Literatur

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Autor(en)	Titel	Quelle
Taher AT, Musallam KM, Cappellini MD	β-Thalassemias. Reply.	The New England journal of medicine 2021, 384: 2166
Takeuchi S, Bartram C, Ludwig R, Royer-Pokora B, Schneider S, Imamura J, Koeffler H	Mutations of p53 in Wilms' tumors.	Mod Pathol 1995, 8: 483
Takeuchi S, Bartram C, Seriu T, Miller C, Tobler A, Janssen J, Reiter A, Ludwig W, Zimmermann M, Schwaller J	Analysis of a family of cyclin-dependent kinase inhibitors.	Blood 1995, 86: 755
Takeuchi S, Bartram C, Wada M, Reiter A, Hatta Y, Seriu T, Lee E, Miller C, Miyoshi I, Koeffler H	Allelotype analysis of childhood acute lymphoblastic leukemia.	Cancer Res 1995, 55: 5377
Takeuchi S, Bartram C, Miller C, Reiter A, Seriu T, Zimmerann M, Schrappe M, Mori N, Slater J, Miyoshi I, Koeffler H	Acute lymphoblastic leukemia of childhood.	Blood 1996, 87: 3368
Takeuchi S, Koike M, Seriu T, Bartram C, Schrappe M, Reiter A, Park S, Taub H, Kubonishi I, Miyoshi I, Koeffler H	Frequent loss of heterozygosity on the long arm of chromosome 6	Cancer Res 1998, 58: 2618
Takeuchi S, Cho S, Seriu T, Koike M, Bartram C, Reiter A, Schrappe M, Takeuchi C, Taguchi H, Koeffler H	Identification of three distinct regions of deletion on the long arm of chromosome 11 in childhood acute lymphoblastic leukemia.	Oncogene 1999, 18: 7387
Takeuchi S, Takeuchi N, Tsukasaki K, Bartram C, Zimmermann M, Schrappe M, Taguchi H, Koeffler H	Genetic polymorphisms in the tumour necrosis factor locus in childhood acute lymphoblastic leukaemia.	Br J Haematol 2002, 119: 985
Takeuchi S, Tsukasaki K, Bartram C, Seriu T, Zimmermann M, Schrappe M, Takeuchi N, Park S, Taguchi H, Koeffler H	Long-term study of the clinical significance of loss of heterozygosity in childhood acute lymphoblastic leukemia.	Leukemia 2003, 17: 149
Tallman MS	Differentiating therapy with all-trans retinoic acid in acute myeloid leukemia.	Leukemia 1996, 10 Supplement 1: 12
Tallen G, Dworzak M, Gadner H, Masera G, Schrappe M, Biondi A, Vassal G, Pieters R, Jazbec J, Morland B, Creutzig U	Imperative of continual support by the European Community for future advances in paediatric oncology in Europe: meeting report of the EC-funded sciencecommunication project DIRECT “Overcoming Cancer with Research”	memo (2009) Vol. 2: 234–245
Tallen G, Dworzak M, Gadner H, Masera G, Haupt R, Eggert A, Schrappe M, Biondi A, Vassal G, Creutzig U	More and better cure for an orphan: priorities for future paediatric cancer research in Europe – Meeting report of the EC-funded science-communication project DIRECT “Overcoming Cancer with Research”	memo (2009) Vol. 2: 246–254
Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, Ebell W, Escherich G, Schrappe M, Klingebiel T, Fengler R, Henze G, von Stackelberg A	Long-Term Outcome in Children With Relapsed Acute Lymphoblastic Leukemia After Time-Point and Site-of-Relapse Stratification and Intensified Short-Course Multidrug Chemotherapy: Results of Trial ALL-REZ BFM 90.	Journal of clinical oncology 2010, 28: 2339
PURPOSE: The multicenter trial ALL-REZ BFM (ie, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Munster) 90 was designed to improve prognosis for children with relapsed acute lymphoblastic leukemia (ALL) by time-to-relapse- and site-of-relapse-adapted stratification and by introduction of novel chemotherapy elements and to evaluate new prognostic parameters in a large, population-based cohort. PATIENTS AND METHODS: Five hundred twenty-five patients stratified into risk groups A (early bone marrow [BM] relapses), B (late BM relapses), and C (isolated extramedullary relapses) received alternating short-course intensive polychemotherapy (in blocks R1, R2, or R3) and cranial/craniospinal irradiation followed by maintenance therapy. Block R3 (high-dose cytarabine and etoposide) was introduced to improve the outcome compared with historical controls. Patients with early BM or T-ALL relapse (poor prognosis group [PPG]) were eligible for experimental regimens. One hundred seventeen patients received stem-cell transplantation (SCT). RESULTS: The probabilities (and standard deviations) of event-free survival (pEFS) and overall survival (pOS) at 10 years were 0.30 +/- .02 and 0.36 +/- .02, respectively. Significant differences existed between strategic groups (pEFSA = .17 +/- .03; pEFSB = .43 +/- .04; pEFSC = .54 +/- .06; pEFSPPG = .15 +/- .03; log-rank P < .001). Patients of high-risk groups A plus PPG did better with SCT than with chemotherapy (pEFS = .33 +/- .05 v 0.20 +/- .05; P = .005). The pEFS was similar to trials ALL-REZ BFM 85/87 (.36 +/- .03. v 0.37 +/- .03; P = .419; PPG excluded). Time point, site of relapse, immunophenotype, and SCT were significant predictors of pEFS in multivariate analyses. CONCLUSION: More than one third of patients in this large, population-based trial were cured. Neither R3 nor adaptation of chemotherapy intensity was capable of improving pEFS or of overcoming prognostic factors. In high-risk patients, remission induction regimens must be improved, and allogeneic SCT should be recommended in patients achieving second complete remission.
Tallen G, Henze G, Creutzig U, Dworzak M, Klingebiel T	Auswirkungen der EU-Direktive für klinische Studien auf Kinder und Jugendliche mit Krebserkrankungen in Europa.	FORUM 2010 25: 42
Tallroth GA	Long-term prophylaxis of hereditary angioedema with a pasteurized C1 inhibitor concentrate.	International archives of allergy and immunology 2011, 154: 356
Hereditary angioedema (HAE) is a relatively rare genetic disorder caused by a deficiency of C1 esterase inhibitor (C1-INH). Common clinical presentations are abdominal pain and localized edema of the skin, with laryngeal edema being potentially life-threatening. Replacement therapy with C1-INH concentrate is recommended for treatment of acute HAE attacks and results in rapid resolution of symptoms. C1-INH concentrate can also be used for prophylaxis of HAE and is recommended in cases where standard prophylactic agents are ineffective or not tolerated. This case study describes the use of C1-INH concentrate as a home therapy for on-demand and prophylactic self-administration in a patient with HAE. This treatment approach was well tolerated and effective, leading to a dramatic improvement in symptoms and improved quality of life.
Tallen G, Henze G, von Stackelberg A	Treatment of children and adolescents with relapsed ALL: therapy target long-term healing.	Pharm Unserer Zeit 2012, 41: 214
Tallen G et al.	Musculoskeletal Pain: A New Algorithm for Differential Diagnosis of a Cardinal Symptom in Pediatrics.	Klin Pädiatr 2014; 226: 86
Tallen G, Resch A, Calaminus G, Wiener A, Leiss U, Pletschko T, Friedrich C, Langer T, Grabow D, Driever PH, Kortmann RD, Timmermann B, Pietsch T, Warmuth-Metz M, Bison B, Thomale UW, Krauss J, Mynarek M, von Hoff K, Ottensmeier H, Frühwald M, Kramm CM, Temming P, Müller HL, Witt O, Kordes U, Fleischhack G, Gnekow A, Rutkowski S, German Paediatric Brain Tumour Consortium (HIT-Network)	Strategies to improve the quality of survival for childhood brain tumour survivors.	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2015, 19: 619
Tumours of the central nervous system (CNS) are the most frequent solid tumours and the second most frequent type of cancer in children and adolescents. Overall survival has continuously improved in Germany, since an increasing number of patients have been treated according to standardised, multicentre, multimodal treatment recommendations, trials of the German Paediatric Brain Tumour Consortium (HIT-Network) or the International Society of Paediatric Oncology-Europe (SIOP-E) during the last decades. Today, two out of three patients survive. At least 8000 long-term childhood brain tumour survivors (CBTS) are currently living in Germany. They face lifelong disease- and treatment-related late effects (LE) and associated socioeconomic problems more than many other childhood cancer survivors (CCS).
Tallen G, Riabowol K	DisorderING promotes epigenetic order.	FEBS letters 2017, 591: 257
Tamm I, Richter S, Oltersdorf D, Creutzig U, Harbott J, Scholz F, Karawajew L, Ludwig W, Wuchter C	High expression levels of x-linked inhibitor of apoptosis protein and survivin correlate with poor overall survival in childhood de novo acute myeloid leukemia.	Clin Cancer Res 2004, 10: 3737
Tamannai M, Farhangi S, Truss M, Sinn B, Wurm R, Bose P, Henze G, Riabowol K, von Deimling A, Tallen G	The inhibitor of growth 1 (ING1) is involved in trichostatin A-induced apoptosis and caspase 3 signaling in p53-deficient glioblastoma cells.	Oncology research 2010, 18: 469
Prognosis for patients with glioblastoma multiforme (GBM) is poor. Inhibitors of histone deacetylases (HDACi) like trichostatin A (TSA) are promising alternatives to conventional treatment. Deficient tumor suppressor functions, such as TP53 mutations and p14(ARF)/p16(INK4a) deletions, are characteristic for GBM and can cause resistance to DNA damaging agents such as cisplatin and to HDACi like TSA. The type II tumor suppressor Inhibitor of growth 1 (ING1) is involved in DNA damage response and histone modification. We have previously shown that ING1 is downregulated in GBM and involved in glioma-induced angiogenesis and in cisplatin-induced apoptosis in malignant glioma cells. Hence, the goal of our present study was to investigate whether TSA affects ING1 protein expression and also whether modulating ING1 levels affects TSA-induced apoptosis in malignant glioma cells that contain deficient p53 function and inactive pl4(ARF)/p16(INK4a) signaling. If so, we asked, which apoptotic pathway might be the major mediator beyond this interaction. To test whether ING1 proteins function in TSA-induced apoptosis in GBM, we analyzed TSA effects in LN229 GBM cells, which harbor TP53 mutations and INK4a deletion, following ING1 knockdown by siRNA. Expression of ING1, acetylated core histones H3 and H4, and the proapoptotic proteins caspase 3 and Fas-associated death domain (FADD) was determined by Western blotting. Percentages of apoptotic cells were obtained by flow cytometry. TSA induced the major ING1 isoform p33(ING1b) and increased levels of both histone acetylation and apoptosis in LN229 cells. ING1 knockdown cells revealed marked resistance to TSA-induced apoptosis, impairment of caspase 3 activation, and suppression of FADD. The data suggest that ING1 contributes to TSA-induced apoptosis in GBM cells with deficient p53 and p14(ARF)/p16(INK4a) functions, possibly by regulating FADD/caspase 3 signaling.
Tamamyan G, Dominkus M, Lang S, Diakos C, Mittheisz E, Horcher E, Holter W, Zoubek A, Bielack S, Kager L	Multiple relapses in high-grade osteosarcoma: When to stop aggressive therapy?	Pediatric blood & cancer 2015, 62: 529
The prognosis after relapse of high-grade osteosarcoma is poor and complete resection of all tumors is essential for survival. A 6-year old was diagnosed with high-grade osteosarcoma and treated according to the COSS-96 protocol. Within 5 years from initial diagnosis, five osteosarcoma relapses occurred and every time it was possible to achieve complete surgical remission. Additional treatments included chemotherapy and dendritic cell-based cancer immune therapy. Since the end of therapy of the 5th relapse, he is alive for 11½ years. Our experience further supports that aggressive surgery can help to achieve long-term survival even in patients with multiple osteosarcoma relapses. Pediatr Blood Cancer 2015;62:529-530. © 2014 Wiley Periodicals, Inc.
Tarbell NJ, Loeffler JS, Silver B, Lynch E, Lavally BL, Kupsky WJ, Scott RM, Sallan SE	The change in patterns of relapse in medulloblastoma.	Cancer 1991, 68: 1600
The authors reviewed 89 patients treated for cerebellar medulloblastoma between 1970 and 1989 to determine the impact of changing treatment (high-dose posterior fossa radiation therapy and chemotherapy) on the pattern of failure in medulloblastoma. Between 1970 and 1983, 50 patients (median follow-up, 110 months) were treated with surgery and postoperative craniospinal irradiation (CSI). Nineteen of the 50 (38%) recurred in the central nervous system (CNS). Isolated systemic (bone) metastases occurred in six. The median time to the development of bone metastases was 12 months. Since 1984, 39 patients (median follow-up, 27 months) were treated with preradiation chemotherapy consisting of cisplatin and vincristine for 9 weeks before initiation of CSI. Nine of the 39 (23%) patients recurred in the CNS. There were no systemic failures in this cohort. The actuarial 5-year disease-free survival was 55 +/- 7% for the earlier cohort and 72 +/- 8% for the later cohort (P equals 0.3). Posterior fossa recurrence was associated with radiation therapy to this area. The cumulative incidence of posterior fossa relapse was 50 +/- 13% in patients who received less than 5300 cGy and 18 +/- 7% in those who received 5300 cGy or more (P equals 0.005). All six bone relapses were in patients treated with CSI alone and 5300 cGy or more to the posterior fossa for a 5-year cumulative incidence of bone metastases of 18 +/- 7% compared with 0% for patients treated with 5300 cGy or more and chemotherapy (P equals 0.03). The authors concluded that high-dose radiation therapy has altered the pattern of relapse with an increase in systemic recurrence after radiation therapy alone that is now equivalent to the risk of recurrence in the posterior fossa. Chemotherapy may be indicated in an attempt to decrease this high risk of systemic metastases.
Tartaglia M, Niemeyer C, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht J, Gelb B	Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.	Nat Genet 2003, 34: 148
Tarantino MD	The treatment of immune thrombocytopenic purpura in children.	Current hematology reports 2006, 5: 89
Immune thrombocytopenic purpura (ITP) is an enigmatic, usually transient disorder in children, largely thought to be a self-limited, postinfectious, autoimmune phenomenon. The often strikingly low platelet count, coupled with the sometimes dramatic cutaneous manifestations of thrombocytopenia, compels most clinicians to prescribe drug therapy. However, closer scrutiny reveals that although most children with newly diagnosed ITP have platelet counts less than 10,000/microL, very few will experience severe or life-threatening hemorrhage, leading to perpetual controversy over whether to give drug therapy to minimally or moderately symptomatic children with ITP. This review focuses on when and how to use drug therapy to treat ITP in children.
Taube T Eckert	Real-time quantification of TEL-AML1 fusion transcripts for MRD detection in relapsed childhood acute lymphoblastic leukaemia. Comparison with antigen receptor-based MRD quantification methods.	Leuk Res 2004
Tauer JT, Gneuss A, Lohse JE, Jürgens T, Knöfler R	Evaluation of desmopressin effect on primary haemostasis in pediatric patients with aspirin-like defect as hereditary thrombocytopathy.	Klinische Padiatrie 2011, 223: 169
Despite about 3 decades of clinical experience with the therapy of inherited thrombocytopathies (HTP) with desmopressin (DDAVP) the mechanisms of haemostatic effects of DDAVP in these diseases remain unclear. Therefore platelet function diagnostics was carried out in whole blood (WB) from children with aspirin-like defect as one of the clinically mild forms of HTP after DDAVP administration.
Taub JW, Berman JN, Hitzler JK, Sorrell AD, Lacayo NJ, Mast K, Head D, Raimondi S, Hirsch B, Ge Y, Gerbing RB, Wang YC, Alonzo TA, Campana D, Coustan-Smith E, Mathew P, Gamis AS	Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial.	Blood 2017 Jun 22; 129: 3304
Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.
Taylor R, Walker D, Gnekow A, Perilongo G, Zanetti I, Garree M, Kühl J	A Preliminary Report of the SIOP/GPOH/UKCCSG Low grade glioma Study.	Medical and Pediatric Oncology 1998, 31: 1
Tegeder I, Thiel K, Erkek S, Johann PD, Berlandi J, Thatikonda V, Frühwald MC, Kool M, Jeibmann A, Hasselblatt M	Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors.	Journal of neuro-oncology 2019, 141: 43
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency.
Telen MJ, Afenyi-Annan A, Garrett ME, Combs MR, Orringer EP, Ashley-Koch AE	Alloimmunization in sickle cell disease: changing antibody specificities and association with chronic pain and decreased survival.	Transfusion 2014, Epub ahead of print
Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD.
Temming P, Corson TW, Lohmann DR	Retinoblastoma tumorigenesis: genetic and epigenetic changes walk hand in hand.	Future oncology (London, England) 2012, 8: 525
The rate-limiting step in retinoblastoma tumorigenesis is inactivation of both RB1 alleles, but it has remained unclear how this tumor acquires the additional changes that constitute a malignant phenotype. Zhang et al. characterized the genetic and epigenetic alterations in four retinoblastomas using whole-genome analysis techniques. In these samples, the retinoblastoma genome was found to be remarkably stable genetically, although recurrent mutations in BCOR were identified in 13% of patients. However, an approach that integrated the results of ChIP, methylation and expression analysis identified multiple, more frequent alterations of the epigenetic landscape. One of the leading genes on the list the authors obtained was SYK, a kinase epigenetically upregulated. Knockdown of this gene and exposure to small molecules inhibiting the kinase function stopped tumor growth in vitro and in vivo, thus offering a new therapeutic target for the treatment of retinoblastoma.
Temming P, Lohmann D, Bornfeld N, Sauerwein W, Goericke SL, Eggert A	Current concepts for diagnosis and treatment of retinoblastoma in Germany: aiming for safe tumor control and vision preservation.	Klinische Padiatrie 2012, 224: 339
Retinoblastoma affects approximately 40 children in Germany per year. Most children are diagnosed early with localized intraocular disease, and the overall survival rate exceeds 95%. However, the prognosis of metastasized retinoblastoma remains poor. In 40% of the patients, retinoblastoma occurs bilaterally and, especially for these children, the salvage of the eye and visual function is of major importance. The variety of conservative treatment options for localized retinoblastoma includes laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. While systemic chemotherapy has nearly completely replaced external beam radiotherapy in the primary treatment of intraocular retinoblastoma, intra-arterial, intravitreal and periocular application of chemotherapy was also shown to be effective in treating intraocular retinoblastoma in case series. Genetic testing is an integral part of the routine diagnostics of all patients. Available tumor material should be analyzed to detect mutational mosaicism, that affects >10% of children with unilateral retinoblastoma. Genetic testing also identifies children with heritable (50% of patients) retinoblastoma. These children have a genetic predisposition for second malignancies. For this reason, late effects are an increasing concern and the care of patients with retinoblastoma requires a multidisciplinary approach to tailor therapy and long-term follow-up. Multicenter clinical trials are being developed to evaluate evidence-based treatment concepts for localized and metastasized retinoblastoma to improve survival rates and quality of life of children with retinoblastoma.
Temming P, Viehmann A, Biewald E, Lohmann DR	Sporadic unilateral retinoblastoma or first sign of bilateral disease?	Br J Ophthalmol 2013, 97: 475
A small number of children with unilateral retinoblastoma later develop retinoblastoma in the contralateral eye (metachronous bilateral retinoblastoma). METHODS: We analysed the clinical and genetic characteristics of children with sporadic unilateral retinoblastoma to identify risk factors for the development of metachronous bilateral disease. RESULTS: Fifteen (3.1%) of 480 children with unilateral retinoblastoma later developed metachronous bilateral retinoblastoma (latency period >30 days). The maximum latency period was 2.3 years after initial diagnosis. Nine (22.5%) of 40 children with a RB1 mutation detectable in blood developed metachronous bilateral disease while all 155 children proved to be without a germline RB1 mutation remained unilaterally affected. Clinically, the risk of developing metachronous bilateral retinoblastoma was higher for age at diagnosis ≤0.5 years compared with >0.5 years (19.6% vs 1.2%), and for multifocal compared with unifocal unilateral retinoblastoma (17.1% vs 2.2%). CONCLUSIONS: This study shows that an oncogenic RB1 mutation in the blood is a risk factor for metachronous bilateral retinoblastoma. Additional clinical risk factors for metachronous bilateral disease are diagnosis at young age (≤0.5 years) and multifocal unilateral retinoblastoma. Early genetic analysis may identify children at high risk of developing metachronous bilateral disease and may help to preserve vision using risk-adapted follow-up and early treatment.
Temming P, Eggert A, Bornfeld N, Sauerwein W, Göricke S, Lohmann DR	[Diagnosis and treatment of retinoblastoma: current strategies for effective tumour control and preservation of vision].	Klinische Monatsblatter fur Augenheilkunde 2013, 230: 232
There are approximately 40 new cases of retinoblastoma in Germany per year. Children in whom the tumour is detected when still intraocular have an excellent overall survival rate (> 95%). However, the prognosis of metastasised retinoblastoma remains poor. About 40% of retinoblastoma patients have tumours in both eyes. For these children in particular it is important to save the eye and visual function as much as possible. There are several options for conservative treatment of localised retinoblastoma including laser coagulation, thermotherapy, cryotherapy, brachytherapy and chemotherapy. In recent years, systemic chemotherapy has become the established standard for primary treatment of intraocular retinoblastoma. In case series, intra-arterial, intravitreal and periocular applications of chemotherapy were also shown to be effective in treating intraocular retinoblastoma. Genetic testing is an integral part of the routine diagnostics of all patients. Mutation analysis of tumour material is invaluable for identification of somatic mutations including mutational mosaicism. Genetic testing also identifies children with heritable retinoblastoma, which represent 50% of cases. These children also have a predisposition for the development of tumours outside of the eye (second primary neoplasm). To adequately address these and other late effects in survivors of retinoblastoma, a multidisciplinary approach is needed that optimises therapy and long-term follow-up. Upcoming multicentre clinical trials will evaluate treatment concepts for localised and metastasised retinoblastoma to improve survival rates and quality of life of children with retinoblastoma. This article was translated and modified and was primarily published in Klin Padiatr 2012; 224: 339-347.
Temming P, Viehmann A, Arendt M, Eisele L, Spix C, Bornfeld N, Sauerwein W, Jöckel KH, Lohmann DR	Pediatric second primary malignancies after retinoblastoma treatment.	Pediatric blood & cancer 2015, 62: 1799
Children with retinoblastoma carry a high risk to develop second primary malignancies in childhood and adolescence. This study characterizes the type of pediatric second primary malignancies after retinoblastoma treatment and investigates the impact of different treatment strategies and prognostic factors at presentation.
Temming P, Arendt M, Viehmann A, Eisele L, Le Guin CH, Schündeln MM, Biewald E, Mäusert J, Wieland R, Bornfeld N, Sauerwein W, Eggert A, Lohmann DR, Jöckel KH	How Eye-Preserving Therapy Affects Long-Term Overall Survival in Heritable Retinoblastoma Survivors.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016 Jul 5;
Intraocular retinoblastoma is curable, but survivors with a heritable predisposition are at high risk for second malignancies. Because second malignancies are associated with high mortality, prognostic factors for second malignancy influence long-term overall survival. This study investigates the impact of all types of eye-preserving therapies on long-term survival in the complete German cohort of patients with heritable retinoblastoma.
Temming P, Arendt M, Viehmann A, Eisele L, Le Guin CH, Schündeln MM, Biewald E, Astrahantseff K, Wieland R, Bornfeld N, Sauerwein W, Eggert A, Jöckel KH, Lohmann DR	Incidence of second cancers after radiotherapy and systemic chemotherapy in heritable retinoblastoma survivors: A report from the German reference center.	Pediatric blood & cancer 2017, 64: 71
Tenardi RD, Frühwald MC, Jürgens H, Hertroijs D, Bauer J	Nutritional status of children and young adults with Ewing sarcoma or osteosarcoma at diagnosis and during multimodality therapy.	Pediatric blood & cancer 2013, 60: 166
Teofili L, Foà R, Giona F, Larocca LM	Childhood polycythemia vera and essential thrombocythemia: does their pathogenesis overlap with that of adult patients?	Haematologica 2008, 93: 169
The incidence of polycythemia vera (PV) and essential thrombocythemia (ET) in children and adolescents is extremely low. The annual incidence of PV in patients aged less than 20 years is estimated to be about 2 new cases every 10 million people.1 Similarly, the annual incidence of ET ranges from 1 to 4 new cases every 10 million people. Therefore, on the whole it can be assumed that PV and ET are between 40 and 90 fold less frequent in children than in adults. The rarity of pediatric PV and ET has determined that, for many years, data on their clinical presentation and biologic features have been sparse and anecdotal. Furthermore, it has been generally accepted that specific diagnostic criteria developed for adult patients with PV and ET should also apply to pediatric cases. Two recent reviews have extensively evaluated the pathogenesis of primary erythrocytosis and thrombocytosis (myeloproliferations independent of external influences) occurring in childhood. The authors indicate that, as in the adult population, pediatric age PV and ET can also present as sporadic diseases. In addition, they underline that several cases of PV and ET reported in children are in fact familial diseases, caused by hereditary defects consisting of specific mutations of the erythropoietin receptor, thrombopoietin or MPL genes.
Terpe H, Christiansen H, Gonzalez M, Berthold F, Lampert F	Differentiation and prognosis of neuroblastoma in correlation to the expression of CD44s.	Eur J Cancer 1995, 31A: 549
Testi AM, Attarbaschi A, Valsecchi MG, Moericke A, Cario G, Niggli F, Silvestri D, Bader P, Kuhlen M, Parasole R, Putti MC, Lang P, Flotho C, Mann G, Rizzari C, Barisone E, Locatelli F, Linderkamp C, Lauten M, Suttorp M, Zimmermann M, Basso G, Biondi A, Conter V, Schrappe M, AIEOP-BFM (Associazione Italiana di Ematologia e Oncologia Pediatrica & Berlin-Frankfurt-Muenster) Study Group	Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study.	European journal of cancer (Oxford, England : 1990) 2019, 122: 61
Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years.
Rossig C, Jürgens H, Schrappe M, Moericke A, Henze G, von Stackelberg A, Reinhardt D, Burkhardt B, Woessmann W, Zimmermann M, Gadner H, Mann G, Schellong G, Mauz-Koerholz C, Dirksen U, Bielack S, Berthold F, Graf N, Rutkowski S, Calaminus G, Kaatsch P, Creutzig U	Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria.	Pediatric blood and cancer 2013, 60: 1574
In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.
Teuffel O, Dettling M, Cario G, Stanulla M, Schrappe M, Buhlmann P, Niggli F, Schafer B	Gene expression profiles and risk stratification in childhood acute lymphoblastic leukemia.	haematologica 2004, 89: 801
Teuffel O, Stanulla M, Cario G, Ludwig WD, Rottgers S, Schafer BW, Zimmermann M, Schrappe M, Niggli FK	Anemia and survival in childhood acute lymphoblastic leukemia.	Haematologica 2008, 93: 1652
BACKGROUND: Several studies have demonstrated that patients with childhood acute lymphoblastic leukemia presenting with mild anemia at diagnosis have an increased risk of poor outcome compared to patients with more severe anemia. However, it has not been reported whether there is any correlation between degree of anemia and leukemia subtype. DESIGN AND METHODS: In a cohort of 1162 patients with childhood acute lymphoblastic leukemia we analyzed whether there was a correlation between degree of anemia and leukemia subtype. We also studied the association between degree of anemia and event-free survival within the subtypes. RESULTS: Hemoglobin levels at diagnosis were distributed in a non-random pattern. The degree of anemia was significantly different for three distinct groups of patients compared to the remaining patients (mean hemoglobin; T-cell leukemia: 106 g/L versus 76 g/L (precursor B-cell acute lymphoblastic leukemia); within precursor B-cell ALL: TEL-AML1 positive: 68 g/L versus 79 g/L; BCR-ABL positive: 93 g/L versus 76 g/L; each p<0.05). Furthermore, in contrast to the entire study group, patients with T-cell leukemia, TEL-AML1(+), and BCR-ABL(+) precursor B-cell leukemia had a more favorable prognosis if presenting with a higher hemoglobin level (>/=80 g/L). CONCLUSIONS: These observations indicate that the formerly reported direct correlation between severity of anemia and survival in childhood acute lymphoblastic leukemia mainly reflects differences in the degree of anemia between distinct biological subgroups with different treatment outcomes. On the other hand, the inverse relationship between severity of anemia and survival found within specific subgroups suggests that very low hemoglobin levels at diagnosis are associated with more advanced disease in these subgroups.
Theobald M, Christiansen H, Schmidt A, Melekian B, Wolkewitz N, Christiansen N, Brinkschmidt C, Berthold F, Lampert F	Sublocalization of putative tumor suppressor gene loci on chromosome arm 14q in neuroblastoma.	Genes Chromosomes Cancer 1999, 26: 40
Theissen J, Boensch M, Spitz R, Betts D, Stegmaier S, Christiansen H, Niggli F, Schilling F, Schwab M, Simon T, Westermann F, Berthold F, Hero B	Heterogeneity of the MYCN oncogene in neuroblastoma.	Clinical cancer research 2009, 15: 2085
PURPOSE: MYCN amplification is an important therapy-stratifying marker in neuroblastoma. Fluorescence in situ hybridization with signal detection on the single-cell level allows a critical judgement of MYCN intratumoral heterogeneity. EXPERIMENTAL DESIGN: The MYCN status was investigated by fluorescence in situ hybridization at diagnosis and relapse. Heterogeneity was defined as the simultaneous presence of amplified cells (>/=5 cells per slide) and nonamplified cells within one tumor or sequential change of the amplification status during the course of the disease. Likewise, heterogeneity can be detected between primary tumor and metastasis. RESULTS: From 1,341 patients analyzed, 1,071 showed no amplification, 250 showed homogeneous amplification, and 20 patients showed MYCN heterogeneity. Of the patients with heterogeneity, 12 of 20 had clusters of MYCN amplifications, 3 of 20 had amplified single cells, 3 of 20 showed MYCN amplifications in the bone marrow but not in the primary tumor, and 2 of 20 acquired MYCN amplification during the course of the disease. All stage 4 patients were treated according to high-risk protocols; 7 of 8 later progressed. Four patients with localized disease were treated according to high-risk protocol because of MYCN-amplified clusters; 1 of 4 later progressed. One patient treated with mild chemotherapy experienced progression. Seven patients with localized/4S disease underwent no chemotherapy: 4 of 5 patients with MYCN heterogeneity at diagnosis remained disease-free, and 1 of 5 experienced local progression. Two patients had normal MYCN status at diagnosis but acquired MYCN amplification during the course of the disease. CONCLUSION: MYCN heterogeneity is rare. Our results suggest that small amounts of MYCN-amplified cells are not correlated to adverse outcomes. More patients with heterogeneity are warranted to clarify the role of MYCN heterogeneity for risk classification.
Theruvath J, Sotillo E, Mount CW, Graef CM, Delaidelli A, Heitzeneder S, Labanieh L, Dhingra S, Leruste A, Majzner RG, Xu P, Mueller S, Yecies DW, Finetti MA, Williamson D, Johann PD, Kool M, Pfister S, Hasselblatt M, Frühwald MC, Delattre O, Surdez D, Bourdeaut F, Puget S, Zaidi S, Mitra SS, Cheshier S, Sorensen PH, Monje M, Mackall CL	Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors.	Nature medicine 2020, 26: 712
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. ), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
Thies, K-C, Boos, K Buscher H, Townsend P, Kettler, D	Postoperative Schmerztherapie im Kindesalter: Ein internationaler Vergleich.	Dtsach arztebl 2009, 97
Thieme B, Gnekow A	Niedriggradige Gliome im Kindesalter.	Monatschrift Kinderheilkunde 2008, Volume 156, Number 12, 1173
Niedriggradige Gliome der WHO-Grade I und II aller ZNS-Lokalisationen sind die häufigsten primären Hirntumoren im Kindesalter. Über 40% sind in der supratentoriellen Mittellinie lokalisiert, diese Kinder können mit Visuseinschränkungen oder dienzephalen Störungen symptomatisch werden. Der natürliche Verlauf ist schwer vorhersehbar, das Spektrum reicht von spontaner Tumorregression bis zu rasch progredienten Verläufen. In der Studie SIOP-LGG 2004 werden primär chirurgische Optionen geprüft. Nur bei Lokalisation im Zerebellum und den zerebralen Hemisphären kann ein relevanter Anteil der Tumoren primär vollständig entfernt werden. Eine nichtchirurgische Therapie (Radio- oder Chemotherapie) wird bei genau definierten Indikationen eingeleitet und ist bei etwa 1/3 der Patienten erforderlich. Ziel der Chemotherapie ist, für die jüngeren Kinder die Durchführung einer Radiotherapie zeitlich zu verzögern, um radiogene Folgeschäden, besonders auf die psychointellektuelle Entwicklung, zu vermeiden. Auch bei der fokalen Bestrahlung sollten Risikoorgane durch den Einsatz moderner Techniken geschont werden. Das Gesamtüberleben der Patienten liegt bei 78–95% nach 5 Jahren, jedoch verläuft die Erkrankung bei vielen Betroffenen „chronisch“. Low-grade gliomas (World Health Organisation grades I and II) of all central nervous system locations are the most frequent brain tumours in childhood. More than 40% are located in the supratentorial midline; these children become symptomatic with visual or diencephalic impairment. The natural history is difficult to foresee and ranges from spontaneous tumour regression to relentless progression. In the SIOP-LGG 2004 trial, the possibility of primary surgical resection should be assessed. Complete resection of a relevant percentage of tumours is possible only within the cerebral hemispheres and cerebellum. Nonsurgical therapy (radiotherapy or chemotherapy) is started upon a defined indication and is necessary for about one-third of patients. The aim of chemotherapy is to defer the start of radiation to avoid radiation-induced late effects, especially on psycho-intellectual development. The use of modern radiation techniques for focal radiotherapy shall spare organs at risk as well. The 5-year overall survival of these children is 78–95%, but the course of disease is chronic for many patients.
Thiel U, Wawer A, Wolf P, Badoglio M, Santucci A, Klingebiel T, Basu O, Borkhardt A, Laws HJ, Kodera Y, Yoshimi A, Peters C, Ladenstein R, Pession A, Prete A, Urban EC, Schwinger W, Bordigoni P, Salmon A, Diaz MA, Afanasyev B, Lisukov I, Morozova E, Toren A, Bielorai B, Korsakas J, Fagioli F, Caselli D, Ehninger G, Gruhn B, Dirksen U, Abdel-Rahman F, Aglietta M, Mastrodicasa E, Torrent M, Corradini P, Demeocq F, Dini G, Dreger P, Eyrich M, Gozdzik J, Guilhot F, Holler E, Koscielniak E, Messina C, Nachbaur D, Sabbatini R, Oldani E, Ottinger H, Ozsahin H, Schots R, Siena S, Stein J, Sufliarska S, Unal A, Ussowicz M, Schneider P, Woessmann W, Jürgens H, Bregni M, Burdach S, on behalf of the Solid Tumor Working Party (STWP) and the Pediatric Disease Working Party (PDWP) of the European Group for Blood and Marrow Transplantation (EBMT), the Asia Pacific Blood and Marrow Transplantation (APBMT), the Pediatric Registry for Stem	No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients.	Ann Oncol 2011, 22: 1614
BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced-intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [±1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (±1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols.
Thiel U, Wolf P, Wawer A, Blaeschke F, Grunewald TG, von Lüttichau IT, Klingebiel T, Bader P, Borkhardt A, Laws HJ, Handgretinger R, Lang P, Schlegel PG, Eyrich M, Gruhn B, Ehninger G, Koscielniak E, Klein C, Sykora KW, Holler E, Mauz-Körholz C, Woessmann W, Richter GH, Schmidt AH, Peters C, Dirksen U, Jürgens H, Bregni M, Burdach S	Human Leukocyte Antigen Distribution in German Caucasians with Advanced Ewing's Sarcoma.	Klinische Padiatrie 2012, Epub ahead of print
Risk stratification criteria for patients with Ewing's sarcoma family of tumors (ESFT) are still limited. We hypothesized divergent human leukocyte antigen (HLA) patterns in ESFT patients and compared HLA-A, -B and -DR phenotype frequencies of patients with advanced ESFT with those of healthy controls.HLA types of all German Caucasian patients with advanced ESFT and available HLA-A, -B and -DR data registered in the European Group for Blood and Marrow Transplantation, Paediatric Registry for Stem Cell Transplantation and the MetaEICESS data bases (study group, n=30) were retrospectively compared with HLA types of healthy German stem cell donors (control group, n=8 862 for single HLA frequencies and n=8 839 for allele combinations). Study group patients had been immuno-typed due to eligibility for allogeneic stem cell transplantation for high risk of treatment failure, and thus constituted a selected subgroup of ESFT patients.After Bonferroni correction for multiple testing (PC), phenotype frequencies of HLA-A24 remained significantly higher in the study group compared to controls (PC<0.05). Furthermore, several HLA combinations were significantly more frequent in the study group compared to controls (all PC<0.05).We report an increased incidence of circumscribed HLA patterns in German Caucasians with advanced ESFT. The possible clinical significance of this observation has to be re-assessed in prospective trials comprising larger ESFT patient numbers of all risk groups.
Thiel U, Wawer A, von Luettichau I, Bender HU, Blaeschke F, Grunewald TG, Steinborn M, Röper B, Bonig H, Klingebiel T, Bader P, Koscielniak E, Paulussen M, Dirksen U, Jürgens H, Kolb HJ, Burdach SE	Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow.	Oncotarget 2016 Oct 25; 7: 70959
Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols.
Thiel U, Schober SJ, Ranft A, Gassmann H, Jabar S, Gall K, von Lüttichau I, Wawer A, Koscielniak E, Diaz MA, Ussowicz M, Kazantsev I, Afanasyev B, Merker M, Klingebiel T, Prete A, Gruhn B, Bader P, Jürgens H, Dirksen U, Handgretinger R, Burdach S, Lang P	No difference in survival after HLA mismatched versus HLA matched allogeneic stem cell transplantation in Ewing sarcoma patients with advanced disease.	Bone marrow transplantation 2021, 56: 1550
Patients with advanced Ewing sarcoma (AES) carry a poor prognosis. Retrospectively, we analyzed 66 AES patients treated with allogeneic stem cell transplantation (allo-SCT) receiving HLA-mismatched (group A, n = 39) versus HLA-matched grafts (group B, n = 27). Median age at diagnosis was 13 years, and 15 years (range 3-49 years) at allo-SCT. The two groups did not differ statistically in distribution of gender, age, remission status/number of relapses at allo-SCT, or risk stratum. 9/39 (23%) group A versus 2/27 (7%) group B patients developed severe acute graft versus host disease (GvHD). Of patients alive at day 100, 7/34 (21%) group A versus 9/19 (47%) group B patients had developed chronic GvHD. In group A, 33/39 (85%) versus 20/27 (74%) group B patients died of disease and 1/39 (3%) versus 1/27 (4%) patients died of complications, respectively. Altogether 12/66 (18%) patients survived in CR. Median EFS 24 months after allo-SCT was 20% in both groups, median OS was 27% (group A) versus 17% (group B), respectively. There was no difference in EFS and OS in AES patients transplanted with HLA-mismatched versus HLA-matched graft in univariate and multivariate analyses. In this analysis, CR at allo-SCT is a condition for survival (p < 0.02).
Thompson MP, Kurzrock R	Epstein-Barr virus and cancer.	Clinical cancer research : an official journal of the American Association for Cancer Research 2004 Feb 1; 10: 803
EBV was the first human virus to be directly implicated in carcinogenesis. It infects >90% of the world's population. Although most humans coexist with the virus without serious sequelae, a small proportion will develop tumors. Normal host populations can have vastly different susceptibility to EBV-related tumors as demonstrated by geographical and immunological variations in the prevalence of these cancers. EBV has been implicated in the pathogenesis of Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals. The presence of this virus has also been associated with epithelial malignancies arising in the gastric region and the breast, although some of this work remains in dispute. EBV uses its viral proteins, the actions of which mimic several growth factors, transcription factors, and antiapoptotic factors, to usurp control of the cellular pathways that regulate diverse homeostatic cellular functions. Recent advances in antiviral therapeutics, application of monoclonal antibodies, and generation of EBV-specific CTLs are beginning to show promise in the treatment of EBV-related disorders.
Thorer H, Zimmermann M, Makarova O, Oschlies I, Klapper W, Lang P, von Stackelberg A, Fleischhack G, Worch J, Jürgens H, Woessmann W, Reiter A, Burkhardt B	Primary central nervous system lymphoma in children and adolescents: low relapse rate after treatment according to Non-Hodgkin-Lymphoma Berlin-Frankfurt-Münster protocols for systemic lymphoma.	Haematologica 2014,
Thomas C, Ruland V, Kordes U, Hartung S, Capper D, Pietsch T, Gerß J, Wolff JE, Paulus W, Hasselblatt M	Pediatric atypical choroid plexus papilloma reconsidered: increased mitotic activity is prognostic only in older children.	Acta neuropathologica 2015, 129: 925
Thomas C, Sill M, Ruland V, Witten A, Hartung S, Kordes U, Jeibmann A, Beschorner R, Keyvani K, Bergmann M, Mittelbronn M, Pietsch T, Felsberg J, Monoranu CM, Varlet P, Hauser P, Olar A, Grundy RG, Wolff JE, Korshunov A, Jones DT, Bewerunge-Hudler M, Hovestadt V, von Deimling A, Pfister SM, Paulus W, Capper D, Hasselblatt M	Methylation profiling of choroid plexus tumors reveals 3 clinically distinct subgroups.	Neuro-oncology 2016, 18: 790
Thobakgale CF, Ndung'u T	Neutrophil counts in persons of African origin.	Current opinion in hematology 2014, 21: 50
Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarré C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M	Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia.	The New England journal of medicine 2018 Apr 19; 378: 1479
Thole TM, Toedling J, Sprüssel A, Pfeil S, Savelyeva L, Capper D, Messerschmidt C, Beule D, Groeneveld-Krentz S, Eckert C, Gambara G, Henssen AG, Finkler S, Schulte JH, Sieber A, Bluethgen N, Regenbrecht CRA, Kuenkele A, Lodrini M, Eggert A, Deubzer HE	Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model.	International journal of cancer 2019 Jul 15;
Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80-540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.
Thomas C, Knerlich-Lukoschus F, Reinhard H, Johann PD, Sturm D, Sahm F, Bens S, Vogt J, Nemes K, Oyen F, Kordes U, Siebert R, Schneppenheim R, Messing-Jünger M, Pietsch T, von Deimling A, Paulus W, Pfister SM, Kool M, Frühwald MC, Hasselblatt M	Two molecularly distinct atypical teratoid/rhabdoid tumors (or tumor components) occurring in an infant with rhabdoid tumor predisposition syndrome 1.	Acta neuropathologica 2019, 137: 847
No abstract available
Thomas C, Wefers A, Bens S, Nemes K, Agaimy A, Oyen F, Vogelgesang S, Rodriguez FJ, Brett FM, McLendon R, Bodi I, Burel-Vandenbos F, Keyvani K, Tippelt S, Poulsen FR, Lipp ES, Giannini C, Reifenberger G, Kuchelmeister K, Pietsch T, Kordes U, Siebert R, Frühwald MC, Johann PD, Sill M, Kool M, von Deimling A, Paulus W, Hasselblatt M	Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults.	Acta neuropathologica 2020, 139: 277
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40ÃÂ years (range 15-61ÃÂ years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2ÃÂ bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48ÃÂ months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
Thomas C, Metrock K, Kordes U, Hasselblatt M, Dhall G	Epigenetics impacts upon prognosis and clinical management of choroid plexus tumors.	Journal of neuro-oncology 2020, Epup ahead of print
Choroid plexus tumors comprise of choroid plexus papilloma (CPP, WHO grade I), atypical choroid plexus papilloma (aCPP, WHO grade II) and choroid plexus carcinoma (CPC, WHO grade III). Molecular events driving the majority of choroid plexus tumors remain poorly understood. Recently, DNA methylation profiling has revealed different epigenetic subgroups.
Thomas C, Soschinski P, Zwaig M, Oikonomopoulos S, Okonechnikov K, Pajtler KW, Sill M, Schweizer L, Koch A, Neumann J, Schüller U, Sahm F, Rauschenbach L, Keyvani K, Proescholdt M, Riemenschneider MJ, Segewiß J, Ruckert C, Grauer O, Monoranu CM, Lamszus K, Patrizi A, Kordes U, Siebert R, Kool M, Ragoussis J, Foulkes WD, Paulus W, Rivera B, Hasselblatt M	The genetic landscape of choroid plexus tumors in children and adults.	Neuro-oncology 2021, 23: 650
Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs).
Thomas C, Oehl-Huber K, Bens S, Soschinski P, Koch A, Nemes K, Oyen F, Kordes U, Kool M, Frühwald MC, Hasselblatt M, Siebert R	Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor.	Genes, chromosomes & cancer 2021, 60: 586
No abstract available
Thomas C, Federico A, Sill M, Bens S, Oyen F, Nemes K, Johann PD, Hartmann C, Hartmann W, Sumerauer D, Paterno V, Samii A, Kordes U, Siebert R, Frühwald MC, Paulus W, Kool M, Hasselblatt M	Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.	The American journal of surgical pathology 2021, online ahead of print
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences.
Tiemann M, Claviez A, Lüders H, Zimmermann M, Schellong G, Dörffel W, Parwaresch R	Proliferation characteristics in pediatric Hodgkin's disease point to a cell cycle arrest in G 1 phase.	American Journal of Pathology 2004
Tiemann M, Claviez A, Riener M, Stankewitz K, Dörffel W, Reiter A, Parwaresch R	Proliferation rate and outcome in children with T-cell rich B-cell-lymphoma. A clinicopathologic study of the NHL-BFM-study group.	Leukemia and Lymphoma 2004
Tiemann M, Riener MO, Claviez A, Meyer U, Dörffel W, Reiter A, Parwaresch R	Proliferation rate and outcome in children with T-cell rich B-cell lymphoma: a clinicopathologic study from the NHL-BFM-study group.	Leuk Lymphoma 2005, 46: 1295
Tiede A	[Perioperative hemostasis management].	Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen 2007, 78: 69-79; quiz 80
Hemostasis management plays an important role in surgery. Anti-platelet drugs and oral anticoagulants are taken by an increasing number of patients. Perioperative management must take into account bleeding as well as thromboembolic risks when withholding these medications. Patients with inherited or acquired hemostatic disorders should receive interdisciplinary care in order to optimise perioperative substitution therapy. For the diagnosis of acquired coagulopathy secondary to massive bleeding, point of care tests have been introduced that should help focus substitution therapy in emergency situations. However, physicians should be aware of the limitations of these methods, and a full diagnostic workup should be done in order to uncover hemorrhagic diatheses not detected by point of care testing.
Tiede A, Rand JH, Budde U, Ganser A, Federici AB	How I treat the acquired von Willebrand syndrome.	Blood 2011, 117: 6777
The acquired von Willebrand syndrome (AVWS) is a bleeding disorder that is frequently unrecognized or is misdiagnosed as von Willebrand disease. AVWS is characterized by structural or functional defects of von Willebrand factor (VWF) that are secondary to autoimmune, lymphoproliferative or myeloproliferative, malignant, cardiovascular, or other disorders. VWF abnormalities in these disorders can result from (1) antibody-mediated clearance or functional interference, (2) adsorption to surfaces of transformed cells or platelets, or (3) increased shear stress and subsequent proteolysis. Diagnosis can be challenging as no single test is usually sufficient to prove or exclude AVWS. Furthermore, there are no evidence-based guidelines for management. Treatments of the underlying medical condition, including chemo/radiotherapy, surgery, or immunosuppressants can result in remission of AVWS, but is not always feasible and successful. Because of the heterogeneous mechanisms of AVWS, more than one therapeutic approach is often required to treat acute bleeds and for prophylaxis during invasive procedures; the treatment options include, but are not limited to, desmopressin, VWF-containing concentrates, intravenous immunoglobulin, plasmapheresis or recombinant factor VIIa. Here, we review the management of AVWS with an overview on the currently available evidence and additional considerations for typical treatment situations.
Tillmann B, Krümpelmann S, Wagner A, Schulze-Westhoff P, Jürgens H, Boos J	Aufteilung der täglichen Etoposiddosis 50 mg/m2 in 2*25 mg/m2 bewirkt längere Dauer effektiver Serumkonzentrationen.	Monatsschr Kinderheilkd 1996, 144:V190-S41
Tillmann B, Krümpelmann S, Würthwein G, Wagner A, Schulze-Westhoff P, Hempel G, Jürgens H, Boos J	Pharmakokinetische Aspekte der oralen Applikation von Etoposid.	Klin Pädiatr 1998, 210: 159
van Tilburg CM, Pfaff E, Pajtler KW, Langenberg KPS, Fiesel P, Jones BC, Balasubramanian GP, Stark S, Johann PD, Blattner-Johnson M, Schramm K, Dikow N, Hirsch S, Sutter C, Grund K, von Stackelberg A, Kulozik AE, Lissat A, Borkhardt A, Meisel R, Reinhardt D, Klusmann JH, Fleischhack G, Tippelt S, von Schweinitz D, Schmid I, Kramm CM, von Bueren AO, Calaminus G, Vorwerk P, Graf N, Westermann F, Fischer M, Eggert A, Burkhardt B, Wossmann W, Nathrath M, Hecker-Nolting S, Fruhwald MC, Schneider DT, Brecht IB, Ketteler P, Fulda S, Koscielniak E, Meister MT, Scheer M, Hettmer S, Schwab M, Tremmel R, Ora I, Hutter C, Gerber NU, Lohi O, Kazanowska B, Kattamis A, Filippidou M, Goemans B, Zwaan CM, Milde T, Jager N, Wolf S, Reuss D, Sahm F, von Deimling A, Dirksen U, Freitag A, Witt R, Lichter P, Kopp-Schneider A, Jones DTW, Molenaar JJ, Capper D, Pfister SM, Witt O	The pediatric precision oncology INFORM registry: clinical outcome and benefit for patients with very high-evidence targets.	Cancer discovery 2021,online ahaed of print
INFORM is a prospective, multi-national registry gathering clinical and molecular data of relapsed, progressive or high-risk pediatric cancer patients. This report describes long-term follow-up of 519 patients in whom molecular alterations were evaluated according to a pre-defined 7-scale target prioritization algorithm. Mean turnaround time from sample receipt to report was 25.4 days. The highest target priority level was observed in 42 patients (8.1%). Of these, twenty patients received matched targeted treatment with a median PFS of 204 days (95% CI 99 - N.A.), compared with 117 days (95% CI 106 - 143; P=0.011) in all other patients. The respective molecular targets were shown to be predictive for matched treatment response and not prognostic surrogates for improved outcome. Hereditary cancer predisposition syndromes were identified in 7.5% of patients, half of which were newly identified through the study. Integrated molecular analyses resulted in a change or refinement of diagnoses in 8.2% of cases.
Timmermann B, Kortmann R, Kühl J, Meisner C, Bamberg M	Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91.	Int J Radiat Oncol Biol Phys 2000, 46: 287
Timmermann B, Kortmann R, Kühl J, Meisner C, Dieckmann K, Pietsch T, Bamberg M	Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood.	J Clin Oncol 2002, 20: 842
Timmermann B	Therapie von Ependymomen im Kindesalter - Eine aktuelle Übersicht.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2002, 4: 21
Timmermann B, Kortmann RD, Kühl J, Willich N, Bamberg M	[Interdisciplinary therapy of childhood ependymomas].	Strahlenther Onkol 2002, 178: 469-79.
BACKGROUND: Ependymomas represent about 10% of CNS tumors in children. The proportion of cases defined as anaplastic is about 25%. Prognosis depends on extent of resection, and postoperative radiotherapy, the overall survival rate is 30-60%. Further investigations should clarify the impact of chemotherapy, histological grading, dose, and volume of radiotherapy. MATERIAL AND METHOD: Based on historical reports, the recent literature, present guidelines, and ongoing trials an overview is provided for the management of ependymomas in childhood. RESULTS: Local tumor control is the most important aim. Recurrences occur predominantly at the primary tumor region. The main instrument is surgery to effect maximal tumor resection. The addition of radiotherapy could improve survival significantly from 10% to 50%. Regarding the volume of irradiation there is confidence today that local fields are sufficient for all non-disseminated ependymomas. Local dose escalation has been introduced using hyperfractionated schedules. In recent studies this has been shown to increase local control up to 70%. Regarding chemotherapy in ependymomas trials have shown limited efficacy to date. For metastatic disease standard treatment has shown to be insufficient and high dose chemotherapy regimens to increase survival are in study. In younger children radiotherapy should be delayed using early chemotherapy. With pre-irradiation chemotherapy survival rates of 63.3% for children under age of 3 were achieved. CONCLUSIONS: At present the cooperating clinicians are optimizing treatment procedures to improve results and to reduce toxicity. In radiotherapy reduction of target volume to the involved field for all non-disseminated ependymomas as well as the introduction of hyperfractionated schedules and conformal therapy with dose escalation are important developments
Timmermann B, Kortmann RD, Kühl J, Rutkowski S, Dieckmann K, Meisner C, Bamberg M	Role of radiotherapy in anaplastic ependymoma in children under age of 3 years: results of the prospective German brain tumor trials HIT-SKK 87 and 92.	Radiotherapy and oncology 2005, 77: 278
BACKGROUND AND PURPOSE: To evaluate the outcome of very young children with anaplastic ependymoma after delayed or omitted radiotherapy (RT). MATERIALS AND METHODS: Children under age of 3 years with anaplastic ependymoma were enrolled in the HIT-SKK 87 trial from 1987. After surgery, low-risk patients (R0, M0) received maintenance chemotherapy until elective RT at age of three. In high-risk patients (R+, M+) intensive induction chemotherapy was followed by maintenance chemotherapy and subsequently delayed RT. If there was, progression radiotherapy started immediately. In the HIT-SKK 92, trial MTX-based chemotherapy was applied. RT was administered in non-responders only. RESULTS: Thirty-four children with anaplastic ependymoma were eligible (age 1.0-33.0 months). All children received chemotherapy. In 13 children, no RT was administered. Preventive RT after chemotherapy was given in nine, and salvage RT in 12 children. OS and PFS rates after 3-year were 55.9 and 27.3%, respectively. Twenty-five children relapsed. Positive impact on survival was observed in children with higher age, M0-stage, complete resection, and treatment with radiotherapy. Without RT only 3/13, children survived. CONCLUSION: Delaying RT jeopardizes survival even after intensive chemotherapy. Predominant site of failure is the primary tumor site. RT of the neuraxis should be omitted in localized disease.
Timmermann B, Kortmann RD, Kühl J, Rutkowski S, Meisner C, Pietsch T, Deinlein F, Urban C, Warmuth-Metz M, Bamberg M	Role of radiotherapy in supratentorial primitive neuroectodermal tumor in young children: results of the German HIT-SKK87 and HIT-SKK92 trials.	Journal of clinical oncology 2006, 24: 1554
PURPOSE: To assess the outcome of young children with supratentorial primitive neuroectodermal tumor (stPNET) treated by intensive postoperative chemotherapy alone compared with treatment with chemotherapy and delayed radiotherapy (RT). PATIENTS AND METHODS: From 1987 to 1992, children younger than 3 years of age with stPNET were enrolled in the HIT-SKK87 trial in Germany and Austria. After surgery, low-risk patients received maintenance chemotherapy before RT. In high-risk patients, intensive induction chemotherapy was followed by maintenance chemotherapy until delayed RT was initiated. In the following trial, HIT-SKK92 methotrexate-based chemotherapy was applied. In children with complete remission after three cycles, therapy was finished without irradiation. Otherwise, radiotherapy or salvage chemotherapy was administered. RESULTS: Twenty-nine children were eligible (age, 3.0 to 37.0 months). All children received chemotherapy. In 15 children, no RT was administered. Four children had tumor progression during chemotherapy and underwent irradiation. In 10 patients, RT was given after chemotherapy. Overall survival (OS) and progression-free survival (PFS) rates after 3 years were 17.2% and 14.9%, respectively. Twenty-four children relapsed (13 at the tumor site only, three at distant site, and eight at both local and distant sites). Positive impact on survival was observed in children with complete resection but without statistical significance. Administration of RT was the only significant predictive factor for OS and PFS. Only one child not having RT survived. CONCLUSION: Outcome of infants and babies with stPNET is unsatisfactory. Omission of RT jeopardizes survival, even if intensive chemotherapy is applied. We suggest to limit any delay of RT to a maximum of 6 months even in young children.
Timmermann B, Schuck A, Niggli F, Weiss M, Lomax AJ, Pedroni E, Coray A, Jermann M, Rutz HP, Goitein G	Spot-scanning proton therapy for malignant soft tissue tumors in childhood: First experiences at the Paul Scherrer Institute.	International journal of radiation oncology, biology, physics 2007 Feb 1; 67: 497
Timmermann B	Die Protonentherapie. Chancen zur besseren Verträglichkeit der Tumorbestrahlung bei Kindern.	Wir 2010, 1: 33
Wir ist Die Zeitschrift der Deutschen Kinderkrebsstiftung und der Deutschen Leukämie-Forschungshilfe e.V.
Timmermann B	Ependymome.	S1-Leitlinie 025/025, AWMF online 2018
Timmermann B, Dieckmann K	Strahlentherapie.	In: Niemeyer C, Eggert A. ed. Pädiatrische Hämatologie und Onkologie Springer; 2018, 199
Timmermann B	Strahlentherapie bei Krebserkrankungen im Kindesalter.	Wir 2018, 4: 28 - 31
Wir ist Die Zeitschrift der Deutschen Kinderkrebsstiftung und der Deutschen Leukämie-Forschungshilfe e.V.
Tiphaine AB, Hjalgrim LL, Nersting J, Breitkreutz J, Nelken B, Schrappe M, Stanulla M, Thomas C, Bertrand Y, Leverger G, Baruchel A, Schmiegelow K, Jacqz-Aigrain E	Evaluation of a pediatric liquid formulation to improve 6-mercaptopurine therapy in children.	Eur J Pharm Sci 2015 Dec 2; 83: 1-7.
BACKGROUND: 6-mercaptopurine (6-MP), a key drug for treatment of acute lymphoblastic leukemia (ALL), has until recently had no adequate formulation for pediatric patients. Several approaches have been taken but the only oral paraben-free 6-MP liquid formulation named Loulla was developed and evaluated in the target population. Preclinical and clinical evaluations were performed according to a Pediatric Investigation Plan, in order to apply for a Pediatric Use Marketing Authorization. METHODS: The pre-clinical study assessed the maximum tolerated dosage-volume and evaluated local mucosal toxicity of 28 daily administrations in treated compared to controls gold hamsters. The multi-centre clinical study was single-dose, open-label, crossover trial, conducted in 15 ALL children during maintenance therapy. The bioavailability and palatability of a single 50mg fixed dose of Loulla compared to 50mg registered tablets were evaluated in a random order on two consecutive days. Seven blood samples over 9h were obtained each day to determine 6-MP pharmacokinetic parameters, including Tmax, Cmax, AUC0-9 and AUC0-∞. A questionnaire adapted to children testing Loulla palatability and preference for either Loulla or the usual 6-MP tablet was completed. Occurrence of adverse events was determined at study visits by vital sign measurements, patient's spontaneous reporting, investigator's questioning and clinical examination. RESULTS: The preclinical study in gold hamsters showed that dosage-volume of 75mg/kg/day was well tolerated. The relative bioavailability of liquid Loulla formulation compared to the reference presentation is 76% for AUC0-9 and AUC0-∞ and 80% for Cmax. The taste of Loulla and the mouth feeling after ingestion compare favorably to the tablet. No adverse event occurred. CONCLUSION: Pharmacokinetic, palatability and safety data support the use of Loulla in children.
Tischkowitz MD, Hodgson SV	Fanconi anaemia.	Med Genet 2003, 40: 1
Fanconi anaemia (FA) is an autosomal recessive disease characterised by congenital abnormalities, defective haemopoiesis, and a high risk of developing acute myeloid leukaemia and certain solid tumours. Chromosomal instability, especially on exposure to alkylating agents, may be shown in affected subjects and is the basis for a diagnostic test. FA can be caused by mutations in at least seven different genes. Interaction pathways have been established, both between the FA proteins and other proteins involved in DNA damage repair, such as ATM, BRCA1 and BRCA2, thereby providing a link with other disorders in which defective DNA damage repair is a feature. This review summarises the clinical features of FA and the natural history of the disease, discusses diagnosis and management, and puts the recent molecular advances into the context of the cellular and clinical FA phenotype.
Titgemeyer C, Grois N, Minkov M, Flucher-Wolfram B, Gatterer-Menz I, Gadner H	Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.	Med Pediatr Oncol 2001, 37: 108
Titgemeyer C, Grois N, Minkov M, Flucher-Wolfram B, Gatterer-Menz I, Gadner H	Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.	Medical and pediatric oncology 2001, 37: 108
BACKGROUND: Single-system (SS) disease is the most common presentation in Langerhans cell histiocytosis (LCH) with a heterogenous clinical picture and course. Mostly bone and rarely skin or lymph nodes are involved. PROCEDURE: One hundred and seventy patients with SS-LCH were registered in the DAL-HX 83/90 studies. They were diagnosed according to uniform diagnostic criteria and followed by a standardised schedule. RESULTS: Single bone lesions were most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node involvement (4 patients). In the detection of bone lesions radiographic skeletal survey proved to be superior to bone scan (97% vs. 82%). Treatment comprised surgery, irradiation and local instillation of steroids, and standardised chemotherapy for multifocal bone disease. After initial therapy 81% of the patients remained disease free. Reactivations restricted to the skeleton occurred in 18% of both unifocal and multifocal bone disease. Two skin patients had a chronic course. Fatality occurred only in one infant with skin disease who progressed to multi-system disease. Twenty-five percent of all patients developed permanent consequences, which were already present at diagnosis in about half of these patients and comprised mainly orthopedic problems related to lesional sites. Diabetes insipidus occurred in 3% and anterior pituitary dysfunction in 2% of the patients. CONCLUSIONS: The course in SS%LCH was benign. In bone disease reactivations remained restricted to the skeleton and did not influence survival. However, reactivations had an impact on morbidity, as permanent consequences were mostly related to the site of disease activity. Med Pediatr Oncol 2001;37:108-114.
Tomita T, Das L, Radkowski MA	Bone metastases of medulloblastoma in childhood; correlation with flow cytometric DNA analysis.	J Neurooncol 1990, 8: 149
Thirty children with medulloblastoma who were treated between 1980 and 1986 are presented. Flow cytometric DNA analysis using formalin-fixed and paraffin-embedded tissues showed that 15 were DNA aneuploid, 13 diploid and 2 tetraploid. After homogeneous treatment with a combination of radical resection and radiation therapy, patients with DNA aneuploid medulloblastoma showed significantly better outcome (p = 0.003). Among these 30 patients, 6 (20%) had bone metastases of medulloblastoma during a minimum of 2-year follow-up period. DNA ploidy of these patients was diploid in 5 and aneuploid in 1. Incidence of bone metastases appears to correlate with DNA ploidy (p = 0.046). At the time of discovery of bone metastases, 4 had no demonstrable recurrence in the central nervous system (CNS). Radionuclide bone scan was more sensitive in disclosing these lesions, while only one patient had positive results of bone marrow aspirates/biopsy. Three patients were treated with chemotherapy, two had a combination of regional irradiation and chemotherapy and one refused treatment. All treated bone metastases in 5 patients responded clinically and radiographically, but only one patient is alive 66 months after therapy. Four patients died due to either CNS recurrence of septic complication of chemotherapy. Early detection of bone metastases by use of frequent bone scans is important. Patients with diploid medulloblastoma should be treated with adjuvant chemotherapy in order to prevent recurrences and metastases.
Tomeczkowski J, Beilken A, Frick D, Wieland B, König A, Falk M, Reiter A, Welte K, Sykora K	Absence of c-kit receptor and absent proliferative response to stem cell factor in childhood Burkitt's lymphoma cells.	Blood 1995, 86: 1469
Tomeczkowski J, Yakisan E, Wieland B, Reiter A, Welte K, Sykora K	Absence of G-CSF receptors and absent response to G-CSF in childhood Burkitt's lymphoma and B-ALL cells.	Br J Haematol 1995, 89: 771
Tomeczkowski J, Frick D, Schwinzer B, Reiter A, Welte K, Sykora K	Expression and regulation of c-kit receptor and proliferative response to stem cell factor in childhood lymphoma and leukemia.	Molecular Biology of Hematopoiesis 1996, 173
Tomeczkowski J, Zur, Reiter A, Welte K, Sykora K	Absence of IL-6 receptor expression in fresh childhood Burkitt's lymphoma cells and induction of IL-6 receptors by Epstein-Barr virus in vitro.	Br J Haematol 1997, 97: 400
Tomeczkowski J, Frick D, Schwinzer B, Wittner N, Ludwig W, Reiter A, Welte K, Sykora K	Expression and regulation of c-kit receptor and response to stem cell factor in childhood malignant T-lymphoblastic cells.	Leukemia 1998, 12: 1221
Topp MS, Stelljes M, Zugmaier G, Barnette P, Heffner LT Jr, Trippett T, Duell J, Bargou RC, Holland C, Benjamin JE, Klinger M, Litzow MR	Blinatumomab retreatment after relapse in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia.	Leukemia 2018, 32: 562
No abstract available
Tormey CA, Hendrickson JE	Routine non-ABO blood group antigen genotyping in sickle cell disease: the new frontier in pretransfusion testing?	Transfusion 2015, 55(6 Pt 2): 1374
Tournade M, de Kraker J, Graf N	The SIOP 93-01 Wilms' tumor study.	Med Pediatr Oncol 1999
Tournade M, Com-Nougue C, de Kraker J, Ludwig R, Rey A, Burgers J, Sandstedt B, Godzinski J, Carli M, Potter R, Zucker J	International Society of Pediatric Oncology Nephroblastoma Trial and Study Committee. Optimal duration of preoperative therapy in unilateral and nonmetastatic Wilms' tumor in children older than 6 months.	J Clin Oncol 2001, 19: 488
Tramsen L, Salzmann-Manrique E, Bochennek K, Klingebiel T, Reinhardt D, Creutzig U, Sung L, Lehrnbecher T	Lack of Effectiveness of Neutropenic Diet and Social Restrictions as Anti-Infective Measures in Children With Acute Myeloid Leukemia: An Analysis of the AML-BFM 2004 Trial.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016, 34: 2776
PURPOSE: Although nonpharmacologic anti-infective measures are widely used in children treated for acute myeloid leukemia (AML), there is little evidence of their effectiveness. PATIENTS AND METHODS: We analyzed infectious complications in children during intensive treatment of AML according to the AML-BFM 2004 trial and surveyed sites on institutional standards regarding recommended restrictions of social contacts (six items), pets (five items), and food (eight items). A scoring system was developed with a restriction score for each item. Multivariable Poisson regression adjusted for sex, age, weight group, risk stratification, and prophylactic antibiotics was used to estimate the impact of the restrictions on the incidence ratios of fever of unknown origin, bacteremia, pneumonia, and gastroenteritis. RESULTS: Data on recommendations of nonpharmacologic anti-infective measures and infectious complications were available in 339 patients treated in 37 institutions. Analyses did not demonstrate a significant benefit of any of the restrictions regarding food, social contacts, and pets on the risk of fever, bacteremia, pneumonia, and gastroenteritis. In contrast, age, weight group, risk stratification, and nonabsorbable antibiotics had some influence on infections complications. CONCLUSION: The lack of effectiveness of dietary restrictions and restrictions regarding social contacts and pets should result in reconsideration of anti-infective policies.
Treuner J	Ifosfamide in the treatment of soft-tissue sarcoma.	Am J Hem/Oncol 1993, 521
Treuner J	Die Behandlung der Weichteilsarkome im Kindes- und Jugendalter.	Klin Onkol 1994, 44
Treuner J, Morgan M	Clinical management of soft tissue sarcomas.	Curr Top Pathol 1995, 89: 17
Treuner J	Weichteilsarkome im Kindes- und Jugendalter; in Schmoll,H-J, Höffken K, Possinger K (Hrsg.)	Kompendium internistischer Onkolgie 1996, 1
Trepel M	Neuroanatomie - Struktur und Funktion.	Elsevier GmbH, Urban & Fischer Verlag 3. Auflage 2004
Treuner J, Brecht I	Weichteilsarkome.	in: Gadner H, Gaedicke G, Niemeyer CH, Ritter J (Hrsg.): Pädiatrische Hämatologie und Onkologie Springer-Verlag 2006, 865
Trottestam H, Horne A, Aricò M, Egeler RM, Filipovich AH, Gadner H, Imashuku S, Ladisch S, Webb D, Janka G, Henter JI, Histiocyte Society	Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol.	Blood 2011, 118: 4577
Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.
Trottestam H, Berglöf E, Horne A, Onelöv E, Beutel K, Lehmberg K, Sieni E, Silfverberg T, Aricò M, Janka G, Henter JI	Risk factors for early death in children with haemophagocytic lymphohistiocytosis.	Acta paediatrica (Oslo, Norway : 1992) 2012, 101: 313
Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disturbance of immunoregulation. HLH comprises primary and acquired forms with different disease severity. A large proportion of deaths occur early into treatment. We investigated association with early death for laboratory and clinical parameters before the start of and 2 weeks into therapy.
Trobaugh-Lotrario AD, Chaiyachati BH, Meyers RL, Häberle B, Tomlinson GE, Katzenstein HM, Malogolowkin MH, von Schweinitz D, Krailo M, Feusner JH	Outcomes for patients with congenital hepatoblastoma.	Pediatric blood & cancer 2013, epub ahead of print
Congenital hepatoblastoma, diagnosed in the first month of life, has been reported to have a poor prognosis; however, a comprehensive evaluation of this entity is lacking.
Tucker MA, Meadows AT, Boice JD Jr et al.	Leukemia after therapy with alkylating agents for childhood cancer.	J Natl Cancer Inst 1987, 78: 459
Tulla M, Berthold F, Graf N, Rutkowski S, von Schweinitz D, Spix C, Kaatsch P	Incidence, Trends, and Survival of Children With Embryonal Tumors.	Pediatrics 2015, 136:e623
BACKGROUND: Central nervous system (CNS) and non-CNS embryonal tumors occur principally in children and are rarely seen in adults. The incidence rates for rare entities such as atypical teratoid/rhabdoid tumors (AT/RT) or primitive neuroectodermal tumors in the CNS are rarely published. Incidence rates for certain subgroups, such as hepatoblastomas, have been increasing in some countries. METHODS: Data of 8337 embryonal tumors, registered in children (0-14 years) between 1991 and 2012 (for AT/RT 2000-2012) in the population-based German Childhood Cancer Registry with complete national coverage were analyzed for incidence rates, time trends, and survival. RESULTS: For most entities, the incidence rates were the highest for children <1 year. An important exception was medulloblastomas, which occurred mainly in 1- to 9-year-olds. Neuroblastomas and ganglioneuroblastomas as well as Wilms tumors (nephroblastomas) had the highest age standardized incidence rates (13.7 and 9.4 per million, respectively). A statistically significant increasing trend for hepatoblastomas (annual average percent change 4.6%) was detected. The survival probabilities varied between the diagnostic groups: primitive neuroectodermal tumors and AT/RT had the lowest and retinoblastomas the highest. The survival was dependent on the age at diagnosis, the most extreme examples being neuroblastomas, for which the survival probability declined steeply for children ≥1 year and medulloblastomas, for which the highest survival was seen for 10- to 14-year-olds. CONCLUSIONS: This study presents a comprehensive overview of pediatric embryonal tumors from a well-established, complete nationwide cancer registry. Significant increasing trend for hepatoblastomas was detected for the first time in Europe. Copyright © 2015 by the American Academy of Pediatrics.
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