88 results on '"Fink FM"'
Search Results
2. Double high-dose chemotherapy with autologous peripheral stem cell rescue in relapsed Wilms’ tumor
- Author
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Maurer, K, Heitger, A, Schwaighofer, H, Fink, FM, and Niederwieser, D
- Published
- 1997
- Full Text
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3. Hämangioendotheliom der Leber - Ursache für eine akute Herzinsuffizienz beim Neugeborenen
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Hager, J, Häussler, B, Fink, FM, Klein-Franke, A, and Jaschke, W
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ddc: 610 - Published
- 2005
4. Rehospitalisation von Frühgeborenen < 32 Schwangerschaftswochen in ihren ersten 2 Lebensjahren
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Ralser, E, primary, Müller, W, additional, Haberland, C, additional, Fink, FM, additional, Gutenberg, KH, additional, and Kiechl-Kohlendorfer, U, additional
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- 2011
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5. Variability of EWS chimaeric transcripts in Ewing tumours: a comparison of clinical and molecular data
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Zoubek, A, primary, Pfleiderer, C, additional, Salzer-Kuntschik, M, additional, Amann, G, additional, Windhager, R, additional, Fink, FM, additional, Koscielniak, E, additional, Delattre, O, additional, Strehl, S, additional, Ambros, PF, additional, Gadner, H, additional, and Kovar, H, additional
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- 1994
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6. Rapid discrimination of early CD34+ myeloid progenitors using CD45-RA analysis
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Fritsch, G, primary, Buchinger, P, additional, Printz, D, additional, Fink, FM, additional, Mann, G, additional, Peters, C, additional, Wagner, T, additional, Adler, A, additional, and Gadner, H, additional
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- 1993
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7. The translocation t(1;22)(p13;q13) is a nonrandom marker specifically associated with acute megakaryocytic leukemia in young children
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Lion, T, primary, Haas, OA, additional, Harbott, J, additional, Bannier, E, additional, Ritterbach, J, additional, Jankovic, M, additional, Fink, FM, additional, Stojimirovic, A, additional, Herrmann, J, additional, and Riehm, HJ, additional
- Published
- 1992
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8. Retrospective identification of the first cord blood-transplanted severe aplastic anemia in a STAT1 -associated chronic mucocutaneous candidiasis family: case report, review of literature and pathophysiologic background.
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Fink FM, Höpfl R, Witsch-Baumgartner M, Kropshofer G, Martin S, Fink V, Heeg M, Peters C, Zschocke J, and Haas OA
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- Humans, Male, Female, Cord Blood Stem Cell Transplantation, Retrospective Studies, Adult, Pedigree, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Anemia, Aplastic genetics, Candidiasis, Chronic Mucocutaneous genetics
- Abstract
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome whose development can be triggered by environmental, autoimmune, and/or genetic factors. The latter comprises germ line pathogenic variants in genes that bring about habitually predisposing syndromes as well as immune deficiencies that do so only occasionally. One of these disorders is the autosomal dominant form of chronic mucocutaneous candidiasis (CMC), which is defined by germ line STAT1 gain-of-function (GOF) pathogenic variants. The resultant overexpression and constitutive activation of STAT1 dysregulate the Janus kinase/signal transducer and activator of transcription 1 (STAT) signaling pathway, which normally organizes the development and proper interaction of different components of the immunologic and hematopoietic system. Although SAA is an extremely rare complication in this disorder, it gained a more widespread interest when it became clear that the underlying causative pathomechanism may, in a similar fashion, also be instrumental in at least some of the idiopathic SAA cases. Based on these premises, we present herein what is the historically most likely first cord blood-transplanted SAA case in a CMC family with a documented STAT1 GOF pathogenic variant. In addition, we recapitulate the characteristics of the six CMC SAA cases that have been reported so far and discuss the significance of STAT1 GOF pathogenic variants and other STAT1 signaling derangements in the context of these specific types of bone marrow failure syndromes. Because a constitutively activated STAT1 signaling, be it driven by STAT1 GOF germ line pathogenic variants or any other pathogenic variant-independent events, is apparently important for initiating and maintaining the SAA disease process, we propose to acknowledge that SAA is one of the definite disease manifestations in STAT1 -mutated CMC cases. For the same reason, we deem it necessary to also incorporate molecular and functional analyses of STAT1 into the diagnostic work-up of SAA cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Fink, Höpfl, Witsch-Baumgartner, Kropshofer, Martin, Fink, Heeg, Peters, Zschocke and Haas.)
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- 2024
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9. Terminal Ileitis as the Exclusive Manifestation of COVID-19 in Children.
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Schuler LM, Falkensammer B, Orlik P, Auckenthaler M, Kranewitter C, Bante D, von Laer D, and Fink FM
- Abstract
The clinical presentation, organ involvement, and severity of disease caused by SARS-CoV-2 are highly variable, ranging from asymptomatic or mild infection to respiratory or multi-organ failure and, in children and young adults, the life-threatening multisystemic inflammatory disease (MIS-C). SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 receptor (ACE-2), which is expressed on the cell surfaces of all organ systems, including the gastrointestinal tract. GI manifestations have a high prevalence in children with COVID-19. However, isolated terminal ileitis without other manifestations of COVID-19 is rare. In March 2023, two previously healthy boys (aged 16 months and 9 years) without respiratory symptoms presented with fever and diarrhea, elevated C-reactive protein levels, and low procalcitonin levels. Imaging studies revealed marked terminal ileitis in both cases. SARS-CoV-2 (Omicron XBB.1.9 and XBB.1.5 variants) was detected by nucleic acid amplification in throat and stool samples. Both patients recovered fast with supportive measures only. A differential diagnosis of acute abdominal pain includes enterocolitis, mesenteric lymphadenitis, appendicitis, and more. During SARS-CoV-2 epidemics, this virus alone may be responsible for inflammation of the terminal ileum, as demonstrated. Coinfection with Campylobacter jejuni in one of our patients demonstrates the importance of a complete microbiological workup.
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- 2024
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10. Case report: metoclopramide induced acute dystonic reaction in adolescent CYP2D6 poor metabolizers.
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Fink FM, Bognar M, Hengl P, Paulmichl M, and Nofziger C
- Abstract
Metoclopramide is indicated for the management of gastroesophageal reflux, gastric stasis, nausea, and vomiting. Metoclopramide-induced acute dystonic reactions (MIADRs), along with repetitive involuntary protrusion of the tongue, are well-known phenomena in children and young adults that may appear after the first dose. The drug is primarily metabolized via oxidation by the cytochrome P450 enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. A recommendation to decrease metoclopramide dosing in patients with severely limited to no CYP2D6 activity (i.e., poor metabolizers, PMs) is included in the drug label. It is important to note, however, that a requirement or recommendation for pre-emptive testing for CYP2D6 metabolizer status is not included in the drug label. We present two cases of acute dystonia in two non-consanguineous male adolescents: one following metoclopramide and cimetidine administration in a 14-year-old to treat gastroesophageal reflux, and another following metoclopramide and pantoprazole administration in a 17-year-old with acute gastroenteritis. A retrospective pharmacogenetic analysis revealed both patients as CYP2D6 PMs., Competing Interests: CN was employed by PharmGenetix GmbH, a private laboratory providing PGx testing, reporting, and interpretation services. The authors declare that this study received funding from the Österreichische Forschungsförderungsgesellschaft GmbH (FFG). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication., (Copyright © 2023 Fink, Bognar, Hengl, Paulmichl and Nofziger.)
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- 2023
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11. Differential diagnosis of blue toes in a newborn baby: might have been maternal infection with COVID-19?
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Hochmayr C, Auckenthaler M, Fink FM, Kiechl-Kohlendorfer U, and Griesmaier E
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- Infant, Newborn, Humans, Diagnosis, Differential, Toes, Medical History Taking, COVID-19 Testing, COVID-19
- Abstract
Competing Interests: Declaration of interests We declare no competing interests.
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- 2023
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12. Development of treatment and clinical results in childhood AML in Austria (1993-2013).
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Boztug H, Mühlegger N, Glogova E, Mann G, Urban C, Meister B, Schmitt K, Jones N, Attarbaschi A, Haas O, Strehl S, Lion T, Pötschger U, Fink FM, Gadner H, and Dworzak M
- Abstract
Background: Since the early 1990s, three consecutive pediatric acute myeloid leukemia (AML) trials have been performed in Austria (AML-Berlin-Frankfurt-Münster (BFM) 93, AML-BFM 98, and AML-BFM 2004) in close cooperation with the international BFM study center. Herein, we review the pertinent patient characteristics, therapy, and outcome data., Patients and Methods: From January 1993 to April 2013, 249 children and adolescents (193 protocol patients) diagnosed with AML were enrolled in the three BFM studies. Patients were mainly treated in one of five pediatric hematology/oncology centers distributed over Austria., Results: Many characteristics and outcome parameters were not statistically different between the three trials. Almost similar proportions of patients were stratified into two risk groups: standard risk (SR) (approximately 37 % overall) and high-risk (HR) (61 %). MLL rearrangements were found in 23 % of patients overall as the most frequent genetic aberration subtype. Complete remission (CR) was achieved by 84-95 % of patients. The most important type of event was leukemic relapse (5-year cumulative incidence 40 ± 8 %, 21 ± 5 %, and 39 ± 6 %; p = 0.058), with a trend to a higher rate specifically in SR patients of study AML-BFM 2004 compared with AML-BFM 98. Importantly, the frequency of death from causes other than relapse sequelae declined over the years (AML-BFM 93: 5/42 12 %, AML-BFM 98: 5/57 9 %, and AML-BFM 2004: 5/94 5 %). Altogether, event-free survival at 5 years varied insignificantly (48 ± 8 %, 61 ± 7 %, and 50 ± 6 %; p = 0.406). Nevertheless, survival (pSU) apparently improved from BFM 93 to subsequent studies, both overall (57 ± 8 %, 75 ± 6 %, and 62 ± 6 %; p = 0.046) and regarding the HR group (5-year-probability of survival (pSU) 40 ± 10 %, 66 ± 8 %, and 52 ± 8 %; p = 0.039)., Conclusion: Treatment of pediatric AML in Austria renders survival rates in the range of international best practice. However, unambiguous statistical comparison of treatment periods is eventually hampered by small numbers and inequalities of recruitment. Hence, only internationally collaborative trials will allow developing treatment further to achieve higher cure rates with fewer events., (© Springer-Verlag Wien 2014.)
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- 2014
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13. Rehospitalization in the first 2 years of life in children born preterm.
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Ralser E, Mueller W, Haberland C, Fink FM, Gutenberger KH, Strobl R, and Kiechl-Kohlendorfer U
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- Austria epidemiology, Chronic Disease, Female, Gestational Age, Humans, Infant, Infant, Newborn, Lung Diseases epidemiology, Lung Diseases etiology, Male, Pregnancy, Prenatal Exposure Delayed Effects, Prospective Studies, Respiratory Tract Diseases epidemiology, Respiratory Tract Diseases etiology, Risk Factors, Sex Factors, Smoking adverse effects, Infant, Premature, Patient Readmission statistics & numerical data
- Abstract
Aim: Aim of the study is to investigate the frequency of and predictors for rehospitalization within the first 2 years of life among preterm infants., Methods: All children born before 32 weeks of gestation in Northern Tyrol between January 2003 and July 2008 were prospectively enrolled. Data on rehospitalizations were obtained from hospital admission records. The association between candidate risk factors and readmission was analysed by means of logistic regression analysis., Results: In the first and second years of life, 151 and 93 of 377 children (40.1% and 24.7%), respectively, were readmitted to one of the hospitals in Northern Tyrol. The most common causes of rehospitalization were respiratory disorders, accounting for 42.1% and 47.4% of total readmissions in the first and second years of life. Chronic lung disease (CLD), male sex and smoking in pregnancy were risk conditions relevant to readmission in the first year of life, but only CLD in the second year., Conclusion: Infants born before 32 weeks of gestation have a high risk of rehospitalization with respiratory illness significantly contributing to postdischarge morbidity. Neonatal intensive care should aim to further improve respiratory health in preterm infants, and adequate follow-up services must be offered., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)
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- 2012
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14. Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group.
- Author
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Prucker C, Attarbaschi A, Peters C, Dworzak MN, Pötschger U, Urban C, Fink FM, Meister B, Schmitt K, Haas OA, Gadner H, and Mann G
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- Cause of Death, Child, Female, Humans, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Antineoplastic Agents toxicity, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Remission Induction
- Abstract
In the management of the childhood acute lymphoblastic leukemia (ALL), 5% of failures are due to induction death and treatment-related deaths in first complete remission. We retrospectively analyzed the incidence, pattern and causes of death and its risk factors for 896 children with ALL enrolled into five Austrian (A) Berlin-Frankfurt-Münster (BFM) trials between 1981 and 1999. The estimated 10-year cumulative incidence of death significantly decreased from 6+/-1% (n=16/268) in trials ALL-BFM-A 81 and ALL-A 84 to 2+/-1% (n=15/628) in trials ALL-BFM-A 86, 90 and 95 (P=0.006). A significant reduction of death was evident during induction therapy (2.2% in trials ALL-BFM-A 81 and ALL-A 84 and 0.2% in trials ALL-BFM-A 86, 90 and 95, P=0.001). Of 31 patients, 21 (68%) patients died from infectious and 10 (32%) from noninfectious complications. Treatment in trial ALL-BFM-A 81, infant age and female gender were independent predictors of an enhanced risk for death. Conclusively, we found a progressive reduction of death rates that may be explained by the increasing experience in specialized hemato-oncologic centers and improved supportive and intensive care. We also identified a distinct subset of patients who are especially prone to death and may need a special focus when receiving intense chemotherapy.
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- 2009
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15. Long-term outcome of initially homogenously treated and relapsed childhood acute lymphoblastic leukaemia in Austria--a population-based report of the Austrian Berlin-Frankfurt-Münster (BFM) Study Group.
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Reismüller B, Attarbaschi A, Peters C, Dworzak MN, Pötschger U, Urban C, Fink FM, Meister B, Schmitt K, Dieckmann K, Henze G, Haas OA, Gadner H, and Mann G
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Austria epidemiology, Child, Child, Preschool, Epidemiologic Methods, Female, Hematopoietic Stem Cell Transplantation, Humans, Immunophenotyping, Infant, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma epidemiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Prognosis, Recurrence, Research Design, Time Factors, Treatment Outcome, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Relapsed acute lymphoblastic leukaemia (ALL) is the most common cause for a fatal outcome in paediatric oncology. Although initial ALL cure rates have improved up to 80%, the prognosis of recurrent ALL remains dismal with event-free-survival (EFS) rates about 35%. In order to analyse a population-based cohort with uniform treatment of initial disease, we examined the outcome of children suffering from relapsed ALL in Austria for the past 20 years and the validity of the currently used prognostic factors (e.g. time to and site of relapse, immunophenotype). Furthermore, we compared survival rates after chemotherapy alone with those after allogeneic stem cell transplantation (SCT). All 896 patients who suffered from ALL in Austria between 1981 and 1999 were registered in a prospectively designed database and treated according to trials ALL-Berlin-Frankfurt-Münster (BFM)-Austria (A) 81, ALL-A 84 and ALL-BFM-A 86, 90 and 95. Of these, 203 (23%) suffered from recurrent disease. One-hundred-and-seventy-two patients (85%) achieved second complete remission. The probability of 10-year EFS for the total group was 34 +/- 3%. Clinical prognostic markers that independently influenced survival were time to relapse, site of relapse and the immunophenotype. Additionally, a Cox regression model demonstrated that allogeneic SCT after first relapse was associated with a superior EFS compared with chemo/radiotherapy only (hazard ratio = 0.254; P = 0.0017).
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- 2009
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16. Neonatal characteristics and risk of atopic asthma in schoolchildren: results from a large prospective birth-cohort study.
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Kiechl-Kohlendorfer U, Horak E, Mueller W, Strobl R, Haberland C, Fink FM, Schwaiger M, Gutenberger KH, Reich H, Meraner D, and Kiechl S
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- Asthma prevention & control, Austria epidemiology, Breast Feeding, Child, Disease Susceptibility, Family Characteristics, Female, Humans, Infant, Newborn, Logistic Models, Male, Medical Records statistics & numerical data, Prospective Studies, Risk Factors, Sex Factors, Surveys and Questionnaires, Asthma epidemiology, Health Surveys, Hospitalization statistics & numerical data, Risk Assessment
- Abstract
Aim: Asthma is among the most common chronic diseases in childhood and steadily increasing in prevalence. Identification of risk predictors for a hospitalization for atopic asthma in childhood may help design prevention programmes and improve our understanding of disease pathobiology., Methods: An ongoing birth-cohort study prospectively enrolled all liveborn infants in Tyrol. Between 1994 and 1999 baseline data were collected for 33,808 infants. From 2000 to 2005, all children hospitalized for atopic asthma at an age of 6 years or over (n = 305) were identified in a careful search of hospital databases. Disease status was ascertained from the typical medical history, a thorough examination and proof of atopy., Results: Male sex (relative risk 2.11, 95% CI 1.65-2.70), urban living environment (vs. rural) (1.93, 1.47-2.54), neonatal admission to hospital (1.70, 1.20-2.40), lack of breastfeeding (1.32, 1.02-1.70), postnatal smoking (1.31, 1.00-1.72) and low birth weight (1.45, 0.94-2.23) all emerged as adverse risk predictors for hospitalization for atopic asthma whereas a low risk was found among children living on a farm (0.22, 0.05-0.87) and children with two to three siblings (vs. no or one sibling) (0.71, 0.51-0.97)., Conclusion: In this study a number of neonatal characteristics and environmental exposures were associated with hospitalization for atopic asthma in childhood, suggesting that early life is crucial for disease determination and lending further indirect support to the hygiene hypothesis.
- Published
- 2007
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17. Transient symptomatic zinc deficiency in a breast-fed preterm infant.
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Kiechl-Kohlendorfer U, Fink FM, and Steichen-Gersdorf E
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- Humans, Infant, Infant, Low Birth Weight, Infant, Newborn, Male, Skin Diseases metabolism, Zinc blood, Breast Feeding, Gluconates administration & dosage, Infant, Premature, Skin Diseases diet therapy, Skin Diseases etiology, Zinc deficiency
- Abstract
Transient, symptomatic zinc deficiency in breast-fed, low-birthweight infants is a rare, but probably underrecognized disorder hallmarked by periorificial and acral dermatitis. Unlike in acrodermatitis enteropathica, symptoms disappear when nursing ends. We report a breast-fed, preterm infant with demarcated, erythematous, and exudative patches with overlying crusts on the perioral, perianal, and acral areas. Laboratory investigations revealed lowered zinc levels in the infant's serum, but normal levels in his mother's milk. Oral zinc supplementation resulted in total clearing of skin lesions within 4 weeks. Our patient's presentation illustrates the importance of zinc in rapidly growing preterm infants and aims to stimulate awareness for this disorder. Symptomatic zinc deficiency can be easily diagnosed by careful examination and effectively treated with oral zinc substitution.
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- 2007
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18. Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group.
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Attarbaschi A, Dworzak M, Steiner M, Urban C, Fink FM, Reiter A, Gadner H, and Mann G
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- Adolescent, Child, Child, Preschool, Disease Progression, Drug Resistance, Neoplasm, Female, Humans, Infant, Leukemia, B-Cell pathology, Lymphoma, Non-Hodgkin pathology, Male, Prognosis, Recurrence, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, B-Cell drug therapy, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Background: Children and adolescents with Non-Hodgkin lymphoma (NHL) and mature B-cell leukemia (B-ALL) have an excellent prognosis with contemporary chemotherapy stratified according to the histologic subtype and clinical stage of disease. However, a small subset of patients does not respond to front-line therapy or suffers from an early relapse., Procedure: A retrospective analysis was performed to assess the incidence, treatment, and outcome of all children with relapsed or progressed NHL and B-ALL diagnosed in Austria between 1986 and 2003 (n = 22/234)., Results: Nine of 140 (6.5%) patients with B-cell NHL/B-ALL (relapse, n = 6; progress, n = 3) failed initial treatment. Four of them underwent a hematopoietic stem cell transplantation (HSCT) as second-line therapy, two patients received intensive chemotherapy alone and in three patients treatment was palliative. Eight of the nine patients died of their disease. Four of 65 (6%) patients with lymphoblastic lymphoma (LBL) (relapse, n = 2; progress, n = 2) had a treatment failure. High-dose chemotherapy followed by HSCT was performed in two of the four patients; another two patients received chemotherapy alone. Three of the four patients died of resistant disease. Nine of 29 (31%) patients with anaplastic large cell lymphoma (ALCL) (relapse, n = 7; progress, n = 2) failed first-line therapy. Six underwent a HSCT (autologous, n = 3; allogeneic, n = 3) and are currently in second complete remission. Treatment of the other three patients consisted of chemotherapy alone-they all died of tumor progression., Conclusions: Conclusively, patients with early relapsed and progressive B-cell neoplasia or LBL have a very poor prognosis with current treatment approaches, while those with ALCL have a respectable chance to achieve a sustained complete second remission with high-dose chemotherapy and HSCT., ((c) 2004 Wiley-Liss, Inc.)
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- 2005
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19. Malignant non-Hodgkin's lymphoma of childhood and adolescence in Austria--therapy results between 1986 and 2000.
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Attarbaschi A, Mann G, Dworzak M, Trebo M, Urban C, Fink FM, Horcher E, Reiter A, Riehm H, and Gadner H
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- Adolescent, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Burkitt Lymphoma diagnosis, Burkitt Lymphoma drug therapy, Burkitt Lymphoma mortality, Child, Child, Preschool, Data Interpretation, Statistical, Disease-Free Survival, Female, Follow-Up Studies, Humans, Infant, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell mortality, Lymphoma, B-Cell therapy, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Prognosis, Prospective Studies, Risk Factors, Survival Analysis, Time Factors, Treatment Outcome, Burkitt Lymphoma therapy, Lymphoma, Non-Hodgkin therapy
- Abstract
Between 1986 and 2000 183 Austrian children and adolescents with non-Hodgkin's lymphoma (NHL) and mature B-cell acute leukemia (B-ALL) were enrolled in 3 consecutive studies of the Berlin-Frankfurt-Münster (BFM) Group. In trial NHL-BFM 86, patients were stratified according to the histologic subtype and clinical stage. In the succeeding studies NHL-BFM 90 and 95, treatment stratification was additionally based on the speed of tumor response to therapy and for children with B-cell NHL/B-ALL also on the pre-therapeutic serum lactic dehydrogenase level. Event-free survival rates were 84% +/- 6% in trial NHL-BFM 86 (n = 39) and 86% +/- 4% in both trials NHL-BFM 90 (n = 67) and NHL-BFM 95 (n = 77). Patients with lymphoblastic lymphoma (mainly with T-cell phenotypes) had an excellent prognosis with an ALL-type chemotherapy regimen (n = 49; relapse, n = 1), whereas an intensive, short-pulse therapy delivered within a 2- to 4-month period was found to be highly efficacious in children with B-cell NHL/B-ALL (n = 114; relapse, n = 6; progression, n = 5). Patients with anaplastic large cell lymphoma (ALCL) who were treated with similar alternating short courses of multi-agent chemotherapy had a less good outcome (n = 20; relapse, n = 6, progression, n = 3). Children with B-cell NHL and B-ALL who failed initial therapy also had a dismal prognosis (10/11 patients died). Local radiotherapy as a part of lymphoma therapy was completely abandoned in study NHL-BFM 90 and surgical interventions were confined to specific situations such as complete resection in localized B-cell NHL and ALCL, diagnostic biopsy and second-look operation. In conclusion, our results showed that the BFM treatment strategy for lymphoblastic lymphoma and B-cell NHL/B-ALL was highly successful in the majority of patients; however, optimal treatment for children with ALCL has not yet been defined. As a consequence, larger trials at an international level are necessary to find new prognostic markers that might define more precisely those patients who need further intensification of first-line treatment or novel therapy.
- Published
- 2002
20. Rhinocerebral mucormycosis in a boy with recurrent acute lymphoblastic leukemia: long-term survival with systemic antifungal treatment.
- Author
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Wehl G, Hoegler W, Kropshofer G, Meister B, Fink FM, and Heitger A
- Subjects
- Brain Diseases microbiology, Brain Diseases mortality, Cord Blood Stem Cell Transplantation, Disease-Free Survival, Humans, Infant, Liposomes, Male, Mucormycosis microbiology, Mucormycosis mortality, Neoplasm Recurrence, Local, Paranasal Sinus Diseases microbiology, Paranasal Sinus Diseases mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma microbiology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation, Homologous, Amphotericin B therapeutic use, Antifungal Agents therapeutic use, Brain Diseases drug therapy, Mucormycosis drug therapy, Paranasal Sinus Diseases drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications
- Abstract
Rhinocerebral mucormycosis is rare in hematologic malignancies and usually leads to death within weeks. In contrast, chronic rhinocerebral mucormycosis takes a slowly progressive course and has not been reported in hematologic malignancies in children so far. The authors report the long-term survival of a boy with rhinocerebral mucormycosis in a relapse of acute lymphoblastic leukemia after allogeneic cord blood transplantation. The disease started acutely but took a chronic course thereafter. No surgical debridement was performed because of extensive involvement of the sinuses, orbits, and cerebrum. His long-term survival of 15 months is attributed to the long-range administration of liposomal amphotericin B, early neutrophil recovery, and slow progression of the relapsing acute lymphoblastic leukemia.
- Published
- 2002
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21. Treatment results of childhood acute lymphoblastic leukemia in Austria--a report of 20 years' experience.
- Author
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Attarbaschi A, Mann G, Dworzak M, Urban C, Fink FM, Dieckmann K, Riehm H, and Gadner H
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- Adolescent, Austria, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Infant, Male, Multicenter Studies as Topic, Neoplasm, Residual drug therapy, Neoplasm, Residual mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Retrospective Studies, Risk, Antineoplastic Combined Chemotherapy Protocols, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Between 1981 and 1999, 890 Austrian children with acute lymphoblastic leukemia (ALL) were treated in 5 consecutive trials using protocols from the Berlin-Frankfurt-Münster (BFM) Group. In the trials BFM-A (Austria) 81 and ALL A 84, treatment stratification was performed using a risk factor, which was calculated from the initial peripheral blast cell count, and size of liver and spleen. In the following studies (BFM-A 86, 90 and 95) early response to a 7-day systemic mono-therapy with prednisone (as measured by the peripheral blast cell count) was used as an overriding stratification factor; in order to reduce the need for cranial radiotherapy, all patients received high-dose methotrexate (5 g/m2) for preventive central nervous system treatment. Event-free survival (EFS) rates increased from study BFM-A 81 (n = 141, probability (p) of EFS: 59% +/- 4%) and study ALL A 84 (n = 127, pEFS: 67% +/- 4%) to 77% +/- 4% in trial BFM-A 86 (n = 142), 79% +/- 3% in trial BFM-A 90 (n = 256), and 84% +/- 3% in trial BFM-A 95 (n = 224). However, the prognosis for high-risk patients has not significantly improved within the last 20 years (pEFS: 50%). Furthermore, conventional risk factors such as leukocyte count and age at time of diagnosis, could not be used to indicate patients in the low and intermediate risk group who might eventually relapse. Thus, in trial BFM-A 2000, detection of minimal residual disease by polymerase chain reaction-based methods after 5 and 12 weeks of therapy was introduced for treatment stratification. Minimal residual disease was prospectively shown to predict relapses more precisely and, as a matter of fact, may allow a more exact definition of which patients are at risk and which patients belong to the subgroup with a good prognosis despite reduced treatment.
- Published
- 2002
22. High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia.
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Crazzolara R, Kreczy A, Mann G, Heitger A, Eibl G, Fink FM, Möhle R, and Meister B
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- Antibodies, Monoclonal pharmacology, Biomarkers analysis, Chemokine CXCL12, Chemokines, CXC metabolism, Chemotaxis, Leukocyte drug effects, Child, Child, Preschool, Female, Flow Cytometry methods, Humans, Immunohistochemistry methods, Infant, Jurkat Cells, Liver pathology, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Receptors, CXCR4 immunology, Receptors, CXCR4 metabolism, Spleen pathology, Leukemic Infiltration diagnosis, Lymphocytes metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Receptors, CXCR4 analysis
- Abstract
Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell-derived factor-1 (SDF-1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF-1 (r = 0.73, P = 0.001). Inhibition of SDF-1-induced migration by an anti-CXCR4 monoclonal antibody (78.33 +/- 23.86% inhibition) evidenced the specificity of CXCR4 to SDF-1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66.12 +/- 66.17) than patients without extramedullary organ infiltration (median 17.56 +/- 19.29; P < 0.001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102.74 +/- 92.13; P < 0.003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.
- Published
- 2001
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23. Image fusion of magnetic resonance and F-18 FDG positron emission tomography using a dual-head camera in coincidence mode to determine the viability of an embryonic rhabdomyosarcoma residual mass after proton radiation and chemotherapy.
- Author
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Zaknun JJ, Fink FM, Felber S, and Zaknun D
- Subjects
- Antineoplastic Agents therapeutic use, Child, Preschool, Female, Fluorodeoxyglucose F18, Humans, Protons, Radiopharmaceuticals, Rhabdomyosarcoma radiotherapy, Skull Neoplasms radiotherapy, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Rhabdomyosarcoma diagnostic imaging, Rhabdomyosarcoma therapy, Skull Neoplasms diagnostic imaging, Skull Neoplasms therapy, Tomography, Emission-Computed methods
- Published
- 2001
- Full Text
- View/download PDF
24. Prognostic significance of DNA di-tetraploidy in neuroblastoma.
- Author
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Ladenstein R, Ambros IM, Pötschger U, Amann G, Urban C, Fink FM, Schmitt K, Jones R, Slociak M, Schilling F, Ritter J, Berthold F, Gadner H, and Ambros PF
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Austria epidemiology, Biomarkers, Tumor blood, Chemotherapy, Adjuvant, Child, Child, Preschool, Cohort Studies, Combined Modality Therapy, Disease-Free Survival, Female, Follow-Up Studies, Gene Amplification, Genes, myc, Germany epidemiology, Humans, In Situ Hybridization, Fluorescence, Infant, Infant, Newborn, Life Tables, Male, Neoplasm Staging, Neuroblastoma blood, Neuroblastoma mortality, Neuroblastoma therapy, Poland epidemiology, Prognosis, Proportional Hazards Models, Radiotherapy, Adjuvant, Risk, Survival Analysis, Aneuploidy, DNA, Neoplasm genetics, Neuroblastoma genetics
- Abstract
Background: Identification of biological factors may provide tools to discriminate poor risk neuroblastoma patients of diagnosis, to ultimately offer risk adapted treatment intensity., Procedures: Tumour cell DNA content, MYCN amplification (NMA), deletion of the short arm of chromosome 1 (del 1p) as well as three serological markers were assessed in 179 children with neuroblastoma., Results: Localised regional disease (stage 1 to 3) was diagnosed in 98 patients, and disseminated disease in 81 patients (65 with stage 4, 16 with stage 4s). Median age at diagnosis was 12 months and the median observation time 4 years. Sixty-seven of 179 patients had near di-tetraploid tumours (37%), with a significantly worse prognosis of 44% overall survival at 4 years in comparison with 88% in near triploid tumours (P < .001). The near di-tetraploid group showed a significant correlation with additional adverse biological factors (NMA, del 1p: P < 0.001), age over 1 year (P< 0.001), clinical stage 4 (P< 0.001), elevated ferritin (P = 0.023), and elevated LDH (P< 0.001). Multivariate analysis based on the overall (OS) and event free survival (EFS) estimations revealed that near di-tetraploidy was the most powerful biological factor, with a P-value of <0.001 for EFS and OS, followed by NMA (P = 0.015) for OS and del 1p (P= 0.047) for EFS., Conclusions: This analysis underlines the important influence of near di-tetraploidy on prognosis, and suggests that more efforts should be undertaken to implement this factor in future studies.
- Published
- 2001
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- View/download PDF
25. Chromosomal regions involved in the pathogenesis of osteosarcomas.
- Author
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Stock C, Kager L, Fink FM, Gadner H, and Ambros PF
- Subjects
- Adolescent, Adult, Child, Chromosome Disorders, Chromosome Painting, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Nucleic Acid Hybridization, Bone Neoplasms etiology, Bone Neoplasms genetics, Chromosome Aberrations etiology, Chromosome Aberrations genetics, Osteosarcoma etiology, Osteosarcoma genetics
- Abstract
The comparative genomic hybridization technique (CGH) was used to identify common chromosomal imbalances in osteosarcomas (OS), which frequently display complex karyotypic changes. We analyzed 13 high-grade primary tumors, 5 corresponding cell lines, 2 primary tumors grade 2, and 1 recurrent tumor from a total of 16 patients. Some of the CGH results have been verified by fluorescence in situ hybridization (FISH) studies. Gains of chromosomal material were more frequent than losses. Most common gains were observed at 8q (11 cases), 4q (9 cases), 7q (8 cases), 5p (7 cases), and 1p (8 cases). The smallest regions of overlap have been narrowed down to 8q23 (10 cases), 4q12-13 (8 cases), 5p13-14 (7 cases), 7q31-32 (7 cases), 8q21 (7 cases), and 4q28-31 (5 cases). These data demonstrate that a number of chromosomal regions and even two distinct loci on 4q and 8q are involved in the pathogenesis of OS, with gain of 4q12-13 chromosomal material representing a newly identified locus. Seven of 16 cases displayed, besides gain of 8q23 sequences, gain of MYC copies in CGH and FISH. Previous CGH reports confined gain of 8q material to 8cen-q13, 8q21.3-8q22, and 8q23-qter, whereas our data suggest that the loci 8q21 and 8q23-24 are affected in the development of OS. In contrast to recent reports, copy number increases at 8q and 1q21 did not have an unfavorable impact on prognosis in the present series. Genes Chromosomes Cancer 28:329-336, 2000., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
- Full Text
- View/download PDF
26. Requirement of residual thymus to restore normal T-cell subsets after human allogeneic bone marrow transplantation.
- Author
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Heitger A, Greinix H, Mannhalter C, Mayerl D, Kern H, Eder J, Fink FM, Niederwieser D, and Panzer-Grümayer ER
- Subjects
- Adolescent, Adult, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Child, Child, Preschool, Female, Humans, Leukocyte Common Antigens analysis, Male, Middle Aged, Postoperative Period, Receptors, Antigen, T-Cell analysis, T-Lymphocytes transplantation, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer pathology, Thymectomy, Tissue Donors, Transplantation, Homologous, Bone Marrow Transplantation, T-Lymphocyte Subsets pathology, Thymus Gland physiopathology
- Abstract
Background: To determine the effect of residual thymic activity in reconstituting the T-cell system after T cell-depleting therapy, we monitored T-cell subsets of a unique thymectomized cancer patient in comparison to thymus-bearing patients after allogeneic bone marrow transplantation (BMT)., Methods: T cells and T-cell subsets previously shown in murine studies to be regulated by the thymus were analyzed by FACS from 6 to >48 months after BMT. The investigation of thymus-bearing patients included 32 examinations of 9 children and 14 adults. None of the investigated cases had severe graft-versus-host disease or severe infections when examined., Results: In the thymectomized host, T-cell regeneration occurred by donor cell expansion and was characterized by two prominent features: (i) a persistent failure to regenerate naive (CD45RA+) T-helper cells (14%, median), consistent with the recently developed concept of a thymus-dependency; and (ii) persistently elevated proportions of CD3+CD4-CD8- cells (double-negative cells, median 29%), which were identified in T cell receptor (TCR)gamma delta+ (22%, median of CD3+ cells, 88% double negatives) but also TCRalpha beta+ T-cell populations (78%, median of CD3+ cells, 17% double negatives). In thymus-bearing patients, 10 of 12 and 6 of 14 examinations of children and adults, respectively, performed later than 12 months after BMT showed the proportion of CD4+CD45RA+ cells appropriate for age (>52% and >28% in children and adults, respectively). Elevated double-negative cells (>10%) were found in only three patients, but none had elevated double-negative cells with a TCRalpha beta+ phenotype., Conclusion: Residual thymic activity might, in addition to its well-established role for regenerating naive T-helper (CD4+CD45RA+) cells, control the expansion of double-negative cells. A normal T-cell subset regeneration in a proportion of thymus-bearing adult hosts indicates the potential of an effective residual thymic activity even beyond childhood.
- Published
- 2000
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27. Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP).
- Author
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Brandau O, Schuster V, Weiss M, Hellebrand H, Fink FM, Kreczy A, Friedrich W, Strahm B, Niemeyer C, Belohradsky BH, and Meindl A
- Subjects
- DNA Mutational Analysis, Dysgammaglobulinemia complications, Epstein-Barr Virus Infections complications, Exons, Gene Deletion, Haplotypes, Humans, Infectious Mononucleosis complications, Lymphoma, Non-Hodgkin complications, Lymphoproliferative Disorders complications, Male, Molecular Sequence Data, Pedigree, Point Mutation, RNA Splicing, Signaling Lymphocytic Activation Molecule Associated Protein, Carrier Proteins genetics, Intracellular Signaling Peptides and Proteins, Lymphoma, Non-Hodgkin genetics, Lymphoproliferative Disorders genetics
- Abstract
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency, which most often manifests itself after Epstein-Barr virus (EBV) infection. The main clinical phenotypes include fulminant or fatal infectious mononucleosis, dysgammaglobulinaemia and malignant lymphoma. We have recently cloned the SH2D1A gene, which has been shown to be mutated in approximately 70% of XLP patients. Now we report five novel SH2D1A mutations in patients from five unrelated XLP families. No mutations were found in another three XLP families. In three boys with early onset non-Hodgkin lymphoma (NHL) from two unrelated families a deletion of SH2D1A exon 1 and a splice site mutation were found, respectively. These patients did not show any laboratory or clinical signs of a previous EBV infection. A fourth EBV-uninfected and unrelated boy with a stop mutation in the SH2D1A gene shows only signs of dysgammaglobulinaemia. Development of dysgamma-globulinaemia and lymphoma without evidence of prior EBV infection in four of our patients suggests that EBV is unrelated to these phenotypes, in contrast to fulminant or fatal infectious mononucleosis. The role of SH2D1A as a putative tumour suppressor gene remains to be investigated.
- Published
- 1999
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28. Cryptic exons as a source of increased diversity of Ewing tumor-associated EWS-FLI1 chimeric products.
- Author
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Kovar H, Jugovic D, Melot T, Zoubek A, Lenoir G, Fink FM, Philip I, Turc-Carel C, Thomas G, and Zucman-Rossi J
- Subjects
- Adolescent, Amino Acid Sequence, Child, Exons, Female, Gene Rearrangement, Genetic Variation, Humans, Male, Molecular Sequence Data, Proto-Oncogene Protein c-fli-1, RNA genetics, RNA-Binding Protein EWS, Sequence Analysis, DNA, Oncogene Proteins, Fusion genetics, Recombinant Fusion Proteins genetics, Sarcoma, Ewing genetics, Transcription Factors genetics
- Abstract
In the Ewing family of tumors (EFT), the EWS gene is rearranged with members of the ets oncogene family. Variability in genomic breakpoint locations is the source of significant heterogeneity in fusion product structure. As a consequence of variably included exon sequences from the two partner genes, a variable amount of additional peptide sequence is inserted in between the minimal transforming domains. Some of this molecular diversity has recently been correlated with disparate clinical outcome. Here we report on cryptic exons found in the chimeric RNA of three EFT with different EWS-FLI1 fusions. In two tumors, the emergence of a cryptic exon from FLI1 intron 5 in the chimeric RNA was apparently unrelated to the genomic rearrangement that occurred in FLI1 introns 4 and 5, respectively. In one case, a novel exon was generated through the creation of an artificial splice acceptor site in FLI1 intron 6 by the genomic rearrangement that occurred in EWS intron 8. These results further extend the spectrum of molecular diversity in EFT., (Copyright 1999 Academic Press.)
- Published
- 1999
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29. Transplantation of related and unrelated umbilical cord blood stem cells in Austria. Austrian Working Party for Stem Cell Transplantation. Austrian Society of Hematology and Oncology.
- Author
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Schwinger W, Urban C, Lackner H, Kerbl R, Sovinz P, Gardner H, Peters C, Niederwieser D, Fink FM, and Kögler G
- Subjects
- Anemia, Aplastic blood, Anemia, Aplastic therapy, Austria, Child, Child, Preschool, Female, Follow-Up Studies, Graft vs Host Disease blood, Graft vs Host Disease prevention & control, Humans, Immunosuppression Therapy, Infant, Leukemia, Myelomonocytic, Chronic blood, Leukemia, Myelomonocytic, Chronic therapy, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma blood, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation, Homologous, Transplantation, Isogeneic, Treatment Outcome, Fetal Blood cytology, Hematopoietic Stem Cell Transplantation
- Abstract
Allogeneic bone marrow transplantation is limited by the availability of suitable HLA-matched donors and the risk of graft versus host disease (GvHD). In an attempt to overcome these limitations umbilical cord blood (UCB), has become a further alternative. UCB transplantations in Austria were started in 1991. As of September 31, 1998, six patients have been transplanted. Diagnoses were severe aplastic anaemia (SAA) (n = 2), acute lymphoblastic leukaemia (ALL) (n = 1), familial hemophagocytic syndrome (FHL) (n = 2) and chronic myelomonocytic leukaemia (CMML) (n = 1). Three patients received UCB grafts from HLA-identical siblings and three patients from unrelated donors, of whom two were disparate at two HLA loci (A/B) and one mismatched at one locus (C). Five patients were engrafted with complete donor hematopoiesis, with a median time of 26.5 days (range 14 to 39 days) to an ANC count of > or = 0.5 x 10(9)/L and a median time of 42.5 days (range 24 to 67 days) to a platelet count of > or = 20 x 10(9)/L. One patient with FHL had partial engraftment and died due to reactivation of cytomegalovirus (CMV) infection and CMV pneumonia on day +25. Of the five patients surviving the post-transplant period, one with CMML had a relapse on day +128 and died after a HLA-matched bone marrow transplantation from the same sibling donor in the second relapse. Another patient with ALL relapsed on day +200 but is still alive under palliative treatment; one patient with SAA showed graft rejection and autologous hematopoietic reconstitution and later had a successful CD34(+)-selected allogeneic peripheral stem cell transplant from a C-locus mismatched unrelated donor. Two patients (one with SAA and one with FHL) are alive with complete remission of the underlying disease. This report reflects the experience and results of UCB transplantation in Austria and discusses the position of UCB transplantation in the context of the other stem cell alternatives available today.
- Published
- 1999
30. Trends in infection morbidity in a pediatric oncology ward, 1986-1995.
- Author
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Wehl G, Allerberger F, Heitger A, Meister B, Maurer K, and Fink FM
- Subjects
- Adolescent, Child, Child, Preschool, Clostridioides difficile drug effects, Clostridioides difficile pathogenicity, Drug Resistance, Microbial, Enterocolitis, Pseudomembranous microbiology, Enterocolitis, Pseudomembranous mortality, Female, Fever complications, Granulocyte Colony-Stimulating Factor therapeutic use, Hospitalization, Humans, Incidence, Infant, Infant, Newborn, Male, Neoplasms drug therapy, Neoplasms mortality, Neutropenia chemically induced, Neutropenia complications, Prognosis, Retrospective Studies, Antineoplastic Agents adverse effects, Bacterial Infections mortality, Immunocompromised Host, Morbidity trends, Neoplasms immunology
- Abstract
Background and Procedure: We retrospectively studied the type, severity, frequency, and outcome of febrile infectious complications in 217 cancer patients receiving cytotoxic chemotherapy (603 episodes) over a 10-year period in a single pediatric institution., Results: A total of 48.8% of the episodes occurred in severely leukopenic patients (WBC < 1.0 x 10(9)/l, absolute neutrophil count < 500 x 10(6)/l). In the second half of the study period febrile episodes occurred at increased frequency. The number of patients with gram-positive isolates in blood cultures increased over the years, most frequently coagulase-negative staphylococci were found. Remarkably, gram-negative bacteria increasingly resistant to the administered first-line antibiotic regimen emerged, necessitating modifications of the antimicrobial strategy every 3 years. Furthermore, Clostridium difficile-associated enterocolitis posed a clinical problem at increasing frequency since 1993. As expected, the speed of leukocyte recovery within 5 days from the onset of a febrile complication had an influence on the outcome of these episodes., Conclusions: Rapid recovery of the WBC was associated with an excellent prognosis whereas persisting neutropenia was found to be a negative factor associated with fatal outcomes. The fatality rate of all febrile episodes (2.3%) remained the same throughout the study period despite the availability and wider use of recombinant hematopoietic growth factors since 1991.
- Published
- 1999
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31. Expression of vascular endothelial growth factor (VEGF) and its receptors in human neuroblastoma.
- Author
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Meister B, Grünebach F, Bautz F, Brugger W, Fink FM, Kanz L, and Möhle R
- Subjects
- Adolescent, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Female, Humans, Infant, Male, Neovascularization, Pathologic, Neuroblastoma blood supply, RNA, Messenger metabolism, Receptors, Vascular Endothelial Growth Factor, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Endothelial Growth Factors metabolism, Lymphokines metabolism, Neuroblastoma metabolism, Receptor Protein-Tyrosine Kinases metabolism, Receptors, Growth Factor metabolism
- Abstract
Angiogenic factors may play a role in the biology of neuroblastoma, a well vascularised tumour, which frequently spreads haematogenously. Therefore, we analysed expression of vascular endothelial growth factor (VEGF) in six human neuroblastoma cell lines and five primary neuroblastomas. High VEGF levels (1-3 ng/10(6) cells/day) were found in the supernatant of all cell lines examined (SK-N-LO, SK-N-SH, LS, SH-SY5Y, IMR-32, Kelly). VEGF peptide was also detected in tissue homogenates from four of five primary tumours. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that VEGF165 is the major isoform produced by neuroblastomas. In addition, all cell lines and primary tumours expressed the mitogenic VEGF receptor FLK-1, whilst the non-mitogenic receptor FLT-1 was less frequently positive, suggesting that the tyrosine kinase FLK-1 is involved in malignant transformation of neuroblastoma cells. However, neutralising antibodies to VEGF did not inhibit growth of neuroblastoma cell lines, which argues against a role of VEGF as an autocrine growth factor, at least for cell lines in vitro. We conclude that neuroblastoma cells produce VEGF, which may contribute to tumour vascularisation, growth and invasion.
- Published
- 1999
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32. Effective T cell regeneration following high-dose chemotherapy rescued with CD34+ cell enriched peripheral blood progenitor cells in children.
- Author
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Heitger A, Kern H, Mayerl D, Maurer K, Nachbaur D, Frühwirth M, Fink FM, and Niederwieser D
- Subjects
- Child, Child, Preschool, Combined Modality Therapy, Female, Hematopoietic Stem Cell Mobilization, Humans, Lymphocyte Depletion, Male, Transplantation Immunology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms immunology, Brain Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Neuroblastoma immunology, Neuroblastoma therapy, Rhabdomyosarcoma immunology, Rhabdomyosarcoma therapy, T-Lymphocytes immunology
- Abstract
The ex vivo enrichment for the CD34+ cell fraction of PBPC, while it retains the capacity to restore haematopoiesis and potentially reduces a contamination by tumour cells, implements a depletion of T cells. To test whether such a setting adversely affects T cell reconstitution, we monitored T cells in four paediatric patients after CD34+ selected PBPC transplantation. The dose of CD34+ cells, which were enriched to 74%, median, was 7.1 x 10(6)/kg, median, that of T cells was 0.071 x 10(6)/kg, median. The patients were homogenous with respect to features with a potential to effect T cell reconstitution (low median age, (35 years); stage IV malignant tumours in first CR, uncomplicated post-treatment course). The results of sequential FACS analyses showed that by 9 months after treatment all four patients had recovered (1) a normal T cell count (CD3+ cells 1434/microl, median); (2) a normal CD4+ cell count (816/microl, median), while CD8+ cells were recovered (>330/microl) already by 3 months; (3) a normal CD4/CD8 ratio (1.8, median), as a result of an augmented growth of CD4+ cells between 3 and 6 months (increase of CD4+ cells 4.9-fold, median, CD8+ cells 1.1-fold, median). Expansion of cells with a CD45RA+ phenotype (thymus-derived T cells) predominated; from 3 to 6 months the increase of CD4+/CD45RA+ T cells was 130-fold, that of CD4+/CD45RO+ cells was 1.7-fold; CD8+/CD45RA+ cells increased 9-fold, CD8+/CD45RO+ cells increased 2.1-fold, indicating effective thymopoiesis. The findings demonstrate that in paediatric patients the setting of HD-CTX rescued with autologous CD34+ selected PBPC per se is not predictive of an impaired T cell recovery. High thymic activity may be a key factor for the rapid restoration of T cells.
- Published
- 1999
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33. Capillary leak syndrome in a patient with septicemia and granulocyte-colony-stimulating factor (G-CSF)-induced accelerated granulopoiesis.
- Author
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Heitger A, Maurer K, Neu N, and Fink FM
- Subjects
- Adolescent, Bacteremia blood, Capillary Leak Syndrome blood, Hematopoiesis drug effects, Humans, Male, Mediastinal Neoplasms drug therapy, Sarcoma drug therapy, Antineoplastic Agents adverse effects, Bacteremia etiology, Capillary Leak Syndrome etiology, Granulocyte Colony-Stimulating Factor adverse effects, Granulocytes drug effects
- Published
- 1998
- Full Text
- View/download PDF
34. Antiproliferative activity and apoptosis induced by retinoic acid receptor-gamma selectively binding retinoids in neuroblastoma.
- Author
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Meister B, Fink FM, Hittmair A, Marth C, and Widschwendter M
- Subjects
- Apoptosis drug effects, Binding, Competitive, Cell Division drug effects, Humans, Kinetics, Neuroblastoma, Receptors, Retinoic Acid biosynthesis, Receptors, Retinoic Acid drug effects, Retinoic Acid Receptor alpha, Structure-Activity Relationship, Tumor Cells, Cultured, Retinoic Acid Receptor gamma, Receptors, Retinoic Acid metabolism, Retinoids metabolism, Retinoids toxicity, Tretinoin toxicity
- Abstract
Retinoids modulate several cell functions and especially inhibit the growth of tumor cells. Their biological activity is mediated by retinoic acid receptors (RARs), of which three subtypes (alpha, beta, gamma) have been identified. In human neuroblastoma (NB) reduced endogenous RAR-gamma expression was suggested to diminish the sensitivity for retinoids, to promote proliferation, and to contribute to the malignant phenotype. To correlate receptor selectivity with in vitro activity, we analysed the effect of six synthetic retinoids with selectivity for human RAR-alpha/beta/gamma on the human LAN-5 NB cell line and compared it with the natural compound all-trans-retinoic acid (ATRA). Apoptosis was determined by flow-cytometry using terminal-deoxynucleotidyl transferase to end-label DNA fragments in situ in apoptotic cells. The antagonist for RAR-beta/gamma CD2665 as well as the selective agonists for RAR-alpha CD336 and RAR-beta CD2019 were less effective in growth inhibition than ATRA. In contrast, the synthetic RAR-gamma selective agonists CD437 and CD2325 induced a concentration- and time-dependent antiproliferative effect, which was similar or even more pronounced than ATRA. In contrast to ATRA, the adition of CD437 and CD2325 did not induce morphological changes typical of NB cell maturation but resulted in morphological features consistent with the occurrence of programmed cell death. Flow-cytometric analysis showed that in contrast to ATRA the addition of CD 437 and CD 2325 results in progressive time-dependent increase of apoptotic cells (25.9% and 57.7% after 72 hours). In conclusion, our study demonstrates RAR-gamma selectively binding retinoids dramatically suppress NB cell growth, primarily by inducing programmed cell death rather than by cell differentiation. Since advanced or disseminated NB tumors endogenously express low levels of RAR-gamma and lack of apoptosis is involved in tumor progression, RAR-gamma selectively binding retinoids may be more appropriate retinoids for clinical trials in NB.
- Published
- 1998
35. CD34+-selected autologous peripheral blood stem cell transplantation (PBSCT) in patients with poor-risk hematological malignancies and solid tumors. A single-centre experience.
- Author
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Nachbaur D, Fink FM, Nussbaumer W, Gächter A, Kropshofer G, Ludescher C, and Niederwieser D
- Subjects
- Antigens, CD34 analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bone Marrow Transplantation, Combined Modality Therapy, Graft Survival, Granulocyte Colony-Stimulating Factor therapeutic use, Hematopoietic Stem Cell Mobilization, Humans, Immunologic Factors therapeutic use, Interferon alpha-2, Interferon-alpha therapeutic use, Opportunistic Infections epidemiology, Recombinant Proteins, Remission Induction, Retrospective Studies, Survival Analysis, Time Factors, Transplantation Conditioning, Treatment Outcome, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Neoplasms therapy
- Abstract
Between July 1994 and December 1996, PBSC were mobilized in 28 patients with poor-risk hematological malignancies and solid tumors. CD34+ cells were positively immunoselected using the Ceprate CS System. By December 1996, 22 patients had been reinfused with a median of 3.325 (0.078-9.5) x 10(6)/kg CD34+ cells. In three patients unselected back-up PBSC had to be transfused along with selected CD34+ cells because of a CD34+ cell number <0.5 x 10(6)/kg. G-CSF (10 microg/kg) was started on day +1 and all patients engrafted within a median day number of 12 (range, 10-22) until leukocytes >1.0 x 10(9)/l and a median day number of 56 (range, 10-180) until platelets >20.0 x 10(9)/l (ie platelet transfusion independence). Time to leukocyte and platelet recovery was significantly shorter in patients receiving >2.0 x 10(6)/kg purified CD34+ cells as compared to patients reinfused with <2.0 x 10(6)/kg CD34+ cells. The hematopoietic recovery time was similar to that of 18 historical control patients treated with unseparated ABMT +/- PBSCT with the exception of a significantly faster leukocyte engraftment in patients receiving >2.0 x 10(6)/kg CD34+ cells and a significantly delayed platelet recovery time in patients receiving <2.0 x 10(6)/kg purified CD34+ cells. There was a trend for a better overall survival and a lower probability of progression/relapse as compared to the historical controls. We observed five episodes of serious opportunistic infections (three pulmonary fungal infections, two cases of cryptosporidiosis) after the take. Four of these patients had been reinfused with <2.0 x 10(6)/kg CD34+ cells probably indicating a delayed immune reconstitution after CD34+-selected PBSCT.
- Published
- 1997
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36. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation.
- Author
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Heitger A, Neu N, Kern H, Panzer-Grümayer ER, Greinix H, Nachbaur D, Niederwieser D, and Fink FM
- Subjects
- Adolescent, Adult, Antigens, CD, Child, Child, Preschool, Cyclosporine therapeutic use, Female, Flow Cytometry, Graft vs Host Disease prevention & control, Histocompatibility Testing, Humans, Immunosuppression Therapy methods, Infant, Male, Regeneration, T-Lymphocyte Subsets immunology, Thymectomy, Transplantation, Homologous, Whole-Body Irradiation, Bone Marrow Transplantation immunology, Leukocyte Common Antigens, T-Lymphocytes, Helper-Inducer immunology, Thymus Gland immunology
- Abstract
To contribute to the understanding of the role of the thymus in humans in the reconstitution of naive (CD45RA+) T cells after bone marrow transplantation (BMT), we compared T-cell regeneration in a unique situation, namely a thymectomized cancer patient (15 years old), with that of thymus-bearing patients after allogeneic BMT. These cases shared features of transplantation (total body irradiation, HLA-matched donors, and graft-versus-host disease prophylaxis with cyclosporine A) and all had an uncomplicated post-transplantation course. As shown by fluorescence-activated cell sorting analyses, the thymectomized host failed to reconstitute CD45RA+ T-helper cells even 24 months after BMT (11% CD45RA+ of CD4+ cells). In this patient, preferentially CD45RO+ cells contributed to the recovery of CD4+ cells (206 of 261/microL at 6 months and 463 of 558/microL at 24 months after BMT, CD45RA+ of CD4+ cells), whereas CD45RA+ cells remained low (<60/microL). In contrast, nine thymus-bearing hosts (5 children and 4 adults) examined between 6 and 24 months after BMT effectively reconstituted CD4+/CD45RA+ cells according to their normal age-related range (> or = 28% in adults and > or = 50% in children). Five of these were analyzed sequentially at 6 and 9 months after BMT. Within this period, CD45RA+ cells increasingly contributed to the recovery of CD4+ cells (median, +21%), even when total CD4+ cells decreased. With respect to T-cytotoxic/suppressor cells, the thymectomized host retained the capacity to recover CD45RA+ cells (137 of 333/microL at 6 months and 596 of 1,046/microL at 24 months after BMT, CD45RA+ of CD8+ cells), a proportion similar to that seen in thymus-bearing hosts. These findings suggest that a thymus-independent pathway exists to regenerate CD45RA+ T-cytotoxic/suppressor cells, but residual thymus is essential to reconstitute naive (CD45RA+) T-helper cells after BMT in humans.
- Published
- 1997
37. A single centre experience with allogeneic stem cell transplantation for severe aplastic anaemia in childhood.
- Author
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Ladenstein R, Peters C, Minkov M, Emminger-Schmidmeier W, Mann G, Höcker P, Hawliczek R, Rosenmayr A, Fink FM, Niederwieser D, and Gadner H
- Subjects
- Anemia, Aplastic etiology, Anemia, Aplastic mortality, Child, Child, Preschool, Female, Follow-Up Studies, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Histocompatibility Testing, Humans, Immunosuppressive Agents adverse effects, Immunosuppressive Agents therapeutic use, Male, Survival Rate, Transplantation, Homologous, Treatment Outcome, Anemia, Aplastic therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Background: Severe aplastic anaemia (SAA) is a rare disorder which has a fatal course when allogeneic stem cell transplantation (SCT) or an immunosuppressive regimen is not applied. Stem cell replacement is the only curative approach for these patients but it is limited by the availability of a compatible donor., Patients: Between 1982 and 1993, 18 children (15 boys, 3 girls) with SAA and HLA identical, MLC negative donors underwent SCT in our institution. SAA was preceded by viral infection in 8 patients (3x hepatitis, 1x measles, 1x herpes simplex infection and 3x viral upper respiratory tract infections). It was drug-associated in one and idiopathic in the 9 others. The median age at diagnosis was 9.7 years (range, 2 months to 16 years). Pretreatments included corticosteroids in 11/18 patients, androgens in 4 patients in addition, two had received cyclosporin A (CSA). One patient progressing from Diamond- Blackfan anaemia to SAA had multiple immunosuppressive treatment courses over 7 years before his grand-uncle was identified as donor while 4 patients had no treatment prior to SCT., Methods: Early SCT (within 90 days after diagnosis) was performed in 9/18 patients and the median interval between diagnosis and SCT was 2.6 months (range, 0.5 to 7 years). The stem cell source was the bone marrow (BM) of a syngeneic twin in 2 patients, the BM (13 patients) or the cord blood (1 patient) of a sibling whilst it was BM from a HLA-phenotypical family donor (1 father, 1 grand-uncle) in two patients. Cyclophosphamide 50 mg/kg on 4 consecutive days was given as preparative regimen to 16 patients but not to the two syngeneic twins. Rejection prophylaxis included total lymphoid irradiation in 5/16 patients while in the other 11 patients donor buffy coat cells were given on days +1 to +4. The syngeneic twins had no need for either approach. Patients received a median number of 3.7 x 10(8)/kg nucleated cells (range, 2.6 to 6.7). Prophylaxis of graft versus host disease (GVHD) was carried out with MTX alone (n = 12), with CSA alone (n = 2) or with both (n = 4). All patients received standard supportive care., Results: The overall survival is 89% at the median observation time of 100 months. The median time to reach 500 granulocytes was 24 days (range, 15 to 40). Median time to become transfusion independent after BMT was 30 days for platelets (range, 2 to 111) and was 28 days for packed red blood cells (range, 6 to 128). Acute GVHD was observed in 10/18 patients and involved only skin in 6 patients, skin and liver or gut in two patients and all 3 organs in another two patients. Seven of 10 patients had grade 1 to 2 a GVHD toxicity, whereas 3 patients experienced grade 3 to 4 acute GVHD. Chronic GVHD developed in 5 patients. Acute transplant related mortality was 5.5%. Cause of death was persisting non engraftment till day +180 after 2 transplant procedures in a boy with previous platelet transfusions from his mother. Late mortality occurred in 2 patients: one chronic GVHD associated haemorrhage 20 months after SCT and one chronic GVHD associated septicaemia 10 years after SCT., Conclusion: Although this report reflects patients data accumulated over 15 years, results compare favourably with more recent survival data. Acute and late transplant related toxicity was low in patients undergoing early transplantation with adequate prior supportive care. This data confirms that SCT still should be the first treatment choice if an HLA identical sibling is available.
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- 1997
- Full Text
- View/download PDF
38. Partial nephrectomy in a cystic partially differentiated nephroblastoma.
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Streif W, Gassner I, Janetschek G, Kreczy A, Judmaier W, and Fink FM
- Subjects
- Cysts pathology, Cysts surgery, Diagnosis, Differential, Humans, Infant, Newborn, Kidney Neoplasms pathology, Kidney Neoplasms surgery, Nephrectomy methods, Wilms Tumor pathology, Wilms Tumor surgery
- Abstract
Cystic partially differentiated nephroblastoma (CPDN) is a rare neoplastic disorder consisting of a well-demarcated cystic lesion of the kidney where blastemal or other embryonic cells are present in the septa of the cysts. Magnetic resonance imaging can detect the cystic character of the lesion and will produce imaging features that are highly suggestive of either CPDN or cystic nephroma (CN) (synonym: multilocular cyst of the kidney), a benign entity. Although malignant potential exists in CPDN, all cases reported to date have had a favorable prognosis after surgery alone. Partial nephrectomy is considered safe, and the treatment of choice in the newborn period. We report a case of CPDN in a newborn that was successfully treated with partial nephrectomy. More than five years after nephron sparing surgery, the involved kidney shows normal anatomical structure except for a diminished upper pole, no evidence of tumor recurrence and good renal function.
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- 1997
- Full Text
- View/download PDF
39. Deletion mapping on chromosome 17p in medulloblastoma.
- Author
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Steichen-Gersdorf E, Baumgartner M, Kreczy A, Maier H, and Fink FM
- Subjects
- Adolescent, Child, Child, Preschool, Genes, Tumor Suppressor, Humans, Loss of Heterozygosity, Chromosome Mapping, Chromosomes, Human, Pair 17, Medulloblastoma genetics
- Abstract
Medulloblastoma is the most frequent paediatric brain tumour. Because of the uniform histology, a common genetic mechanism has been postulated. Loss of heterozygosity (LOH) studies support evidence that a candidate gene, which functions as a tumour-suppressor gene, is located in 17p13. Eighteen tumours were examined for loss of heterozygosity at 15 different loci at chromosome 17p. Nine of 18 (50%) tumours had allelic loss in 17p 13.3-13.2. The smallest region of overlap, which harbours the disease gene, includes markers from UT222 (D17S675) to UT49 (D17S731) and spans a region of less than 6 cM. Candidate genes within this region are HIC-1, a potential tumour-suppressor gene, and DPH2L, a gene that has been cloned from the ovarian critical region. The putative region excludes the p53 gene and the ABR gene, which have been favoured by others. LOH of chromosome 17p may be used as a new prognostic biological marker. Children with an allelic loss had a poorer prognosis than those patients without loss of heterozygosity (P<0.05).
- Published
- 1997
- Full Text
- View/download PDF
40. The effect of recombinant human erythropoietin on circulating hematopoietic progenitor cells in anemic premature infants.
- Author
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Meister B, Maurer H, Simma B, Kern H, Ulmer H, Hittmair A, and Fink FM
- Subjects
- Antigens, CD34 blood, Antigens, CD34 drug effects, Blood Transfusion, Cell Count drug effects, Colony-Forming Units Assay, Erythrocyte Count, Female, Gestational Age, Hematocrit, Hematopoietic Stem Cells immunology, Hemoglobins drug effects, Humans, Infant, Newborn, Infant, Premature, Leukocyte Common Antigens blood, Leukocyte Common Antigens drug effects, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Male, Neutrophils drug effects, Neutrophils immunology, Recombinant Proteins therapeutic use, Reticulocytes drug effects, Reticulocytes immunology, Anemia blood, Anemia drug therapy, Erythropoietin therapeutic use, Hematopoietic Stem Cells drug effects
- Abstract
In vitro and animal studies suggest that high concentrations of recombinant human erythropoietin (rHuEPO) might divert multipotent progenitors into erythroid maturation at the expense of granulocyte production. We determined whether changes of number and lineage commitment of peripheral blood progenitor cells occur in premature infants during therapy with rHuEPO. Thirty preterm infants were randomly assigned either to receive 300 IU of eopoetin alpha s.c. per kilogram body weight three times a week for four weeks or to a control group. At study entry and after two weeks of treatment the numbers of circulating BFU-E, granulocyte-macrophage colony-forming units (CFU-GM) and granulocyte-erythrocyte-macrophage-megakaryocyte CFU (CFU-GEMM) were analyzed by semisolid culture technique, CD34+ cells and early myeloid CD34+CD45RA- progenitors by flow cytometry. As compared with the control group, rHuEPO treatment did not exert any significant modulatory effect on numbers of CFU-GM, nor was there a significant change in numbers of BFU-E, CFU-GEMM, total-CFU, percentage of CD34+ or CD34+CD45RA- cells. Mean neutrophil count was not significantly reduced at any period during the study. Compared with the control group, the infants receiving rHuEPO had higher hematocrit values (p = 0.003) and absolute reticulocyte counts (p < 0.001). The median cumulative volume of blood transfused per kilogram per day was 0.86 ml (first quartile 0.5 ml; third quartile 1.1 ml) in the control group and 0 ml (first quartile 0 ml; third quartile 0.47 ml) in the rHuEPO group (p = 0.038). We conclude using a relatively high dose of rHuEPO in premature infants, no significant in vivo effect on circulating peripheral blood progenitor or neutrophil count could be detected.
- Published
- 1997
- Full Text
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41. Isochromosome 12p and maternal loss of 1p36 in a pediatric testicular germ cell tumor.
- Author
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Stock C, Strehl S, Fink FM, Bauer S, Lion T, Kreczy A, Gadner H, and Ambros PF
- Subjects
- Adolescent, Chromosome Banding, Humans, Karyotyping, Male, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 12, Germinoma genetics, Isochromosomes, Testicular Neoplasms genetics
- Abstract
Analysis of a pediatric germ cell tumor by conventional cytogenetic investigation and fluorescence in situ hybridization showed consistently the presence of two isochromosomes 12p, loss of the maternal band 1p36, and other numerical and structural chromosome changes. The rearrangements observed resulted mainly from breaks occurring at paracentromeric regions. This report represents the first description of i(12)(p10) in a pediatric testicular embryonal carcinoma.
- Published
- 1996
- Full Text
- View/download PDF
42. Circulating interleukin-1 receptor antagonist levels in neonates.
- Author
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Geiger R, Ellemunter H, Fink FM, Falk M, and Tilg H
- Subjects
- Biomarkers, Case-Control Studies, Female, Humans, Infant, Newborn, Infant, Premature, Interleukin 1 Receptor Antagonist Protein, Male, Sex Factors, Statistics, Nonparametric, Infant, Newborn, Diseases blood, Receptors, Interleukin-1 antagonists & inhibitors, Sialoglycoproteins blood
- Abstract
Unlabelled: Circulating interleukin-1 receptor antagonist (IL-1 Ra) levels have been shown to reflect disease activity in certain conditions in adults. We determined circulating IL-1Ra references values for healthy neonates (healthy preterms and term infants with mild disease only) on days 2 (n = 17) and 4 of life (n = 23). Mean gestational age was 35 +/- 2.6 weeks. On the 2nd day of life IL1-Ra levels were 0.78 ng/ml (0.49/2.65), on day 4 0.38 ng/ml (0.20/0.48) (median, 25th/75th percentile, P = 0.01). The values were not influenced by gender. In neonates with severe illness (septicaemia, asphyxia, neonatal respiratory distress syndrome), who received invasive intensive care, circulating IL-1Ra levels were significantly higher than in the reference group of healthy newborns. On the 2nd day of life (14.72 ng/ml (4.38/18.67) versus 0.78 ng/ml (0.49/2.65), P < 0.0001; on day 4 of life, 3.38 ng/ml (0.80/11.99) versus 0.38 ng/ml (0.20/0.48), P < 0.005 (values are median; 25th/75th percentile, Mann-Whitney U-Wilcoxon Rank Sum W Test, two-tailed P)., Conclusion: Compared to healthy individuals beyond the neonatal period, Il-1Ra concentrations are physiologically elevated within the first days of life and decline to low levels within days. In contrast, IL-1Ra levels are strikingly elevated in sick neonates.
- Published
- 1996
- Full Text
- View/download PDF
43. Peripheral blood stem cell (PBSC) collection in extremely low-weight infants.
- Author
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Nussbaumer W, Schönitzer D, Trieb T, Fink FM, Maurer-Dengg K, Höcker P, Wagner A, Schwaighofer H, Nachbaur D, and Niederwieser D
- Subjects
- Adrenal Gland Neoplasms drug therapy, Adrenal Gland Neoplasms therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Body Weight, Bone Marrow drug effects, Bone Marrow pathology, Cell Count, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Erythrocyte Transfusion, Female, Graft Survival, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Leukapheresis instrumentation, Male, Neuroblastoma drug therapy, Neuroblastoma pathology, Neuroblastoma therapy, Platelet Transfusion, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Granulocyte Colony-Stimulating Factor pharmacology, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cells drug effects, Infant, Leukapheresis methods
- Abstract
While PBSC collection has become a safe procedure for adults, only a few reports exist about its efficacy, safety and feasibility in paediatric patients, especially extremely low-weight infants. We describe successful PBSC collection in three infants of less than 10 kg body weight (BW; range: 6.92-9.4 kg) suffering from stage IV neuroblastoma. Harvest of PBSC started after mobilisation with high-dose chemotherapy and G-CSF, as soon as 1.0% CD34+ cells were detected. Collections were performed using a Baxter CS-3000 Plus separator primed with a mixture of irradiated, white cell-depleted and CMV-negative packed red cells resuspended in 5% human albumin and diluted with saline to match the patient's haematocrit. Performing a median of four, (4-7, median, range) procedures we collected at least 4 x 10(8)/kg BW nucleated cells (NC) from all three patients. The infants were not sedated and showed no serious side-effects. All three children were successfully transplanted with myeloid engraftment in 8 (7-9) days, independence from red cell support was achieved in 15 (10-20) days and from platelet transfusions in 25 (14-29) days after PBSC infusion. We conclude that PBSC harvesting using continuous flow cell separators is safe, even in low-weight infants of less than 7 kg BW.
- Published
- 1996
44. [Value of prognostic factors in the Austrian A-NB87 Neuroblastoma Study].
- Author
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Ladenstein R, Ambros PF, Urban C, Ambros IM, Fink FM, Zoubek A, Grienberger H, Schmitt K, Kerbl R, Horcher E, Amann G, Höfler G, Heinzl H, Gadner H, and Mutz I
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Austria epidemiology, Biomarkers, Tumor analysis, Chemotherapy, Adjuvant, Child, Child, Preschool, Combined Modality Therapy, Female, Hematopoietic Stem Cell Transplantation, Humans, Infant, Male, Neoplasm Staging, Neuroblastoma mortality, Neuroblastoma pathology, Neuroblastoma therapy, Prognosis, Prospective Studies, Risk Factors, Survival Rate, Neuroblastoma diagnosis
- Abstract
Aims: A multivariate analysis was performed to evaluate the impact of various prospectively evaluated risk factors., Patients and Methods: From January 1987 to December 1993, 120 patients were registered in the study. 108/120 patients were eligible. There were 49 girls and 59 boys with a median age at diagnosis of 14 months (range, 0 to 224 months). Patients were classified according to the Evans classification system. LDH, NSE, Ferritin, N-myc amplification, 1p-deletion and ploidy were evaluated at diagnosis. Treatment intensity was based on the results of primary surgery: surgery only for 22 (20%) stage I and IIA patients (macroscopic residue without lymph node involvement), the 9 IIB patients (8,5%) (macroscopic residue with lymph node involvement) had mild chemotherapy in addition (6 x VCR/CYC) and elective radiation (Rx). Stage III patients were divided into 2 groups: IIIA patients (n = 17/16%) had to have ferritin levels under 300 micrograms/ml, NSE lower than 100 ng/ml and age below 2 years at diagnosis and received 6 alternating cycles of DAMO/ MVDOC. If one of these three criteria was not fulfilled, patients were assigned to the more intensive treatment arm stage IIIB (n = 12/11%), i.e. 9 alternating cycles of DAMO/MVDOC/IPE. Stage IV pts (n = 35/32.5%) received 8 MVDOC/IPE cycles and 20 patients received megatherapy followed by stem cell reinfusion in addition. 13 stage IVs patients (12%) were registered and had elective VCR/CYC and/or liver radiation in case of poor clinical condition. The median observation time is 4.2 years (range, 1 to 7.5)., Results: The survival rate at 3 years was excellent for localized disease and stage IVs with survival rates of 100% for stage I/IIA and 92% for stage IVs. Stage IIIA patients had an EFS rate of 81% whereas stage IIB patients achieved only 69%. Stage IV patients reached 51%, however outcome was especially poor for stage IIIB patients (20%) due to treatment related toxicities. The toxic death rate in the study was 13% (2 surgical deaths, 8 infections, 4 multiple organ failures). Univariate analysis demonstrated the following significant unfavorable risk factors: age over 1 year at diagnosis (58/108 pts, p = 0.006), NSE > 100 ng/ml (26/95 pts, p < 0.0001), Ferritin > 300 ng/ml (19/98 pts, p = 0.007), LDH > 300 (400) U/L, 51/87 pts, p = 0.004), presence of N-myc amplification (17/59 pts, p = 0.001), deletion of the short arm of chromosome 1 (19/74 pts, p < 0.0001) and di/tetraploidy (32/72 pts, p = 0.008). The power of these factors was even stronger in patients with localized disease whereas no significant prediction was observed for stage IV patients. Furthermore a significant correlation of the serological (NSE, ferritin, LDH) and biological factors (N-myc, deletion 1p, di/tetraploidy) was detected in this study. Only NSE was identified as an independent prognostic factor (p = 0.018) whereas no independent factor could be identified within the 3 biological parameters due to their high correlations (Kendall's tau for N-myc and deletion 1p:0.7). However, N-myc (p = 0.005) as well as deletion 1p (p = 0.01) were found significantly more important than di/tetraploidy., Conclusions: Biological classification of neuroblastomas should be mandatory and be the prerequisite for any risk adapted treatment. One serological and 2 biological factors could be a good standard evaluation to identify neuroblastoma patients at risk.
- Published
- 1996
- Full Text
- View/download PDF
45. Persistent rubella infection after erroneous vaccination in an immunocompromised patient with acute lymphoblastic leukemia in remission.
- Author
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Geiger R, Fink FM, Sölder B, Sailer M, and Enders G
- Subjects
- Adolescent, Antibodies, Viral blood, DNA, Viral, Follow-Up Studies, Humans, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma virology, Remission Induction, Rubella virus genetics, Rubella virus immunology, Rubella virus isolation & purification, Vaccines, Attenuated adverse effects, Viral Envelope Proteins genetics, Immunocompromised Host, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Rubella etiology, Rubella Vaccine adverse effects, Vaccination adverse effects
- Abstract
A 16-year-old male patient with acute lymphoblastic leukemia in complete remission and on maintenance treatment with weekly oral methotrexate and daily oral 6-mercaptopurine for 3 months was immunized in error with the WI-RA 27/3-HDC live attenuated rubella vaccine. Increasing rubella HAI antibodies were noted from 3 to 7 months post-vaccination as well as high levels of IgM antibody up to 8 months in three different tests. High HAI antibody titers persisted for 12-18 months after vaccination. Persisting rubella virus was indicated by PCR detection of rubella-specific nucleic acid in whole blood, non-stimulated and stimulated mononuclear cells 8 months following vaccination. Further attempts to detect rubella virus RNA in two subsequent blood samples were negative. Since acute arthritis and arthralgia occurred in the second month (days 51-63) after vaccination, antileukemic chemotherapy had to be interrupted. Evidence of higher risk for chronic or relapsing rubella-associated arthropathy in immunologically compromised patients and the need to interrupt antileukemic chemotherapy should warrant immunoprophylaxis with polyvalent immune globulin in rubella-susceptible patients who are immunocompromised.
- Published
- 1995
- Full Text
- View/download PDF
46. Granulocyte-macrophage colony-stimulating factor therapy in patients with chemotherapy-induced aplasia and Clostridium difficile enterocolitis.
- Author
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Geiger R, Fussenegger J, Allerberger F, Maurer K, and Fink FM
- Subjects
- Adolescent, Anemia, Aplastic complications, Anemia, Aplastic etiology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Preschool, Enterocolitis, Pseudomembranous complications, Enterocolitis, Pseudomembranous etiology, Female, Humans, Male, Recombinant Proteins therapeutic use, Anemia, Aplastic therapy, Enterocolitis, Pseudomembranous therapy, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use
- Published
- 1995
- Full Text
- View/download PDF
47. Recombinant human granulocyte-macrophage colony-stimulating factor in septic neutropenic pediatric cancer patients: detection of circulating hematopoietic precursor cells correlates with rapid granulocyte recovery.
- Author
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Fink FM, Maurer-Dengg K, Fritsch G, Mann G, Zoubek A, Falk M, and Gadner H
- Subjects
- Adolescent, Adult, Antigens, CD analysis, Antigens, CD34, Biomarkers, Tumor analysis, Cell Count, Child, Child, Preschool, Colony-Forming Units Assay, Female, Flow Cytometry, Granulocyte-Macrophage Colony-Stimulating Factor administration & dosage, Humans, Infant, Leukocyte Count, Male, Neutrophils pathology, Platelet Count, Recombinant Proteins, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bacteremia therapy, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Granulocytes pathology, Hematopoietic Stem Cells pathology, Neoplasms drug therapy, Neutropenia therapy
- Abstract
Cycling intensive chemotherapy currently used to treat pediatric solid tumors induces severe neutropenia. Prolonged neutropenia is a major risk factor for septic death which occurs in up to 5% of febrile or septic neutropenic episodes. We treated 18 neutropenic pediatric cancer patients (eight females, 10 males) during 30 febrile and/or septic episodes with single daily doses of E. coli-derived non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF, 5 micrograms per kg of body weight). The cytokine was administered for a median period of 6.5 days (2-12 days). Analysis of circulating hematopoietic progenitor cells was performed at day 1 (baseline) and day 5 of rh-GM-CSF treatment and included flow cytometric CD34 analysis as well as the methylcellulose-based clonogenic assay. Prompt hematopoietic recovery and resolution of septic problems was observed in all children. The counts of leukocytes (WBC), absolute neutrophils (ANC), and platelets (PLT) rose above 1,000/microL, 1,000/microL, and 50,000/microL within 4 days (0-9), 5.5 days (2-13), and 6 days (0-14), respectively. Faster granulocyte recovery and improved recruitment of circulating hemopoietic precursors was observed in children with detectable amounts (> 0.1%) of CD34-positive mononuclear cells prior to rh-GM-CSF treatment. We conclude that, to some extent, the efficacy of rh-GM-CSF treatment in neutropenic cancer patients is influenced by the hematopoietic recovery status on the progenitor cell level. Although they respond more slowly to the treatment, patients without circulating CD34-positive progenitor cells may gain most from growth factor therapy. Rh-GM-CSF can be safely administered to febrile and/or septic neutropenic children treated for cancer.
- Published
- 1995
- Full Text
- View/download PDF
48. Cardiac troponin T and creatine kinase MB mass concentrations in children receiving anthracycline chemotherapy.
- Author
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Fink FM, Genser N, Fink C, Falk M, Mair J, Maurer-Dengg K, Hammerer I, and Puschendorf B
- Subjects
- Adolescent, Analysis of Variance, Antibiotics, Antineoplastic adverse effects, Child, Child, Preschool, Female, Heart Diseases blood, Humans, Infant, Isoenzymes, Male, Neoplasms blood, Prospective Studies, Troponin T, Antibiotics, Antineoplastic therapeutic use, Creatine Kinase blood, Heart Diseases chemically induced, Neoplasms drug therapy, Troponin blood
- Abstract
Anthracyclines (doxorubicin, daunorubicin, and derivatives) are among the most effective antineoplastic drugs for pediatric cancer with dose-limiting acute and long-term cardiotoxicity. The exact mechanism of the development of cardiomyopathy is still not clear. Anthracyclines may induce subclinical acute myocardial injury leading to lysis of a limited number of myocytes. Alternatively, myocytes may experience a transient loss of cytoplasmic membrane integrity. Both conditions may lead to a transient efflux of small amounts of cytoplasmic enzymes and other proteins specific to the heart muscle fibers. To test these hypotheses we assayed plasma creatine kinase (CK) MB mass and cardiac specific troponin T (TnT). CKMB may be released even in case of reversible cell membrane injury, while prolonged elevation of TnT is the most sensitive and specific marker of limited myocardial necrosis. Thirty-five anthracycline-containing chemotherapy courses in 22 children with cancer were analyzed. CKMB mass and TnT concentrations were within the normal range in all children before anthracycline therapy. Within 72 hours from anthracycline therapy no increment of one of these two marker proteins was detected (ANOVA for repeated measures, P = 0.94 [TnT] and 0.25 [CKMB]). We conclude that only minimal if any acute necroses of cardiac myocytes occur after anthracycline therapy. Even membrane integrity appears to be maintained within the first 3 days after anthracycline therapy, in the absence of electrocardiographic or echocardiographic signs of acute cardiotoxicity.
- Published
- 1995
- Full Text
- View/download PDF
49. [Cytogenetic aspects of pediatric germ cell tumors].
- Author
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Stock C, Ambros IM, Strehl S, Zoubek A, Fink FM, Gadner H, and Ambros PF
- Subjects
- Adolescent, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Child, Child, Preschool, Chromosome Deletion, Chromosome Disorders, Chromosomes, Human, Pair 1, Coccyx, Female, Humans, Infant, Male, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Neoplasms, Germ Cell and Embryonal mortality, Neoplasms, Germ Cell and Embryonal pathology, Ovarian Neoplasms genetics, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Prognosis, Sacrum, Spinal Neoplasms genetics, Spinal Neoplasms mortality, Spinal Neoplasms pathology, Testicular Neoplasms genetics, Testicular Neoplasms mortality, Testicular Neoplasms pathology, Chromosome Aberrations genetics, In Situ Hybridization, Karyotyping, Neoplasms, Germ Cell and Embryonal genetics
- Abstract
We have performed in situ hybridization (ISH) studies predominantly on paraffin sections and on isolated nuclei of 22 pediatric germ cell tumors (GCTs) from 18 patients including 4 recurrences from three patients. In addition, we performed conventional cytogenetic analyses in three tumor samples. Because reports on cytogenetic studies in pediatric GCTs are scarce we focused our studies on those chromosome abnormalities frequently observed in adult GCTs. These included numeric and structural abnormalities of chromosomes 1 and 12 (e.g. isochromosome 12p) and numeric deviations of chromosomes 8, 10, X and Y. The histological subsets of the tumors investigated included two dysgerminomas (DGE), one seminoma (SE), one combined seminoma, two embryonal carcinomas (EC), two recurrent ECs, six pure yolk sac tumors (YST), five combined teratomas, one immature teratoma (IT) and two recurrences of IT, and three differentiated teratomas (TD). Similar to the GCTs in adults, additional copies of chromosome 12 were the most frequently observed numeric abnormalities. The analysis of two paraffin-embedded tumors suggested that changes in the size of the pericentromeric hybridization signals of chromosome 12 may be attributed to the presence of i(12)(p10). This was confirmed following the karyotype analysis of one EC which unequivocally revealed the presence of two i(12)(p10). Interestingly, using these probes, no chromosomal abnormalities were found in the pure TD or in the TD cells of mixed tumors containing a YST component. In the YST portion, however, the 1p deletions and/or numeric chromosome changes were present. Surprisingly, deletions at the short arm of chromosome 1, del(1)(p36.3), were frequently observed in malignant pediatric GCTs and were the sole abnormality detected in one case.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
- Full Text
- View/download PDF
50. Response of untreated stage IV Wilms' tumor to single dose carboplatin assessed by "up front" window therapy.
- Author
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Zoubek A, Kajtar P, Flucher-Wolfram B, Holzinger B, Mostbeck G, Thun-Hohenstein L, Fink FM, Urban C, Mutz I, and Schuler D
- Subjects
- Austria, Carboplatin administration & dosage, Child, Child, Preschool, Female, Humans, Hungary, Infant, Liver Neoplasms drug therapy, Liver Neoplasms secondary, Lung Neoplasms drug therapy, Lung Neoplasms secondary, Male, Neoplasm Staging, Wilms Tumor secondary, Carboplatin therapeutic use, Kidney Neoplasms drug therapy, Wilms Tumor drug therapy
- Abstract
A total of nine children with previously untreated stage IV Wilms' tumor of favorable histology were treated according to the Austrian/Hungarian Wilms' Tumor Protocol 89 and received a preoperative single dose of carboplatin as an "up front" window therapy. The treatment consisted of carboplatin as a single-dose of 600 mg/m2 over 30 minutes on day 1. Response evaluation by chest X-ray, serial CT scans, and sonography was performed on day 22. Investigation of the abdominal tumors revealed seven partial responses (78%), one nonresponse, and one progressive disease with a median tumor volume reduction of 62%. Response of metastases evaluated by CT scans was as follows: four complete remission, four partial response, and one nonresponse. Thrombocytopenia (WHO grade III 1, grade II 2, grade I 2) and leukocytopenia (WHO grade II 1, grade I 5) were the main side effects. No renal or liver toxicity were observed. The overall response rate after a preoperative single-dose of 600 mg/m2 carboplatin in untreated patients with stage IV Wilms' tumor is encouraging and the toxicity acceptable. This data indicate that carboplatin seems to be an additional effective drug in patients with previously untreated Wilms' tumor of favorable histology.
- Published
- 1995
- Full Text
- View/download PDF
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