moderate the correspondence between these reports would be useful. This study attempted to identify the cross-informant variance (CIV) in child, parent and teacher reports about the child’s HRQL in a large sample of elementary school children. We used the Austrian-German version of the generic core Pediatric Quality of Life Inventory™ (PedsQL™) for children and parents as well as a short HRQL rating scale derived from PedsQL™ for teachers. We identified the CIV with the use of intraclass correlation and paired score differences in 620 triple assessments, compared them to results of other PedsQL™ studies and tried to identify the factors having an impact on CIV and on the self-reported HRQL of children whose proxy ratings demonstrated a large CIV. On the whole, our results indicated low to medium agreement between children and parents, similar to results of other PedsQL™ studies in schoolchildren. The only variable that was found explaining child-parent variance was the child’s gender, with girls deviating more from their parents than boys. Child-teacher and parent-teacher CIV seemed to be primarily an effect of the child’s school performance and the teacher-parent relationship. Children whose proxy ratings differed by more than ± 15 scores showed significantly lower self-reported HRQL in some areas as compared to children whose proxy ratings showed less CIV. Our results underline that it is more difficult to get concordant HRQL ratings of schoolchildren as compared to children with chronic disease.

Haemophagocytic lymphohistiocytosis (HLH) may cause meningoencephalitis and significant neurological sequelae. We examined the relationship between neurological symptoms and cerebrospinal fluid (CSF) at diagnosis, and long-term outcome, in all children enroled in the HLH-94-study prior to July 1, 2003, for whom information on CSF at diagnosis was available (n = 193). Patients were divided into four groups: (i) normal CSF (cells/protein) and no neurological symptoms (n = 71); (ii) normal CSF but neurological symptoms (n = 21); (iii) abnormal CSF but no symptoms (n = 50); and (iv) abnormal CSF with neurological symptoms (n = 51). At diagnosis, neurological symptoms were reported in 72/193 (37%) (seizures = 23); abnormal CSF in 101/193 (52%), and either or both in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow-up (median 5.3 years). Multivariate hazard ratios (HR) for mortality were 0.98 [95% confidence interval (CI) = 0.42-2.31], 1.52 (0.82-2.82) and 2.05 (1.13-3.72) for groups 2-4, compared with group 1. Moreover, sequelae were more frequent in group 4 (7/21, 33%) compared to groups 1-3 (9/86, 10%) (P = 0.015). Patients with abnormal CSF at diagnosis had significantly increased mortality [HR = 1.78 (95% CI = 1.08-2.92), P = 0.023]. Thus, a substantial proportion of HLH survivors suffer neurological sequelae, and children with abnormal CSF have increased risk of mortality and neurological sequelae. Prompt treatment of HLH at onset or relapse may reduce these complications.

In children with malignant disorders, autologous haematopoietic stem cell transplantation (HSCT) represents a therapeutic option, but several possible complications, such as life-threatening pulmonary disease, make appropriate diagnostic procedures essential. We describe two cases with bronchiolitis obliterans with organizing pneumonia after HSCT, with a brief review of important differential diagnoses.

Purpose: We did a controlled study to assess adverse psychological reactions (APR) associated with high-dose glucocorticoid therapy and tried to detect somatic correlates for the observed reactions. Patients and Methods: Our study included 37 patients with acute lymphoblastic leukemia (ALL) and 11 patients with Morbus Hodgkin (MH) disease, who were treated with high-dose glucocorticoid therapy, and 26 control patients with other types of malignancies. APRs were assessed with a standardized measure via parent-report. Patients with ALL and MH were further analyzed for signs of neuronal cell death in the cerebrospinal fluid, polymorphisms of the glucocorticoid receptor gene, as well as cortisol, adrenocorticorticotropic hormone, and dehydroepiandrosterone sulfate blood levels. Results: Fifty-four percent of ALL, 36% of MH, and 23% of control patients developed APR in the first few weeks of therapy. Approximately 3.5 months later, the majority of patients with ALL showed no APR, similar to control patients. Patients demonstrating a higher, nonsuppressible secretion of cortisol and/or adrenocorticorticotropic hormone during glucocorticoid therapy were found to be more likely to develop APR. No sign of neuronal cell destruction and no correlation of APR with specific glucocorticoid receptor polymorphisms were found. Conclusion: Our results suggest that the development of APR due to glucocorticoid therapy is measurable and correlates with hormonal reaction patterns.

Background Bone marrow changes and their relation to blood cytopenia in patients with Langerhans cell histiocytosis (LCH) have not been extensively studied to date. The aim of the present study was to characterize the bone marrow changes in LCH patients and to ascertain their relation to disease severity. Methods Fifty-seven marrow samples of LCH patients were studied by conventional cytology, immunocytochemistry (ICC) and flow cytometry (FCM). Results On conventional cytology there was no significant difference between LCH cases and controls with respect to cellularity, number of monocytes and progenitor cells, and presence of histiocytes and hemophagocytosis. The numbers of nucleated cells, CD34pos cells, and CD14pos cells on FCM did not differ, either. The CD1a staining by ICC was positive in 14/41 LCH samples, and was consistently negative in controls. FCM staining for CD1a was positive in 12/54 samples, but also in 5/35 controls. The number of the CD1apos cells in LCH marrows was usually very low (

Intrathecal (IT) treatment of neoplastic meningitis secondary to relapsed or refractory malignancies is a major challenge for clinicians. We studied feasibility and toxicity of IT administered liposomal cytarabine on a compassionate basis in 5 patients (male, n=4; female, n=1; age at diagnosis 5 to 18 y) with recurrent acute lymphoblastic leukemia (n=3), primary refractory acute myeloid leukemia (n=1), or relapsed medulloblastoma (n=1). All of them had evidence of meningeal involvement as shown by presence of leukemic blasts or solid tumor cells on cytologic examination of cerebrospinal fluid and were refractory to standard central nervous system (CNS) therapy. A total of 33 doses were given. Leukemic blasts or solid tumor cells were cleared from cerebrospinal fluid in all patients. IT liposomal cytarabine was well tolerated in 2 patients, but may have contributed to neurologic side effects in 2 other patients with 1 patient who received high-dose methotrexate 96 hours before IT liposomal cytarabine developing transient encephalopathy. Another patient experienced seizures after 6 well-tolerated doses of IT liposomal cytarabine. In the fifth patient, treatment with IT liposomal cytarabine was not continued after a single dose because of toxic cauda equina syndrome, resulting from previous intensive CNS therapy. If administered simultaneously to other neurotoxic drugs, IT liposomal cytarabine may contribute to neurologic side effects in patients who had received prior intensive CNS-directed therapy. IT liposomal cytarabine should, therefore, be used cautiously, if a patient receives other potentially neurotoxic drugs simultaneously.

The t(4;11)-positive acute lymphoblastic leukemia (ALL) is a rare disease in children above the age of 1 year. We studied the clinical and biological characteristics in 32 consecutively diagnosed childhood cases (median age 10.0 years, range 1.0-17.1 years). Immunophenotyping revealed a pro-B and a pre-B stage in 24 and eight cases, respectively. IGH genes were rearranged in 84% of leukemias with a predominance of incomplete DJ(H) joints. Whereas IGK-Kde and TCRD rearrangements were rare, TCRG rearrangements were present in 50% of cases and involved mainly Vgamma11 or Vgamma9 together with a Jgamma1.3./2.3 gene segment, an unusual combination among t(4;11)-negative B-cell precursor ALL. Oligoclonality was found in about 30% as assessed by heterogeneous IGH and TCRG rearrangements. Our data are in line with transformation of a precursor cell at an early stage of B-cell development but retaining the potential to differentiate to the pre-B cell stage in vivo. Although a distinct difference between infant and older childhood cases with t(4;11) became evident, no age-related biological features were found within the childhood age group. In contrast to infants with t(4;11)-positive ALL, childhood cases had a relatively low cumulative incidence of relapse of 25% at 3.5 years with BFM-based high-risk protocols.

The incidence of gastrointestinal stromal tumors (GISTs) in children is exceptionally low. However, during the last decade these tumors attracted increasing attention, because they were found to express the cell surface transmembrane receptor kit (CD117) that has tyrosine kinase activity. This tyrosine kinase can be semi-selectively inhibited by signal transduction inhibitors such as imatinib mesylate (Glivec), which is a competitive inhibitor of c-kit, c-abl, platelet-derived growth factor receptor-alpha (PDGFR-alpha) and PDGFR-beta, and abl-related gene (arg). The authors present the clinical, radiographic, and pathological findings of 4 children who were diagnosed with gastric GIST. One of them had an incomplete Carney triad including GIST and mediastinal paraganglioma. All 4 patients presented with anemia and anemia-related symptoms and underwent total resection of the tumor. One patient received additional chemotherapy (in the pre-imatinib era) and 2 patients received a short course of imatinib mesylate. With a follow-up of 116, 55, 23, and 10 months all patients are alive in first complete continuous remission. In children and adolescents, particularly in female patients, GISTs should be included in the differential diagnosis of anemia secondary to gastrointestinal hemorrhage. Complete surgical resection is the mainstay of treatment for this tumor, with imatinib mesylate restricted to patients with advanced or metastatic tumors. Since late recurrences (up to 30 years following initial diagnosis) are reported, a life-long follow-up is mandatory in these patients.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

The results of a 5-year longitudinal prospective study about the health-related quality of life (HRQL) of pediatric patients receiving allogeneic bone marrow or stem cell transplantation (BMT) are described. The patients' HRQL was assessed twice before, and five times after BMT, the end point being 1 year after BMT. For the measurement of HRQL, standardized questionnaires were completed by patients, parents and physicians. The final sample consisted of 68 patients aged 4-18 years, of which 19 were lost in the course of the study owing to relapse, transplant rejection and/or death. The worst HRQL was seen shortly after transplant and HRQL thereafter improved steadily, although the improvement was not always linear and not all patients drew benefit from this average positive evolution. Compromised emotional functioning, a high level of worry and reduced communication during the acute phase of treatment had a negative impact on HRQL 1 year after BMT. Nausea and pain during the acute phase of treatment did not have an effect on later HRQL. The interobserver agreement of HRQL reports between parents and their children was moderate to good, and generally better than child-physician and parent-physician agreement.

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.

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.

Background 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. Procedure 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. Results 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. Conclusion 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. Pediatr Blood Cancer 2007;48:50–56. © 2006 Wiley-Liss, Inc.

To analyze the dose effects of rabbit-derived antithymocyte globulin (ATG) in children after allogeneic hematopoietic stem cell transplantation (HSCT), ATG serum levels were monitored in 32 children and adolescents (median age 3.42 years, range 0.34-18.67 years) and the incidence of acute and chronic graft-versus-host disease, rejection, viral infections, EBV-lymphoproliferative disease, and survival was correlated with the ATG dose used. Cumulative doses from 7.5 to 20 mg/kg showed a constant half-life and linear correlation between dose and Cmax, whereas higher doses (30-40 mg/kg) accumulated in the body. High-dose ATG is of no benefit for preventing graft-versus-host disease but is associated with a significant increase in EBV-linked disease, and it appears to enhance the susceptibility to fatal viral infections and rejection. These data strongly support the use of a low-dose ATG regimen in pediatric HSCT.

A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Munster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.

Summary Haemophagocytic lymphohistiocytosis (HLH) poses major therapeutic challenges, and the primary inherited form, familial haemophagocytic lymphohistiocytosis (FHL), is usually fatal. We evaluated, including Cox regression analysis, survival in 86 children (29 familial) that received HLH-94-therapy (etoposide, dexamethasone, ciclosporin) followed by allogeneic stem cell transplantation (SCT) between 1995 and 2000. The overall estimated 3-year-survival post-SCT was 64% [confidence interval (CI) ¼ ±10%] (n ¼ 86); 71 ± 18% in those patients with a matched related donor (MRD, n ¼ 24), 70 ± 16% with a matched unrelated donor (MUD, n ¼ 33), 50 ± 24% with a family haploidentical donor (haploidentical, n ¼ 16), and 54 ± 27% with a mismatched unrelated donor (MMUD, n ¼ 13). After adjustment for potential confounding factors, estimated odds ratios (OR) for mortality were 1AE93 (CI ¼ 0AE61‐6AE19) for MUD, 3AE31 (1AE02‐10AE76) for haploidentical, and 3AE01 (0AE91‐9AE97) for MMUD, compared with MRD. In children with active disease after 2-months of therapy (n ¼ 43) the OR was 2AE75 (1AE26‐5AE99), compared with inactive disease (n ¼ 43). In children with active disease at SCT (n ¼ 37), the OR was 1AE80 (0AE80‐4AE06) compared with inactive disease (n ¼ 49), after adjustment for disease activity at 2-months. Mortality was predominantly transplant-related. Most HLH patients survived SCT using MRD or MUD, and survival with partially mismatched donors was also acceptable. Patients that responded well to initial pretransplant-induction therapy fared best, but some persisting HLH activity should not automatically preclude performing SCT.

OBJECTIVE: The aim of the CWS 96 Study was to achieve an optimal treatment in children and adolescents with soft tissue sarcoma (STS) implementing a further refinement of risk-adapted allocation to chemotherapy, surgery and radiotherapy. METHODS: Treatment stratification was based on tumour histology, TNM status, postsurgical stage, localisation and age. Local tumour control was ensured by surgery and risk-adapted radiotherapy. RESULTS: From 1995 to 2002, 89 patients were registered in Austria. The 3-year event-free survival (EFS) and overall survival rates (OS) were 63% ± 6% and 71% ± 6%, respectively. 59/89 patients had localised RMS-like (rhabdomayosarcoma) STS (EFS 73% ± 7%), 14 had localised Non-RMS STS (EFS, 54% ± 16%) and 15 patients had metastatic disease at diagnosis (EFS, 33% ± 12%), 1 patient had fibromatosis. The EFS rates at 3 years in patients with localised RMS-like tumours according to risk group were 92% ± 8% for low and standard risk (12 patients) and 67% ± 8% for high risk (47 patients). Favourable primary tumour sites of nonmetastatic RMS-like STS i.e. orbit, head/neck nonparameningeal or genitourinary non-bladder/prostate were diagnosed in 15 patients (1 of 15 patients died). In 44 patients with unfavourable localisation such as parameningeal, genitourinary bladder/prostate, extremity and others, 7 deceased. The 3-year EFS according to histology in patients with RMS-like STS was 61% ± 11% for RME (embryonal RMS ) (28 patients) and 71% ± 15% for RMA (alveolar RMS) (10 patients). The most common treatment failure was local relapse occurring in 21% of patients in the high-risk group. CONCLUSION: Risk-adapted individualisation of treatment led to a reduction of chemotherapy in the low- and standard-risk group without compromising survival. The outcome of RME and RMA was similar in this cohort of patients. These preliminary results after a median observation time of 2.5 years confirm the CWS 96 strategy.

Background To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). Procedure 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. Results 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. Conclusions 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. © 2005 Wiley-Liss, Inc.

Background 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. Results 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. Conclusions 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. © 2005 Wiley-Liss, Inc.

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposingfactor.

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, two of whom who suffered from a TEL/AML1+ leukemia. Based on this observation they concluded that individuals with BCP leukemia and a constitutional trisomy 21 may have similar likelihood to have a TEL/AML1 rearrangement as BCP ALL patients without this specific predisposing factor.

The purpose of the present study was the assessment of health-related quality of life in adult long-term survivors of childhood cancer and the detection of possible treatment- and cancer-related late effects. The relation of objective medical data and subjective appraisal was also examined by combining the doctor’s and the patient’s views of the perceived health status. Seventy-eight young adults at the age of at least 18 years who had been diagnosed with cancer in the years 1975–1995 and were off therapy at least 5 years with no evidence of disease participated. Cancer survivors completed self-rating instruments [SF-36 Health Survey, Nottingham Health Profile (NHP), Beck’s Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI) trait-anxiety scale]; the doctor assessed the patient’s health by means of the Common Toxicity Criteria (CTCv2). The cancer survivors showed a mostly higher-than-average positive subjective rating of the various areas of quality of life. In comparison to the general population, the cancer survivors showed lower extents of depression. In 64.1% of the cancer survivors, medical rating and self-assessment regarding the perceived health status corresponded. Cancer survivors who felt severely impaired regarding their subjectively perceived well-being showed worse results in some dimensions of quality of life than persons who subjectively felt mildly impaired. The so-called “unfortunate” persons showed the worst assessment of quality of life and the highest extent of depression and anxiety. The results of the present study may be helpful in planning an appropriate multidisciplinary, long-term follow-up of childhood cancer survivors.

Background Diabetes insipidus (DI) is the most frequent sequela in Langerhans cell histiocytosis (LCH). The clinical relevance and therapeutic impact of brain magnetic resonance imaging (MRI) findings in LCH patients with LCH during the disease course is unclear. Procedure In this retrospective study, we reviewed 113 brain MRIs from 59 DI patients, in 17 of these serial follow up MR-examination findings were correlated to the clinical course and therapy. Results At DI diagnosis, 71% patients showed a thickened stalk, in 24% the stalk was still thickened on MRIs done more than 5 years after DI onset, and in two patients the stalk was already thickened several months before DI onset. The changes of the pituitary stalk thickness were highly variable and did not clearly correlate with the treatment. Regression of pituitary thickness on MRI did not concur with clinical recovery of DI, which persisted in all but one patient with initially partial DI. The occurrence of anterior pituitary hormone deficiencies appeared to be linked to a thickening of the stalk at DI diagnosis. LCH-lesions in the craniofacial bones were seen in 75% DI patients, and 76% of DI patients with follow up MRIs done 5 years or longer after DI diagnosis had parenchymal neurodegenerative brain changes. Conclusions Our study indicates that repeated MR-examinations in DI patients are of limited value for assessing a response to therapy in the pituitary stalk, but are important for the monitoring of craniofacial bone lesions and for the detection of parenchymal CNS disease. © 2004 Wiley-Liss, Inc.

Chimaerism of FACS-sorted leucocyte subsets (CD14+, CD15+, CD3-/56+, CD3+/4+, CD3+/8+, CD19+) was monitored prospectively between days +14 and +100 in 39 children undergoing allogeneic stem cell transplantation with reduced intensity-conditioning regimens. Cell subsets exceeding 1% of nucleated cells were subject to cell sorting. Chimaerism was analysed by dual-colour FISH and/or by short tandem repeat-polymerase chain reaction. The chimaerism pattern on day +28 was evaluated with regard to its correlation with graft rejection. Of 39 patients, nine patients had donor chimaerism (DC) in all subsets. Mixed/recipient chimaerism (MC/RC) was detectable within T cells in 62%, within NK cells in 39% and within monocytes and granulocytes in 38% of the patients. The correlation of secondary graft rejection with the chimaerism pattern on day +28 revealed the strongest association between RC in NK-cells (P