Literatür

Last modification: 2011/08/22 https://kinderkrebsinfo.de/doi/e8952

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Autor(en)	Titel	Quelle
Zanella A, Bianchi P, Fermo E, Valentini G	Hereditary pyrimidine 5'-nucleotidase deficiency: from genetics to clinical manifestations.	British journal of haematology 2006, 133: 113
Hereditary pyrimidine 5'-nucleotidase (P5'N) deficiency is the most frequent abnormality of the red cell nucleotide metabolism causing hereditary non-spherocytic haemolytic anaemia. The disorder is usually characterised by mild-to-moderate haemolytic anaemia associated with the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The precise mechanisms leading to the destruction of P5'N deficient red cells are still unclear. The pyrimidine 5'-nucleotidase type-I (P5'N-1) gene is localised on 7p15-p14 and the cDNA has been cloned and sequenced; 20 mutations have been identified so far in 30 unrelated families, most of them at the homozygous level. Recently, the comparison of recombinant mutants of human P5'N-1 with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.
Zahm SH, Ward MH	Pesticides and childhood cancer.	Environ Health Perspect 1998, 106 (Suppl 3): 893
Zahn S, Sievers S, Alemazkour K, Orb S, Harms D, Schulz WA, Calaminus G, Göbel U, Schneider DT	Imbalances of chromosome arm 1p in pediatric and adult germ cell tumors are caused by true allelic loss: a combined comparative genomic hybridization and microsatellite analysis.	Genes, chromosomes & cancer 2006, 45: 995
Previous studies on childhood germ cell tumors (GCTs) report highly variable frequencies of losses at chromosome arm 1p. Since deletions at 1p portend a poor prognosis in other embryonal tumors, this study aims to clarify the question of the frequency of true allelic loss at 1p and whether it constitutes a prognostic parameter. We analyzed 13 GCTs from different gonadal and extragonadal sites of children (4 teratomas, 9 malignant GCTs) and 18 GCTs of adolescents and adults (3 teratomas; 15 malignant GCTs) using automated microsatellite analysis with 23 polymorphic markers and chromosomal
Zanella A, Bianchi P, Fermo E, Valentini G	Hereditary pyrimidine 5'-nucleotidase deficiency: from genetics to clinical manifestations.	British journal of haematology 2006, 133: 113
Hereditary pyrimidine 5'-nucleotidase (P5'N) deficiency is the most frequent abnormality of the red cell nucleotide metabolism causing hereditary non-spherocytic haemolytic anaemia. The disorder is usually characterised by mild-to-moderate haemolytic anaemia associated with the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The precise mechanisms leading to the destruction of P5'N deficient red cells are still unclear. The pyrimidine 5'-nucleotidase type-I (P5'N-1) gene is localised on 7p15-p14 and the cDNA has been cloned and sequenced; 20 mutations have been identified so far in 30 unrelated families, most of them at the homozygous level. Recently, the comparison of recombinant mutants of human P5'N-1 with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined and help to correlate genotype to clinical phenotype.
Zanichelli A, Magerl M, Longhurst H, Fabien V, Maurer M	Hereditary angioedema with C1 inhibitor deficiency: delay in diagnosis in Europe.	Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 2013, 9: 29
Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation.
Zapka P, Dörner E, Dreschmann V, Sakamato N, Kristiansen G, Calaminus G, Vokuhl C, Leuschner I, Pietsch T	Type, Frequency, and Spatial Distribution of Immune Cell Infiltrates in CNS Germinomas: Evidence for Inflammatory and Immunosuppressive Mechanisms.	Journal of neuropathology and experimental neurology 2018, 77: 119
Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% ± 3.1% (mean ± SE) CD3-positive T cells, including 45.2% ± 3.5% of CD4-positive T-helper cells, 23.4% ± 1.5% of CD8-positive cytotoxic T cells, 5.5% ± 0.9% of FoxP3-positive regulatory T cells, and 11.9% ±1.3% PD-1-positive TILs. B cells accounted for 35.8% ± 2.9% of TILs and plasma cells for 9.3% ± 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti-PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches.
Zeidler C, Schwinzer B, Welte K	[Severe congenital neutropenia: trends in diagnosis and therapy].	Klinische Padiatrie 2000, 212: 145
Severe congenital neutropenia (CN; Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia with absolute neutrophil counts (ANC) less than 0.2 x 10(9)/l associated with severe systemic bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 indicate that > 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF) treatment with an ANC > 1.0 x 10(9)/l. In these patients rHuG-CSF is required daily as subcutaneous injection with individual doses ranging between 0.27 and 120 mcg/kg/day to maintain ANC above 1.0 x 10(9)/l. Adverse events documented in this group of patients include splenomegaly, thrombocytopenia, osteoporosis and malignant transformation into MDS/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. For those patients who are refractory to rHuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation (HSCT) is still the only currently available treatment.
Zeidler C, Boxer L, Dale DC, Freedman MH, Kinsey S, Welte K	Management of Kostmann syndrome in the G-CSF era.	British journal of haematology 2000, 109: 490
Zeidler C, Welte K	Kostmann syndrome and severe congenital neutropenia.	Seminars in hematology 2002, 39: 82
Congenital neutropenia (CN) includes hematologic disorders characterized by severe neutropenia with an absolute neutrophil count (ANC) below 0.5 x 10(9)/L associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, was originally described as an autosomal-recessive disorder, characterized by early-stage maturation arrest of myelopoiesis. Autosomal-dominant and sporadic cases have also been reported. Recent studies on the genetic bases of CN have detected different inherited or spontaneous point mutations in the neutrophil elastase gene. Development of additional genetic defects during the course of disease, such as granulocyte colony-stimulating factor (G-CSF)-receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability. Data on more than 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) since 1994 demonstrate that, independent of the CN subtype, more than 90% of patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained at approximately 1.0 x 10(9)/L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how rHuG-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation (HSCT) is still the only available treatment for patients refractory to rHuG-CSF treatment.
Zeidler C, Schwinzer B, Welte K	Congenital neutropenias.	Reviews in clinical and experimental hematology 2003, 7: 72
The term congenital neutropenia (CN) has been used for a group of hematologic disorders characterized by severe neutropenia with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L associated with increased susceptibility to bacterial infections. This group of diseases includes primary bone marrow failure syndromes with isolated neutropenias and neutropenias associated with metabolic or immunologic disorders or with a complex syndrome. To avoid confusion, we prefer using the term CN only for the most severe disorder among this group: severe neutropenia characterized by an early stage maturation arrest of myelopoiesis leading to bacterial infections from early infancy. This disease has originally been described as Kostmann syndrome with an autosomal recessive inheritance. Recent pathogenetic investigations have demonstrated that this clinical phenotype includes also autosomal dominant and sporadic cases with different point mutations in the neutrophil elastase gene in a subgroup of patients. Data on over 400 patients with CN collected by the Severe Chronic Neutropenia International Registry demonstrate that independent from the CN-subtype more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF filgrastim, lenograstim) with ANC that can be maintained around 1.0 x 10(9)/L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis and malignant transformation into myelodysplastic syndrome/leukemia. Development of additional genetic aberrations, e.g., G-CSF-receptor gene mutations, monosomy 7 or ras mutations during the course of the disease indicate an underlying genetic instability leading to an increased risk of malignant transformation. If and how G-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation is still the only available treatment for patients refractory to G-CSF treatment.
Zeidler, C	Granulozytopenien.	In: Gadner, H, Gaedicke, G, Niemeyer, C, Ritter, J (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer Medizin Verlag 2006, pp. 192
Zeidler C, Welte K	Hematopoietic growth factors for the treatment of inherited cytopenias.	Seminars in hematology 2007, 44: 133
The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.
Zeidler C, Welte K	[Congenital bone marrow failure syndromes. The last 20 years by the example of congenital neutropenia].	Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 2007, 50: 1564
Congenital bone marrow failure syndromes are rare diseases characterised by a reduction of mature blood cells (erythrocytes, platelets, neutrophils). Examples of such disorders include congenital aplastic anemia (Fanconi anemia), congenital hypoplastic anemia (Diamond-Blackfan anemia), congenital neutropenias (Kostmann syndrome, cyclic neutropenia, Shwachman-Diamond syndrome and others), and congenital thrombocytopenias (TAR syndrome, amegacaryocytic thrombocytopenia). In Germany the prevalence of congenital bone marrow failure syndromes can be estimated to be 10/1,000,000 children and adolescents. Although rare, these diseases contributed significantly to the current knowledge on normal haematopoiesis. The documentation of rare diseases by patient registries and the cooperation of clinical centres within networks are most important for the resolution of such disorders. In the following, congenital neutropenia will be presented as an example: Until the 1980s congenital neutropenia could only be classified clinically. Few cases had been reported in the literature. All subtypes were therefore collected under the general term
Zeidler C, Germeshausen M, Klein C, Welte K	Clinical implications of ELA2-, HAX1-, and G-CSF-receptor (CSF3R) mutations in severe congenital neutropenia.	British journal of haematology 2009, 144: 459
Congenital Neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte/myelocyte stage with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l. There are two major subtypes of CN as judged by inheritance: an autosomal dominant subtype, e.g. defined by neutrophil elastase mutations (approximately 60% of patients) and an autosomal recessive subtype (approximately 30% of patients), both presenting with the same clinical and morphological phenotype. Different mutations have been described (e.g. HAX1, p14 etc) in autosomal recessive CN, with HAX1 mutations in the majority of these patients. CN in common is considered as a preleukemic syndrome, since the cumulative incidence for leukemia is more than 25% after 20 years of observation. Leukemias occur in both, the autosomal dominant and recessive subtypes of CN. The individual risk for each genetic subtype needs to be further evaluated. Numbers of patients tested for the underlying genetic defect are still limited. Acquired G-CSFR (CSF3R) mutations are detected in approximately 80% of CN patients who developed acute myeloid leukemia independent of the ELA2 or HAX1 genetic subtype, suggesting that these mutations are involved in leukemogenesis. As the majority of patients benefit from G-CSF administration, HSCT should be restricted to non-responders and patients with leukaemic transformation.
Zeidler L, Zimmermann M, Möricke A, Meissner B, Bartels D, Tschan C, Schrauder A, Cario G, Goudeva L, Jäger S, Ratei R, Ludwig WD, Teigler-Schlegel A, Skokowa J, Koehler R, Bartram CR, Riehm H, Schrappe M, Welte K, Stanulla M	Low platelet counts after induction therapy for childhood acute lymphoblastic leukemia are strongly associated with poor early response to treatment as measured by minimal residual disease and are prognostic for treatment outcome.	Haematologica 2012, 97: 402
Numerous reports have been published on the association between kinetics of leukemic cells during early treatment of childhood acute lymphoblastic leukemia and therapeutic outcome. In contrast, little is known about the prognostic relevance of normal blood counts in this setting.
Zeidler C	[Primary and secondary neutropenia].	Zeitschrift fur Rheumatologie 2013, 72: 663
Severe chronic neutropenia (SCN) comprises a heterogeneous group of disorders with a common hematological and clinical phenotype characterized by absolute neutrophil counts (ANC) below 0,5 • 10(9)/l and increased risk of severe bacterial infections. The differentiation between primary and secondary neutropenia and the identification of causative gene mutations is of great importance for the estimation of prognosis. During childhood primary autoimmune neutropenia is the most frequent diagnosis, while secondary neutropenia predominates in adulthood. Despite the rarity, congenital, genetic neutropenias are of great value for research on normal and pathological hematopoiesis and have a fundamental impact on the current knowledge on hematopoiesis. To date mutations in more than 10 genes have been described which are mainly associated with an increased risk for leukemia.The treatment with hematopoietic growth factors has improved the long-term prognosis of SCN patients dramatically: Bacterial infections can be prevented and a normal participation in everyday life is possible.
Zeidler C, Grote UA, Nickel A, Brand B, Carlsson G, CortesÃ£o E, Dufour C, Duhem C, Notheis G, Papadaki HA, Tamary H, TjÃ¸nnfjord GE, Tucci F, Van Droogenbroeck J, Vermylen C, Voglova J, Xicoy B, Welte K	Outcome and management of pregnancies in severe chronic neutropenia patients by the European Branch of the Severe Chronic Neutropenia International Registry.	Haematologica 2014, 99: 1395
Long-term granulocyte-colony stimulating factor treatment has been shown to be safe and effective in severe chronic neutropenia patients. However, data on its use during pregnancy are limited. To address this issue, we analyzed all pregnancies reported to the European branch of the Severe Chronic Neutropenia International Registry since 1994. A total of 38 pregnancies in 21 women with chronic neutropenia (16 pregnancies in 10 women with congenital, 10 in 6 women with cyclic, 12 in 5 women with idiopathic neutropenia) were reported. Granulocyte-colony stimulating factor was administered throughout pregnancy in 16 women and for at least one trimester in a further 5 women. No major differences were seen between treated and untreated women with respect to pregnancy outcome, newborn complications and infections. In addition, we evaluated the genetic transmission of known or suspected genetic defects in 16 mothers having 22 newborns as well as in 8 men fathering 15 children. As a proof of inheritance, neutropenia was passed on to the newborn in 58% from female and in 62% from male patients with ELANE mutations, but also to some newborns from parents with unknown gene mutation. Based on our results, granulocyte-colony stimulating factor therapy has been shown to be safe for mothers throughout pregnancies and for newborns without any signs of teratogenicity. With an increasing number of adult patients, genetic counseling prior to conception and supportive care of mothers during pregnancy are crucial. The acceptance of having affected children may reflect the high quality of life obtained due to this treatment.
Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, Allen JC, Stevens KR, Stanley P, Li H, Wisoff JH, Geyer JR, McGuire-Cullen P, Stehbens JA, Shurin SB, Packer RJ	Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.	J Clin Oncol 1999, 17: 832
Zeng L, Wang C, Jiang M, Chen K, Zhong H, Chen Z, Huang L, Li H, Zhang L, Choonara I	Safety of ceftriaxone in paediatrics: a systematic review.	Archives of disease in childhood 2020 Mar 6; ePub
To determine the safety of ceftriaxone in paediatric patients and systematically evaluate the categories and incidences of adverse drug reactions (ADRs) of ceftriaxone in paediatric patients.
Zernikow B, Griessinger N, Fengler R	[Practice of pain control in paediatric oncology--recommendations of the quality-monitoring group of the German Society for Paediatric Oncology and Haematology (GPOH)].	Schmerz (Berlin, Germany) 1999 Jun 11; 13: 213
In paediatric oncology, optimal pain control is still a challenge.A structured pain history and the regular scoring of pain intensity using age-adapted measuring tools are hallmarks of optimal pain control. Psychological measures are as important as drug therapy in prophylaxis or control of pain, especially when performing invasive procedures. Pain control is oriented on the WHO analgesic ladder. On no account the paediatric patient should have to climb up the 'analgesic ladder'- strong pain requires the primary use of strong drugs. Opioids should be given by the oral route and by the clock - short acting opioids should be used to treat break-through pain. Alternatives are IV infusion and patient-controlled analgesia. Constipation is the adverse effect most often seen with (oral) opioid therapy. Adverse effects should be anticipated, and prophylactic treatment should be given consistently. The assistance of paediatric nurses is of utmost importance in paediatric pain control. Nurses' deliver the basis for rational and effective pain control by scoring pain intensity and documenting drug administration as well as adverse effects. The nurses task is also to prepare the patient for and monitor the patient during painful procedures. It is the responsibility of both nurse and doctor to guarantee emergency intervention during sedation whenever needed. In our paper we comment on drug selection and dosage, pain measurement tools, and documentation tools for the purpose of pain control. Those tools may be easily integrated into daily routine.
Zernikow B	Schmerztherapie in der Kinderhämatologie, in Zernikow B: Schmerztherapie bei Kindern.	Springer Verlag, Berlin, Heidelberg, New York 2001, 176
Zernikow B, Bauer AB, Andler W	Pain control in German pediatric oncology. An inventory.	Schmerz (Berlin, Germany) 2002, 16: 140
As part of a nationwide quality improvement programme, our aim is the assessment of the quality of pain control in German paediatric oncology to tailor the intervention to specific needs. Here we report on the results of a questionnaire-based nationwide survey which addressed the head of the department, one supervising physician, one ward physician, one nurse, and one psychologist/social worker in each of the 76 german paediatric oncology departments. 210/380 health care professionals of 60/76 departments responded to the survey. According to 17% of the physicians (41% of the nurses, p = 0.004) there still exists '(very) often' pain despite pain therapy. Procedures are seen as the main causes of pain. According to 58% of the heads of the department and supervising physician (35% of the nurses and ward physicians, p = 0.005), faces scales are regularly used to score pain intensity. In 80% of the departments a written therapy protocol addressing procedure-related, or postoperative pain is lacking. When larger and smaller departments are compared, in former ones the significantly preferred routes for opioid administration are i. v., or oral for slow release preparations (p = 0.01). The i. m. route is exclusively used in smaller departments. In the treatment of neuropathic pain, only 5% of the physicians regard morphine, but 25% of them regard antidepressants and antiepileptics as ineffective. Only 72% of the physicians (39% of the nurses, p = 0.001) are convinced that during opioid-based pain therapy addiction 'seldom/never' developes. Nurses are less satisfied with pain therapy than are physicians, and they feel more frequently that pain therapy '(very) often' starts too late (p <0.005). The questionnaire revealed obvious deficits in both physicians' and nurses' knowledge regarding pain therapy. Deficits were also addressed by the health care professionals themselves.
Zernikow B	STOP dem Schmerz – Schmerz-Therapie in der Onkologischen Pädiatrie (STOP) – Ergebnisse eines bundesweiten Qualitätsmanagement-Programms.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2004, 4: 19
Zernikow B	Schmerztherapie in der Kinderhämatonkologie, in Zernikow B: Schmerztherapie bei Kindern.	Springer Medizin Verlag Heidelberg 3. Aufl. 2005, 217
Zernikow B , Wamsler C, Schiessl C	Palliativmedizin und Schmerztherapie bei krebskranken Kindern und Jugendlichen.	Kinder- und Jugendarzt 2006, 10, 649
Zernikow B, Schiessl C, Wamsler C, Janssen G, Griessinger N, Fengler R, Nauck F	Practical pain control in pediatric oncology. Recommendations of the German Society of Pediatric Oncology and Hematology, the German Association for the Study of Pain, the German Society of Palliative Care, and the Vodafone Institute of Children's Pain Therapy and Palliative Care.	Schmerz 2006, 20: 24
In pediatric oncology, optimal pain control is still a challenge. A structured pain history and the regular scoring of pain intensity using age-adapted measuring tools are hallmarks of optimal pain control. Psychological measures are as important as drug therapy in the prophylaxis or control of pain, especially when performing invasive procedures. Pain control is oriented toward the WHO multistep therapeutic schedule. On no account should the pediatric patient have to climb up the
Zernikow B, Smale H, Michel E, Hasan C, Jorch N, Andler W	Paediatric cancer pain management using the WHO analgesic ladder--results of a prospective analysis from 2265 treatment days during a quality improvement study.	European journal of pain 2006t; 10: 587
To collect data on pain management in paediatric oncology with respect to the WHO ladder approach. SETTING, DESIGN, PATIENTS AND METHODS: Eight German tertiary care paediatric oncology centres prospectively documented all their in-patient pain treatment courses from June 1999 to December 2000. Pain was scored using a 1-6 faces scale.
Zernikow B, Hasan C, Hechler T, Huebner B, Gordon D, Michel E	Stop the pain! A nation-wide quality improvement programme in paediatric oncology pain control.	European journal of pain 2008, 12: 819
Little is known about the impact of translation of pain management clinical practice guidelines on pain control in paediatrics. In an effort to overcome this, a longitudinal, nation-wide, multi-centre paediatric quality improvement (QI) study was initiated by the German Society of Pediatric Haematology and Oncology (GPOH) entitled Schmerz-Therapie in der Onkologischen Paediatrie (STOP).
Zernikow B	Palliativmedizin und Schmerztherapie.	in: C. P. Speer et al. (Hrsg.): Pädiatrie; Springer-Verlag GmbH Deutschland 2019
Pädiatrische Palliativversorgung richtet sich an Kinder, Jugendliche und junge Erwachsene mit lebensbedrohlichen und lebenslimitierenden Erkrankungen sowie deren Familien. Im Fokus steht die Verbesserung der Lebensqualität. Oft beginnt pädiatrische Palliativversorgung bereits mit der Diagnosestellung. Sie beschränkt sich nicht auf eine Begleitung am Lebensende. Die allgemeine Palliativversorgung wird von niedergelassenen Kinder- und Jugendärzten, Kinderkrankenpflegediensten sowie den Kinderkliniken in Deutschland geleistet. Wichtige tertiäre Versorgungselemente sind die spezialisierte ambulante Palliativversorgung, die seit dem Jahre 2007 eine Kassenleistung darstellt, die Kinderpalliativstationen in Datteln und München sowie Entlastungsangebote in stationären Kinderhospizen. Die Patienten sind oft verbal nicht mitteilungsfähig. Symptombeurteilung und -kontrolle sind eine Herausforderung für die oft multidisziplinären Teams. Viele Medikamente sind für die Indikation, die Altersgruppe oder den verwendeten Applikationsweg nicht zugelassen. Schmerzen, Atemnot, Spastik und Ernährungsstörungen sind die häufigsten Symptome. Nicht selten werden starke Opioide eingesetzt – auch bei nicht-onkologischen Patienten.
Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, Rey S, Hammers H, Chang D, Pili R, Dang CV, Liu JO, Semenza GL	Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth.	Proc Natl Acad Sci U S A 2008, 105: 19579
A library of drugs that are in clinical trials or use was screened for inhibitors of hypoxia-inducible factor 1 (HIF-1). Twenty drugs inhibited HIF-1-dependent gene transcription by >88% at a concentration of 0.4 microM. Eleven of these drugs were cardiac glycosides, including digoxin, ouabain, and proscillaridin A, which inhibited HIF-1alpha protein synthesis and expression of HIF-1 target genes in cancer cells. Digoxin administration increased latency and decreased growth of tumor xenografts, whereas treatment of established tumors resulted in growth arrest within one week. Enforced expression of HIF-1alpha by transfection was not inhibited by digoxin, and xenografts derived from these cells were resistant to the anti-tumor effects of digoxin, demonstrating that HIF-1 is a critical target of digoxin for cancer therapy.
Zhou AW, Knoche EM, Engle EK, Ban-Hoefen M, Kaiwar C, Oh ST	Clinical Improvement with JAK2 Inhibition in Chuvash Polycythemia.	The New England journal of medicine 2016, 375: 494
Zhu K, Levine RS, Gu Y, Brann EA, Hall I, Caplan LS et al.	Non-Hodgkin's lymphoma and family history of malignant tumor in a case -control study (United States).	Cancer Causes Control 1998, 9: 77
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, Weaver MS, Ding L, Mardis ER, Wilson RK, Gajjar A, Ellison DW, Pappo AS, Pui CH, Nichols KE, Downing JR	Germline Mutations in Predisposition Genes in Pediatric Cancer.	The New England journal of medicine 2015 Dec 10; 373: 2336
The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.
Zierk J, Hirschmann J, Toddenroth D, Arzideh F, Haeckel R, Bertram A, Cario H, Frühwald MC, Groß HJ, Groening A, Grützner S, Gscheidmeier T, Hoff T, Hoffmann R, Klauke R, Krebs A, Lichtinghagen R, Mühlenbrock-Lenter S, Neumann M, Nöllke P, Niemeyer CM, Razum O, Ruf HG, Steigerwald U, Streichert T, Torge A, Rascher W, Prokosch HU, Rauh M, Metzler M	Next-generation reference intervals for pediatric hematology.	Clinical chemistry and laboratory medicine 2019 Sep 25; 57: 1595
Zils K, Ebner F, Ott M, Müller J, Baumhoer D, Greulich M, Rehnitz D, Rempen A, Schaetzle S, Wilhelm M, Bielack S	Extraskeletal Osteosarcoma of the Breast in an Adolescent Girl.	Journal of pediatric hematology/oncology 2012 Jan ; [Epub ahead of print]
Extraskeletal osteosarcoma (ESOS) is a rare malignancy, usually arising in older adults. We were unable to find reports of children or adolescents affected by an ESOS of the breast. Here, we present the case of a high-grade osteosarcoma arising in the breast of a 16-year-old girl. The tumor was treated with breast-conserving resections and adjuvant multiagent chemotherapy, based on a regimen of doxorubicin, high-dose methotrexate, cisplatin, and ifosfamide. At last follow-up, the patient was in first complete remission, 29 months after initial diagnosis.
Zils K, Bielack S, Wilhelm M, Werner M, Schwarz R, Windhager R, Hofmann-Wackersreuther G, Andus T, Kager L, Kuehne T, Reichardt P, von Kalle T	Osteosarcoma of the mobile spine.	Annals of oncology 2013, Epub ahead of print
BACKGROUND: The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. PATIENTS AND METHODS: Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. RESULTS: The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age <40 years, nonmetastatic disease at diagnosis and complete remission predicted for better overall survival (OS, P < 0.05). CONCLUSIONS: Osteosarcomas of the mobile spine are rare. With complete resection (and potentially radiotherapy) and chemotherapy, prognosis may be comparable with that of appendicular osteosarcomas.
Zils K, Bielack S	Osteosarcoma After Bone Marrow Transplantation: Still a Challenge.	Journal of pediatric hematology/oncology 2013, epub ahead of print
Zils K, Klingebiel T, Behnisch W, Mueller HL, Schlegel PG, Fruehwald M, Suttorp M, Simon T, Werner M, Bielack S	Osteosarcoma in patients with rothmund-thomson syndrome.	Pediatric hematology and oncology 2015, 32: 32
Rothmund-Thomson syndrome (RTS) is associated with an increased risk of osteosarcoma, but information about affected patients is limited.
Zin F, Cotter JA, Haberler C, Dottermusch M, Neumann J, Schüller U, Schweizer L, Thomas C, Nemes K, Johann PD, Kool M, Frühwald MC, Paulus W, Judkins A, Hasselblatt M	Histopathological patterns in atypical teratoid/rhabdoid tumors are related to molecular subgroup.	Brain pathology 2021,e12967
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor that may not only contain rhabdoid tumor cells but also poorly differentiated small-round-blue cells as well as areas with mesenchymal or epithelial differentiation. Little is known on factors associated with histopathological diversity. Recent studies demonstrated three molecular subgroups of AT/RT, namely ATRT-TYR, ATRT-SHH, and ATRT-MYC. We thus aimed to investigate if morphological patterns might be related to molecular subgroup status. Hematoxylin-eosin stained sections of 114 AT/RT with known molecular subgroup status were digitalized and independently categorized by nine blinded observers into four morphological categories, that is, "rhabdoid," "small-round-blue," "epithelial," and "mesenchymal." The series comprised 48 ATRT-SHH, 40 ATRT-TYR, and 26 ATRT-MYC tumors. Inter-observer agreement was moderate but significant (Fleiss' kappa = 0.47; 95% C.I. 0.41-0.53; p < 0.001) and there was a highly significant overall association between morphological categories and molecular subgroups for each of the nine observers (p < 0.0001). Specifically, the category "epithelial" was found to be over-represented in ATRT-TYR (p < 0.000001) and the category "small-round-blue" to be over-represented in ATRT-SHH (p < 0.01). The majority of ATRT-MYC was categorized as "mesenchymal" or "rhabdoid," but this association was less compelling. The specificity of the category "epithelial" for ATRT-TYR was highest and accounted for 97% (range: 88-99%) whereas sensitivity was low [49% (range: 35%-63%)]. In line with these findings, cytokeratin-positivity was highly overrepresented in ATRT-TYR. In conclusion, morphological features of AT/RT might reflect molecular alterations and may also provide a first hint on molecular subgroup status, which will need to be confirmed by DNA methylation profiling.
Zirn B, Wittmann S, Graf N, Gessler M	Chibby, a novel antagonist of the Wnt pathway, is not involved in Wilms tumor development.	Cancer letters 2005, 220: 115
Deregulation of the Wnt signalling pathway is a key event in the development of a broad spectrum of human malignancies and mutations in beta-catenin (CTNNB1), a central component of the Wnt pathway, have been detected in 10-15% of Wilms tumors (nephroblastoma). Furthermore, nuclear immunoreactivity for beta-catenin has been described even in the absence of detectable beta-catenin mutations. This suggests that other components of the Wnt pathway may be involved in the pathogenesis of a subgroup of Wilms tumors. Chibby (C22ORF2) is a recently identified antagonistic component of the Wnt pathway that inhibits the transcriptional activity of beta-catenin. Our study addresses the question whether mutation or down-regulation of Chibby is involved in Wilms tumorigenesis. We analysed the expression of Chibby by real time RT-PCR in 142 Wilms tumors, but there was no significant expression difference in any group of tumors stratified according to clinical, histological and mutational criteria. Mutation analysis of a smaller cohort did not reveal any mutations of the coding sequence. We only detected a constitutive splice variant leading to the absence of exon 4 in all Wilms tumors as well as in normal tissues. In addition, we detected a frequent silent polymorphism in the Chibby exon 4 sequence (435T/C). These data strongly suggest that despite its attractive function as a modulator of beta-catenin activity, Chibby is not involved in Wilms tumorigenesis.
Zirn B, Samans B, Spangenberg C, Graf N, Eilers M, Gessler M	All-trans retinoic acid treatment of Wilms tumor cells reverses expression of genes associated with high risk and relapse in vivo.	Oncogene 2005, 24: 5246
Wilms tumor is one of the most frequent neoplasias in children. Our previous microarray screening in a large series of Wilms tumors revealed several candidate genes that are deregulated in advanced tumors and are part of the retinoic acid signaling pathway. To investigate whether retinoic acid could be employed as a novel therapeutic agent in these tumors, we treated cultured Wilms tumor cells with different concentrations of all-trans retinoic acid (ATRA) and assessed gene expression changes by real-time RT-PCR as well as microarray analysis. Several genes like RARRES1, RARRES3, CTGF, CKS2, CCNA2, IGFBP3, UBE2C, CCL2 or ITM2B that were previously found to be deregulated in advanced tumors exhibited opposite expression changes after ATRA treatment. In addition to enhanced retinoid signaling, the transforming growth factor-beta (TGFbeta) pathway was strongly activated by ATRA treatment of Wilms tumor cells. Both the retinoic acid and the TGFbeta pathway mediate inhibition of cell growth. These findings represent the first molecular evidence of a potential benefit from ATRA treatment in Wilms tumors.
Zirn B, Samans B, Wittmann S, Pietsch T, Leuschner I, Graf N, Gessler M	Target genes of the WNT/beta-catenin pathway in Wilms tumors.	Genes, chromosomes & cancer 2006, 45: 565
The WNT/beta-catenin pathway is involved in numerous human cancers. Mutations of the CTNNB1 (beta-catenin) gene have also been detected in a subset of pediatric Wilms tumors, but the target genes of the deregulated WNT/beta-catenin pathway in these tumors have yet to be identified. To compare gene expression profiles of Wilms tumors with and without mutations of CTNNB1, we used 11.5-k cDNA microarrays. Most of the tumors (86%) had received preoperative chemotherapy as mandated by the European SIOP protocol. The comparison between Wilms tumors with and without CTNNB1 mutations revealed several target genes specifically deregulated in CTNNB1-mutated Wilms tumors. Among these, PITX2, APCDD1, and two members of the endothelin axis (EDN3 and EDNRA) are directly activated downstream targets of the WNT/beta-catenin pathway that may enhance proliferation of these tumor cells. In addition, several upstream inhibitors of WNT/beta-catenin signaling like WIF1 and PRDC were also strongly up-regulated in the CTNNB1-mutated Wilms tumors. This overexpression may be a negative feedback mechanism in tumors with uncontrolled WNT signaling. Moreover, we identified deregulated genes in both the retinoic acid and the RAS pathways, such as ATX/ENPP2 and RIS1, suggesting an association between these two pathways with that of WNT. In addition, the strong representation of muscle-related genes in the expression profile of CTNNB1-mutated Wilms tumors corresponded to histologically detectable areas of myomatous cells in these tumors that displayed intense and preferential nuclear beta-catenin antibody staining. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (c) 2006 Wiley-Liss, Inc.
Zirn B, Hartmann O, Samans B, Krause M, Wittmann S, Mertens F, Graf N, Eilers M, Gessler M	Expression profiling of Wilms tumors reveals new candidate genes for different clinical parameters.	International journal of cancer 2006, 118: 1954
Wilms tumor is the most frequent renal neoplasm in children, but our understanding of its genetic basis is still limited. We performed cDNA microarray experiments using 63 primary Wilms tumors with the aim of detecting new candidate genes associated with malignancy grade and tumor progression. All tumors had received preoperative chemotherapy as mandated by the SIOP protocol, which sets this study apart from related approaches in the Unites States that are based on untreated samples. The stratification of expression data according to clinical criteria allowed a rather clear distinction between different subsets of Wilms tumors. Clear-cut differences in expression patterns were discovered between relapse-free as opposed to relapsed tumors and tumors with intermediate risk as opposed to high risk histology. Several differentially expressed genes, e.g.TRIM22, CENPF, MYCN, CTGF, RARRES3 and EZH2, were associated with Wilms tumor progression. For a subset of differentially expressed genes, microarray data were confirmed by real-time RT-PCR on the original set of tumors. Interestingly, we found the retinoic acid pathway to be deregulated at different levels in advanced tumors suggesting that treatment of these tumors with retinoic acid may represent a promising novel therapeutic approach.
Zirngibl F, Ivasko SM, Grunewald L, Klaus A, Schwiebert S, Ruf P, Lindhofer H, Astrahantseff K, Andersch L, Schulte JH, Lode HN, Eggert A, Anders K, Hundsdoerfer P, Künkele A	GD2-directed bispecific trifunctional antibody outperforms dinutuximab beta in a murine model for aggressive metastasized neuroblastoma.	Journal for immunotherapy of cancer 2021, 9
Neuroblastoma is the most common extracranial solid tumor of childhood. Patients with high-risk disease undergo extremely aggressive therapy and nonetheless have cure rates below 50%. Treatment with the ch14.18 monoclonal antibody (dinutuximab beta), directed against the GD2 disialoganglioside, improved 5-year event-free survival in high-risk patients when administered in postconsolidation therapy and was recently implemented in standard therapy. Relapse still occurred in 57% of these patients, necessitating new therapeutic options. Bispecific trifunctional antibodies (trAbs) are IgG-like molecules directed against T cells and cancer surface antigens, redirecting T cells (via their CD3 specificity) and accessory immune cells (via their functioning Fc-fragment) toward tumor cells. We sought proof-of-concept for GD2/CD3-directed trAb efficacy against neuroblastoma.
Zöllner SK, Amatruda JF, Bauer S, Collaud S, de Álava E, DuBois SG, Hardes J, Hartmann W, Kovar H, Metzler M, Shulman DS, Streitbürger A, Timmermann B, Toretsky JA, Uhlenbruch Y, Vieth V, Grünewald TGP, Dirksen U	Ewing Sarcoma-Diagnosis, Treatment, Clinical Challenges and Future Perspectives.	Journal of clinical medicine 2021 Apr 14; 10
Ewing sarcoma, a highly aggressive bone and soft-tissue cancer, is considered a prime example of the paradigms of a translocation-positive sarcoma: a genetically rather simple disease with a specific and neomorphic-potential therapeutic target, whose oncogenic role was irrefutably defined decades ago. This is a disease that by definition has micrometastatic disease at diagnosis and a dismal prognosis for patients with macrometastatic or recurrent disease. International collaborations have defined the current standard of care in prospective studies, delivering multiple cycles of systemic therapy combined with local treatment; both are associated with significant morbidity that may result in strong psychological and physical burden for survivors. Nevertheless, the combination of non-directed chemotherapeutics and ever-evolving local modalities nowadays achieve a realistic chance of cure for the majority of patients with Ewing sarcoma. In this review, we focus on the current standard of diagnosis and treatment while attempting to answer some of the most pressing questions in clinical practice. In addition, this review provides scientific answers to clinical phenomena and occasionally defines the resulting translational studies needed to overcome the hurdle of treatment-associated morbidities and, most importantly, non-survival.
Zöllner SK, Kauertz KL, Kaiser I, Kerkhoff M, Schaefer C, Tassius M, Jabar S, Jürgens H, Ladenstein R, Kühne T, Haveman LM, Paulussen M, Ranft A, Dirksen U	Ewing Sarcoma as Secondary Malignant Neoplasm-Epidemiological and Clinical Analysis of an International Trial Registry.	Cancers 2022, 14
Ewing sarcoma (EwS) is the second most common bone and soft tissue tumor, affecting primarily adolescents and young adults. Patients with secondary EwS are excluded from risk stratification in several studies and therefore do not benefit from new therapies. More knowledge about patients with EwS as secondary malignant neoplasms (SMN) is needed to identify at-risk patients and adapt follow-up strategies. Epidemiology, clinical characteristics, and survival analyses of EwS as SMN were analyzed in 3844 patients treated in the last three consecutive international EwS trials, EICESS 92, Euro-E.W.I.N.G. 99, and EWING 2008. Forty-two cases of EwS as SMN (approximately 1.1% of all patients) were reported, preceded by a heterogeneous group of malignancies, mainly acute lymphoblastic leukemias ( = 7) and lymphomas ( = 7). Three cases of EwS as SMN occurred in the presumed radiation field of the primary tumor. The median age at diagnosis of EwS as SMN was 19.4 years (range, 5.9-72) compared with 10.8 years (range, 0.9-51.2) for primary EwS. The median interval between first malignancy and EwS diagnosis was 7.4 years. The 3-year overall survival (OS)/event-free survival (EFS) was 0.69 (SE = 0.09)/0.53 (SE = 0.10) for localized patients and 0.36 (SE = 0.13)/0.29 (SE = 0.12) for metastatic patients (OS: = 0.02; EFS: = 0.03). Survival in patients with EwS as SMN did not differ between hematologic or solid primary malignancies. EwS as SMN is rare; however, survival is similar to that of primary EwS, and its risk-adjusted treatment should be curative, especially in localized patients.
Zolk O, von dem Knesebeck A, Graf N, Simon T, Hero B, Abdul-Khaliq H, Abd El Rahman M, Spix C, Mayer B, Elsner S, Gebauer J, Langer T	Cardiovascular Health Status And Genetic Risk In Survivors of Childhood Neuroblastoma and Nephroblastoma Treated With Doxorubicin: Protocol of the Pharmacogenetic Part of the LESS-Anthra Cross-Sectional Cohort Study.	JMIR research protocols 2022, 11:e27898
In childhood cancer survivors (survival of 5 years or more after diagnosis), cardiac toxicity is the most common nonmalignant cause of death attributed to treatment-related consequences. Identifying patients at risk of developing late cardiac toxicity is therefore crucial to improving treatment outcomes. The use of genetic markers has been proposed, together with clinical risk factors, to predict individual risk of cardiac toxicity from cancer therapies, such as doxorubicin.
Zotz R B, Scharf R E	Rekombinanter Faktor VIIa bei Patienten mit Plättchenfunktionsstörungen oder Thrombozytopenien.	Hämostaseologie 2007, 27; 237
Rekombinanter Faktor VIIa (rFVIIa) wird über die zugelassenen Indikationen hinaus zunehmend zur Behandlung lebensbedrohlicher Blutungsereignissen bei Versagen der jeweiligen Standardtherapien eingesetzt. Kasuistiken und Fallserien dokumentieren die Wirksamkeit und Sicherheit von rFVIIa zur Blutstillung bei Patienten mit Thrombozytopathien und Thrombozytopenien verschiedener Ursache. Eine Zulassung zur Anwendung von rFVIIa liegt bei Patienten mit Thrombasthenie Glanzmann im Falle eines Refraktärzustandes auf die Transfusion von Thrombozytenkonzentraten vor. rFVIIa-Bolusapplikationen mit Dosierungen zwischen 80 und 120 μg/kg Körpergewicht alle 1,5 bis 3 Stunden werden auch bei Bernard-Soulier-Syndrom, Plättchen- Storage-Pool-Defekten und verschiedenen erworbenen Thrombozytopathien erfolgreich eingesetzt. Bei Thrombasthenie Glanzmann sind zur Gewährleistung einer effektiven Hämostase mindestens drei Bolusgaben notwendig. Bei Thrombozytopenie hat sich bei annähernd der Hälfte der Patienten ein einzelner rFVIIa-Bolus zur Beherrschung sonst unstillbarer Blutungen als ausreichend erwiesen. Dabei kann eine Blutstillung unter rFVIIa auch bei Thrombozytenwerten unter 20 000/μl erreicht werden, wenngleich bei höheren Thrombozytenkonzentrationen eine bessere Wirksamkeit erzielbar ist.
Zoubek A, Dockhorn-Dworniczak B, Delattre O, Christiansen H, Niggli F, Gatterer-Menz I, Smith T, Jürgens H, Gadner H, Kovar H	Does expression of different EWS chimeric transcripts define clinically distinct risk groups of Ewing tumor patients?	J Clin Oncol 1996, 14: 1245
Zoubek A, Windhager R, Bielack S	Osteosarkome.	in: Gadner H, Gaedicke G, Niemeyer CH, Ritter J (Hrsg.): Pädiatrische Hämatologie und Onkologie Springer-Verlag 2006, 882
Zschernack V, Jünger ST, Mynarek M, Rutkowski S, Garre ML, Ebinger M, Neu M, Faber J, Erdlenbruch B, Claviez A, Bielack S, Brozou T, Frühwald MC, Dörner E, Dreschmann V, Stock A, Solymosi L, Hench J, Frank S, Vokuhl C, Waha A, Andreiuolo F, Pietsch T	Supratentorial ependymoma in childhood: more than just RELA or YAP.	Acta neuropathologica 2021, 141: 455
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
Zsíros J, Maibach R, Shafford E, Brugieres L, Brock P, Czauderna P, Roebuck D, Childs M, Zimmermann A, Laithier V, Otte JB, de Camargo B, MacKinlay G, Scopinaro M, Aronson D, Plaschkes J, Perilongo G	Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: final results of the SIOPEL-3HR study.	Journal of clinical oncology 2010, 28: 2584
PURPOSE: The primary objective was to determine the efficacy of a newly designed preoperative chemotherapy regimen in an attempt to improve the cure rate of children with high-risk hepatoblastoma. PATIENTS AND METHODS: High risk was defined as follows: tumor in all liver sections (ie, Pretreatment Extension IV [PRETEXT-IV]), or vascular invasion (portal vein [P+], three hepatic veins [V+]), or intra-abdominal extrahepatic extension (E+), or metastatic disease, or alpha-fetoprotein less than 100 ng/mL at diagnosis. Patients were treated with alternating cycles of cisplatin and carboplatin plus doxorubicin (preoperatively, n = 7; postoperatively, n = 3) and delayed tumor resection. RESULTS: Of the 151 patients (150 evaluable for response) 118 (78.7%) achieved a partial response to chemotherapy. Complete resection of the liver tumor could be achieved in 115 patients (76.2%) either by partial hepatectomy (55.6%) or by liver transplantation (20.6%). In 106 children (70.2%), complete resection of all tumor lesions (including metastases) was achieved. Among the patients with initial lung metastases, 52.2% achieved complete remission of the lung lesions with chemotherapy alone. In half of the patients with initial PRETEXT-IV tumor as the only high-risk feature, the tumor could be completely resected with partial hepatectomy. Event-free (EFS) and overall survival (OS) estimates at 3 years were 65% (95% CI, 57% to 73%) and 69% (95% CI, 62% to 77%) for the whole group. EFS and OS for all patients with PRETEXT-IV tumor were 68% and 69%, respectively, and they were 56% and 62%, respectively, for patients with metastasis. CONCLUSION: The applied treatment rendered a great proportion of tumors resectable, and, in comparison with previously published results, led to an improved survival in patients with high-risk hepatoblastoma.
Zubair A	Therapeutic phlebotomy.	Clinical liver disease 2014, 4: 102
Zucchetti G, Rossi F, Chamorro Vina C, Bertorello N, Fagioli F	Exercise program for children and adolescents with leukemia and lymphoma during treatment: A comprehensive review.	Pediatric blood & cancer 2018, 65:e26924
An exercise program (EP) during cancer treatment seems to be a valid strategy against physiological and quality-of-life impairments, but scientific evidence of benefits among pediatric patients is still limited. This review summarizes the literature focused on randomized controlled trials of EP offered to patients during leukemia and lymphoma treatment. Studies published up to June 2017 were selected from multiple databases and assessed by three independent reviewers for methodological validity. The review identified eight studies, but several types of bias have to be avoided to provide evidence-based recommendations accessible to patients, families, and professionals.
Zuna J, Moericke A, Arens M, Koehler R, Panzer-Grümayer R, Bartram CR, Fischer S, Fronkova E, Zaliova M, Schrauder A, Stanulla M, Zimmermann M, Trka J, Stary J, Attarbaschi A, Mann G, Schrappe M, Cario G	Implications of delayed bone marrow aspirations at the end of treatment induction for risk stratification and outcome in children with acute lymphoblastic leukaemia.	British journal of haematology 2016, 173: 742
Zuna J, Hovorkova L, Krotka J, Koehrmann A, Bardini M, Winkowska L, Fronkova E, Alten J, Koehler R, Eckert C, Brizzolara L, Trkova M, Stuchly J, Zimmermann M, De Lorenzo P, Valsecchi MG, Conter V, Stary J, Schrappe M, Biondi A, Trka J, Zaliova M, Cazzaniga G, Cario G	Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease.	Leukemia 2022, 36: 2793
zur Stadt, Harms D, Schluter S, Jorch N, Spaar H, Nurnberger W, Volpel S, Gutjahr P, Schrappe M, Janka G, Kabisch H	Minimal residual disease analysis in acute lymphoblastic leukemia of childhood within the framework of COALL Study.	Klin Pädiatr 2000, 212: 169
zur Stadt, Harms D, Schluter S, Schrappe M, Goebel U, Spaar H, Janka G, Kabisch H	MRD at the end of induction therapy in childhood acute lymphoblastic leukemia.	Leukemia 2001, 15: 283
Zur Stadt U, Isbarn H, Schneppenheim R, Kabisch H	DHPLC based fraction collection of TCR-gamma rearrangements in childhood ALL: direct sequencing of products amplified by a single or a multiplex PCR approach.	International journal of oncology 2005, 27: 547
Clonal T-cell receptor gamma (TCR-gamma) rearrangements are frequently used for detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia. In approximately 70-80% of cases PCR amplified clonal rearrangements can be sequenced directly. The remaining 20-30% are rearranged on both alleles for the same target and disables direct sequencing. Here we describe a novel HPLC based method for identification and characterisation of TCR-gamma rearrangements either by a single or a multiplex PCR approach. The latter one amplifies several Vgamma segments in two distinct reactions either with a Jgamma1.3/2.3 or a Jgamma1.1/2.1 specific primer. The clonality status was evaluated on a high resolution micropellicular DNASep matrix (WAVE, Transgenomic) at different temperatures. From 331 samples analysed, 151 samples were positive for VgammaI-Jgamma1.3/2.3 including 51 biclonal rearrangements. For characterisation of these biclonal products or for products generated by multiplex-PCR, a second HPLC run was performed utilising a tandem arranged fraction collector. From clearly separated biclonal/biallelic products, several collected fractions were air-dried and afterwards sequenced directly with the appropriate Jgamma primer. We conclude from our results that HPLC is a fast and reliable method for identification of TCR-gamma rearrangements. The fraction collection simplifies the characterisation of single alleles within biclonal or biallelic rearrangements or within multiplex PCR products. The target identification process prior to routine MRD analysis will be shortened due to a simplified screening and sequencing strategy.
Zwaan C, Kaspers G, Pieters R, Ramakers-van Woerden N, Den Boer M, Wunsche R, Rottier M, Hahlen K, van Wering E, Janka-Schaub G, Creutzig U, Veerman A	Cellular drug resistance profiles in childhood acute myeloid leukemia.	Blood 2000, 96: 2879
Zwaan C, Kaspers G, Pieters R, Hahlen K, Huismans D, Zimmermann M, Harbott J, Slater R, Creutzig U, Veerman A	Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities.	Blood 2002, 100: 3352
Zwaan C, Kaspers G, Pieters R, Hahlen K, Janka-Schaub G, van Zantwijk C, Huismans D, de Vries E, Rots M, Peters G, Jansen G, Creutzig U, Veerman A	Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome.	Blood 2002, 99: 245
Zwaan C, Meshinchi S, Radich J, Veerman A, Huismans D, Munske L, Podleschny M, Hahlen K, Pieters R, Zimmermann M, Reinhardt D, Harbott J, Creutzig U, Kaspers G, Griesinger F	FLT3 internal tandem duplication in 234 children with acute myeloid leukemia.	Blood 2003, 102: 2387
Zwaan C, Reinhardt D, Corbacioglu S, van Wering E, Bokkerink J, Tissing W, Samuelsson U, Feingold J, Creutzig U, Kaspers G	Gemtuzumab ozogamicin.	Blood 2003, 101: 3868
Zwaan Ch, Kaspers G, Pieters R, Huismans D, Creutzig U, Hählen K, van Wering E, Veerman A	Age-Related Differences in Cellular Drug Resistance in Children with Acute Myeloid Leukemia (AML).	Haematology and Blood Transfusion 2003,IX: 291
Zwaan Ch, Reinhardt D, Corbacioglu S, van Wering E, Bokkerink J, Tissing W, Samuelsson U, Feingold J, Creutzig U, Kaspers G	Gemtuzumab ozogamicin.	Blood 2003, 101: 3868
Zwaan Ch, Reinhardt D, Jürgens H, Huismans D, Hahlen K, Smith O, Biondi A, van Wering E, Feingold J, Kaspers G	Gemtuzumab ozogamicin in pediatric CD33-positive acute lymphoblastic leukemia.	Leukemia 2003, 17: 468
Zwaan MC, Reinhardt D, Hitzler J, Vyas P	Acute leukemias in children with down syndrome.	Pediatric clinics of North America 2008, 55: 53
Children with Down syndrome have an increased risk for developing both acute myeloid as well as lymphoblastic leukemia. These leukemias differ in presenting characteristics and underlying biology when compared with leukemias occurring in non-Down syndrome children. Myeloid leukemia in children with Down syndrome is preceded by a preleukemic clone (transient leukemia or transient myeloproliferative disorder), which may disappear spontaneously, but may also need treatment in case of severe symptoms. Twenty percent of children with transient leukemia subsequently develop myeloid leukemia. This transition offers a unique model to study the stepwise development of leukemia, and of gene dosage effects mediated by aneuploidy.
Zwaan CM, Reinhardt D, Hitzler J, Vyas P	Acute leukemias in children with Down syndrome.	Hematology/oncology clinics of North America 2010, 24: 19
Children with Down syndrome have an increased risk for developing both acute myeloid as well as lymphoblastic leukemia. These leukemias differ in presenting characteristics and underlying biology when compared with leukemias occurring in non-Down syndrome children. Myeloid leukemia in children with Down syndrome is preceded by a preleukemic clone (transient leukemia or transient myeloproliferative disorder), which may disappear spontaneously, but may also need treatment in case of severe symptoms. Twenty percent of children with transient leukemia subsequently develop myeloid leukemia. This transition offers a unique model to study the stepwise development of leukemia and of gene dosage effects mediated by aneuploidy.
Zwaan CM, Reinhardt D, Zimmerman M, Hasle H, Stary J, Stark B, Dworzak M, Creutzig U, Kaspers GJ, International BFM Study Group on Paediatric AML	Salvage treatment for children with refractory first or second relapse of acute myeloid leukaemia with gemtuzumab ozogamicin: results of a phase II study.	British journal of haematology 2010, 148: 768
The prognosis of children with relapsed/refractory acute myeloid leukaemia (AML) is poor, and new therapies are needed. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to the antitumor antibiotic calicheamicin. We conducted an investigator-initiated phase II study with GO to assess its efficacy and safety, administering two dosages of 7.5 mg/m(2) with a 14 d-interval. Thirty children who were refractory to re-induction at first relapse or suffered from second relapse of AML received a total of 64 infusions of GO. The response rate [complete remission (CR) and CR with insufficient platelet recovery] was 37%. Nine patients were subsequently transplanted (median time to transplant, 4 weeks, range 3-21 weeks), and three of these patients are currently in continuous CR with a median follow-up of >3 years, and can considered to be cured. This resulted in a statistically significant survival advantage for children who responded to GO versus those who did not [27% (standard error 13%) vs. 0%, respectively, P = 0.001]. All other children died, mainly from progressive disease. The treatment was generally well tolerated by most patients. The frequency of transient transaminatis was low. All but one patient received defibrotide prophylaxis during the transplant procedure, and no cases of veno-occlusive disease were noted. This study showed a favourable safety/efficacy profile of single-agent GO in children with refractory first or second relapse of AML.
Zylka-Menhorn V, Richter-Kuhlmann E, Meißner M	RADIOAKTIVITÄT Folgen von Reaktorunfällen – Fakten und Vermutungen.	Dtsch Arztebl 2011 108: A-700 / B-568 / C
Zynda A, Reinmuth S, Pfitzer C, Hohmann C, Keil T, Borgmann-Staudt A	Childhood leukemia and its impact on graduation and having children: results from a national survey.	Leukemia & lymphoma 2012, 53: 2419
To assess the level of graduation, the wish to have children and the course of pregnancy among former patients with childhood leukemia in comparison to the general German population and depending on gender, a nationwide survey was conducted in 2008. In total 63.6% (1476/2319) of the contacted survivors of childhood leukemia participated (mean age 25.7 years, range 19-43 years). Survivors graduated at higher levels of school compared to the general population, with 48.6% (female) versus 38.0% and 52.6% (male) versus 35.8% (p < 0.001). Also, 93.3% of female and 89.3% of male survivors indicated a similar general wish to have children compared to the general population. Survivors reported parenthood less frequently compared to the general population (p < 0.001). The course of pregnancy in survivors was characterized by fewer abortions (p < 0.001). Having leukemia in childhood and adolescence impairs the likelihood of becoming a parent but reduces neither the wish to have children nor the level of graduation.
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