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Background Neuroblastoma screening aims to reduce neuroblastoma-related mortality. A controlled trial showed no reduction in stage 4 disease incidence and preliminary mortality data. This article presents epidemiologic and clinical data 20 years after cessation of the screening program. Methods The patients with detected disease in the screening area were compared with the clinically diagnosed patients in the control area and in the prestudy and poststudy cohorts. All statistical tests were 2-sided. Results The cumulative incidence for children aged 1 to 6 years in the birth study cohorts (1994-1999) in the screening arm was 13.4 cases per 100 000 births (95% confidence interval [CI] = 12.2 to 14.6) based on 61.2% of screening participants and 38.8% of nonparticipants. Screening participants had a cumulative incidence of 15.7 (95% CI = 14.0 to 17.4) per 100 000 births. The cumulative incidence in the contemporary control cohort was 9.3 (95% CI = 8.2 to 10.3) per 100 000 births, 7.6 (95% CI = 6.8 to 8.4) in the prestudy cohort, and 8.1 (95% CI = 7.4 to 8.9) in the poststudy cohort from 2000 to 2004 (P Conclusions Neuroblastoma screening at 1 year of age reduced neither stage 4 incidence nor neuroblastoma mortality and was affected by overdiagnosis, leading to unnecessary treatment. A few screening-detected stage 4 cases represent a biologically interesting subgroup but do not change the recommendation to close the “catecholamine-based neuroblastoma screening book.”

Background: Childhood cancer patients are at increased risk of second primary neoplasms (SPNs). We assessed incidence and risk factors for early SPNs with a focus on cancer predisposition syndromes (CPSs). Patients and methods: This cohort study used data from the Swiss Childhood Cancer Registry. We included patients with first primary neoplasms (FPNs) diagnosed before age 21 years from 1986 to 2015 and identified SPNs occurring before age 21. We calculated standardised incidence ratios (SIRs) and absolute excess risks (AERs) using Swiss population cancer incidence data, and cumulative incidence of SPNs. We calculated hazard ratios (HRs) of risk factors for SPNs using Fine and Gray competing risk regression. Results: Among 8074 childhood cancer patients, 304 (4%) were diagnosed with a CPS and 94 (1%) developed early SPNs. The incidence of SPNs was more than 10-fold higher in childhood cancer patients than the incidence of neoplasms in the general population (SIR = 10.6, 95% confidence interval [CI]: 8.7-13.1) and the AER was 179/100,000 person-years (CI: 139-219). Cumulative incidence of SPNs 20 years after FPN diagnosis was 23% in patients with CPSs (CI: 12-41%) and 2.7% in those without (CI: 2.0-3.6%). Risk factors for SPNs were CPSs (HR = 7.8, CI: 4.8-12.7), chemotherapy (HR = 2.2, CI: 1.1-4.6), radiotherapy (HR = 1.9, CI = 1.2-2.9), haematopoietic stem cell transplantation (HR = 1.8, CI: 1-3.3), and older age (15-20 years) at FPN diagnosis (HR = 1.9, CI: 1.1-3.2). Conclusion: CPSs are associated with a high risk of SPNs before age 21 years. Identification of CPSs is important for appropriate cancer surveillance and targeted screening.

Introduction The survival of children with stage 4(M) neuroblastoma without MYCN amplification and below the age of 18 months is considered better than the still dismal outcome of older high-risk neuroblastoma patients. This study analyzes the impact of clinical and molecular characteristics on the long-term outcome. Patients and methods Clinical presentation, survival, and recurrence patterns of patients enrolled onto trials NB90, NB97, and NB2004 were retrospectively analyzed. Gene expression signatures based on RNA microarrays (TH10) were investigated if tumor material was available. Results Between 1990 and 2015, 177 patients with stage 4(M) MYCN nonamplified neuroblastoma aged less than 18 months at diagnosis were eligible. After a median follow-up of 9.7 years (IQR 5.0, 13.4), the proportions of 10-year event-free survival (EFS) and overall survival (OS) were 73% (95% confidence interval [CI] 67-79%) and 86% (95% CI 80-92%), respectively. Of the 27 neuroblastoma recurrences, 44% occurred in more than one site. Four additional patients presented histologically mature ganglioneuroma at recurrence. Six patients developed a secondary malignancy. The secondary 5-year EFS and OS of the 27 patients with neuroblastoma recurrence were 44% and 59%, respectively. TH10 gene expression signature was not prognostically predictive in the investigated subcohort. Conclusion The outcome of patients with stage 4(M) neuroblastoma aged less than 18 months is favorable when treated with high-risk or otherwise intensive therapy. The development of secondary malignancies and the potential of maturation to ganglioneuroma call for a controlled stepwise reduction of treatment intensity.

International audience; Introduction - Antihaemophilic factor (recombinant) (rAHF; ADVATE ) is approved for prophylaxis and treatment of bleeding in children and adults with haemophilia A. Reconstitution in 2 mL sterile water for injection instead of 5 mL allows for a 60% reduction in infusion volume and administration time, but could increase the likelihood of hypersensitivity and infusion-related reactions, especially in children. Aim - To assess local tolerability, safety and effectiveness of rAHF 2 mL during routine clinical practice factor VIII (FVIII) replacement (on-demand and prophylaxis) in children with severe (FVIII

Patients suffering from haemophilia encounter various phases in life, in which individual needs, life situations, and self- and disease perception change rapidly. One of these phases spans from the beginning of puberty until early adulthood, in which individuals gain self-responsibility and reach independence and autonomy. In this challenging time that determines future health, adolescents and young adults need sustainable familiar and professional support. A change in health care team and treatment centre may expose adolescent patients to threats but also provides the possible opportunity to be well prepared. While there is emerging evidence that the so-called health care transition programmes are effective in maintaining quality of care in other disease areas, transition programmes for patients with haemophilia are still rare in Germany, and the evidence is limited. We describe the situation in Germany, discuss our experience in Munich and review some of the available guidance; we conclude that transition programmes should become a standard of care in haemophilia.Patienten mit Hämophilie durchlaufen verschiedene Lebensabschnitte, in denen sich ihre Bedürfnisse, Lebensumstände und ihr Blick auf die Erkrankung und sich selbst verändern. Eine dieser Phasen umfasst die Pubertät und den Übergang ins Erwachsenenalter. In dieser Zeit erlangen die Patienten Eigenverantwortung und streben nach Unabhängigkeit und Autonomie. Diese Phase ist herausfordernd und bestimmend für die gesundheitliche Zukunft. Daher benötigen die Patienten eine tragfähige familiäre und professionelle Unterstützung, um Ängsten zu begegnen und mögliche Chancen herauszuarbeiten. Die Effektivität von Transitions-Programmen wird bereits für viele Krankheitsbilder in der Literatur beschrieben, allerdings werden diese im Bereich der Hämophilie in Deutschland selten angewendet. Wir beschreiben die Situation in Deutschland, erläutern unsere Münchner Erfahrungen und besprechen einige der verfügbaren Empfehlungen aus der Literatur. Zusammenfassend sollten Transitions-Program Teil der Routinebehandlung bei Hämophilie werden.

Background Long-term survival of high-risk neuroblastoma patients is still below 50% despite intensive multimodal treatment. This trial aimed to address whether the addition of two topotecan-containing chemotherapy courses compared to standard induction therapy improves event-free survival (EFS) of these patients. Patients and methods An open-label, multicenter, prospective randomized controlled trial was carried out at 58 hospitals in Germany and Switzerland. Patients aged 1–21 years with stage 4 neuroblastoma and patients aged 6 months to 21 years with MYCN-amplified tumors were eligible. The primary endpoint was EFS. Patients were randomly assigned to standard induction therapy with six chemotherapy courses or to experimental induction chemotherapy starting with two additional courses of topotecan, cyclophosphamide, and etoposide followed by standard induction chemotherapy (eight courses in total). After induction chemotherapy, all patients received high-dose chemotherapy with autologous hematopoietic stem cell rescue and isotretinoin for consolidation. Radiotherapy was applied to patients with active tumors at the end of induction chemotherapy. Results Of 536 patients enrolled in the trial, 422 were randomly assigned to the control arm (n = 211) and the experimental arm (n = 211); the median follow-up time was 3.32 years (interquartile range 1.65–5.92). At data lock, the 3-year EFS of experimental and control patients was 34% and 32% [95% confidence Interval (CI) 28% to 40% and 26% to 38%; P = 0.258], respectively. Similarly, the 3-year overall survival of the patients did not differ [54% and 48% (95% CI 46% to 62% and 40% to 56%), respectively; P = 0.558]. The response to induction chemotherapy was not different between the arms. The median number of non-fatal toxicities per patient was higher in the experimental group while the median number of toxicities per chemotherapy course was not different. Conclusion While the burden for the patients was increased by prolonging the induction chemotherapy and the toxicity, the addition of two topotecan-containing chemotherapy courses did not improve the EFS of high-risk neuroblastoma patients and thus cannot be recommended. Clinical Trials.gov number NCT number 03042429.

Amplification of MYCN is the signature genetic aberration of 20–25% of neuroblastoma and a stratifying marker associated with aggressive tumor behavior. The detection of heterogeneous MYCN amplification (hetMNA) poses a diagnostic dilemma due to the uncertainty of its relevance to tumor behavior. Here, we aimed to shed light on the genomic background which permits hetMNA in neuroblastoma and tied the occurrence to other stratifying markers and disease outcome. We performed SNP analysis using Affymetrix Cytoscan HD arrays on 63 samples including constitutional DNA, tumor, bone marrow and relapse samples of 26 patients with confirmed hetMNA by MYCN‐FISH. Tumors of patients ≤18m were mostly aneuploid with numeric chromosomal aberrations (NCAs), presented a prominent MNA subclone and carried none or a few segmental chromosomal aberrations (SCAs). In older patients, tumors were mostly di‐ or tetraploid, contained a lower number of MNA cells and displayed a multitude of SCAs including concomitant 11q deletions. These patients often suffered disease progression, tumor dissemination and relapse. Restricted to aneuploid tumors, we detected chromosomes with uniparental di‐ or trisomy (UPD/UPT) in almost every sample. UPD11 was exclusive to tumors of younger patients whereas older patients featured UPD14. In this study, the MNA subclone appears to be constraint by the tumor environment and thus less relevant for tumor behavior in aggressive tumors with a high genomic instability and many segmental aberrations. A more benign tumor background and lower tumor stage may favor an outgrowth of the MNA clone but tumors generally responded better to treatment., What's new? MYCN amplification (MNA) in neuroblastoma (NB) generally associates with an aggressive tumor behavior and detection of MNA leads to an automatic upstaging of the tumor in non‐stage 1 tumors. But what if only a fraction of the tumor cells is MYCN‐amplified? To investigate the diagnostic importance of heterogeneous MNA, the authors conducted a genetic analysis of samples from 26 NB patients with a particular focus on accompanying genetic aberrations. They concluded that tumor behavior is largely dependent on patient age and other chromosomal alterations in the genetic tumor background rather than the mere presence of the MNA clone.

Background: This study was done to investigate the long-term event free and overall survival of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), compared to maintenance chemotherapy (MT). Patterns of recurrences and late sequelae of both arms were analysed. Methods: A randomised open label trial was conducted nationwide during 1997–2004 in Germany and Switzerland. 295 patients with high-risk neuroblastoma were randomly assigned to high-dose chemotherapy with autologous stem cell transplantation (ASCT) or maintenance chemotherapy (MT) for consolidation. Analyses were done by intention-to-treat (ITT: ASCT/MT N = 149/146), as treated (AT: N = 110/102), and treated as randomised (TAR: N = 75/70). Results: The event free survival was superior for the patients receiving ASCT compared to patients treated with MT in all three cohorts (hazard ratio [HR] for ITT 1.39, 95% confidence interval (CI) 1.05-1.85, P = 0.022, HR for AT 1.75, CI 1.24-2.47, P = 0.001; HR for TAR 2.07, CI 1.36-3.16, P = 0.001). Overall survival was also in favour of the ASCT groups (ITT: P = 0.075; AT: P = 0.017; TAR: P = 0.005). The frequencies of late sequelae were not different except for focal nodular hyperplasia of the liver observed more frequently in the ASCT arm. Conclusions: High-dose chemotherapy with autologous stem cell transplantation had a better long-term outcome compared to maintenance chemotherapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ZusammenfassungAngeborene Thrombozytopathien sind komplexe Erkrankungen. Zur optimalen Blutungsprophylaxe und -behandlung empfehlen wir eine Abklärung und Diagnose der zugrunde liegenden Funktionsstörung. Dazu steht eine interdisziplinäre Leitlinie zur Verfügung (AWMF # 86–003 S2K; Hämostaseologie 2014; 34: 201–212).Die Behandlung ist auf den Defekt, die Thrombozytenzahl, das Lebensalter und die klinischen Umstände abzustimmen. Die Transfusion von Thrombozyten allein kann wegen der damit verbundenen Risiken unangemessen sein. Empfohlen wird ein stufenweiser und individualisierter Behandlungsplan. Antifibrinolytika sind generell anwendbar, besonders bei der Quebec-Erkrankung. Desmopressin ist älteren Kindern vor behalten und vor allem zur Behandlung der Storage- Pool-Erkrankungen und nicht klassifizierter Defekte geeignet. Rekombinanter FVIIa ist zwar nur für die Behandlung der Thrombasthenie Glanzmann mit Alloantikörpern zugelassen, wird jedoch in der klinischen Praxis auch bei Thrombozytendefekten mit schwerer Blutungsneigung eingesetzt. Das Ziel dieser Leitlinie ist die Behandlung von Patienten mit angeborenen Thrombozytenfunktionsstörungen bestmöglich zu unterstützen.

Aim Prospective trials on neuroblastoma-induced myelopathy are lacking. Therefore, we retrospectively analysed patients in four national neuroblastoma trials. Method Neuroblastoma patients diagnosed between August 1989 and December 2008 were included. Clinical and molecular data were available in the national trials database. Additional details on neurological findings, treatment, and outcome were collected using a questionnaire. Results Among 2603 patients, 122 (61 males and 61 females) had symptoms of spinal cord compression (SCC), and 99 of these were included in the final long-term analysis. The survival of patients with symptoms of SCC was better than that of patients without symptoms. Patients first presented with lower extremity motor impairment (95%), impaired cutaneous sensibility (58%), neuropathic pain (56%), bladder dysfunction (44%), and/or constipation (34%). Symptoms improved after first-line neurosurgery in 36 out of 52 patients and after first line chemotherapy in 30 out of 47 patients (p=0.77). After a median observation time of 8 years 1 month (range 1mo–19y 6mo), 71 out of 99 patients still had residual impairments: motor impairment (43%), scoliosis (31%), impaired bladder function (26%), constipation (19%), impaired cutaneous sensibility (17%), growth delay (14%), and neuropathic pain (5%). The initial treatment had no clear impact on the frequency of late effects. Interpretation This retrospective analysis showed no clear advantage of either first-line neurosurgery or chemotherapy and that most patients still exhibit residual symptoms and require specialized care.

Objective In screening programmes there is recognized bias introduced through participant self-selection (the healthy screenee bias). Methods used to evaluate screening programmes include Intention-to-screen, per-protocol, and the “post hoc” approach in which, after introducing screening for everyone, the only evaluation option is participants versus non-participants. All methods are prone to bias through self-selection. We present an overview of approaches to correct for this bias. Methods We considered four methods to quantify and correct for self-selection bias. Simple calculations revealed that these corrections are actually all identical, and can be converted into each other. Based on this, correction factors for further situations and measures were derived. The application of these correction factors requires a number of assumptions. Results Using as an example the German Neuroblastoma Screening Study, no relevant reduction in mortality or stage 4 incidence due to screening was observed. The largest bias (in favour of screening) was observed when comparing participants with non-participants. Conclusions Correcting for bias is particularly necessary when using the post hoc evaluation approach, however, in this situation not all required data are available. External data or further assumptions may be required for estimation.

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.

Neuroblastoma is the second most frequent malignancy in childhood. We investigated whether screening for neuroblastoma at 1 year of age reduces the incidence of metastatic disease or mortality. Screening was offered in 6 of the 16 German states from 1995 to 2000 with the remaining states serving as controls. We studied 2,581,188 children in the screening area born between 1994 and 1999 and 2,117,600 in the control area. We compared mortality from neuroblastoma and the incidence of disseminated disease in the two groups. The screened group and the control group had similar rates of stage 4 neuroblastoma and mortality due to neuroblastoma. Comparison of the screened group and the control area revealed substantial over diagnosis in the screened participants. The present findings provide no support for mass screening for neuroblastoma at 1 year of age.

Chronic recurrent multifocal osteomyelitis (CRMO) is a systemic osteo-articular disease that is characterized by a sterile, primarily chronic osteomyelitis with various distribution patterns of the individual lesions. In this article, we describe the "axial type" with predominant involvement of the spine, which represents 13 of our 41 CRMO cases of different age groups. The important element of its diagnosis is the typical lympho-plasmacellular spondylitis that can be detected and staged by scintigraphy, MRI and conventional radiography. Potentially affected are all vertebrae from the mid-cervical spine to the sacrum. One or several segments can be involved, sometimes as transient inflammatory edema, sometimes as "migratory spondylitis" or "saltatory spondylitis", but also as chronic sclerosing type with early radiographically detectable manifestation. Vertebral deformity due to compression and total collapse (vertebra plana) are rare. A complicated course with patulous perivertebral edema can lead to concomitant symptomatic inflammatory changes in adjacent regions and organs. In the course of CRMO, spondylodiscitis only develops as secondary destruction following the spondylitis. This can help to differentiate spondyloarthropathies from CRMO that is initially detected as primary lesion in the spine. While CRMO generally has a good prognosis, its radiological differentiation from rheumatologic conditions plays an important role.

Background Neuroblastoma is the second most common type of childhood tumor. It is not known whether screening for neuroblastoma at one year of age reduces the incidence of metastatic disease or mortality due to neuroblastoma. Methods We offered urine screening for neuroblastoma at approximately one year of age to 2,581,188 children in 6 of 16 German states from 1995 to 2000. A total of 2,117,600 eligible children in the remaining states served as controls. We compared the two groups in terms of the incidence of disseminated disease and mortality from neuroblastoma. Results A total of 1,475,773 children (61.2 percent of those who were born between July 1, 1994, and October 31, 1999) underwent screening. In this group, neuroblastoma was detected by screening in 149 children, of whom 3 have died. Fifty-five children who had negative screening tests were subsequently given a diagnosis of neuroblastoma; 14 of these children have died. The screened group and children in the control area had a similar incidence ...

Juvenile and adolescent Chronic Recurrent Multifocal Osteomyelitis (CRMO) is described on the basis of literature and analysis of 43 own cases (23 cases in children or adolescents). This systemic, non-purulent inflammatory disease occurs mainly metaphyseal in long bones, in pelvic bones or as spondylitis and is not as rare as it seemed. Basis of the disease is a primarily chronic, sterile, in phase of onset often monotopic (e.g. clavicle) and later frequently polytopic osteomyelitis, possibly triggered by an immuno-pathological process (e.g. Proprionibacterium acnes), and showing histologically plasmacellular invasion and a sclerosing process in different stages. Association with pustulous dermatosis (psoriasis, acne, palmo-plantar pustulosis) is found in about 25% of children and adolescents and in more than 50% of the adult patients. 5 differents types of distribution of osteomyelitic lesions can be found by using Te99m-bone scan primarily, of which the pelvic type is the most common. Because of the close neighbourhood of meta-/epiphyseal osteomyelitic focuses, sympathetic arthritis with synovitis is seen frequently. A therapeutic approach with azithromycine and calcitonine is presented.

With the aid of IGF2 and VEGF in situ hybridization; tyrosine hydroxylase, chromogranin A, and Ki67 immunohistochemistry; and TUNEL staining applied to a large series of clinical neuroblastomas and to an animal model, we show here that stroma-poor neuroblastomas show evidence of chromaffin differentiation similar to that of type 1 small intensely fluorescent (SIF) cells and that this occurs in a vascular-dependent fashion, indicating a role for local tumor hypoxia in the differentiation process.

Clinical and genetic heterogeneity renders confirmation or exclusion of autoimmune lymphoproliferative syndrome difficult. To re-evaluate and improve the currently suggested diagnostic approach to patients with suspected FAS mutation, the most frequent cause of autoimmune lymphoproliferative syndrome, we prospectively determined 11 biomarkers in 163 patients with splenomegaly or lymphadenopathy and presumed or proven autoimmune cytopenia(s). Among 98 patients sequenced for FAS mutations in CD3(+)TCRα/β(+)CD4(-)CD8(-) "double negative" T cells, 32 had germline and six had somatic FAS mutations. The best a priori predictor of FAS mutations was the combination of vitamin B12 and soluble FAS ligand (cut-offs 1255 pg/mL and 559 pg/mL, respectively), which had a positive predictive value of 92% and a negative predictive value of 97%. We used these data to develop a web-based probability calculator for FAS mutations using the three most discriminatory biomarkers (vitamin B12, soluble FAS ligand, interleukin-10) of the 11 tested. Since more than 60% of patients with lymphoproliferation and autoimmune cytopenia(s) in our cohort did not harbor FAS mutations, 15% had somatic FAS mutations, and the predictive value of double-negative T-cell values was rather low (positive and negative predictive values of 61% and 77%, respectively), we argue that the previously suggested diagnostic algorithm based on determination of double-negative T cells and germline FAS sequencing, followed by biomarker analysis, is not efficient. We propose vitamin B12 and soluble FAS ligand assessment as the initial diagnostic step with subsequent decision on FAS sequencing supported by a probability-calculating tool. peerReviewed

The aim of this paper is to give a detailed description of the so-called "chronic recurrent multifocal osteomyelitis" (CRMO). The clinical, radiological and histopathological results of an analysis of 29 cases (15 children/adolescents and 14 adults) are presented and correlated to current data from the literature. We could delinate the following points: 1. CRMO is a systemic aseptic inflammation of the bone marrow (Osteitis), it can occur polytopically and association with pustulous dermatologic symptoms is possible. 2. It is not a rare disease 3. Osteomyelitis is probably "reactive" and a plasma-cell sclerotic process with ist own characteristic histologic three-phase course. 4. We could observe 5 specific types of localization which can be documented by X-ray or bone scan. 5. Accompanying arthritis os often present, especially "sympathetic coxitis". 6. The use of drugs in treatment of CRMO (i.e. azithromycin, calcitonin, and bisphosphonates) is discussed. In conclusion we want to point out, that 1. 99mTC bone scan should always be performed when there is suspicion for CRMO to reveal the pattern of affection, 2. the rheumatologist and dermatologist should be contacted, 3. operation is normally not necessary for treatment of the mostly self-limitin disease, and 4. the term "SAPHO syndrome" should be avoided, further differentiation of the diagnosis is necessary.

BACKGROUND The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10-18 months). PROCEDURE Screening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Registry enables a mostly complete follow-up and detection of false-negative patients. RESULTS Up to December, 1999, 1,199,165 children were examined for urinary catecholamine metabolites and 124 cases of neuroblastoma were detected preclinically, giving a detection rate of 10.3/100,000. Within this cohort, 33 false-negative cases were found. CONCLUSIONS The results of this screening program will be crucial for further implementation of neuroblastoma screening.

Background The question of whether screening for neuroblastoma (NB) results in a substantial improvement of the prognosis of the disease is still open. All data, including those of the European pilot studies, indicate the possibility of overdiagnosis in the case of possibly spontaneously regressing NBs if the screening is performed before 6 months of age. Based on two pilot studies (at 6 and 12 months), an epidemiological approach to evaluate NB screening at 12 months of age was started in May 1995. Procedure Extensive statistical considerations about the assessment of a the sample size and overdiagnosis have been made in preparing the study design of the controlled and population-based screening validation study. Screening takes place in 6 of the 16 German states, with the remaining serving as controls. A minimum of 1,250,000 children will be tested during the study period and the same number will be followed without screening. The German Children's Cancer Registry enables a nearly complete follow-up of all NB patients in Germany. By postponing the procedure to a later age, it should be possible to control the phenomenon of overdiagnosis at a reasonable level. Results Until December 31, 1997, 644,396 children were examined and 67 cases of NB detected preclinically (detection rate: 10.4/100,000). Within this cohort, three false negative cases were found. One child with stage 2B neuroblastoma died of a surgical complication. The compliance rate in this study is 65% and thus lower than expected. Preliminary results on overdiagnosis will be available in late 1998. Med. Pediatr. Oncol. 31:435–441, 1998. © 1998 Wiley-Liss, Inc.

Chronic recurrent multifocal osteomyelitis (CRMO) is an unusual clinical entity. More than 200 cases are described in the literature and it is presented here with special reference to its radiological aspects. It is an acquired disease of the skeleton which occurs predominantly during childhood and adolescence. About ten per cent of cases begin in early or, rarely, in later adult life. This variant is described here for the first time and is discussed as "adult CRMO". The underlying pathology is a bland, predominantly lympho-plasma cellular osteomyelitis which is self-limiting and leads to bone sclerosis (Garre). It probably involves an abnormal immune process which follows an infection but remains clinically latent and remains aseptic and sterile. In a quarter of cases there is an association with pustulosis palmo-plantaris and its relationship with psoriatic arthropathy is discussed. The clinical, histopathological and imaging features (radiological and particularly MRT) and the bone changes are described. This provides a spectrum of symptoms; the radiological differential diagnosis and the relationship with hyperostotic spondyloarthroses during adult life are discussed. The relationship between CRMO, the SAPHO syndrome and acquired hyperostosis syndrome are analysed.

Prospective trials on neuroblastoma-induced myelopathy are lacking. Therefore, we retrospectively analysed patients in four national neuroblastoma trials.Neuroblastoma patients diagnosed between August 1989 and December 2008 were included. Clinical and molecular data were available in the national trials database. Additional details on neurological findings, treatment, and outcome were collected using a questionnaire.Among 2603 patients, 122 (61 males and 61 females) had symptoms of spinal cord compression (SCC), and 99 of these were included in the final long-term analysis. The survival of patients with symptoms of SCC was better than that of patients without symptoms. Patients first presented with lower extremity motor impairment (95%), impaired cutaneous sensibility (58%), neuropathic pain (56%), bladder dysfunction (44%), and/or constipation (34%). Symptoms improved after first-line neurosurgery in 36 out of 52 patients and after first line chemotherapy in 30 out of 47 patients (p=0.77). After a median observation time of 8 years 1 month (range 1mo-19y 6mo), 71 out of 99 patients still had residual impairments: motor impairment (43%), scoliosis (31%), impaired bladder function (26%), constipation (19%), impaired cutaneous sensibility (17%), growth delay (14%), and neuropathic pain (5%). The initial treatment had no clear impact on the frequency of late effects.This retrospective analysis showed no clear advantage of either first-line neurosurgery or chemotherapy and that most patients still exhibit residual symptoms and require specialized care.

Purpose: MYCN amplification is an important therapy-stratifying marker in neuroblastoma. Fluorescence in situ hybridization with signal detection on the single-cell level allows a critical judgement of MYCN intratumoral heterogeneity. Experimental Design: The MYCN status was investigated by fluorescence in situ hybridization at diagnosis and relapse. Heterogeneity was defined as the simultaneous presence of amplified cells (≥5 cells per slide) and nonamplified cells within one tumor or sequential change of the amplification status during the course of the disease. Likewise, heterogeneity can be detected between primary tumor and metastasis. Results: From 1,341 patients analyzed, 1,071 showed no amplification, 250 showed homogeneous amplification, and 20 patients showed MYCN heterogeneity. Of the patients with heterogeneity, 12 of 20 had clusters of MYCN amplifications, 3 of 20 had amplified single cells, 3 of 20 showed MYCN amplifications in the bone marrow but not in the primary tumor, and 2 of 20 acquired MYCN amplification during the course of the disease. All stage 4 patients were treated according to high-risk protocols; 7 of 8 later progressed. Four patients with localized disease were treated according to high-risk protocol because of MYCN-amplified clusters; 1 of 4 later progressed. One patient treated with mild chemotherapy experienced progression. Seven patients with localized/4S disease underwent no chemotherapy: 4 of 5 patients with MYCN heterogeneity at diagnosis remained disease-free, and 1 of 5 experienced local progression. Two patients had normal MYCN status at diagnosis but acquired MYCN amplification during the course of the disease. Conclusion: MYCN heterogeneity is rare. Our results suggest that small amounts of MYCN-amplified cells are not correlated to adverse outcomes. More patients with heterogeneity are warranted to clarify the role of MYCN heterogeneity for risk classification.

In Pediatric Oncology in Germany, 90% of the patients are treated according to multicenter clinical trials, which means an enormous effort for documentation in the participating clinics. In order to enable multiple use of data for patient records as well as for clinical trials a computer-based documentation system for pediatric oncology (DOSPO) is being developed, which can be used nationwide. DOSPO currently comprises a minimum basic data set, which represents the common core of all multicenter trials and which has been approved by the German Society for Pediatric Oncology and Hematology (GPOH). It is intended to enhance the documentation by specific items of each clinical trial. Functions for computer-aided chemotherapy planning and medical report writing have already been implemented in the documentation system. Various centers in Germany are currently validating the system in routine use.

Purpose The excellent prognosis of localized neuroblastoma in infants, the overdiagnosis observed in neuroblastoma screening studies, and several case reports of regression of localized neuroblastoma prompted us to initiate a prospective cooperative trial on observation of localized neuroblastoma without cytotoxic treatment. Patients and Methods For infants with localized neuroblastoma without MYCN amplification, chemotherapy was scheduled only in cases with threatening symptoms; otherwise, the tumor was either resected or observed by ultrasound and magnetic resonance imaging (MRI). Results Of 340 eligible participants, 190 underwent resection, 57 were treated with chemotherapy, and 93 were observed with gross residual tumor. Of those 93 patients with unresected tumors, spontaneous regression was seen in 44, local progression in 28, progression to stage 4S in seven, and progression to stage 4 in four. Time to regression was quite variable, with first signs of regression noted 1 to 18 months after diagnosis and in 15 of 44 patients even after the first year of life. So far, complete regression was observed in 17 of 44 patients 4 to 20 months after diagnosis. Known clinical risk factors were not able to differentiate between patients with regression and regional or metastatic progression. Overall survival (OS; 3-year OS, 0.99 ± 0.01) and metastases-free survival (rate at 3 years, 0.94 ± 0.03) for patients with unresected tumors was excellent and was not different from patients treated with surgery or chemotherapy. Conclusion Spontaneous regression is regularly seen in infants with localized neuroblastoma and is not limited to the first year of life. A wait-and-see strategy is justified in those patients.

Summary Ubiquitous information is currently one of the most challenging slogans in medical informatics research. An adequate architecture for shared electronic patient records is needed which can use data for multiple purposes and which is extensible for new research questions. We introduce eardap as architecture for using routine data for nationwide clinical research in a multihospital environment. eardap can be characterized as terminology-based. Main advantage of our approach is the extensibility by new items and new research questions. Once the definition of items for a research question is finished, a consistent, corresponding database can be created without any informatics skills. Our experiences in pediatric oncology in Germany have shown the applicability of eardap . The functions of our core system were in routine clinical use in several hospitals. We validated the terminology management system (TMS) and the module generation tool with the basic data set of pediatric oncology. The multiple usability depends mainly on the quality of item planning in the TMS. High quality harmonization will lead to a higher amount of multiply used data. When using eardap , special emphasis is to be placed on interfaces to local hospital information systems and data security issues.

Myeloablative megatherapy is commonly used to improve the poor outlook of children with high-risk neuroblastoma, yet its role is poorly defined. We aimed to assess whether megatherapy with autologous stem-cell transplantation could increase event-free survival and overall survival compared with maintenance chemotherapy.295 patients with high-risk neuroblastoma (ie, patients with stage 4 disease aged older than 1 year or those with MYCN-amplified tumours and stage 1, 2, 3, or 4S disease or stage 4 disease and1 year old) were randomly assigned to myeloablative megatherapy (melphalan, etoposide, and carboplatin) with autologous stem-cell transplantation (n=149) or to oral maintenance chemotherapy with cyclophosphamide (n=146). The primary endpoint was event-free survival. Secondary endpoints were overall survival and the number of treatment-related deaths. Analyses were done by intent to treat, as treated, and treated as randomised.Intention-to-treat analysis showed that patients allocated megatherapy had increased 3-year event-free survival compared with those allocated maintenance therapy (47% [95% CI 38-55] vs 31% [95% CI 23-39]; hazard ratio 1.404 [95% CI 1.048-1.881], p=0.0221), but did not have significantly increased 3-year overall survival (62% [95% CI 54-70] vs 53% [95% CI 45-62]; 1.329 [0.958-1.843], p=0.0875). Improved 3-year event-free survival and 3-year overall survival were also recorded for patients given megatherapy in the as-treated group (n=212) and in the treated-as-randomised group (n=145). Two patients died from therapy-related complications during induction treatment. No patients given maintenance therapy died from acute treatment-related toxic effects. Five patients given megatherapy died from acute complications related to megatherapy.Myeloablative chemotherapy with autologous stem-cell transplantation improves the outcome for children with high-risk neuroblastoma despite the raised risk of treatment-associated death.

In Germany, neuroblastoma is the most frequent extracranial solid childhood tumour. Its properties made it seem an ideal candidate for screening. A German trial assessed the effect of screening at one year of age from 1995-2001 in a nationwide project. We present here the methods developed for the estimation of lead-time and overdiagnosis in this project. Follow up on 1.5 million screened children and 2.1 million control children is currently available until June 2002. Ascertainment of control cohort cases and false negative cases is complete up to this date. A method for determining an empirical lead-time distribution and overdiagnosis estimate from comparing the age specific incidences in the control group and the study group is presented. Lead-time leads to an excess of cases in the screening group at the screening age and cases missing at higher age. If more cases are observed at the screening age than can be explained by lead-time, the difference is attributed to overdiagnosis. The width of the screening age window and the empirical maximum lead-time have to be chosen from graphs. About 1.0/100000 cases (20 per cent of the possible cases) experienced lead-time while 6.8/100000 cases were overdiagnosed. The mean lead-time was estimated to be about 15 months. The number of cases who might benefit is much smaller than was expected before the study while the overdiagnosed group is much larger. The method is robust against the choices that have to be made in the estimation process.

We present evidence that in neuroblastoma, a pediatric malignancy of embryonal sympathetic origin, hypoxia, underlies a phenotypic switch from a primitive neuronal to a chromaffin cell type. This conclusion is based on morphological and molecular data on 116 clinical tumors and is supported by data on the phenotypic effects of hypoxia on neuroblastoma cell lines when studied in monolayer culture and as tumor xenografts. In the clinical material, extensive chromaffin features were seen in regions of chronic tumor hypoxia. This was the exclusive form of intra-tumoral maturation of stroma-poor tumors and was also seen in stroma-rich tumors, either exclusively or in combination with ganglion-like cells. In neuroblastoma cell lines, hypoxia induced changes in gene expression associated with the chromaffin features observed in vivo. We therefore propose tumor hypoxia as a major cue determining phenotype in sympathetic tumors of neuroblastic origin. Because it appears to be reversible upon reoxygenation in monolayer culture, we suggest the term metaplasia for the phenomenon.

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979–2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1–14 years of age; P =0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01±0.01 (NB79) to 0.14±0.03 (NB85), 0.16±0.04 (NB82), 0.27±0.02 (NB90), and 0.33±0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.

Chemotherapy is an important component of childhood cancer treatment. Due to the intensity of this therapy, an error in calculating the dosage of the cytostatic drugs would have severe consequences. Therefore, a computer-aided therapy planning system in pediatric oncology (CATIPO) was introduced into routine use in approximately 20 clinics across Germany. The system consists of a knowledge acquisition module for acquiring knowledge about chemotherapy protocols and a decision support module for producing a patient-specific therapy plan. The main benefits of the system are the reduction of errors and saving time during the development of a particular therapy plan. CATIPO's success is based on the enormous demand for this kind of decision support and its development in tight cooperation with future users.

Background High-affinity somatostatin receptors (SRs) have been characterized in neuroblastomas and may be used as target structures for in vivo detection of SR. Procedure Eighty-eight children with histologically proven neuroblastoma were investigated at diagnosis or relapse by 123I-mIBG and 111In-pentetreotide scintigraphy. All tumors were investigated for MYCN copy number, chromosome 1p36 status, and 68/88 also for DNA content, followed for a median follow-up of 35 months (range 1–88 months). Results SR expression was detected in 56/88 tumors and 123I-mIBG showed positivity in 83/88. 111In-pentetreotide was less sensitive in detecting tumor tissue than was 123I-mIBG (64% vs. 94%, P = 0.005). Survival (SUR) and event-free survival probability (EFS) according to Kaplan-Meier was significantly better for children with positive SR scintigraphy than for the children with a negative SR scan (SUR: 90% vs. 48% at 4 years log rank P < 0.003, EFS: 83% vs. 39% at 4 years, log rank P < 0.0002). Conclusions 123I-mIBG scintigraphy remains the best scintigraphic method for detecting neuroblastoma tumor tissue, whereas additional SR scintigraphy is able to provide significant prognostic information with a minimum of invasiveness. Med. Pediatr. Oncol. 35:688–691, 2000. © 2000 Wiley-Liss, Inc.

Faktor XIII spielt eine wesentliche Rolle in der Hamostase und Fibrinolyse [1, 4]. Der letzte Schritt des physiologischen Gerinnungsablaufes besteht in der Stabilisierung des primaren Fibringerinnsels durch kovalente Vernetzung vermittelt durch thrombinaktivierten Faktor XIII. Faktor XIII zirkuliert im Plasma als Heterotetramer bestehend aus den beiden Homodimeren A2 und B2, auch als Untereinheiten A2 und B2 bezeichnet. In Anwesenheit von Thrombin, Fibrin und Calcium2+ kommt es zur Dissoziation der Untereinheiten und einer Konformationsanderung der Untereinheit A mit Freilegung des aktiven Zentrums, so das die Untereinheit A2 ihre enzymatische Aktivitat bei der Fibrinvernetzung entfalten kann [5, 3].

In a series of 40 neuroblastomas we analyzed the relative mRNA levels of the MDR associated genes encoding MDR1/P-glycoprotein (MDR1), multidrug resistance associated protein (MRP), lung cancer resistance related protein (LRP) and topoisomerase IIalpha (TOPO IIalpha) by cDNA-PCR. Cyclin A (CYCA) was included to examine cellular proliferation activity. MYCN gene expression was analyzed as it was recently shown to be associated with enhanced MRP gene expression in neuroblastomas. We found that tumors with MYCN gene amplification exhibit significantly increased MYCN and MRP gene expression levels. Tumors with an allelic loss of the chromosomal 1p region showed significant (P

Neuroblastoma, a childhood tumour of the sympathetic nervous system, may sometimes regress spontaneously in infants, or progress to a poor clinical outcome despite intensive therapy. Neuroblastomas express neurotrophin receptors and high levels of mRNA for trk-A correlates with favourable outcome, whereas trk-B mRNA is expressed by more unfavourable tumours. Using a sensitive RNase protection assay, mRNA expression for the neurotrophin receptor trk-C was investigated in 50 tumour samples from 45 children at different stages including metastatic and relapsing tumour tissue, out of which 22 were also investigated for trk-A mRNA. Thirty-seven of 43 primary tumours (86%) showed trk-C mRNA with more than 300-fold difference between the highest and the lowest values. A higher trk-C index (trk-C mRNA/GAPDH mRNA) was associated with favourable features such as younger age (P = 0.009-0.003), favourable tumour stage (1, 2 or 4S; P0.001) and favourable prognosis (P = 0.044). Better survival probability was shown in children with intermediate or high trk-C index compared with patients with low or undetectable levels (P = 0.031). All localised tumours co-expressed mRNA for trk-A and trk-C receptors. RT-PCR analysis detected mRNA encoding the cytoplasmic trk-C tyrosine kinase region only in favourable neuroblastomas. We conclude that favourable neuroblastoma may express the full-length trk-C receptor while unfavourable tumours, especially those with MYCN amplification, seem to either express no trk-C or truncated trk-C receptors with unknown biological function. Trk-C and possibly its preferred ligand NT-3 may be involved in the biology of favourable neuroblastomas showing apoptosis or differentiation.

Beginn dieser prospektiven, multizentrischen Studie war Mitte 1993. Die wesentlichen Elemente der Studie sind von Klose et al. Ende 1992 mitgeteilt worden [1].

Neuroblastoma (NB) is a heterogeneous disease. The clinical course may range from spontaneous regression and maturation to very aggressive behaviour. Stage 4s is a unique subcategory of NB, generally associated with good prognosis, despite skin and/or liver involvement and the frequent presence of tumour cells in the bone marrow. Another type of NB is the locally invasive tumour without bone and bone marrow involvement which can also have a good prognosis, irrespective of lymph node involvement. Unfortunately, there is only limited biological information on such tumours which have not been treated with cytotoxic therapy despite lymph node involvement, residual tumour mass after surgery and/or bone marrow infiltration. In order to find specific genetic changes common to NBs with a benign clinical course, we studied the genetic abnormalities of these tumours and compared them with highly aggressive tumours. We analysed a series of 54 localised and stage 4s tumours by means of in situ hybridisation performed on fresh cells or on paraffin embedded tissues. In addition, we performed classical cytogenetics, Southern blotting and PCR analysis on fresh tumour tissue. The majority of patients had been treated with surgery alone, and in a number of patients tumour resection was incomplete. Deletions at 1p36 and amplifications of the MYCN oncogene were absent, and diploidy or tetraploidy were not seen in any case, with residual localised tumours possessing a favourable outcome. Unexpectedly, one patient with a tetraploid 4s tumour without any genetic structural changes not receiving any cytotoxic treatment, did well. Interestingly, this genetic spectrum contrasted with that of progressing tumours, in which most had genetic aberrations, the deletion at 1p36 being the most common event. These data, although limited, suggest that an intact 1p36 (recognised by D1Z2), the absence of MYCN amplification and near-triploidy (at least in localised tumours), represent prerequisites for spontaneous regression and/or maturation.

Background Succinate dehydrogenase (SDH) has been associated with carcinogenesis in pheochromocytoma and paraganglioma. In the present study we investigated components of the oxidative phosphorylation system in human neuroblastoma tissue samples. Methods Spectrophotometric measurements, immunohistochemical analysis and Western blot analysis were used to characterize the aerobic mitochondrial energy metabolism in neuroblastomas (NB). Results Compared to mitochondrial citrate synthase, SDH activity was severely reduced in NB (n = 14) versus kidney tissue. However no pathogenic mutations could be identified in any of the four subunits of SDH. Furthermore, no genetic alterations could be identified in the two novel SDH assembly factors SDHAF1 and SDH5. Alterations in genes encoding nfs-1, frataxin and isd-11 that could lead to a diminished SDH activity have not been detected in NB. Conclusion Because downregulation of other complexes of the oxidative phosphorylation system was also observed, a more generalized reduction of mitochondrial respiration seems to be present in neuroblastoma in contrast to the single enzyme defect found in hereditary pheochromocytomas.