Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR.

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.

[Home Enteral Nutrition (NED) in children and adolescents. Recommendations of the Nutrition Branch of the Chilean Society of Pediatrics]. / Nutrición Enteral Domiciliaria (NED) en niños y adolescentes. Recomendaciones de la Rama de Nutrición de la Sociedad Chilena de Pediatría.

The use of home enteral or parenteral nutrition has been a necessary step in the optimization of nu tritional support in patients who, due to several diseases, fail to meet their nutritional requirements by oral feeding. This article presents the recommendations of the Chilean Pediatric Society Nutritio nal Branch, aimed at health teams that treat pediatric patients who require enteral feeding for a long time. The general objective is to provide guidelines for the proper management of these patients. It describes the ideal conformation of the health team for the care and follow-up of those patients, the program admission criteria, and its evaluation method over time. In addition, it describes general characteristics of enteral feeding, routes of administration, available enteral formulas, complications, and patient follow-up.

Nutrición Enteral Domiciliaria (NED) en niños y adolescentes: recomendaciones de la Rama de Nutrición de la Sociedad Chilena de Pediatría / Home Enteral Nutrition (NED) in children and adolescents: recommendations of the Nutrition Branch of the Chilean Society of Pediatrics

Resumen: El uso de apoyo nutricional ambulatorio, enteral o parenteral, ha sido un paso necesario en la opti mización del soporte nutricional en pacientes, que, por diversas patologías, no logran cumplir con sus requerimientos por vía oral (VO). En el presente artículo se presentan las recomendaciones de la Rama de Nutrición, dirigidas a los equipos de salud que atienden pacientes pediátricos, que requieran alimentación enteral por un tiempo prolongado. Su objetivo general es entregar pautas para un co rrecto manejo en estos pacientes. Se describe la conformación ideal del equipo de salud para atención y seguimiento de dichos pacientes, los criterios de ingreso al programa y su forma de evaluación en el tiempo. Además, se describen características generales de la alimentación enteral, vías de admi nistración, fórmulas enterales disponibles, complicaciones de este soporte nutricional y por último monitorización y seguimiento del paciente.

Abstract The use of home enteral or parenteral nutrition has been a necessary step in the optimization of nu tritional support in patients who, due to several diseases, fail to meet their nutritional requirements by oral feeding. This article presents the recommendations of the Chilean Pediatric Society Nutritio nal Branch, aimed at health teams that treat pediatric patients who require enteral feeding for a long time. The general objective is to provide guidelines for the proper management of these patients. It describes the ideal conformation of the health team for the care and follow-up of those patients, the program admission criteria, and its evaluation method over time. In addition, it describes general characteristics of enteral feeding, routes of administration, available enteral formulas, complications, and patient follow-up.

High pressure induced spin state crossover in Sr2CaYCo4O10.5.

The layered cobaltite Sr(2)CaYCo(4)O(10.5) with formal average cobalt oxidation state close to 3+ has been studied as functions of both temperature and pressure up to 4 GPa by neutron powder diffraction (NPD). The crystal structure is shown to have tetragonal symmetry (space group I4/mmm; 2a(p) × 2a(p) × 4a(p) superstructure), and the magnetic structure at ambient pressure is found to be G-type antiferromagnetic with TN close to 310 K. The magnetic moments within the CoO(6) octahedral layers and anion-deficient CoO(4.5) layers are 1.2µ(B) and 2.8µ(B), respectively. At 25 K, and applied pressure of 3.5 GPa is sufficient to completely suppress a long-range magnetic order. This result is interpreted in terms of a pressure-induced high-to-low spin state crossover of the Co(3+) ions.

[Therapy of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. / Therapie hereditärer Thrombozytopathien. Interdisziplinäre S2K-Leitlinie der Ständigen Kommission Pädiatrie der Gesellschaft für Thrombose- und Hämostaseforschung e. V.

Inherited disorders of platelet function are a heterogeneous group. For optimal prevention and management of bleeding, classification and diagnosis of the underlying defect are highly recommended. An interdisciplinary guideline for a diagnostic approach has been published (AWMF # 086-003 S2K; Hämostaseologie 2014; 34: 201-212). Underlying platelet disorder, platelet count, age and clinical situation modify treatment. Exclusive transfusion of platelet concentrates may be inappropriate as potentially adverse effects can outweigh its benefit. A stepwise and individually adjusted approach for restitution and maintenance of haemostasis is recommended. Administration of antifibrinolytics is generally endorsed, but is of particular use in Quebec disease. Restricted to older children, desmopressin is favourable in storage pool disease and unclassified platelet disorders. Although licensed only for patients with Glanzmann thrombasthenia and alloantibodies, in clinical practice rFVIIa is widely used in inherited platelet disorders with severe bleeding tendency. This guideline aims at presenting the best available advice for the management of patients with inherited platelet function disorders.

A meta-model of chemotherapy planning in the multi-hospital/multi-trial-center-environment of pediatric oncology.

OBJECTIVE: Chemotherapy planning in pediatric oncology is complex and time-consuming. The correctness of the calculation according to state-of-the-art research is crucial for curing the child. Computer-assistance can be of great value. The objective of our research was to work out a meta-model of chemotherapy planning based on the Unified Modeling Language (UML). The meta-model is used for the development of an application system which serves as a knowledge-acquisition tool for chemotherapy protocols in pediatric oncology as well as for providing protocol-based care. METHODS: We applied evolutionary prototyping, software reengineering techniques and grounded theory, a qualitative method in social research. We repeated the following steps several times over the years: Based on a requirements analysis (i) a meta-model was developed or adapted, respectively (ii). The meta-model served as a basis for implementing evolutionary prototypes (iii). Further requirements were identified (i) from clinical use of the systems. RESULTS: We developed a comprehensive UML-based meta-model for chemotherapy planning in pediatric oncology (chemoMM). We implemented it and introduced evolutionary prototypes (CATIPO and DOSPO) in several medical centers. Systematic validation of the prototypes enabled us to derive a final meta-model which covers the requirements that have turned out to be necessary in clinical routine. CONCLUSIONS: We have developed an application system that fits well into clinical routine of pediatric oncology in Germany. Validation results have shown that the implementation of the meta-model chemoMM can adequately support the knowledge acquisition process for protocol-based care.

[Chronic recurrent multifocal osteomyelitis in association with chronic inflammatory bowel disease: entheropathic CRMO]. / Die chronische rekurrierende multifokale Osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO.

The enterogenic reactive arthritides and entheropathic spondyloarthropathies are well-known entities. The so-called gut iteropathy concept offers an interesting working hypothesis to link the gut inflammation and the lymphocytic infiltration of the synovium. However, the association of rheumatic diseases belonging to the entity of the SAPHO syndrome with inflammatory bowel diseases (IBD) has only been rarely described in the literature. Among 138 cases of our (heterogenic) SAPHO cohort, we detected 5 patients (1 male, 4 females) with a proven association of SAPHO syndrome with IBD (in 4 cases Crohn's disease, in 1 case ulcerative colitis). Two patients belonged to the juvenileadolescent form and 3 to the adult form of SAPHO syndrome. In all cases the underlying osteoarticluar disease was classified as chronic recurrent multifocal osteomyelitis (CRMO), 2 of them presenting as inflammatory anterior chest wall syndrome. There was a strong association with psoriatic pustular dermatitis. Thus, we present 5 cases of "enteropathic CRMO" demonstrating several analogies to the enteropathic spondyloarthropathies. Both disease entities have in common i) metachronic development with osteoarticluar manifestations often preceding the gastrointestinal disease; ii) Crohn's like lesions that may develop from the stomach to the colon; iii) concomittent or intermittent skin pustulosis which mostly resolves; iiii) the gastrointestinal disease that often dominates the whole syndrome namely in the longterm follow-up. We suggest to transfer the hypothesis of the gut-synovium axis of enteropathic spondyloarthropathies to the entity of CRMO. This concept offers an opportunity to link the target organs gut mucosa, bone marrow and the skin via homing of antigen specific lymphocytes. This concept may help to better understand the pathogenesis of the "Skibo" (i. e., skin-bone) disease CRMO.

Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age.

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.

[Vertebral manifestation of chronic recurrent multifocal osteomyelitis (CRMO)]. / Wirbelsäulenmanifestationen der chronischen rekurrierenden multifokalen Osteomyelitis (CRMO).

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.

[Chronic recurrent multifocal osteomyelitis-- I. Review]. / Die Chronische rekurrierende multifokale Osteomyelitis (CRMO)* - Teil 1 Ubersicht -

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.

[Pelvic type of chronic recurrent multifocal osteomyelitis]. / Die Chronisch rekurrierende multifokale Osteomyelitis (CRMO)*: - Teil 2 Klinisch-radiologisch-histopathologische Studie zum kindlich-jugendlichen "Beckentyp" bei 11 Patienten -

We report about the juvenile and adolescent pelvic type of CRMO in 7 girls and 4 boys. The results show from solitary up to 7 pelvic lesions (average 3 lesions) predominantly in the acetabular and paraacetabular region (sometimes with hip joint effusion as a sign for concomitant coxitis).Tc99m-bone-scan is helpful to evaluate exactly the pattern of bone affection. We find 3 stages of an primarily chronic, non-purulent osteomyelitis going along with a "plasma-cell-sclerotic process", leading to a Garrè-type sclerosing end-stage, which probably heals after some years spontaneously, projecting on clinical symptoms and radiological appearance. The concomitant coxitis ("sympathetic coxitis") is clinically often in the foreground, but reversible. Pain in case of CRMO responds surprisingly well on medication with acithromycine. Knowing about CRMO in its different clinical appearances - especially concerning what we call "sympathetic coxitis" - can be a useful for pediatric rheumatologists and orthopedic surgeons, as well as MRI-focused radiologists and pathologists. Therapy might find a useful drug in acithromycine. In conclusion we d like to point out, that CRMO is one entity under the "roof" of the so called SAPHO-syndrome, which again shows us, that SAPHO-syndrome ist not a diagnosis itself but more a sign-post on the way to a correct diagnosis.

Object-oriented business process analysis of the cooperative soft tissue sarcoma trial of the german society for paediatric oncology and haematology (GPOH).

The German Society for Paediatric Oncology and Haematology (GPOH) runs nation-wide multicentre clinical trials to improve the treatment of children suffering from malignant diseases. We want to provide methods and tools to support the centres of these trials in developing trial specific modules for the computer-based DOcumentation System for Paediatric Oncology (DOSPO). For this we carried out an object-oriented business process analysis for the Cooperative Soft Tissue Sarcoma Trial at the Olgahospital Stuttgart for Child and Adolescent Medicine. The result is a comprehensive business process model consisting of UML-diagrams and use case specifications. We recommend the object-oriented business process analysis as a method for the definition of requirements in information processing projects in the field of clinical trials in general. For this our model can serve as basis because it slightly can be adjusted to each type of clinical trial.

Evidence of chromaffin oxygen sensing in neuroblastoma.

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.