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Autor(en)	Titel	Quelle
Kaatsch P, Michaelis J	Epidemiological data on childhood malignancies in the first year of life.	Contrib Oncol 1990, 41: 1
Kaatsch P, Haaf G, Michaelis J	Empfehlungen zur Vorgehensweise bei vermuteten regionalen Häufungen von Krebserkrankungen.	Europäische Perspektiven der Medizinischen Informatik, Biometrie und Epidemiologie 1993, 33
Kaatsch P, Haaf G, Michaelis J	Childhood malignancies in Germany - methods and results of a nationwide registry.	Eur J Cancer 1995, 31A: 993
Kaatsch P, Haaf G, Michaelis J	Haben Krebserkrankungen im Kindesalter zugenommen?	Monatsschrift Kinderheilkunde 1995, 143: 554
Kaatsch P, Michaelis J	Wie oft Kinder krank werden.	Leben will ich jeden Tag 1995, 22
Kaatsch P, Michaelis J	Second neoplasms after malignant diseases in childhood.	Klin Pädiatr 1995, 207: 158
Kaatsch P, Michaelis J	Second neoplasms after malignant diseases in childhood.	Klin Pädiatr 1995, 207: 158
Kaatsch P, Kaletsch U, Krummenauer F, Meinert R, Miesner A, Haaf G, Michaelis J	Case control study on childhood leukemia in Lower Saxony, Germany. Basic considerations, methodology, and summary of results.	Klin Pädiatr 1996, 208: 179
Kaatsch P, Kaletsch U, Meinert R, Michaelis J	An extended study on childhood malignancies in the vicinity of German nuclear power plants.	Cancer Causes Control 1998, 9: 529
Kaatsch P, Kaletsch U, Meinert R, Miesner A, Hoisl M, Schuz J, Michaelis J	German case control study on childhood leukaemia--basic considerations, methodology and summary of the results.	Klin Pädiatr 1998, 210: 185
Kaatsch P	Studien des Deutschen Kinderkrebsregisters zum Auftreten von Leukämien und anderen Krebserkrankungen bei Kindern.	Forum Deutsche Krebsgesellschaft 1999, 300
Kaatsch P, Rickert C, Kühl J, Schuz J, Michaelis J	Population-based epidemiologic data on brain tumors in German children.	Cancer 2001, 92: 3155
Kaatsch P	Das Deutsche Kinderkrebsregister zwei Jahrzehnte nach Beginn seiner Tätigkeit.	Monatsschr Kinderheilkd 2002, 150: 966
Kaatsch P, Klein G, Schulz B, Spix C	Epidemiological data on secondary malignant neoplasms after childhood cancer in Germany [Abstract].	Med Ped Oncol 2002, 39: 254
Kaatsch P, Schüz J	Epidemiologische Studien zu politisch kontrovers diskutierten Themen und deren Kommunikation in die Öffentlichkeit - Empfehlungen zur Risikokommunikation.	Informatik, Biometrie und Epidemiologie in Medizin und Biologie 2002, 83
Kaatsch P, Spix C, Michaelis J	German Childhood Cancer Registry - Annual Report 2000 (Jahresbericht 2000 des Deutschen Kinderkrebsregisters).
Kaaijk P, Kaspers G, van Wering E, Broekema G, Loonen A, Hahlen K, Schmiegelow K, Janka-Schaub G, Henze G, Creutzig U, Veerman A	Cell proliferation is related to in vitro drug resistance in childhood acute leukaemia.	Br J Cancer 2003, 88: 775
Kaatsch P	German Childhood Cancer Registry and its favorable setting.	Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2004, 47: 437
Kaatsch P, Blettner M	Das Langzeit-follow-up in der deutschen pädiatrischen Onkologie als Grundlage für Studien mit Langzeitüberlebenden.	Monatsschr Kinderheilkd 2004, 152
Kaatsch P, Spix C	German Childhood Cancer Registry - Annual Report 2003 (Jahresbericht 2003 des Deutschen Kinderkrebsregisters).
Kaatsch P, Spix C	Jahresbericht 2004 des Deutschen Kinderkrebsregisters.	Technischer Bericht, Universität Mainz 2005
Kaatsch P, Blettner M, Spix C, Jürgens H	Follow up of long-term survivors after childhood cancer in Germany.	Klinische Pädiatrie 2005, 217: 169
BACKGROUND: In recent years, the long-term survival of childhood cancer patients has increased considerably. While this is desirable, more patients with late effects are to be expected and studies thereof become increasingly important. We will need to be able to stay in touch with as many former patients as possible in order to make a systematic and comprehensive long-term follow-up possible. PATIENTS: Childhood cancer patients under 15 years of age at diagnosis resident in Germany and registered at the German Childhood Cancer Registry (GCCR). METHODS: The GCCR has established a 3-phase procedure for follow-up. We developed principles for the long-term follow up of these patients. They are based on the many years of experience at the GCCR and were developed based on the long-standing collaboration between the therapy optimization studies (TOS) in the Society for Paediatric Oncology and Haematology (GPOH) and the GCCR. RESULTS: Currently 8 012 adult survivors diagnosed before 2000 are under observation at the GCCR and could be contacted for studies. About half of the children diagnosed in the 1980ies still in follow-up have been under observation more than 14 years. When asked to personally extend the originally parental consent to data storage at the GCCR and the TOS at about 16 years of age, about 85 % of the patients agree. CONCLUSIONS: Establishing an open-end, systematic long-term follow-up will provide a unique and broad basis for paediatric oncology in Germany to perform representative studies regarding long-term survival after childhood cancer in Germany in the long run.
Kaatsch P	Deutsches Kinderkrebsregister - Eine international angesehene Datenquelle.	Dtsch Arztebl 102: A1421-22, 2005
Kaatsch P, Spix C, Schüz J	Epidemiologie, Ätiologie, Prävention.	In: Gadner H, Gaedicke G, Niemeyer C, Ritter J (Hrsg): Pädiatrische Hämatologie und Onkologie, S. 421-35 Springer Medizin Verlag Heidelberg. 2005
Kaatsch P	25 Jahre Deutsches Kinderkrebsregister: Langzeitfolgen rücken ins Blickfeld - Nehmen Krebserkrankungen bei Kindern zu?	WIR-Informationsschrift von DLFH-Dachverband und Aktion für krebskranke Kinder e.V. (Bonn) 2005, 3
Kaatsch P, Spix C	German Childhood Cancer Registry - Annual Report 2005 (Jahresbericht 2005 des Deutschen Kinderkrebsregisters).	Technischer Bericht, Universität Mainz 2006
Kaatsch P, Spix C	Registry - Annual Report 2006/07 (Jahresbericht 2006/07 des Deutschen Kinderkrebsregisters).	Technischer Bericht, Universität Mainz
Kaatsch P, Spix C, Schulze-Rath R, Schmiedel S, Blettner M	Leukaemia in young children living in the vicinity of German nuclear power plants.	International journal of cancer. Journal international du cancer 2008, 122: 721
A case control study was conducted where cases were children younger than 5 years (diseased between 1980 and 2003) registered at the german childhood cancer registry (GCCR). Population-based matched controls (1:3) were selected from the corresponding registrar's office. Residential proximity to the nearest nuclear power plant was determined for each subject individually (with a precision of about 25 m). The report is focused on leukaemia and mainly on cases in the inner 5-km zone around the plants. The study includes 593 leukaemia cases and 1,766 matched controls. All leukaemia combined show a statistically significant trend for 1/distance with a positive regression coefficient of 1.75 [lower 95%-confidence limit (CL): 0.65]; for acute lymphoid leukaemia 1.63 (lower 95%-CL: 0.39), for acute nonlymphocytic leukaemia 1.99 (lower 95%-CL: -0.41). This indicates a negative trend for distance. Cases live closer to nuclear power plants than the randomly selected controls. A categorical analysis shows a statistically significant odds ratio of 2.19 (lower 95%-CL: 1.51) for residential proximity within 5 km compared to residence outside this area. This result is largely attributed to cases in previous studies of the GCCR (especially in the inner zone) as there is clearly some overlap between those studies. The result was not to be expected under current radiation-epidemiological knowledge. Considering that there is no evidence of relevant accidents and that possible confounders could not be identified, the observed positive distance trend remains unexplained.
Kaatsch P, Spix C	Registry - Annual Report 2008 (Jahresbericht 2008 des Deutschen Kinderkrebsregisters).	Technischer Bericht, Universität Mainz 2008
Kaatsch P, Spix C, Jung I, Blettner M	Childhood leukemia in the vicinity of nuclear power plants in Germany.	Deutsches Arzteblatt international 2008, 105: 725
INTRODUCTION: The causes of leukemia are largely unclear. The question whether leukemia rates are increased near nuclear power plants is controversial. The German Childhood Cancer Registry has published an epidemiological case-control study on childhood cancer and nuclear power plants. METHOD: The study was based on the distance of children's residences from nuclear power plants and addressed the question whether children under age 5 with cancer live closer, on average, to nuclear power plants than randomly selected controls. Odds Ratios (OR) for distance categories and standardized incidence ratios (SIR) were calculated. RESULTS: An association was found between the nearness of residence to nuclear power plants and the risk of leukemia (593 cases, 1766 controls). Within the 5-km zone, the OR for the development of leukemia in children under 5 years of age was 2.19 compared to the rest of the region, and this elevation of the OR was statistically significant. The incidence of leukemia in the overall study region was the same as that in Germany as a whole (SIR=0.99; 95% confidence interval 0.92-1.07). DISCUSSION: Based on the available information about radiation emissions from German nuclear power plants, a direct relation to radiation seems implausible. Many factors may conceivably cause leukemia, possibly operating in combination, and these factors may be present to a greater extent in the vicinity of German nuclear power plants.
Kaatsch P, Reinisch I, Spix C, Berthold F, Janka-Schaub G, Mergenthaler A, Michaelis J, Blettner M	Case-control study on the therapy of childhood cancer and the occurrence of second malignant neoplasms in Germany.	Cancer causes & control 2009, 20: 965
We report on a nested case-control study with 328 cases with second malignant neoplasm (SMN) following childhood cancer and 639 matched controls based on the German Childhood Cancer Registry. In the adjusted overall analysis, the odds ratio (OR) for SMN following any radiotherapy or chemotherapy is 2.1 [95% confidence interval (CI): 1.8-3.3] and 1.8 (95% CI: 0.98-3.1), respectively. The strongest effect is seen for alkylating agents (OR=2.0, 95% CI: 1.2-3.3). The risk of SMN after leukemia is pronounced for antimetabolites (OR=17.2, 95% CI: 1.7-177) and asparaginase (OR=4.3, 95% CI: 1.7-11.0). Following solid tumors, the greatest effect is seen for platinum derivatives (OR=4.1, 95% CI: 1.7-10.1). For anthracyclines, a decreased risk is observed (OR=0.3, 95% CI: 0.1-0.6). Secondary solid tumors are mainly associated with radiotherapy (OR=4.5, 95% CI: 2.5-8.0), especially secondary carcinomas. Secondary acute myeloid leukemia and myelodysplastic syndrome are mainly associated with alkylating agents (OR=8.5, 95% CI: 0.97-74.8), asparaginase (OR=6.8, 95% CI: 2.3-20.6), and platinum derivatives (OR=4.5, 95% CI: 1.5-13.6). The observed risks are in many instances lower than the ones published in previous studies relating to earlier treatment eras of the primary diseases. These differences may be attributed to less toxic but still effective treatment regimes but also to differences in the length of follow-up.
Kaatsch P, Debling D, Blettner M, Spix C	Second malignant neoplasms after childhood cancer in Germany - results from the long-term follow-up of the German Childhood Cancer Registry.	Strahlentherapie und Onkologie 2009, 185 Suppl 2: 8
Kaatsch P, Scheidemann-Wesp U, Schüz J	Maternal use of antibiotics and cancer in the offspring: results of a case-control study in Germany.	Cancer causes & control 2010
OBJECTIVE: As previous results were inconsistent, we assessed the association between maternal use of antibiotics during pregnancy or 3 months before conception and childhood cancer in the offspring in a large case-control study in Germany. METHODS: This population-based study on potential risk factors for childhood cancer was conducted by the German Childhood Cancer Registry (GCCR) and included a total of 1,867 registered cancer cases aged 0-14, diagnosed between October 1992 and September 1994. A total of 2,057 controls were randomly drawn from population registries, matched by age, gender, and region. Conditional logistic regression models for frequency-matched datasets were used to estimate odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Positive statistically significant associations with self-reported maternal antibiotic use were observed for acute lymphoid leukemia (based on 59 mothers exposed to antibiotics, OR = 1.47; 95% CI: 1.06-2.04), acute myeloid leukemia (18 exposed, OR = 3.21; 95% CI: 1.83-5.62), and Burkitt lymphoma (three exposed, OR = 5.89; 95% CI: 1.47-23.69), but not other cancer types. CONCLUSIONS: The results provide some support for the hypothesis that maternal use of antibiotics increases the risk of cancer in the offspring. Although recall bias is a concern, it is unlikely that this fully explains the observed effect. Further, the observed associations might be related to the underlying infections.
Kaatsch P, Spix C	Jahresbericht 2011.	Deutsches Kinderkrebsregister, Universitätsmedizin der Johannes Gutenberg-Universität Mainz 2011
Kaatsch P, Spix C	German Childhood Cancer Registry - Report 2012 (1980-2012) (Jahresbericht Deutsches Kinderkrebsregister 2012).	Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin der Johannes Gutenberg-Universität Mainz 2013
Kaatsch P, Spix C	German Childhood Cancer Registry - Jahresbericht / Annual Report 2013/14 (1980-2013).	Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin der Johannes Gutenberg-Universität Mainz 2014
Kaatsch P, Häfner C, Calaminus G, Blettner M, Tulla M	Pediatric germ cell tumors from 1987 to 2011: incidence rates, time trends, and survival.	Pediatrics 2015, 135:e136
Malignant germ cell tumors (GCTs) are a rare and a heterogeneous group of pediatric cancers. The incidence rate has increased in some populations or subgroups. However, only a few recent publications on epidemiologic data showing the trends in incidence of pediatric GCTs are available.
Kaatsch P, Spix C	German Childhood Cancer Registry - Jahresbericht / Annual Report 2015 (1980-2014).	Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin der Johannes Gutenberg-Universität Mainz 2015

Kaatsch P, Grabow D, Spix C	German Childhood Cancer Registry - Jahresbericht / Annual Report 2016 (1980-2015).	Institut für Medizinische Biometrie, Epidemiologie und Informatik (IMBEI), Universitätsmedizin der Johannes Gutenberg-Universität Mainz 2016
Kaatsch P, Strothotte J, Becker C, Bielack S, Dirksen U, Blettner M	Pediatric bone tumors in Germany from 1987 to 2011: incidence rates, time trends and survival.	Acta oncologica (Stockholm, Sweden) 2016 Sep - Oct; 55(9-10): 1145
BACKGROUND: Malignant bone tumors are a rare group of childhood cancer. MATERIALS AND METHODS: This study describes incidence rates, survival probabilities, and time trends for 1831 children below 15 years of age with a bone tumor registered at the population-based German Childhood Cancer Registry between 1987 and 2011. RESULTS: Overall age-standardized annual incidence rate (ASR) was 5.5 per million. Osteosarcomas (ASR 2.8) and Ewing tumors (ASR 2.6) were the most frequent diagnostic groups. The incidence of bone tumors overall tended to increase slightly over time by 0.7% each year on average. Thirty-nine of the bone tumor cases reported were subsequent primaries and not included into the survival analysis. Survival probabilities remained largely constant. DISCUSSION: Possibly survival was largely constant because chemotherapy has not changed much over time. Overall, the results are similar to other results reported from Europe.
Kaatsch P, Grabow D, Spix C	German Childhood Cancer Registry - Annual Report 2017 (1980-2016).	Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz, 2018
German Childhood Cancer Registry - Annual Report 2017 (1980-2016).
Kaatsch P	Epidemiologie von Krebserkrankungen im Kindesalter, in: Niemeyer CH, Eggert A (Hrsg.):	Pädiatrische Hämatologie und Onkologie 2018, 2. Aufl.: 163
Kaatsch P, Grabow D, Spix C	German Childhood Cancer Registry - Anual Report 2018 (1980-2017).	Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz 2019
Kager L, Heise A, Minkov M, Mobius D, Kotte W, Schulte-Overberg U, Henze G, Gadner H	Occurrence of acute nonlymphoblastic leukemia in two girls after treatment of recurrent, disseminated Langerhans cell histiocytosis.	Pediatr Hematol Oncol 1999, 16: 251
Kager L, Zoubek A, Potschger U, Kastner U, Flege S, Kempf-Bielack B, Branscheid D, Kotz R, Salzer-Kuntschik M, Winkelmann W, Jundt G, Kabisch H, Reichardt P, Jürgens H, Gadner H, Bielack S	Primary metastatic osteosarcoma.	J Clin Oncol 2003, 21: 2011
Kager L, Zoubek A, Dominkus M, Lang S, Bodmer N, Jundt G, Klingebiel T, Jürgens H, Gadner H, Bielack S, for the COSS Study Group	Osteosarcoma in very young children: experience of the Cooperative Osteosarcoma Study Group.	Cancer 2010,
BACKGROUND:: This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma. METHODS:: The authors retrospectively analyzed the data of 2706 consecutive COSS patients with newly diagnosed osteosarcoma and identified 28 (1.0%) patients aged younger than 5 years at diagnosis. Demographic, diagnostic, tumor, treatment-related variables, response, and survival data were analyzed. RESULTS:: Of the 28 preschoolers, 27 presented with high-grade central osteosarcoma of an extremity, and 1 had a secondary osteosarcoma of the orbit. This analysis focused on the 27 patients with extremity tumors. The size of the primary was large (>/=one-third of the involved bone) in 20 of 27 patients. Primary metastases were detected in 4 of 27 children. All patients received multiagent chemotherapy, and 11 of 18 analyzed tumors responded well (>90% necrosis) to neoadjuvant chemotherapy. Limb-sparing surgery was performed in 9 cases, ablative procedures were performed in 15, and, in 3 cases, no local surgery was performed. With a median follow-up of 4 years (6.2 years for survivors), 13 patients were alive. Four patients never achieved a complete remission, and 11 developed recurrences; 14 of these 15 patients died. Five-year overall and event-free survival probabilities were 51% (standard error of the mean [SE], 10%) and 48% (SE, 10%). Better survival was correlated with good response to chemotherapy and later time period of diagnosis. CONCLUSIONS:: Osteosarcoma is extremely rare in preschool children. These patients often have large tumors that may require mutilating resections. Prognosis is in the range of that reported for older patients. Cancer 2010. (c) 2010 American Cancer Society.
Kager L, Kempf-Bielack B, Bielack S	Synchronous and metachronous lung metastases in high-grade osteosarcoma.	Japanese journal of clinical oncology 2010, 40: 94
Kager L, Pötschger U, Bielack S	Review of mifamurtide in the treatment of patients with osteosarcoma.	Ther Clin Risk Manag 2010, 24; 6: 279
Osteosarcoma is the most common primary malignant tumor of bone. The disease, however, is very rare with less than 2,000 expected patients at all age groups per year within the European Union and the United States of America. With multimodal therapy, which combines multiagent chemotherapy and complete resection of all macroscopically detectable tumors, about 60%-70% of patients with localized osteosarcoma can be cured. The prognosis, however, is still poor for patients with synchronous or metachronous metastatic or nonresectable primary disease, with reported 5-year event-free survival (EFS) rates of less than 30%. Overall, the EFS rate has been rather stable since the introduction of combination chemotherapy including doxorubicin, cisplatin, high-dose methotrexate with leukovorin rescue, and/or ifosfamide. Mifamurtide, a modulator of innate immunity, which activates macrophages and monocytes, which in turn release chemicals with potential tumoricidal effects, may help to control microscopic metastatic disease and has been safely given together with standard adjuvant chemotherapy to patients with high-grade osteosarcoma. Results of the recently published intergroup study 0133 trial from the Children's Cancer and Pediatric Oncology Groups suggest that mifamurtide is a medicine that deserves further investigation in this orphan disease.
Kager L, Zoubek A, Dominkus M, Lang S, Bodmer N, Jundt G, Klingebiel T, Jürgens H, Gadner H, Bielack S, COSS Study Group	Osteosarcoma in very young children: experience of the Cooperative Osteosarcoma Study Group.	Cancer 2010, 116: 5316
BACKGROUND: This study was conducted to investigate presentation, treatment, and outcome in very young children with osteosarcoma. METHODS: The authors retrospectively analyzed the data of 2706 consecutive COSS patients with newly diagnosed osteosarcoma and identified 28 (1.0%) patients aged younger than 5 years at diagnosis. Demographic, diagnostic, tumor, treatment-related variables, response, and survival data were analyzed. RESULTS: Of the 28 preschoolers, 27 presented with high-grade central osteosarcoma of an extremity, and 1 had a secondary osteosarcoma of the orbit. This analysis focused on the 27 patients with extremity tumors. The size of the primary was large (≥one-third of the involved bone) in 20 of 27 patients. Primary metastases were detected in 4 of 27 children. All patients received multiagent chemotherapy, and 11 of 18 analyzed tumors responded well (>90% necrosis) to neoadjuvant chemotherapy. Limb-sparing surgery was performed in 9 cases, ablative procedures were performed in 15, and, in 3 cases, no local surgery was performed. With a median follow-up of 4 years (6.2 years for survivors), 13 patients were alive. Four patients never achieved a complete remission, and 11 developed recurrences; 14 of these 15 patients died. Five-year overall and event-free survival probabilities were 51% (standard error of the mean [SE], 10%) and 48% (SE, 10%). Better survival was correlated with good response to chemotherapy and later time period of diagnosis. CONCLUSIONS: Osteosarcoma is extremely rare in preschool children. These patients often have large tumors that may require mutilating resections. Prognosis is in the range of that reported for older patients.
Kager L, Bielack S	[Chemotherapeutic concepts for bone sarcomas].	Der Unfallchirurg 2014, 117: 517
Osteosarcoma and Ewing sarcoma are the most common chemosensitive sarcomas of the bone.
Kager L, Tamamyan G, Bielack S	Novel insights and therapeutic interventions for pediatric osteosarcoma.	Future oncology (London, England) 2017, 13: 357
High-grade osteosarcomas are the most common primary malignant tumors of bone. With complete surgical resection and multi-agent chemotherapy up to 70% of patients with high-grade osteosarcomas and localized extremity tumors can become long-term survivors. The prognosis, however, is poor for patients with nonresectable, primary metastatic or relapsed disease. Outcome is essentially unchanged for three decades. Herein, we describe selected novel insights into the genomics, biology and immunology of the disease and discuss selected strategies, which hold promise to overcome the current stagnation in the therapeutic success in childhood osteosarcoma.
Kager L, Bielack S	Osteosarkome.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer-Verlag GmbH Deutschland 2. vollständig überarbeitete Auflage 2018, 509
Kahle W (Hrsg)	Taschenatlas der Anatomie für Studium und Praxis: 3, Nervensystem und Sinnesorgane.	Georg-Thieme-Verlag 6. überarbeitete Aufl. 1991
Kaletsch U, Kaatsch P, Meinert R, Schuz J, Czarwinski R, Michaelis J	Childhood cancer and residential radon exposure - results of a population-based case-control study in Lower Saxony (Germany).	Radiat Environ Biophys 1999, 38: 211
Kallage V, Müller J, Zimmermann M, Beck J, Ritter J, Creutzig U	Prognosis, treatment completion, and complications in nonresponders in the study AML-BFM87.	Klin Pädiatr 1999, 211: 250
Kalden J, Eger, G	Greten, H et altri (Hrsg.): Innere Medizin: Erhöhte Infektanfälligkeit-primäre und sekundäre Immundefekte.	Thieme Verlag 2010
Kalden J, Eger, G	Erhöhte Infektanfälligkeit - primäre und sekundäre Immundefekte.	Greten, K et al. (Hrsg.): Innere Medizin 2910
Kamps W, Bokkerink J, Hahlen K, Hermans J, Riehm H, Gadner H, Schrappe M, Slater R, Ruiter van, Smets L, de Vaan G, Weening R, van Weerden J, van Wering E, Berg den	Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy.	Blood 1999, 94: 1226
Kampers J, Orjuela-Grimm M, Schober T, Schulz TF, Stiefel M, Klein C, Körholz D, Mauz-Körholz C, Kreipe H, Beier R, Maecker-Kolhoff B	Classical Hodgkin lymphoma-type PTLD after solid organ transplantation in children: a report on 17 patients treated according to subsequent GPOH-HD treatment schedules.	Leukemia & lymphoma 2017, 58: 633
Post-transplant lymphoproliferative disease (PTLD) is a severe complication after solid organ transplantation (SOT). Classical Hodgkin lymphoma-type (HL-) PTLD is a rare subtype, and systematic data on treatment and prognosis are lacking. We report on 17 pediatric patients with classical HL-PTLD. HL-PTLD developed late at a median of 8.1 years after SOT. It was commonly EBV-positive (16/17) and expressed both CD30 (all tumors) and CD20 (8/17 tumors). Patients were treated with chemotherapy +/- involved field radiotherapy (IF-RT) according to the respective GPOH-HD protocol tailored by stage and LDH. Overall survival at 2 and 5 years was 86% with 81% of patients surviving event-free. Six patients had additional rituximab treatment; in two it was given as upfront monotherapy and in four was given concurrently with their chemotherapy. Rituximab monotherapy did not lead to long-term remission. In conclusion, treatment of HL-PTLD with classical HL chemotherapy is effective and tolerable. New treatment modalities such as CD30-targeted or EBV-specific agents may diminish toxicity.
Kanitz JL, Pretzer K, Calaminus G, Wiener A, Längler A, Henze G, Driever PH, Seifert G	Eurythmy therapy in the aftercare of pediatric posterior fossa tumour survivors--a pilot study.	Complementary therapies in medicine 2013, 21 Suppl 1:S3
Pediatric posterior fossa brain tumour survivors are burdened with extensive neurologic, emotional, behavioral and mental impairments. Even long-term common remediation therapies such as conventional physical therapy and occupational therapy do not warrant full recovery. Innovative complementary therapy strategies offer a new option that needs evaluation. EYT is a movement therapy that belongs to the field of mind-body therapies (MBTs). This holistic approach aims to promote self-regulation and self-healing powers e.g. in cancer patients. This pilot study is a first attempt to assess the feasibility, treatment adherence and impact of eurythmy therapy (EYT) in pediatric neurooncology.
Kappler R, von Schweinitz D	A better way forward: targeting hedgehog signaling in liver cancer.	Frontiers in bioscience 2012, 4: 277
Accumulated experimental evidence indicates that Hedgehog (Hh) signaling regulates cell proliferation and specification in a variety of organs during embryonic development. However, abnormal activation of this pathway in postnatal tissues has been linked to a large number of human cancers. With respect to the liver, it is known that Hh signaling not only influences bipotential precursor cells capable of pancreas and liver development, but is also implicated in the pathogenesis of liver tumors such as hepatoblastoma, hepatocellular and cholangiocellular carcinoma, if aberrantly activated. Blockade of Hh signaling by several specific inhibitors has been proven to successfully inhibit tumor growth of various Hh-associated cancers in vitro and in preclinical mouse models, and recent clinical data suggest that the implementation of novel anticancer therapeutics based on Hh interference into commonly accepted regimens are within reach. Thus, it is highly probable that Hh targeted therapies could be used for the treatment of Hh-dependent liver cancers in the future.
Karthaus M, Wolf H, Egerer G, Kämpfe D, Ritter J, Jürgens H	Ceftriaxone in the treatment of solid tumor patients with febrile neutropenia.	Onkologie, International Journal for Cancer Treatment and Therapy 1998, 21: 212
Karawajew L, Ruppert V, Wuchter C, Kosser A, Schrappe M, Dorken B, Ludwig W	Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia.	Blood 2000, 96: 297
Karajannis M, Hummel M, Oschlies I, Anagnostopoulos I, Zimmermann M, Stein H, Parwaresch R, Reiter A	Epstein-Barr virus infection in Western European pediatric non-Hodgkin lymphomas.	Blood 2003, 102
Kardos G, Baumann I, Passmore S, Locatelli F, Hasle H, Schultz K, Stary J, Schmitt-Graeff A, Fischer A, Harbott J, Chessells J, Hann I, Fenu S, Rajnoldi A, Kerndrup G, van Wering E, Rogge T, Nollke P, Niemeyer C	Refractory anemia in childhood.	Blood 2003, 102: 1997
Karachunskiy A, Herold R, von Stackelberg A, Miakova N, Timakow A, Mahortih T, Bajdun L, Maschan A, Fechina L, Shamardina A, Dudkin S, Lebedev V, Varfolomeeva S, Timofeeva V, Roumiantseva J, Chipsanova N, Rumjanzew A, Henze G	Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia.	Leukemia 2008, 22: 1144
Until 1990, the survival of children with acute lymphoblastic leukaemia (ALL) in Russia was below 10%. To establish a protocol feasible under conditions there, ALL-MB 91 was designed to avoid prolonged bone marrow aplasia, thereby reducing needs for extensive supportive care, blood transfusions, long-lasting hospitalization and costs. High-dose therapies were avoided, anthracycline use was limited and CNS radiation therapy only foreseen in high-risk patients (about 30%). This was randomized against a modified BFM protocol. From 1995 to 2002, 834 patients of age up to 18 years were registered in 10 centres and 713 received after central randomization the allocated risk-stratified treatment. After a median follow-up of 7 years, the event-free survival (EFS) was 67+/-3% on ALL-MB 91 (N=358) vs 68+/-3% on ALL-BFM 90m (N=355). The overall survival (OS) was 71+/-3% vs 74+/-2%, respectively. Anaemia, thrombocytopenia, agranulocytosis >10 days and hospitalization (median 35 vs 68 days) were lower on ALL-MB 91 (P<0.01, N=197). While EFS and OS were similar with both protocols, ALL-MB 91 significantly incurred fewer toxicity and resource requirements and, therefore, has been increasingly used across Russia.
Karremann M, Butenhoff S, Rausche U, Pietsch T, Wolff JE, Kramm CM	Pediatric giant cell glioblastoma: New insights into a rare tumor entity.	Neuro-oncology 2009, 11: 323
Little is known about giant cell glioblastoma (GCG) in pediatric patients. The present study identified 18 pediatric patients with centrally reviewed GCG from the HIT-GBM database of the Gesellschaft für Paediatrische Onkologie und Haematologie in Germany, Austria, and Switzerland. Clinical and epidemiological data were compared with those of 178 pediatric patients with centrally reviewed glioblastoma multiforme (GBM) from the same database. In this unique series, median age, male preference, and median clinical history did not differ significantly between pediatric GCG and GBM patients. GCG showed a stronger predilection for cerebral hemispheres than did GBM, which may only partly explain the higher percentage of gross total tumor resections in GCG patients. Most surprising, the widely distributed hypothesis that GCG may imply a better prognosis than GBM could not be substantiated for our pediatric series. Future studies with larger patient numbers and molecular pathological analyses are still needed to corroborate the present findings and further elucidate the biology of GCG in children.
Karow A, Baumann I, Niemeyer CM	Morphologic differential diagnosis of juvenile myelomonocytic leukemia--pitfalls apart from viral infection.	Journal of pediatric hematology/oncology 2009, 31: 380
Karremann M, Pietsch T, Janssen G, Kramm CM, Wolff JE	Anaplastic ganglioglioma in children.	J Neurooncol 2009, 92: 157
PURPOSE: Anaplastic gangliogliomas (AGG) are gangliogliomas with areas of pronounced hypercellularity, vascular proliferation, necrosis, and many mitotic figures. As very few pediatric patients have been studied, we analyzed the cases registered in the HIT-GBM database. PATIENTS AND METHODS: Patient data were obtained from the German HIT-GBM database. Inclusion criteria were diagnosis of AGG proven by a central neuropathological review and patient age 0 to 17 years. Eight patients (five male and three female) were identified. RESULTS: Patients' median age was 10 years. The median history of disease was 9 months (range, 1.0-43.0 months). Initial symptoms included signs of raised intracranial pressure, seizures, and, in the case of spinal cord tumor, bladder dysfunction. In five cases, AGGs were localized supratentorially with three patients having multiple lobes involved. The tumors affected the frontal (n = 3 cases), parietal (n = 2), temporal (n = 2), and occipital lobes (n = 1), as well as the brainstem (n = 1) and the spinal cord (n = 2). Gross total tumor resection was achieved in six patients. The estimated 5-year overall survival rate +/- standard error was 88 +/- 12%, and the event-free survival rate was 63 +/- 17%. While gender and tumor location did not affect survival rates, gross total tumor resection provided a better overall survival than non-total resection. CONCLUSION: The prognosis of pediatric patients with AGG is good, especially for those who undergo gross total tumor resection.
Karremann M, Rausche U, Fleischhack G, Nathrath M, Pietsch T, Kramm CM, Wolff JE	Clinical and epidemiological characteristics of pediatric gliosarcomas.	Journal of neuro-oncology 2010, 97: 257
Gliosarcoma (GS) is a glioblastoma with a sarcomatous component that is presumed to be a metaplastic differentiation of glioma cells. We studied the clinical relevance of this histological glioblastoma subentity within the pediatric population. We obtained patient data from the German HIT-GBM database, which contains clinical data for more than 600 pediatric patients with centrally reviewed high-grade gliomas. By applying defined inclusion criteria (diagnosis of GS proven by central neuropathological review; patient age 0 to 21 years), four patients were identified. In addition, after a review of the English medical scientific literature, 19 additional cases were found. The relative frequency of GS in the German HIT-GBM database was only 1.9%. In the whole series of 23 pediatric GS patients, including previously reported cases, the male-to-female-ratio was 1.2:1. GS was found in all pediatric age groups with a median age of 11 years, but there was an unexpectedly high accumulation in infants (6 of 23 <3 years of age, 26%). GS showed a strong predilection of the cerebral hemispheres (22 out of 23 cases). Increased intracranial pressure was the leading symptom of a short clinical history with a median duration of 0.7 month. Interestingly, six patients (26%) were reported with a history of cranial radiotherapy prior to GS diagnosis. In 60% of the GS patients in our series, gross total resection was achieved. Median overall (OS) and event-free survivals (EFS) of the total cohort were 12.1 and 9.8 months, respectively. In conclusion, GS is a very rare tumor entity in children. Literature review suggests a relatively higher incidence in infants and in patients with a previous history of radiotherapy.
Karremann M, Rausche U, Roth D, Kühn A, Pietsch T, Gielen GH, Warmuth-Metz M, Kortmann RD, Straeter R, Gnekow A, Wolff JE, Kramm CM	Cerebellar location may predict an unfavourable prognosis in paediatric high-grade glioma.	British journal of cancer 2013, epub ahead of print
Background:High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation.Methods:Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG.Results:Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92±0.02 vs 2.03±0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019).Conclusion:High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location.British Journal of Cancer advance online publication, 18 July 2013; doi:10.1038/bjc.2013.404 www.bjcancer.com.
Karawajew L, Dworzak M, Ratei R, Rhein P, Gaipa G, Buldini B, Basso G, Hrusak O, Ludwig WD, Henze G, Seeger K, von Stackelberg A, Mejstrikova E, Eckert C	Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia.	Haematologica 2015, 100: 935
Multiparametric flow cytometry is an alternative approach to the polymerase chain reaction method for evaluating minimal residual disease in treatment protocols for primary acute lymphoblastic leukemia. Given considerable differences between primary and relapsed acute lymphoblastic leukemia treatment regimens, flow cytometric assessment of minimal residual disease in relapsed leukemia requires an independent comprehensive investigation. In the present study we addressed evaluation of minimal residual disease by flow cytometry in the clinical trial for childhood relapsed acute lymphoblastic leukemia using eight-color flow cytometry. The major challenge of the study was to reliably identify low amounts of residual leukemic cells against the complex background of regeneration, characteristic of follow-up samples during relapse treatment. In a prospective study of 263 follow-up bone marrow samples from 122 patients with B-cell precursor acute lymphoblastic leukemia, we tested various B-cell markers, adapted the antibody panel to the treatment protocol, and evaluated its performance by a blinded parallel comparison with the polymerase chain reaction data. The resulting eight-color single-tube panel showed a consistently high overall concordance (P<0.001) and, under optimal conditions, sensitivity similar to that of the reference polymerase chain reaction method. Overall, evaluation of minimal residual disease by flow cytometry can be successfully integrated into the clinical management of relapsed childhood acute lymphoblastic leukemia either as complementary to the polymerase chain reaction or as an independent risk stratification tool. ALL-REZ BFM 2002 clinical trial information: NCT00114348.
Karremann M, Krämer N, Hoffmann M, Wiese M, Beilken A, Corbacioglu S, Dilloo D, Driever PH, Scheurlen W, Kulozik A, Gielen GH, von Bueren AO, Dürken M, Kramm CM	Haematological malignancies following temozolomide treatment for paediatric high-grade glioma.	European journal of cancer (Oxford, England : 1990) 2017, 81: 1
Karremann M, Gielen GH, Hoffmann M, Wiese M, Colditz N, Warmuth-Metz M, Bison B, Claviez A, van Vuurden DG, von Bueren AO, Gessi M, Kühnle I, Hans VH, Benesch M, Sturm D, Kortmann RD, Waha A, Pietsch T, Kramm CM	Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location.	Neuro-oncology 2018 Jan 10; 20: 123
Kassim AA, Galadanci NA, Pruthi S, DeBaun MR	How I treat and manage strokes in sickle cell disease.	Blood 2015, 125: 3401
Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD.
Kaspers G, Zwaan M, Creutzig U, Ritter J, Rottier M, Pieters R, Veerman A	In vitro drug resistance in childhood acute myeloid leukemia.	Haematology and Blood Transfusion 1997, 39: 491
Kaspers GJ, Veerman AJ, Pieters R, Van Zantwijk CH, Smets LA, Van Wering ER, Van Der Does-Van Den Berg A	In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia.	Blood 1997, 90: 2723
Kaspers G, Zwaan C, Veerman A, Rots M, Pieters R, Bucsky P, Domula M, Göbel U, Graf N, Havers W, Jorch N, Kabisch K, Spaar H, Ritter J, Creutzig U	Cellular drug resistance in acute myeloid leukemia.	Klin Pädiatr 1999, 211: 239
Kaste SC, Goodman P, Leisenring W, Stovall M, Hayashi RJ, Yeazel M, Beiraghi S, Hudson MM, Sklar CA, Robison LL, Baker KS	Impact of radiation and chemotherapy on risk of dental abnormalities: a report from the Childhood Cancer Survivor Study.	Cancer 2009 Dec 15; 115: 5817
The current study was performed to describe frequencies and risk factors of altered oral health and odontogenesis in childhood cancer survivors.
Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U	Improved Outcome in Pediatric Relapsed Acute Myeloid Leukemia: Results of a Randomized Trial on Liposomal Daunorubicin by the International BFM Study Group.	J Clin Oncol 2013, 31: 599
PURPOSEIn pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group. PATIENTS AND METHODSPatients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years).ResultsThe complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups. CONCLUSIONDNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.
Kaufmann A, Gerber NU, Kandels D, Azizi AA, Schmidt R, Warmuth-Metz M, Pietsch T, Kortmann RD, Gnekow AK, Grotzer MA	Management of Primary Tectal Plate Low-Grade Glioma in Pediatric Patients: Results of the Multicenter Treatment Study SIOP-LGG 2004.	Neuropediatrics 2018, 49: 314
Tectal plate low-grade gliomas (LGGs) most often present with increased intracranial pressure and sometimes as incidental findings from brain imaging. Prognostic factors predicting outcome are largely unknown.
Kazanowska B, Reich A, Stegmaier S, Békássy AN, Leuschner I, Chybicka A, Koscielniak E	Pax3-fkhr and pax7-fkhr fusion genes impact outcome of alveolar rhabdomyosarcoma in children.	Fetal and pediatric pathology 2007, 26: 17
Rhabdomyosarcoma is a highly malignant embryonic tumor of childhood. Two specific translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) have been identified in about 75-80% of ARMS cells. The aim of this multicenter study was to analyze the relationships between the identified fusion transcripts and survival including some selected clinical parameters. The extent of disease was graded according to clinical staging system with following distribution: 3 children with stage I, 4 with stage II, 23 with stage III, and 18 with stage IV spread disease having distant metastases. PAX3-FKHR fusion genes were detected in 28 and PAX7-FKHR fusion genes in 7 tumor biopsy specimens. Children with PAX3-FKHR fusion gene had often distant metastases at presentation (p = 0.03). PAX3-FKHR positive patients with locoregional disease had significantly poorer outcome compared with the ones with PAX7-FKHR positive tumors (p = 0.04). Although analyzed groups were small, significant differences in survival and clinical characteristics between PAX3-FKHR and PAX7-FKHR positive tumors were stated indicating their role in carcinogenesis. In addition, fusion gene analysis is a helpful tool in differential diagnosis of poorly differentiated soft tissue tumors.
Kebelmann-Betzing C, Körner G, Badiali L, Buchwald D, Möricke A, Korte A, Köchling J, Wu S, Kappelmeier D, Oettel K, Henze G, Seeger K	Characterization of cytokine, growth factor receptor, costimulatory and adhesion molecule expression patterns of bone marrow blasts in relapsed childhood B cell precursor ALL.	Cytokine 2001, 13: 39
Kehrer-Sawatzki H, Kordes U, Seiffert S, Summerer A, Hagel C, Schüller U, Farschtschi S, Schneppenheim R, Bendszus M, Godel T, Mautner VF	Co-occurrence of schwannomatosis and rhabdoid tumor predisposition syndrome 1.	Molecular genetics & genomic medicine 2018,
The clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co-occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported.
Keilholz U, Pezzuto A, Eggert A	Langfristige, strukturierte Nachsorge nach kurativer Krebsbehandlung essenziell.	Dtsch Arztebl Int 2014, 111(1-2): 1
Kellie SJ	Chemotherapy of central nervous system tumours in infants.	Childs Nerv Syst 1999, 592
The development of curative strategies for infants and children with central nervous system tumours or acute lymphoblastic leukaemia involve similar clinical research principles. Both areas of paediatric oncology research focus on cancers with a broad range of sensitivity to chemotherapy and radiation therapy, together with concerns about the neurodevelopmental, neuroendocrine and growth outcomes of survivors. These considerations have influenced the design of curative- intent treatments, strategies for successfully eradicating leptomeningeal disease, and the importance of anatomic and functional identification of residual disease. Unlike the situation with childhood leukaemia, the emotional barriers of pessimism or even nihilism previously evident towards infants with brain tumours have only begun to crumble during the past decade. The challenge to improve both the quality and overall survival of infants with CNS tumours described in this chapter is ours to meet as we move into the new millennium. This paper examines the development of 'infant' approaches to the treatment of CNS tumours, including a discussion of epidemiology, the reasons for avoiding or delaying radiation therapy, and traces the chemotherapy hypotheses tested over the past two decades in the process of developing potentially curative therapy. The reasons for the disappointing rate of progress compared with that in childhood leukaemia, despite similar clinical research paradigms, are discussed, and potential opportunities are identified.
Kelly MJ, Pennarola BW, Rodday AM, Parsons SK, on behalf of the Journeys to Recovery Study, the HSCT-CHESS™ Study	Health-related quality of life (HRQL) in children with sickle cell disease and thalassemia following hematopoietic stem cell transplant (HSCT).	Pediatric blood & cancer 2011 Dec 19;
BACKGROUND: Little is known regarding the health-related quality of life (HRQL) trajectory of children with sickle cell disease or thalassemia (
Kelley LM, Schlegel M, Hecker-Nolting S, Kevric M, Haller B, Rössig C, Reichardt P, Kager L, Kühne T, Gosheger G, Windhager R, Specht K, Rechl H, Tunn PU, Baumhoer D, Wirth T, Werner M, von Kalle T, Nathrath M, Burdach S, Bielack S, von Lüttichau I	Pathological Fracture and Prognosis of High-Grade Osteosarcoma of the Extremities: An Analysis of 2,847 Consecutive Cooperative Osteosarcoma Study Group (COSS) Patients.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2020, 38: 823
The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities.
Kempf-Bielack B, Bielack SS, Jürgens H, Branscheid D, Berdel WE, Exner GU, Göbel U, Helmke K, Jundt G, Kabisch H, Kevric M, Klingebiel T, Kotz R, Maas R, Schwarz R, Semik M, Treuner J, Zoubek A, Winkler K	Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS).	Journal of clinical oncology 2005, 23: 559
PURPOSE: To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma. PATIENTS AND METHODS: Five hundred seventy-six consecutive patients who had achieved a first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients). RESULTS: After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy. CONCLUSION: Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.
Kenet G, Lütkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, Chabrier S, Chan A, deVeber G, Fiedler B, Fullerton HJ, Goldenberg NA, Grabowski E, Günther G, Heller C, Holzhauer S, Iorio A, Journeycake J, Junker R, Kirkham FJ, Kurnik K, Lynch JK, Male C, Manco-Johnson M, Mesters R, Monagle P, van Ommen CH, Raffini L, Rostásy K, Simioni P, Sträter RD, Young G, Nowak-Göttl U	Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies.	Circulation 2010 Apr 27; 121: 1838
Kennedy C, Bull K, Chevignard M, Culliford D, Dörr HG, Doz F, Kortmann RD, Lannering B, Massimino M, Navajas Gutiérrez A, Rutkowski S, Spoudeas HA, Calaminus G, PNET4 study group of the Brain Tumour Group of The European branch of the International Society of Paediatric Oncology (SIOP-E)	Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyperfractionated versus conventional radiation therapy for standard-risk medulloblastoma.	International journal of radiation oncology, biology, physics 2014, 88: 292
PURPOSE: To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. METHODS AND MATERIALS: Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. RESULTS: Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). CONCLUSIONS: Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.
Kersten W, Brade W	[Treatment of bronchitis with cefaclor (Panoral) (author's transl)].	MMW, Munchener medizinische Wochenschrift 1979 Feb 16; 121: 247
14 patients from the Allergy Unit of an outpatient clinic suffering from acute exacerbation of chronic bronchitis and 13 outpatients with acute bronchitis were treated with 250 mg cefaclor (Panoral) 3 times daily per os for 5 days. 59% of the organisms isolated from cefaclor-sensitive sputum at the time of prominent clinical symptoms were resistent to tetracycline, 53% of them were resistant to penicillin, and 37% were resistant to ampicillin. 12 out of the 14 patients with acute exacerbation of chronic bronchitis became asymptomatic, and no organisms could be detected in the sputum of 13 out of the same 14 patients two days after cessation of cefaclor treatment. In 12 out of the 13 patients with acute bronchitis, the acute clinical symptoms disappeared and in 11 out of the 13 patients the initial sputum organisms were two days after stopping cefaclor treatment.
Kern W, Büchner T, Wörmann B, Ritter J, Creutzig U, Hiddemann W	Akute Leukämien; Prognostische Faktoren und Therapiestrategien.	Internist 1999, 40: 983
Kersting C, Gebert C, Agelopoulos K, Schmidt H, van Diest PJ, Jürgens H, Winkelmann W, Kevric M, Gosheger G, Brandt B, Bielack S, Buerger H	Epidermal growth factor receptor expression in high-grade osteosarcomas is associated with a good clinical outcome.	Clinical cancer research 2007, 13: 2998
PURPOSE: The expression of the epidermal growth factor receptor (EGFR) in osteosarcomas has repeatedly been described. With the introduction of anti-EGFR-targeted therapies in clinical practice, these findings regain increased attention. Experience with anti-EGFR-targeted therapies in other cancers has made clear that besides the expression status of EGFR, a detailed knowledge about gene mutations is of major predictive power. We therefore aimed to explore the EGFR expression and gene mutation status in high-grade osteosarcomas. EXPERIMENTAL DESIGN: We investigated tumor samples of osteosarcoma patients of all age groups by means of immunohistochemistry (n=111) and egfr fluorescence in situ hybridization (n=39). Sixty-three patients were treated according to the Cooperative Osteosarcoma Study Group protocols and complete clinical follow-up was available in these cases. RESULTS: Ninety-one of 111 (81%) of osteosarcomas revealed an expression of EGFR. EGFR expression showed a dose-response relation with improved event-free and overall survival. This was independent of the degree of tumor regression due to neoadjuvant chemotherapy. Nine of 39 (23%) osteosarcomas showed egfr amplifications by means of fluorescence in situ hybridization. All these cases expressed EGFR. When comparing EGFR expression between primary biopsy and resection specimen (n=19), viable residual tumor cells in resection specimens revealed a lower EGFR expression and a tendency toward membranous staining compared with the initial biopsy. CONCLUSIONS: In conclusion, expression and amplification of EGFR are frequently observed in high-grade osteosarcomas and are associated with improved prognosis in a dose-responsive way. This implies that low EGFR expression possibly predicts lack of response to conventional treatment in high-grade osteosarcomas and may warrant a more intensive therapeutic approach, although not based on EGFR targeting.
Kehrel BE	Platelets: biochemistry and physiology.	Hamostaseologie 2008, 28: 289
This article reviews the roles of blood platelets in haemostasis as well as in the pathogenesis of thromboembolic diseases. Besides the basic processes in primary haemostasis, platelet adhesion, platelet secretion, platelet aggregation, clot retraction, the new model of thrombin formation on the platelet surface is presented. The different signal transduction pathways in platelets are a main focus of this review.
Kerl K, Holsten T, Frühwald MC	Rhabdoid Tumors: Clinical Approaches and Molecular Targets for Innovative Therapy.	Pediatric hematology and oncology 2013, epub ahead of print
Rhabdoid tumors are rare but highly aggressive tumors with a predilection for infants and young children. The majority of these tumors harbor biallelic mutations in SMARCB1/INI1/hSNF5. Rather rare cases with mutations in other SWI/SNF core members such as BRG1 are on record. Rhabdoid tumors have only recently been registered and treated according to specifically designed treatment recommendations and in the framework of clinical trials. Within the last decade, prognosis has improved significantly but at least 50% of patients still relapse and subsequently almost inevitably succumb to their disease. This review summarizes past and current clinical approaches and presents an overview of the rationales for targeted therapy with potential for future clinical treatment trials for rhabdoid tumors.
Kerl K, Oyen F, Giannikopoulou D, Rössig C, Rellensmann G, Sandkötter J, Brentrup A, Selzer G, Schneppenheim R, Frühwald MC	Rapid Diagnosis of an AT/RT by the Detection of a Heterozygous SMARCB1 Germ Line Deletion in an Infant.	Pediatric blood & cancer 2016, 63: 1451
We report the successful use of multiplex ligation-dependent probe amplification (MLPA) to detect heterozygous loss of SMARCB1/INI1/SNF5 in the germ line of an infant with a huge posterior fossa tumor. MLPA and Sanger sequencing of the SMARCB1 gene in the germ line may be useful for the initial diagnosis in a defined subgroup of infants with rhabdoid tumors, in which biopsies cannot be performed.
Khan J, Wei J, Ringner M, Saal L, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu C, Peterson C, Meltzer P	Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks.	Nat Med 2001, 7: 673
Khalil MN, Erb N, Khalil PN, Escherich G, Janka-Schaub GE	Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes.	Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 2005, 821: 105
The determination of the thiopurine S-methyltransferase activity (TPMT; EC 2.1.1.67) has become an important issue during thiopurine therapy due to its known genetic polymorphism resulting in a wide range of TPMT activity. Therefore, the standard thiopurine drug regimen is associated with increased hematopoetic toxicity in patients with low or absent TPMT activity, whereas patients with high activity may be insufficiently treated. However, presently available methods are labour intensive and time consuming and tend towards too high or too low enzyme activity due to their methodological approach. The use of instable substrate solutions (6-MP or 6-TG), organic solvents like dimethyl sulfoxide and too high substrate and co-substrate saturation concentrations contribute to this phenomenon. We therefore, established an optimized and fast isocratic HPLC linked TPMT assay based on the enzymatic methylation of mercaptopurine or thioguanine in RBC lysates with S-adenosyl-l-methionine as methyl donor. Unspecific non-enzymatic methylation was not detectable. The recovery of 6-methyl-mercaptopurine was 97-102%, the intra- and interday variation between 1.0 and 5.0%, respectively. The assay dispenses with a time consuming extraction procedure with organic solvents, a heating step, and a gradient elution and is therefore, favourable for clinical routine application. The TPMT activity was measured in 62 untreated children with acute lymphoblastic leucemia at the time of diagnosis (activity = 34.0+/-10.6 nmol/g Hb/h, range: 11.5-55.4 nmol/g Hb/h) and in 12 adult healthy volunteers (62.8+/-7.7 nmol/g Hb/h, range: 48-82 nmol/g Hb/h) reflecting the wide measurable TPMT activity found in erythrocytes.
Khalil A, Würthwein G, Golitsch J, Hempel G, Fobker M, Gerss J, Möricke A, Zimmermann M, Smisek P, Zucchetti M, Nath C, Attarbaschi A, Von Stackelberg A, Gökbuget N, Rizzari C, Conter V, Schrappe M, Boos J, Lanvers-Kaminsky C	Pre-existing antibodies against polyethylene glycol reduce asparaginase activities on first administration of pegylated E. coli asparaginase in children with acute lymphocytic leukemia.	Haematologica 2020,Online ahead of print
Antibodies against polyethylene glycol (PEG) in healthy subjects raise concerns about the efficacy of pegylated drugs. We evaluated the prevalence of antibodies against PEG among patients with acute lymphoblastic leukemia (ALL) prior to and/or immediately after their first dose of pegylated E.coli asparaginase (PEG-ASNase). Serum samples of 701 children, 673 with primary ALL, 28 with relapsed ALL, and 188 adults with primary ALL were analyzed for anti-PEG IgG and IgM. Measurements in 58 healthy infants served as reference to define cut-points for antibody-positive and -negative samples. Anti-PEG antibodies were detected in ALL patients prior the first PEG-ASNase with a prevalence of 13.9% (anti-PEG IgG) and 29.1% (anti-PEG IgM). After administration of PEG-ASNase the prevalence of anti-PEG antibodies decreased to 4.2% for anti-PEG IgG and to 4.5% for anti-PEG IgM. Pre-existing anti-PEG antibodies did not inhibit PEG-ASNase activity but significantly reduced PEGASNase activity levels in a concentration dependent manner. Although pre-existing anti-PEG antibodies did not boost, pre-existing anti-PEG IgG were significantly associated with firstexposure hypersensitivity reactions (CTCAE grade 2) (p.
Khanam T, Sandmann S, Seggewiss J, Ruether C, Zimmermann M, Norvil AB, Bartenhagen C, Randau G, Mueller S, Herbrueggen H, Hoffmann P, Herms S, Wei L, Woeste M, Wuensch C, Gowher H, Oschlies I, Klapper W, Woessmann W, Dugas M, Burkhardt B	Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance.	Blood 2021, 137: 2347
T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. The dismal outcomes (15%-30%) after T-LBL relapse warrant establishing risk-based treatment. To our knowledge, this study presents the first comprehensive, systematic, integrated, genome-wide analysis including relapsed cases that identifies molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as the putative driver for T-LBL. An activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitute the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47% ± 17% in patients with KMT2D mutations, compared with 14% ± 3% in wild-type KMT2D. Structural analysis of the mutated domains of KMT2D revealed a plausible impact on structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL, including high translational potential. The ongoing LBL 2018 trial (www.clinicaltrials.gov #NCT04043494) allows for prospective validation and subsequent fine tuning of the stratification criteria for T-LBL risk groups to improve survival of pediatric patients.
Kidas E, Möricke A, Beier R, Welte K, Schrappe M, Stanulla M, Grigull L	Genetic polymorphisms of the lymphotoxin alpha gene are associated with increased risk for lethal infections during induction therapy for childhood acute leukemia: a case-control study.	International journal of hematology 2009, 89: 584
Specific mutations of the TNF-alpha (TNF-alpha) and Lymphotoxin-alpha (LT-alpha) genes are correlated to the outcome of patients during serious infections. This study aimed at correlating these polymorphisms to lethal infections during childhood acute lymphoblastic leukemia (ALL). A matched case-control study of 34 patients who died due to infections during ALL treatment and 68 ALL patients without lethal infections was performed. Genomic DNA was isolated from blood smears and specific fragments including the polymorphic site of each gene were amplified. In the total study population, 23/102 (22.5%) of the children carried at least two variant alleles (high-producer haplotype). The variant genotypes were equally distributed between cases and controls [relative risk (RR) 1.17 (CI 0.33-2.22, P = 0.752)]. With regard to infective organisms, no statistically significant differences could be detected between the groups for bacterial infections [RR 1.59 (CI 0.56-4.50), P 0.379]. Patients with a LT-alpha (10.5 kb/5.5 kb; 5.5 kb/5.5 kb) haplotype, however, seemed to have a significant higher risk of attracting a lethal infection during induction/consolidation chemotherapy (RR 2.98, CI 0.98-9.01, P = 0.05). These results support a role of specific genetic polymorphisms on lethal infections during induction chemotherapy of ALL treatment.
Deutsches Krebsforschungszentrum Krebsinformationsdienst	Radioaktivität und Röntgenstrahlung: Quellen, Risiken, Nutzen.	2019
Kilday JP, Caldarelli M, Massimi L, Chen RH, Lee YY, Liang ML, Parkes J, Naiker T, van Veelen ML, Michiels E, Mallucci C, Pettorini B, Meijer L, Dorfer C, Czech T, Diezi M, Schouten-van Meeteren AYN, Holm S, Gustavsson B, Benesch M, Mueller HL, Hoffmann A, Rutkowski S, Flitsch J, Escherich G, Grotzer M, Spoudeas HA, Azquikina K, Capra M, Jimenez-Guerra R, MacDonald P, Johnston DL, Dvir R, Constantini S, Kuo MF, Yang SH, Bartels U	Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.	Neuro-oncology 2017, 19: 1398
Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha.
Kunz J, Kulozik A	Makrozytäre Anämien.	In: Niemeyer C, Eggert A. ed. Pädiatrische Hämatologie und Onkologie Springer; 2018 54
Kircher B, Niederwieser D, Gächter A, Lindner B, Mitterschiffthaler A, Urban C, Greinix H, Peters C, Lätzer K, Gastl G, Nachbaur D	T-cell precursor frequencies and long-term outcome following unrelated hematopoietic stem cell transplantation.	International journal of laboratory hematology 2008, 30: 499
Functional assays measuring alloreactivity of donor cells are desired to detect either cryptic epitopes inducing graft-vs.-host disease (GvHD) after human leukocyte antigen (HLA)-identical hematopoietic stem cell transplantation (HSCT) or permissible HLA mismatches. However, their value in predicting GvHD and survival is still limited. We determined the cytotoxic and helper T-cell precursor (CTLp and HTLp) frequencies by limiting dilution analysis (LDA) in 40 unrelated recipient/donor combinations. The median observation period at the time of this writing was 4.44 years (range from 0.1 to 11.28). Better overall survival was observed in patients with rather low host-specific CTLp and HTLp frequencies, whereas a trend toward high CTLp frequencies was seen in patients with higher incidence of acute GvHD, especially in patients mismatched in HLA-C. CTLp and HTLp frequencies did not correlate with the incidence of chronic GvHD and relapse. In conclusion, we detected a trend toward better overall survival of patient/donor pairs with low CTLp and HTLp frequencies, however, recommend to use LDA as an additional tool for identifying the most suitable donor when more than one fully HLA-matched stem cell donor is available.
Kirton A, deVeber G	Advances in perinatal ischemic stroke.	Pediatric neurology 2009, 40: 205
Kitao H, Takata M	Fanconi anemia: a disorder defective in the DNA damage response.	Int J Hematol 2011, 93: 417
Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin-phosphorylation network called the
Kivela T	Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999, 17: 1829
PURPOSE: To obtain refined knowledge regarding trilateral retinoblastoma (TRb), which is a syndrome that consists of hereditary retinoblastoma associated with an intracranial neuroblastic tumor. MATERIALS AND METHODS: Using a systematic literature review, we contacted authors to obtain missing information. Data from 106 children were used in a meta-analysis including frequency distributions and Kaplan-Meier survival curves. RESULTS: TRb showed no sex predilection. Median age at diagnosis of retinoblastoma was 5 months (range, 0 to 29 months); age at diagnosis was younger among 47 children (47%) with familial retinoblastoma compared with age at diagnosis among 52 children (53%) with sporadic retinoblastoma (2 v 6.5 months, P <.0001). TRb usually affected the second or third generation with retinoblastoma. Median time from retinoblastoma to TRb was 21 months (range, 6 months before to 141 months after); time to TRb was longer for 78 (77%) pineal tumors compared with 23 (23%) suprasellar tumors (32 v 6.5 months, P <.0001). The size (27 v 32 mm, P =.57) and prognosis (survival of 9 v 8 months, P =.91) of pineal and suprasellar tumors were similar. TRb was detected earlier (1 v 22 months, P =.0007) and the child survived longer if neuroimaging was routinely performed (16 v 8 months, P =.001), but age at death was similar (36 v 37 months, P =.98). Cumulative 5-year survival (which was likely to indicate cure) was 27% (v 0%) if screening was undertaken. All children whose TRb exceeded 15 mm in size died. CONCLUSION: The family history, age at diagnosis, and laterality of retinoblastoma in children with TRb resembled that of ordinary hereditary retinoblastoma. Suprasellar TRb were diagnosed earlier, and may arise earlier, than pineal TRb. Screening by neuroimaging could improve the cure rate if cases of TRb were detected when tumors were 15 mm or smaller in size.
Klamt B, Schulze M, Thate C, Mares J, Goetz P, Kodet R, Scheulen W, Weirich A, Graf N, Gessler M	Allele loss in Wilms tumors of chromosome arms 11q, 16q, and 22q correlate with clinicopathological parameters.	Genes Chromosomes Cancer 1998, 22: 287
Klamroth R, Holzhauer S, Zimmermann R, Heller C, Kurnik K, Beriate® Pharmacovigilance Group	Beriate® P in the treatment of patients with haemophilia A: results of a long-term pharmacovigilance study.	Thrombosis research 2014, 134 Suppl 1:S16
The German Beriate(Â®) P pharmacovigilance study started in 2003 and is planned to run until December 2013. This analysis included data from 84 haemophilia A patients treated with the high-purity, plasma-derived coagulation factor VIII concentrate Beriate(®) P. Prior to study start, 69 of the 80 patients for whom data were available had received previous treatment with Beriate(®) P (mean treatment period 7.1 ± 5.4 years). The mean study duration from the start of pharmacovigilance was 43.3 ± 30.3 months (median 43.5 months; range 0-101.9months). The most common treatment at the last visit was prophylaxis (65.7% of patients), which was most commonly administered at a frequency of three infusions/week in 47.3% of patients. RESULTS: Most patients experienced up to six minor bleeds/year. For 1,311 bleeding episodes, a median of one infusion/bleed was administered (mean 2.8 ± 4.7; range 0-83). The clinical response to Beriate(®) P was rated "excellent"/"good" in 94% of 32 visits of patients with major bleeding. The clinical response for patients with minor bleeding was rated "excellent"/"good" in 98.5% of 377 visits. One clinically relevant inhibitor in a previously untreated patient was documented during the study course. There were no reports of virus transmissions suspected to be caused by Beriate(®) P prior to the study start or during the study. CONCLUSIONS: These findings confirm the excellent efficacy, safety, and tolerability of Beriate(®) P in the treatment of a wide spectrum of previously untreated patients up to adult patients with haemophilia A.
Kleinman GM, Hochberg FH, Richardson EP Jr	Systemic metastases from medulloblastoma: report of two cases and review of the literature.	Cancer 1981 Nov 15; 48: 2296
The clinical and pathologic data from two cases of medulloblastoma with systemic metastases, and 101 previously reported cases were evaluated to define better the clinical presentation and natural history. Patients ranged in age from six months to 48 years, with a mean of 13 years; two thirds of the patients were male. Ventricular shunts had been inserted in 20% of the patients. Systemic metastases occurred on an average of two years after the diagnosis of the primary tumor in patients without shunts, but only 1.3 years in patients with shunts. Fifty-nine percent of the patients were known to have experienced recurrence or spread of medulloblastoma within the central nervous system by the time systemic metastases appeared. Ninety percent showed radiologic evidence of bone metastases, of which 60% were osteoblastic. Bones most frequently involved were pelvis, femur and vertebrae; pain was the most common initial symptom. At autopsy, lymph node metastases were found in 65% and liver metastases were found in 28% of all cases in addition to bone metastases in 82%. Lung metastases occurred in 9% of the patients without shunts, compared with 30% of patients with shunts. The average survival was seven months after the appearance of systemic metastases for patients both with and without shunts. Approximately 5% of patients with medulloblastoma may be expected to develop systemic metastases. This development is associated with increased morbidity and a shortened life expectancy.
Klein G, Schulz B, Spix C, Kaatsch P	Risikoabschätzung für Sekundärmalignome nach Krebs im Kindesalter.	Monatsschr Kinderheilkd 2002, 150 : 564
Klein G, Schulz B, Spix C, Kaatsch P	Risikoabschätzung für sekundäre Malignome nach kindlicher Krebserkrankung – bevölkerungsbezogene Analysen des Deutschen Kinderkrebsregisters.	Informatik, Biometrie und Epidemiologie in Medizin und Biologie 2002, 2: 109
Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK	The WHO classification of tumors of the nervous system.	J Neuropathol Exp Neurol 2002, 61: 215
Kleideiter E, Schwab M, Friedrich U, Koscielniak E, Schafer B, Klotz U	Telomerase activity in cell lines of pediatric soft tissue sarcomas.	Pediatr Res 2003, 54: 718
Klein G, Michaelis J, Spix C, Wibbing R, Eggers G, Ritter J, Kaatsch P	Second malignant neoplasms after treatment of childhood cancer.	Eur J Cancer 2003, 39: 808
Klein C, Welte K	Genetic insights into congenital neutropenia.	Clinical reviews in allergy & immunology 2010, 38: 68
Congenital neutropenia syndromes comprise a heterogeneous group of disorders leading to increased susceptibility to bacterial infections. Recent work has elucidated the molecular basis of several congenital neutropenia syndromes such as mutations in ELA2, HAX1, GF11, and WAS. In addition, a number of complex clinical syndromes associating congenital neutropenia have been recognized and elucidated on a genetic level, e.g. p14-deficiency or G6PC3-deficiency. The clinical and genetic findings of various neutropenia syndromes are being discussed.
Klemme M, Gerstl L, Weinberger R, Olivieri M, Flemmer A, von Kries R, Felderhoff-Maeuser U, Dzietko M	Neonatal Arterial Ischemic Stroke - A Hospital Based Active Surveillance Study in Germany.	Klinische Padiatrie 2017, 229: 142
Klingebiel T, Berthold F, Treuner J, Schwabe D, Fischer M, Feine U, Maul F, Waters W, Wehinger H, Niethammer D	Metaiodobenzylguanidine (mIBG) in treatment of 47 patients with neuroblastoma.	Med Pediatr Oncol 1991, 19: 84
Klingebiel T, Feine U, Treuner J, Reuland P, Handgretinger R, Niethammer D	Treatment of neuroblastoma with [131I]metaiodobenzylguanidine.	J Nucl Biol Med 1991, 35: 216
Klingebiel T, Ritter J, Schellong G, Creutzig U, Riehm H, Henze G, Bender-Götze C, Dopfer R, Ebell W, Friedrich W, Haas R, Schmitz N, Stollmann B, Niethammer D	Role and perspectives of BMT in AML.	1991, 7: 66
Klingebiel T, Pertl U, Hess C, Jürgens H, Koscielniak E, Potter R, van Heek-Romanowski R, Rossi R, Schott C, Spaar H, Willnow U, Treuner J	Treatment of children with relapsed soft tissue sarcoma.	Med Pediatr Oncol 1998, 30: 269
Klingebiel T	Knochenmark- und Stammzelltransplantation, in Gutjahr P: Krebs bei Kindern und Jugendlichen.	Deutscher Ärzte-Verlag Köln 5. Aufl. 2004, 83
Klingebiel T, E Koscielniak Weichteilsarkome	In: Kiess/Merckenschlager/Pfäffle/Siekmeyer:Therapie im Kindes-und Jugendalter.	ISBN 3-437-23200-2, im Druck
Klingebiel T, Koscielniak E	Weichteilsarkome, in: Rüben H (Hrsg.): Uroonkologie.	Springer Verlag Heidelberg 4. Aufl. 2007, 657
Klingebiel T, Koscielniak E	Weichteilsarkome, in: Kiess W, Merkenschlager A, Pfäffle R, Siekmeyer W (Hrsg.): Therapie in der Kinder- und Jugendmedizin.	Elsevier, Urban & Fischer, München Jena 1. Aufl. 2007, 820
Klingebiel T, Boos J, Beske F, Hallmen E, Int-Veen C, Dantonello T, Treuner J, Gadner H, Marky I, Kazanowska B, Koscielniak E	Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial.	Pediatric blood & cancer 2008, 50: 739
PURPOSE: We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS). PATIENTS AND METHODS: Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy. RESULTS: From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or
Klingebiel, T	Was Hoffnung kosten darf: Ist die Einlagerung von autologem Nabelschnurblut nötig und sinnvoll?	Dtsch Arztebl 2009, 106: 829
Klingebiel T, Cornish J, Labopin M, Locatelli F, Darbyshire P, Handgretinger R, Balduzzi A, Owoc-Lempach J, Fagioli F, Or R, Peters C, Aversa F, Polge E, Dini G, Rocha V, Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT)	Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group.	Blood 2010, 115: 3437
T cell-depleted haploidentical hematopoietic stem cell transplantation (haploHSCT) is an option to treat children with very high-risk acute lymphoblastic leukemia (ALL) lacking an HLA-identical donor. We analyzed 127 children with ALL who underwent haploHSCT in first (n = 22), second (n = 48), or third (n = 32), complete remission or in relapse (n = 25). The 5-year leukemia-free survival (LFS) was 30%, 34%, 22%, and 0%, respectively. A risk-factor analysis was performed for patients who underwent transplantation in remission (n = 102). Five-year nonrelapse mortality (NRM), relapse incidence (RI), and LFS were 37%, 36%, and 27%, respectively. A trend of improved LFS rate and decreased RI was observed for children given a graft with higher number of CD34(+) cells (adjusted P = .09 and P = .07, respectively). In a multivariate analysis, haploHSCT performed in larger centers (performing > or = 231 allotransplantations in the studied period) was associated with improved LFS rate and decreased RI (adjusted P = .01 and P = .04, respectively), adjusting for different patient-, disease-, and transplant-related factors such as number of previous autotransplantations, cytomegalovirus serology status, type of T-cell depletion, and use of total body irradiation and antithymocyte globulin. In conclusion, higher CD34(+) cell dose and better patient selection may improve outcomes of children with ALL who undergo a haploHSCT. Transplant centers initiating programs on haploHSCT for children may collaborate with more experienced centers.
Klinger M, Brandl C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, Gökbuget N, Neumann S, Goebeler M, Viardot A, Stelljes M, Brüggemann M, Hoelzer D, Degenhard E, Nagorsen D, Baeuerle PA, Wolf A, Kufer P	Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.	Blood 2012, 119: 6226
T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.
Göbel U, Gortner L (Hrsg)	Supplement Zum 80. Geburtstag von Herrn Prof. Riehm.	Klin Pädiatr 2013; 225 (Suppl. 1): S1-S98
Klimenkova O, Ellerbeck W, Klimiankou M,Ãnalan M, Kandabarau S, Gigina A, Hussein K, Zeidler C, Welte K, Skokowa J	A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation.	Blood 2014, 123: 1239
We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34(+) bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor κB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells.
Klimiankou M, Klimenkova O, Uenalan M, Zeidler A, Mellor-Heineke S, Kandabarau S, Skokowa J, Zeidler C, Welte K	GM-CSF stimulates granulopoiesis in a congenital neutropenia patient with loss-of-function biallelic heterozygous CSF3R mutations.	Blood 2015/126: 1865
Klimiankou M, Mellor-Heineke S, Klimenkova O, Reinel E, Uenalan M, Kandabarau S, Skokowa J, Welte K, Zeidler C	Two cases of cyclic neutropenia with acquired CSF3R mutations, with 1 developing AML.	Blood 2016, 127: 2638
Kilday JP, Caldarelli M, Massimi L, Chen RH, Lee YY, Liang ML, Parkes J, Naiker T, van Veelen ML, Michiels E, Mallucci C, Pettorini B, Meijer L, Dorfer C, Czech T, Diezi M, Schouten-van Meeteren AYN, Holm S, Gustavsson B, Benesch M, MÃ¼ller HL, Hoffmann A, Rutkowski S, Flitsch J, Escherich G, Grotzer M, Spoudeas HA, Azquikina K, Capra M, Jimenez-Guerra R, MacDonald P, Johnston DL, Dvir R, Constantini S, Kuo MF, Yang SH, Bartels U	Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.	Neuro-oncology 2017 Oct 1; 19: 1398
Klimiankou M, Uenalan M, Kandabarau S, Nustede R, Steiert I, Mellor-Heineke S, Zeidler C, Skokowa J, Welte K	Ultra-Sensitive CSF3R Deep Sequencing in Patients With Severe Congenital Neutropenia.	Frontiers in immunology 2019, 10: 116
High frequency of acquired (colony stimulating factor 3 receptor, granulocyte) mutations has been described in patients with severe congenital neutropenia (CN) at pre-leukemia stage and overt acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Here, we report the establishment of an ultra-sensitive deep sequencing of a segment encoding the intracellular "critical region" of the G-CSFR known to be mutated in CN-MDS/AML patients. Using this method, we achieved a mutant allele frequency (MAF) detection rate of 0.01%. We detected mutations in CN patients with different genetic backgrounds, but not in patients with other types of bone marrow failure syndromes chronically treated with G-CSF (e.g., Shwachman-Diamond Syndrome). Comparison of deep sequencing results of DNA and cDNA from the bone marrow and peripheral blood cells revealed the highest sensitivity of cDNA from the peripheral blood polymorphonuclear neutrophils. This approach enables the identification of low-frequency mutant clones, increases sensitivity, and earlier detection of mutations acquired during the course of leukemogenic evolution of pre-leukemia HSCs of CN patients. We suggest application of sequencing of the entire CSF3R gene at diagnosis to identify patients with inherited lost-of-function mutations and annual ultra-deep sequencing of the critical region of to monitor acquisition of mutations.
Klingebiel T, Jürgens H, Glauche I, Gnekow A, Kandels D, Woessmann W, Schneider DT, Suttorp M	[Registries and studies in the Society for Pediatric Oncology and Hematology (GPOH) - What contribution do they make to progress?]	Klinische Padiatrie 2020 Apr 20;
Cancer in children and adolescents under the age of 18 is rare; in 2017, approximately 2220 new cases in Germany were reported to the German Childhood Cancer Registry. The aim of the GPOH has always been to treat as many affected patients as possible in a standardized way, preferably in prospective, controlled studies. The Joint Federal Committee has also laid down this requirement in the paediatric oncology guideline. In a survey among the study chairs of the GPOH, it was determined how the number of clinical trials has changed following the amended drug legislation. In 2002, 33 therapy optimization studies (TOS) of the GPOH were open. Overall, TOS decreased from 33 in 2002 to 2 in 2017. The number of drug trials has increased to 16 by 2017 (almost 1100 patients registered). At the time, the number of clinical registries has increased to 28 with a total of more than 1800 registered patents. This observation shows that the clinical registers have taken on a new significance in paediatric oncology. Three examples are used to examine what contributions registries can make in relation to studies on the treatment of patients and to scientific progress. In summary, the experience gained so far from the examples discussed illustrates that studies and registries mutually represent a meaningful and necessary addition to the study group structure in paediatric oncology.
Klinger M, Zugmaier G, Nägele V, Goebeler ME, Brandl C, Stelljes M, Lassmann H, von Stackelberg A, Bargou RC, Kufer P	Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events.	Cancer research 2020, 80: 91
Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell-independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell-dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells , and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. SIGNIFICANCE: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.
Kloos HD	[Methods for pain assessment in nursing practice--1].	Kinderkrankenschwester : 2000, 19: 47
Kloos HD	[Methods of pain diagnosis and measurement of pain level in nursing practice. 2].	Kinderkrankenschwester 2000, 19: 107
Kloos RQ, Pieters R, Escherich G, van der Sluis IM	Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation.	Pediatric blood & cancer 2016, 63: 1928
Kloos RQ, Pieters R, Escherich G, van der Sluis IM	Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation.	Pediatric blood & cancer 2016, 63: 1928
Klothaki P, Grace R, Eber S, Puzik A, Kunz J, Burdach S, Andres O, Nathrath M, Kollmar N	Pyruvatkinasemangel der Erythrozyten in Deutschland - Klinische Merk-male und Lebensqualität der Patienten.	Monatsschrift Kinderheilkunde 2021, in print
Klumper E, Pieters R, Kaspers G, Loonen A, Huismans D, VanZantwijk C, Hählen K, VanWering E, Henze G, Veerman A	Cytostatic drug resistance in childhood relapsed acute lymphoblastic leukemia.	Haematol Blood Transfus 1994, 36: 291
Klumper E, Pieters R, Kaspers G, Huismans D, Loonen A, Rottier M, van Wering E, van der Does-van den Berg A, Hählen K, Creutzig U, Veermann A	In vitro chemosensitivity assessed with the MTT assay in childhood acute nonlymphoblastic leukemia.	Leukemia 1995, 9: 1864
Klumper E, Pieters R, Veerman A, Huismans D, Loonen A, Hahlen K, Kaspers G, van Wering E, Hartmann R, Henze G	In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia.	Blood 1995, 86: 3861
Klusmann JH, Creutzig U, Zimmermann M, Dworzak M, Jorch N, Langebrake C, Pekrun A, Macakova-Reinhardt K, Reinhardt D	Treatment and prognostic impact of transient leukemia in neonates with Down's syndrome.	Blood 2008, 111: 2991
Approximately 10% of the neonates with Down's syndrome (DS) exhibit a unique transient leukemia (TL). Though TL resolves spontaneously in the majority of cases, early death and development of myeloid leukemia (ML-DS) may occur. Prognostic factors as well as treatment indication are currently uncertain. To resolve that issue, we prospectively collected clinical, biological and treatment data of 146 patients with TL. 5-year overall survival (OS) and event free survival (EFS) were 85+/-3% and 63+/-4%, respectively. Multivariate analysis revealed a correlation between high white blood cell (WBC) count, ascites, preterm delivery, bleeding diatheses, failure of spontaneous remission and the occurrence of early death. Treatment with cytarabine (0.5-1.5 mg/kg) was administered to 28 patients with high WBC count, thrombocytopenia or liver dysfunction. The therapy had a beneficial effect on the outcome of those children with risk factors for early death (5-yr EFS 52+/-12% vs. 28+/-11% (no treatment); p=0.02). Multivariate analysis demonstrated its favorable prognostic impact. 29 TL patients (23%) subsequently developed ML-DS. ML-DS patients with a history of TL had a significantly better 5-yr EFS (93+/-5%) than those without documented TL (71+/-4%), primarily due to a lower relapse rate. A history of TL may therefore define a lower-risk ML-DS subgroup. This study was registered at www.ClinicalTrials.gov as #NCT 00111345.
Klusmann JH, Li Z, Böhmer K, Maroz A, Koch ML, Emmrich S, Godinho FJ, Orkin SH, Reinhardt D	miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia.	Genes & development 2010, 24: 478
Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.
Klusmann JH, Reinhardt D, Zimmermann M, Kremens B, Vormoor J, Dworzak M, Creutzig U, Klingebiel T	The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study.	Haematologica 2012, 97: 21
Background. The role of allogeneic stem cell transplantation in post-remission management of pediatric high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission. Design and Methods. HLA-typed high-risk acute myeloid leukemia patients, who achieved first complete remission (n=247), were included in this analysis. All patients received double induction and consolidation. Based on availability of matched-sibling donor, patients were allocated by genetic chance to allogeneic stem cell transplantation (n=61) or chemotherapy-only (i.e. intensification and maintenance therapy; n=181). The main analysis was done on an intention-to-treat basis according to this allocation. Results. Intention-to-treat analysis did not show a significantly different 5-year disease-free survival (49±6% vs. 45±4%, plog rank=0.44) and overall survival (68+/-6% vs. 57+/-4%, plog rank=0.17) between the matched-sibling donor and no-matched-sibling donor groups, whereas late adverse effects occurred more frequently after allogeneic stem cell transplantation (72.5% vs. 31.8%, pFischer<0.01). Those results were confirmed by as-treated analysis corrected for the time until transplantation (5-year overall survival: 72+/-8% vs.60+/-4%, pMantel-byar 0.21). Subgroup analysis demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic stem cell transplantation (5-year overall survival: 94+/-6% vs. 52+/-7%, plog-rank=0.01; n=18 vs. 49) in contrast to patients without 11q23 aberrations (5-year overall survival: 58+/-8% vs. 55+/-5%, plog-rank=0.66). Conclusions. Our analysis defined a genetic subgroup of the high-risk acute myeloid leukemia patients, which showed a benefit from allogeneic stem cell transplantation in the prospective multi-center AML-BFM 98 study. For the remainder of the pediatric high-risk acute myeloid leukemia patients, the prognosis could not be improved by allogeneic stem cell transplantation, which was, however, associated with a higher rate of late sequelae.This trial was registered at www.clinicaltrials.gov as #NCT00111345.
Kluge R, Körholz D	[Role of FDG-PET in Staging and Therapy of Children with Hodgkin Lymphoma.	Klinische Padiatrie 2011, [Epub ahead of print]
The paediatric Hodgkin lymphoma treatment optimisation concepts aim at reduction of treatment intensity with preservation of the high cure rates. A negative interim FDG-PET result after 2 cycles of chemotherapy is associated with a good prognosis. In the current EuroNet-PHL-C1 study radiotherapy is being omitted, if interim PET becomes negative. In addition to the early interim PET after 2 cycles of chemotherapy, all patients undergo an initial PET investigation which is part of the staging processs and plays an essential role for the interpretation of the interim PET. Skeletal involvement can be detected by a typical FDG-PET uptake pattern with high sensitivity and specifity. Therefore, in the forthcoming EuroNet-PHL-C2 study bone marrow biopsy and bone scintigraphy will no longer be part of the staging algorithm.
Klusmann JH, Reinhardt D, Zimmermann M, Kremens B, Vormoor J, Dworzak M, Creutzig U, Klingebiel T	The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study.	Haematologica 2012, 97: 21
The role of allogeneic stem cell transplantation in post-remission management of children with high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission.
Kluge R, Chavdarova L, Hoffmann M, Kobe C, Malkowski B, Montravers F, Kurch L, Georgi T, Dietlein M, Wallace WH, Karlen J, Fernández-Teijeiro A, Cepelova M, Wilson L, Bergstraesser E, Sabri O, Mauz-Körholz C, Körholz D, Hasenclever D	Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.	PloS one 2016, 11:e0149072
The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised.
Kluge R, Wittig T, Georgi TW, Kurch L, Sabri O, Wallace WH, Klekawka T, Fernández-Teijeiro A, Ceppi F, Karlén J, Pears J, Cepelová M, Fosså A, Beishuizen A, Hjalgrim LL, Körholz D, Mauz-Körholz C, Hasenclever D	Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.	Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2021, 62: 338
In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. The findings support that first- and second-line treatments in HL do not require different response criteria.
Knowles DM	Inmunodeficiency-associated lymphoproliferative disorders.	Mod Pathol 1999, 12: 200
Knöfler R, Olivieri M, Weickardt S, Eberl W, Streif W, THROMKID Studiengruppe der Gesellschaft für Thrombose- und Hämostaseforschung eV	[First results of the THROMKID study: a quality project for the registration of children und adolescents with hereditary platelet function defects in Germany, Austria, and Switzerland].	Hamostaseologie 2007, 27: 48
THROMKID is a quality project of the Paediatric Group of German Thrombosis and Haemostasis Research Society (GTH). Data from paediatric patients with hereditary thrombocytopathies (HT) treated in Germany, Austria, and Switzerland were obtained between May 2005 and August 2006. By evaluation of results of platelet function tests criteria were determined to assess the diagnosis in each patient into most likely, likely or unlikely. A total of 215 patients treated in 31 centers were identified. In 95 patients (44%) the diagnosis of HT was most likely, in 28 (13%) likely and in 92 (43%) unlikely. Taken the first two groups together (n = 123) the diagnoses were as follows: Glanzmann thrombasthenia (n = 39, 32%), Aspirin-like defect (n = 26, 21%), thrombocyte receptor defects (n = 21, 17%), storage pool disorders (n = 18, 15%), Bernard-Soulier syndrome (n = 10, 8%), Hermansky-Pudlak syndrome (n = 6, 5%) and MYH9-related hereditary makrothrombocytopenia (n = 3, 2%). The low prevalence of these diseases and the high percentage of patients with unclassified HT stresses the necessity for the establishment of a competence network for comprehensive care of these patients in the three German-speaking countries.
Knöfler R, Streif W	Strategies in Clinical and Laboratory Diagnosis of Inherited Platelet Function Disorders in Children.	Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie 2010, 37: 231
Inherited disorders of platelet function are a rare and heterogeneous group of diseases usually characterised by a mild to moderate bleeding tendency. Typical bleeding symptoms are easy bruising, epistaxis, menorrhagia as well as mucocutaneous and perioperative bleeding. The performance of platelet function diagnostics in children is hampered by age-dependent restriction of blood sample size, poor venous access, and the lack of reproducible test reference ranges for children of different age groups. Platelet function testing is limited to specialised centres, because platelet function test procedures are complicated and time-consuming, which most likely results in a relevant number of undiagnosed and incorrectly classified children with clinically relevant platelet function defects. Evaluation of bleeding history and bleeding symptoms is essential for a rational step-by-step approach to diagnosis. Platelet function diagnostics should be preceded by the exclusion of thrombocytopenia, von Willebrand disease, and secondary haemostasis defects. Light transmission aggregometry is still considered the standard for the assessment of platelet function. Every effort should be made to classify the specific platelet function defect in the patient, because this is essential for accurate treatment and counselling.
Knöfler R, Eberl W, Schulze H, Bakchoul T, Bergmann F, Gehrisch S, Geisen C, Gottstein S, Halimeh S, Harbrecht U, Kappert G, Kirchmaier C, Kehrel B, Lösche W, Krause M, Mahnel R, Meyer O, Pilgrimm AK, Pillitteri D, Rott H, Santoso S, Siegemund A, Schambeck C, Scheer M, Schmugge M, Scholl T, Strauss G, Zieger B, Zotz R, Hermann M, Streif W	[Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)].	Hamostaseologie 2014, 34: 201
Congenital disorders of platelet function are a heterogeneous group of disorders that are often not detected until bleeding occurs. In clinical settings only a few methods have proven to be useful for identification and classification of inherited platelet disorders. For a rational diagnostic approach, a stepwise algorithm is recommended. Patient history and clinical investigation are mandatory. Von Willebrand disease and other coagulation disorders should always be ruled out prior to specific platelet testing. Platelet count, size, volume (MPV) and morphology may guide further investigations. The PFA-100Â® CT is suited for screening for severe platelet defects. Platelet aggregometry allows assessment of multiple aspects of platelet function. Flow cytometry enables diagnosis of thrombasthenia Glanzmann, Bernard-Soulier syndrome and storage pool defects. Molecular genetics may confirm a putative diagnosis or pave the way for identifying new defects. We present an unabridged version of the interdisciplinary guideline.
Knöfler R, Lohse J, Stächele J, Heilmann A, Schwier F, Schmidt U, Erfurt C	Significance of platelet function diagnostics for clarification of suspected battered child syndrome.	Hamostaseologie 2014, 34 Suppl 1:S53
The manifestation of an unclear bleeding tendency in childhood calls for an extended coagulation work-up, particularly when a battered child syndrome is suspected and typical concomitant injuries are absent. The chosen diagnostic tests should be able to detect the presence of relatively common coagulation defects such as von Willebrand syndrome or hemophilia, but also rare diseases such as inherited thrombocytopathies. The PFA-100Â® test does not help to provide a definite diagnosis especially in cases of mild inherited thrombocytopathies, since in most cases the PFA-100Â® test results are normal. For this purpose, specific platelet function testing is needed. However, the methods are only available in some coagulation laboratories. Also, other limitations need to be taken into consideration such as pre-analytical problems and difficulties in the interpretation of test results especially in infants. We present two cases that were diagnosed with an aspirin-like defect as an inherited thrombocytopathy, even though their PFA-100 closure times were within the normal range. Based on pathological findings in the platelet aggregometry test, this diagnosis could be made.
Knörr F, Damm-Welk C, Ruf S, Singh VK, Zimmermann M, Reiter A, Woessmann W	Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma.	Haematologica 2018, 103: 477
Koch A, Dörr H, Beyer R, Erhardt J, Fahlbusch R, Dunst J, Beck J	Wachstum und Wachstumsstörungen von Kindern nach Therapie eines Medulloblastoms.	Monatsschr Kinderheilkd 1994, 142: 884
Kochling J, Konig-Merediz S, Stripecke R, Buchwald D, Korte A, Von Einsiedel H, Sack F, Henze G, Seeger K, Wittig B, Schmidt M	Protection of mice against Philadelphia chromosome-positive acute lymphoblastic leukemia by cell-based vaccination using nonviral, minimalistic expression vectors and immunomodulatory oligonucleotides.	Clin Cancer Res 2003, 9: 3142
Koch A, Weber N, Waha A, Hartmann W, Denkhaus D, Behrens J, Birchmeier W, von Schweinitz D, Pietsch T	Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas.	The Journal of pathology 2004, 204: 546
Hepatoblastoma (HB) is the most frequent malignant liver tumour of childhood. Most HBs develop sporadically but their incidence is highly elevated in patients with familial adenomatous polyposis coli (FAP). These patients carry germline mutations in the adenomatous polyposis coli (APC) tumour suppressor gene. APC forms a multi-protein complex involved in the WNT signalling pathway that controls the stability of beta-catenin, the central effector in this cascade. Whereas APC mutations are rare in sporadic HBs, a high frequency of beta-catenin mutations leading to overactivation of WNT signalling was previously found in these tumours. This pathway is negatively controlled by conductin (axin2), representing a further partner in this signalling complex. To investigate whether alterations in conductin may also be involved in the pathogenesis of sporadic HBs, 37 HBs and five HB cell lines were screened for mutations using single-strand conformation polymorphism (SSCP) analysis, reverse transcription-polymerase chain reaction (RT-PCR), and direct sequencing. In two cases, larger deletions (52 and 1624 bp) leading to frameshifts were found. In addition, one HB carried a somatic point mutation. Expression analysis by competitive RT-PCR in HBs revealed up-regulation of conductin mRNA compared with adjacent liver samples. This mRNA overexpression resulted in increased conductin protein levels demonstrated by western blot analysis. Tumours with activating beta-catenin mutations revealed higher levels of conductin mRNA transcripts. This finding indicates that conductin is a direct target gene of WNT signalling in HBs, as has been demonstrated in other tissues. In summary, conductin mutations may represent an alternative mechanism leading to activation of WNT signalling in HBs. The overexpression of conductin mRNA in HBs reflects activation of the WNT pathway because conductin represents a target gene of WNT signalling in liver tissue.
Koch A, Waha A, Hartmann W, Hrychyk A, Schuller U, Waha A, Wharton KA Jr, Fuchs SY, von Schweinitz D, Pietsch T	Elevated expression of Wnt antagonists is a common event in hepatoblastomas.	Clinical cancer research 2005, 11: 4295
Hepatoblastomas are the most frequent malignant liver tumors of childhood. A high frequency of activating beta-catenin mutations in hepatoblastomas indicates that the Wnt signaling pathway plays an important role in the development of this embryonic neoplasm. Stabilization of beta-catenin leads to an increased formation of nuclear beta-catenin-T-cell factor complexes and altered expression of Wnt-inducible target genes. In this study, we analyzed the mRNA expression levels of nine Wnt genes, including c-JUN, c-MYC, CYCLIN D1, FRA-1, NKD-1, ITF-2, MMP-7, uPAR, and beta-TRCP, by competitive reverse transcription-PCR. We analyzed 23 hepatoblastoma biopsies for which matching liver tissue was available, 6 hepatoblastoma cell lines, and 3 human fetal liver samples. beta-TRCP and NKD-1 were highly expressed in all hepatoblastoma samples, independent of the beta-catenin mutational status, in comparison with their nontumorous counterparts. beta-TRCP mRNA overexpression was associated with accumulation of intracytoplasmic and nuclear beta-TrCP protein. In human liver tumor cells without beta-catenin mutations, Nkd-1 inhibited the Wnt-3a-activated Tcf-responsive-luciferase reporter activity, whereas Nkd-1 in hepatoblastomas with beta-catenin mutations had no antagonistic effect. Our data emphasize the inhibitory effect of beta-TrCP and Nkd-1 on the Wnt signaling pathway in a manner analogous to Conductin (AXIN2) and Dkk-1, inhibitors shown previously to be up-regulated in hepatoblastomas. Our findings indicate that overexpression of the Wnt antagonists Nkd-1 and beta-TrCP reveals an activation of the Wnt signaling pathway as a common event in hepatoblastomas. We propose that Nkd-1 and beta-TrCP may be used as possible diagnostic markers for the activated Wnt signaling pathway in hepatoblastomas.
Koch C, Samareh B, Morishima T, Mir P, Kanz L, Zeidler C, Skokowa J, Welte K	GM-CSF treatment is not effective in congenital neutropenia patients due to its inability to activate NAMPT signaling.	Annals of hematology 2017, 96: 345
Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/μL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor. Recently, we detected that G-CSF induces granulopoiesis in CN patients by hyperactivation of nicotinamide phosphoribosyl transferase (NAMPT)/Sirtuin 1 signaling in myeloid cells. Here, we demonstrated that, in contrast to G-CSF, GM-CSF failed to induce NAMPT-dependent granulopoiesis in CN patients. We further identified NAMPT signaling as an essential downstream effector of the GM-CSF pathway in myelopoiesis.
Koche RP, Rodriguez-Fos E, Helmsauer K, Burkert M, MacArthur IC, Maag J, Chamorro R, Munoz-Perez N, Puiggròs M, Dorado Garcia H, Bei Y, Röefzaad C, Bardinet V, Szymansky A, Winkler A, Thole T, Timme N, Kasack K, Fuchs S, Klironomos F, Thiessen N, Blanc E, Schmelz K, Künkele A, Hundsdörfer P, Rosswog C, Theissen J, Beule D, Deubzer H, Sauer S, Toedling J, Fischer M, Hertwig F, Schwarz RF, Eggert A, Torrents D, Schulte JH, Henssen AG	Extrachromosomal circular DNA drives oncogenic genome remodeling in neuroblastoma.	Nature genetics 2020, 52: 29
Extrachromosomal circularization of DNA is an important genomic feature in cancer. However, the structure, composition and genome-wide frequency of extrachromosomal circular DNA have not yet been profiled extensively. Here, we combine genomic and transcriptomic approaches to describe the landscape of extrachromosomal circular DNA in neuroblastoma, a tumor arising in childhood from primitive cells of the sympathetic nervous system. Our analysis identifies and characterizes a wide catalog of somatically acquired and undescribed extrachromosomal circular DNAs. Moreover, we find that extrachromosomal circular DNAs are an unanticipated major source of somatic rearrangements, contributing to oncogenic remodeling through chimeric circularization and reintegration of circular DNA into the linear genome. Cancer-causing lesions can emerge out of circle-derived rearrangements and are associated with adverse clinical outcome. It is highly probable that circle-derived rearrangements represent an ongoing mutagenic process. Thus, extrachromosomal circular DNAs represent a multihit mutagenic process, with important functional and clinical implications for the origins of genomic remodeling in cancer.
Körholz D, Wirtz I, Vosberg H, Rüther W, Jürgens H, Göbel U	The role of bone scintigraphy in the follow-up of osteogenic sarcoma.	Eur J Cancer 1996, 32A: 461
Körholz D, Kluge R, Wickmann L, Hirsch W, Lüders H, Lotz I, Dannenberg C, Hasenclever D, Dörffel W, Sabri O	Importance of F18-fluorodeoxy-D-2-glucose positron emission tomography (FDG-PET) for staging and therapy control of Hodgkin's lymphoma in childhood and adolescence - consequences for the GPOH-HD 2003 protocol.	Onkologie 2003, 26: 489
The prognosis for children and adolescents with Hodgkin's lymphoma is excellent. However, many patients will show secondary malignancies 15-30 years after the initial diagnosis, which appears to be connected with the intensity of treatment during primary disease. In the GPOH-HD 95 trial, the indication for radiotherapy was limited to patients who did not show a complete remission after chemotherapy, as determined radiographically. In the future protocol, the indication for radiotherapy in patients with early-stage Hodgkin's lymphoma should be further refined by using FDG-PET for evaluating the response to chemotherapy. Furthermore, in patients at an advanced stage of the disease, it should be determined if sequential FDG-PET research during chemotherapy can separate patients into subgroups with an excellent or a poor prognosis. This article gives a review of the current literature on FDG-PET in patients with Hodgkin's lymphoma and outlines the consequences for future protocols.
Körholz D, Claviez A, Hasenclever D, Kluge R, Hirsch W, Kamprad F, Dörffel W, Wickmann L, Papsdorf K, Dieckmann K, Kahn T, Mauz-Korholz C, Dannenberg C, Potter R, Brosteanu O, Schellong G, Sabri O	The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease.	Klin Pädiatr 2004, 216: 150
Körholz D, Mauz-Körholz C, Vordermark D, Kluge R, Dieckmann K	Increased relapse rates in early stage hodgkin lymphoma (HL) patients without radiotherapy: the German Society of Radiooncology (DEGRO) advises to treat all early stage HL patients with radiotherapy.	Klinische Padiatrie 2014, 226(6-7): 307
Körholz D, Mauz-Körholz C	Hodgkin-Lymphom.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 338
Kohne E	Diagnostik von Hämoglobinopathien.	J Lab Med 2004, 28 , 400
Kohne E, Kleihauer E	Hämoglobinopathien - eine Langzeitstudie über vier Jahrzehnte.	Dtsch Arztebl Int 2010, 107: 65
Konemann S, Bolling T, Schuck A, Malath J, Kolkmeyer A, Horn K, Riesenbeck D, Hesselmann S, Diallo R, Vormoor J, Willich N	Effect of radiation on Ewing tumour subpopulations characterized on a single-cell level.	Int J Radiat Biol 2003, 79: 181
Konemann S, Bolling T, Kolkmeyer A, Riesenbeck D, Hesselmann S, Vormoor J, Willich N, Schuck A	Heterogeneity of radiation induced apoptosis in Ewing Tumor cell lines characterized on a single cell level.	Apoptosis 2005, 10: 177
The objective of this study was to investigate heterogeneity of radiation induced apoptosis on a single cell level. Two Ewing tumor cell lines were characterized in vitro before and 24 and 72 h after radiation with 5 Gy by multiparametric flow cytometry. Annexin V, 7-AAD and fluorescence conjugated antibodies that were directed against HLA-ABC, CD11a and CD62L were used. Based on these markers radiation induced apoptosis was quantified, multiple apoptotic subpopulations were identified and a characteristic individual apoptotic profile was characterized. The characterization of HLA-ABC, CD11a and CD62L was informative to detect subpopulations of apoptotic cells. The observed heterogeneity and the identification of multiple apoptotic subpopulations reflect the complexity and diversity of biology of radiation induced cell death. This might be an indication for co-existing apoptotic pathways or it might represent sequential steps of the apoptotic cascade.
Kono T, Sakurai H, Groff WF, Chan HH, Takeuchi M, Yamaki T, Soejima K, Nozaki M	Comparison study of a traditional pulsed dye laser versus a long-pulsed dye laser in the treatment of early childhood hemangiomas.	Lasers in surgery and medicine 2006, 38: 112
The role of pulsed dye laser (PDL) in the treatment of childhood hemangiomas is still controversial because of the inherent characteristics of hemangiomas as well as the side effects of the PDL. Recently, the long pulsed dye laser (LPDL) with cryogen spray cooling (CSC) has been found relatively more effective and safer than the PDL in the treatment of port-wine stains and telangiectasia. This study was designed to compare the efficacy and complication rate of PDL versus LPDL for treating childhood hemangiomas.
Kontny U, Oschlies I, Woessmann W, Burkhardt B, Lisfeld J, Salzburg J, Janda A, Attarbaschi A, Niggli F, Zimmermann M, Reiter A, Klapper W	Non-anaplastic peripheral T-cell lymphoma in children and adolescents - a retrospective analysis of the NHL-BFM study group.	British journal of haematology 2015, 168: 835
Mature (peripheral) T-cell lymphoma (PTCL) other than anaplastic large cell lymphoma is a heterogeneous group of diseases and exceedingly rare in children and adolescents. Survival rates range between 46% and 85%. This study reports the disease characteristics, treatment and outcome of all patients with the diagnosis of mature TCL registered in the Berlin-Frankfurt-Munster non-Hodgkin lymphoma database between 1986 and 2012. All diagnoses were centrally reviewed and revised by clinico-pathological correlation according to the criteria of the current World Health Organization classification. Of the 69 patients originally registered as having PTCL, the diagnosis was confirmed in 38 of them. Most patients were treated with an anaplastic large cell lymphoma (ALCL)-like therapy regimen. Patients with PTCL-not otherwise specified comprised the largest group and showed a 5-year event-free survival rate of 61 ± 11%. Patients suffering from Natural Killer/T-cell- and hepatosplenic TCL had the poorest outcome. Our results suggest that the outcomes of children with mature TCL other than ALCL depend on the subtype and are worse than in all other paediatric lymphomas. The clinical experience presented in this largest study on paediatric mature TCL may serve as basis for future collaborative international prospective clinical trials.
Kontny U, Franzen S, Behrends U, Bührlen M, Christiansen H, Delecluse H, Eble M, Feuchtinger T, Gademann G, Granzen B, Kratz CP, Lassay L, Leuschner I, Mottaghy FM, Schmitt C, Staatz G, Timmermann B, Vorwerk P, Wilop S, Wolff HA, Mertens R	Diagnosis and Treatment of Nasopharyngeal Carcinoma in Children and Adolescents - Recommendations of the GPOH-NPC Study Group.	Klinische Padiatrie 2016, 228: 105
Nasopharyngeal carcinoma (NPC) is a rare malignant tumor arising from epithelial cells of the nasopharynx. Its incidence is highest in Southeast Asia. Age distribution of NPC is bimodal, with one peak in young adolescents and another in patients 55-59 years of age. EBV appears to be the primary etiologic agent in the pathogenesis, environmental factors such as nitrosamines and genetic factors are contributory. NPC is most commonly diagnosed in locally advanced stages, with lymph node metastases occurring in up to 90% of patients. About 5-10% of patients present with distant metastases. Diagnosis of NPC is made histologically, supported by an abnormal anti-EBV-VCA IgA titer and elevated plasma EBV-DNA load. Superior results in children and adolescents with advanced locoregional NPC, with overall and event-free survival rates>90%, have been achieved by neoadjuvant chemotherapy with 5-fluoruracil and cisplatin, followed by synchronous radiochemotherapy and subsequent maintenance therapy with interferon-Ã as demonstrated by the 2 prospective studies GPOH-NPC-91 and -2003. Response to therapy can be assessed by PET-imaging and in patients with complete remission after neoadjuvant chemotherapy, the radiation dose to the primary tumor can be safely reduced from 59.4 to 54.4âGy. Since the majority of long term sequalae such as xerostomia, skin and tissue fibrosis are caused by high radiation dosages, radiotherapy modalities such as intensity-modulated radiotherapy should be used to efficiently spare non-tumorous tissue. For patients with metastatic disease and relapse, survival chances are low. New treatment strategies, such as the application of EBV-specific T-lymphocytes should be considered for these patients.
Kook H	Fanconi anemia: current management.	Hematology 2005, 10 Suppl 1: 108
Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder, characterized by congenital anomalies, defective hematopoiesis and a high risk of developing acute myeloid leukemia and certain solid tumors. All racial and ethnic groups are at risk, and at least 11 complementation groups have been identified and the genes defective in eight of these have been identified (FANCA, C, D2, E, F, G, L and BRCA2). FA-A is the most common complementation group, accounting for approximately 65% of all affected individuals. The gold-standard screening test for FA is based on the characteristic hypersensitivity of FA cells to the crosslinking agents, such as mitomicin C or diepoxybutane. Recent progress has been made in identifying the genes bearing pathogenetically relevant mutations, but slower progress has been made in defining the precise functions of the proteins in normal cells, in part because that the proteins are multifunctional. Molecular studies have established that a common pathway exist, both between the FA proteins and other proteins involved in DNA repair such as NBS1, ATM, BRCA1 and BRCA2. Stem cell transplantation (SCT) is the only option for establishing normal hematopoiesis. To reduce undue toxicities due to inherent hypersensitivity, nonmyeloablative conditioning for transplants has been advocated. This review summarizes the general clinical and hematologic features and the current management of FA. Fanconi anemia (FA) is the commonest type of inherited bone marrow failure syndrome with the birth incidence of around three per million. The inheritance pattern is autosomal recessive with the estimated heterozygote frequency being one in 300 in Europe and the US.
Kortmann R, Timmermann B, Becker G, Kühl J, Bamberg M	Advances in treatment techniques and time/dose schedules in external radiation therapy of brain tumours in childhood.	Klin Pädiatr 1998, 210: 220
Kortmann R, Timmermann B, Kühl J, Willich N, Flentje M, Meisner C, Bamberg M	HIT '91 (prospective, co-operative study for the treatment of malignant brain tumors in childhood).	Strahlenther Onkol 1999, 175: 162
Korte A, Köchling J, Badiali L, Eckert C, Andreae J, Geilen W, Kebelmann-Betzing C, Taube T, Wu S, Henze G, Seeger K	Expression analysis and characterization of alternatively spliced transcripts of human IL-7R alpha chain encoding two truncated receptor proteins in relapsed childhood ALL.	Cytokine 2000, 12: 1597
Kortmann R, Klingebiel Th, Timmermann B, Kühl J, Müller S, Göbel U, Bamberg M	Aktuelle radioonkologische Strategien bei der Behandlung von malignen Tumoren im Kindesalter.	Onkologe 2000, 6: 854
Kortmann R, Kühl J, Timmermann B, Mittler U, Urban C, Budach V, Richter E, Willich N, Flentje M, Berthold F, Slavc I, Wolff J, Meisner C, Wiestler O, Sörensen N, Warmuth-Metz M, Bamberg M	Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood.	Int J Radiat Oncol Biol Phys 2000, 46: 269
Kortmann R, Kühl J, Timmermann B, Calaminus G, Dieckmann K, Wurm R, Sörensen N, Urban C, Göbel U, Bamberg M	Current and future strategies in interdisciplinary treatment of medulloblastomas, supratentorial PNET (primitive neuroectodermal tumors) and intracranial germ cell tumors in childhood.	Strahlenther Onkol 2001, 177: 447
Kortmann R, Timmermann B, Taylor R, Scarzello G, Plasswilm L, Paulsen F, Jeremic B, Gnekow A, Dieckmann K, Kay S, Bamberg M	Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part I	Strahlenther Onkol 2003, 179: 509
Kortmann R, Timmermann B, Taylor R, Scarzello G, Plasswilm L, Paulsen F, Jeremic B, Gnekow A, Dieckmann K, Kay S, Bamberg M	Current and future strategies in radiotherapy of childhood low-grade glioma of the brain. Part II.	Strahlenther Onkol 2003, 179: 585
Kortmann RD, Timmermann B, Rutkowski S, Bamberg M	Re: B. Beuthien-Baumann, et al. Differentiation between recurrent tumor and radiation necrosis in a child with anaplastic ependymoma after chemotherapy and radiation therapy. Strahlenther Onkol 2003;179:819-22.	Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. 2004, 180: 245
Korinthenberg R, Warmuth-Metz M, Rutkowski S	Leitsymptome und Diagnostik der Hirntumoren im Kindes- und Jugendalter.	Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft (Gemeinsame Leitlinie der Gesellschaft für Neuropädiatrie und der Gesellschaft für Pädiatrische Onkologie und Hämatologie 2007
Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, Milde T, Bender S, Wittmann A, Schöttler A, Kulozik AE, Witt O, von Deimling A, Lichter P, Pfister S	Molecular staging of intracranial ependymoma in children and adults.	J Clin Oncol 2010, 28: 3182
The biologic behavior of intracranial ependymoma is unpredictable on the basis of current staging approaches. We aimed at the identification of recurrent genetic aberrations in ependymoma and evaluated their prognostic significance to develop a molecular staging system that could complement current classification criteria.
Korinthenberg R, Neuburger D, Nikkhah G, Teske C, Schnabel K, Calaminus G	Assessing Quality of Life in Long-Term Survivors after 125I Brachytherapy for Low-Grade Glioma in Childhood.	Neuropediatrics 2011, 42: 110
Quality of life (QOL) is important for the survivors of malignancies. We investigated health-related QOL in 51 patients treated with iodine-125 (125I) brachytherapy for childhood low-grade gliomas. Instruments included a questionnaire on life situation, German versions of PEDQOL (8-18 years), EORTC QLQ-30 and head and neck module H&N-35 (>18 years), strength and difficulties questionnaire, "Fertigkeitsskala Münster Heidelberg", and an adapted Rankin score. The time lapsed since 125I-brachytherapy was 134 months (median, range: 29-293 months). 57% of the patients were over 18 years of age, 34% were 11-17 years old and 8% were younger. 14 had undergone other treatments after 125I brachytherapy. Over half of the >18 year olds reported residual problems; 68% were disabled, 38% to a severe degree. Many of the young adults still lived with their parents and 17% were jobless. 43% of the children/adolescents needed rehabilitative treatment, 20% visited special schools and 71% were disabled, 33% severely. The patients and their caregivers rated their QOL as not different from that of the normal population. However, many QOL dimensions correlated to the severity of disability. Comparison of QOL outcomes between different treatment measures would require a prospective study controlling for the most important factors of influence.
Kordes U, Flitsch J, Hagel C, Goebell E, Schwarz R, Herberhold T, von Bueren AO, Rutkowski S, Müller HL	Ectopic craniopharyngioma.	Klin padiatr 2011, 223: 176
Introduction Ectopic extra-axial craniopharyngioma may be caused by surgical tumor seeding, demonstrating viability and metastatic potential of primary craniopharyngioma tumor cells. It is a rare but distinct post-operative complication of craniopharyngioma that is different from leptomeningeal progression of other low grade pediatric brain tumors such as pilocytic astrocytoma. We present clinical pathological data from a young boy who suffered a metastasis of his craniopharyngioma along the surgical route shortly after irradiation for progressive disease at the primary site.
Korinthenberg R, Neuburger D, Trippel M, Ostertag C, Nikkhah G	Long-term results of brachytherapy with temporary iodine-125 seeds in children with low-grade gliomas.	International journal of radiation oncology, biology, physics 2011 Mar 15; 79: 1131
To retrospectively review the results of temporary I-125 brachytherapy in 94 children and adolescents with low-grade glioma.
Korte E, Schilling R, Balcerek M, Byrne J, Dirksen U, Herrmann G, Kepak T, Klco-Brosius S, Kruseova J, Kunstreich M, Langer T, Panasiuk A, Stefanowicz J, Strauß G, Wiegele K, Borgmann-Staudt A	Fertility-Related Wishes and Concerns of Adolescent Cancer Patients and Their Parents.	Journal of adolescent and young adult oncology 2020, 9: 55
Within a multicenter European study, we explored fertility-related wishes, concerns, and decision-making of adolescent cancer patients and their parents. Patients and parents were each asked to complete a fertility-related questionnaire 3 months after initial diagnosis. In total, 113 of 142 (79.6%) eligible patients participated; 53.1% were male and the median age was 16 years (range 13-20 years). The questionnaire was completed by 111 parents. Univariate analyses were conducted using nonparametric methods with alpha = 5%. For multivariate analyses, binary logistic regression was conducted. Both patients (86.1%) and parents (96.3%) indicated a strong desire for biological parenthood for themselves/their children. Female patients (odds ratio [OR] = 3.70; confidence interval [CI]: 1.43-9.50) and parents (OR = 2.70; CI: 1.21-6.00) were more likely to report a high fear of cancer recurrence. Patients who estimated their risk for fertility impairment being high were more likely to be concerned about their fertility (OR = 5.69; CI: 1.41-22.98). Parents who received fertility preservation information were more likely to recommend its use to their children (OR = 5.50; CI: 1.07-28.40), whereas parents of female patients were less likely to do so (OR = 0.13; CI: 0.03-0.61). The prospect of fertility following cancer treatment is important for adolescent cancer patients and their parents, yet it is associated with many concerns. Counseling regarding fertility preservation can be more effective when the individual needs of patients and their parents are taken into consideration.
Korte E, Schilling R, Balcerek M, Campbell H, Dirksen U, Herrmann G, Kepakova K, Kepak T, Klco-Brosius S, Kruseova J, Kunstreich M, Lackner H, Langer T, Panasiuk A, Stefanowicz J, Strauß G, Ranft A, Byrne J, Goldbeck L, Borgmann-Staudt A	Fertility education for adolescent cancer patients: Gaps in current clinical practice in Europe.	European journal of cancer care 2020, 29:e13279
As adolescent cancer patients may suffer from infertility following treatment, fertility counselling is essential. Our aim was to explore the current situation in four European countries in terms of (I) education about the risk for infertility, (II) counselling on fertility preservation, (III) patients' knowledge on fertility, (IV) sufficiency of information and (V) uptake of cryopreservation.
Koscielniak E, Treuner J, Jürgens H, Winkler K, Bürger D, Herbst M, Ritter J, Niethammer D, Müller-Weihrich S, Bernhard G	Treatment of soft tissue sarcomas in childhood and adolescence.	Klinische Pädiatrie 1991, 203: 211
Koscielniak E, Jürgens H, Winkler K, Bürger D, Herbst M, Keim M, Bernhard G, Treuner J	Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study.	Cancer 1992, 70: 2557
Koscielniak E, Rodary C, Flamant F, Carli M, Treuner J, Pinkerton C, Grotto P	Metastatic soft tissue sarcoma in childhood.	Med Pediatr Oncol 1992, 209
Koscielniak E, Rodary C, Flamant F, Carli M, Treuner J, Pinkerton C, Grotto P	Metastatic rhabdomyosarcoma and histologically similar tumors in childhood.	Med Pediatr Oncol 1992, 20: 209
Koscielniak E, Hammer S, Blank J	Effects of rh-GM-GSF on hematopoietic recovery and infections complications in children with solid tumors after high-dose chemotherapy followed by ABMT.	Br J Haematology 1994
Koscielniak E, Herbst M, Niethammer D, Treuner J	Improved local tumor control by early and risk-adjusted use of radiotherapy in primary non-resectable rhabdomyosarcomas.	Klinische Pädiatrie 1994, 206: 269
Koscielniak E, Klingebiel T, Peters C, Hermann J, Burdach S, Bender-Götze C, Müller-Weihrich S, Treuner J	Do patients with metastatic and recurrent rhabdomyosarcoma benefit from high-dose therapy with hematopoietic rescue?	Bone Marrow Transplant 1997, 19: 227
Koscielniak E, Harms D, Henze G, Jürgens H, Gadner H, Herbst M, Klingebiel T, Schmidt B, Morgan M, Knietig R, Treuner J	Results of treatment for soft tissue sarcoma in childhood and adolescence.	J Clin Oncol 1999, 17: 3706
Koscielniak E, Morgan M, Treuner J	Soft tissue sarcoma in children.	Paediatr Drugs 2002, 4: 21
Koscielniak E, T Klingebiel, A Schuck, I Leuschner	Weichteilsarkome im Kindesalter. Diagnostik und Therapie.	Der Onkologe 2005 (electronic on line first article)
Koscielniak E, Treuner J	Weichteilsarkome.	Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und Leitlinien und der Gesellschaft für Pädiatrische Onkologie und Hämatologie 2008
Koscielniak E, Dantonello T, Klingebiel T	Weichteiltumoren – Neue Projekte der CWS-Studiengruppe: das Register „SoTiSaR für Weichteilsarkome und –tumoren sowie die multizentrische Studie CWS-2007-HR zur Behandlung von Patienten mit lokalisierten rhabdomyosarkomartigen Weichteilsarkomen.	Wir – die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 3/2009
Koscielniak E	Weichteilsarkome.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie AWMF online 2011
Koscielniak E, Fuchs J, Leuschner I, Greulich M, Kllingebiel T	Weichteiltumoren.	in: Solide Tumoren im Kindesalter. Fuchs J (Hrsg.) Schattauer GmbH Stuttgart 2012, 197
Koscielniak E, Klingebiel T	Weichteilsarkome.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) AWMF
Koscielniak E, Klingebiel T	Weichteilsarkome.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer-Verlag GmbH Deutschland 2. vollständig überarbeitete Auflage 2018, 475
Koscielniak E, Klingebiel T	A new standard of care for patients with high-risk rhabdomyosarcoma?	The Lancet. Oncology 2020, 21:e1
No abstract available
Koscielniak E, Sparber-Sauer M, Scheer M, Vokuhl C, Kazanowska B, Ladenstein R, Niggli F, Ljungman G, Paulussen M, Bielack SS, Seitz G, Fuchs J, Hallmen E, Klingebiel T, On Behalf Of The Cws Study Group	Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS).	Pediatric blood & cancer 2021,e29145
We have analyzed the outcome of patients with localized extraskeletal Ewing sarcoma (EES) treated in three consecutive Cooperative Weichteilsarkomstudiengruppe (CWS) soft tissue sarcoma (STS) studies: CWS-91, CWS-96, and CWS-2002P.
Koustenis E, Pfitzer C, Balcerek M, Reinmuth S, Zynda A, Stromberger C, Hohmann C, Keil T, Borgmann-Staudt A	Impact of cranial irradiation and brain tumor location on fertility: a survey.	Klinische Padiatrie 2013, 225: 320
As survival rates of patients with childhood brain tumors have increased to 75%, treatment related side effects are of particular importance. The present study evaluated questionnaire-based fertility characteristics in cancer survivors treated with irradiation to the hypo-thalamic-pituitary-axis.A nationwide survey was conducted in collaboration with the German Childhood Cancer Registry. Questionnaire and treatment data could be retrieved for 1110 former childhood cancer patients with cranial irradiation and/or chemotherapy.Survivors receiving â¥30 gray vs. 18-29 gray and 0-17 gray to the pituitary gland reported less pregnancies or less with their partners (7.4% vs. 32.8% vs. 12.4%; p<0.001), were more often infertile (40% vs. 9.4% vs. 12.5%; p<0.001) and the female participants, had a higher frequency of permanent amenorrhea (16.7% vs. 1.7% vs. 0%; p<0.001).Irradiation of the pituitary gland â¥â30 gray seemed to be associated with less pregnancies and increased permanent amenorrhea in women. Future studies need to be conducted to confirm these results. Increased knowledge of treatment related side effects might help brain tumor patients to improve their family planning if necessary by gonadotropine replacement.
Kovnar E, Kun L, Burger P, et al.	Patterns of dissemination and recurrence in childhood ependymoma: Preliminary results of Pediatric Oncology Group Protocol #8532.	Ann Neurol 30: 457, 1991
Kovnar EH	Hyperfractionated irradiation for childhood ependymoma: early results of a phase III Pediatric Oncology Group study.	VIIth Symposium Pediatric Neurooncology Abstract 31, Washington 1996
Kovac M, Woolley C, Ribi S, Blattmann C, Roth E, Morini M, Kovacova M, Ameline B, Kulozik A, Bielack S, Hartmann W, Ballinger ML, Thomas DM, Tomlinson I, Nathrath M, Heinimann K, Baumhoer D	Germline RET variants underlie a subset of paediatric osteosarcoma.	Journal of medical genetics 2021, 58: 20
Although considerable effort has been put into decoding of the osteosarcoma genome, very little is known about germline mutations that underlie this primary malignant tumour of bone.
Kraus J, Albrecht S, Wiestler O, von Schweinitz D, Pietsch T	Loss of heterozygosity on chromosome 1 in human hepatoblastoma.	Int J Cancer 1996, 67: 467
Krams M, Hero B, Berthold F, Parwaresch R, Harms D, Rudolph P	Proliferation marker KI-S5 discriminates between favorable and adverse prognosis in advanced stages of neuroblastoma with and without MYCN amplification.	Cancer 2002, 94: 854
Krams M, Hero B, Berthold F, Parwaresch R, Harms D, Rudolph P	Full-length telomerase reverse transcriptase messenger RNA is an independent prognostic factor in neuroblastoma.	Am J Pathol 2003, 162: 1019
Krams M, Heidebrecht HJ, Hero B, Berthold F, Harms D, Parwaresch R, Rudolph P	Repp86 expression and outcome in patients with neuroblastoma.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003, 21: 1810
PURPOSE: Given the well-known challenges of neuroblastoma prognosis, we investigated whether the expression of restrictedly expressed proliferation-associated protein of 86 kDa theoretical molecular mass (repp86), a proliferation-associated protein expressed in S, G2, and M phases of the cell cycle, correlates with the clinical outcome in patients with neuroblastoma. PATIENTS AND METHODS: 161 children with different stages of neuroblastoma were studied; the median follow-up time was 72.8 months. The patients were staged according to the International Neuroblastoma Staging System, and histologic grading of the tumors was performed according to the criteria of Hughes and those of the International Neuroblastoma Pathology Classification. The MYCN gene copy number was determined by Southern blot analysis or fluorescence in situ-hybridization, and repp86 expression was assessed immunohistochemically by means of monoclonal antibody Ki-S2 on paraffin sections from archival tumor samples. RESULTS: A repp86 labeling index (RI) of more than 10% positive tumor cells significantly predicted a shortened disease-free interval and an increased tumor mortality (both P <.0001). Moreover, the RI allowed the identification of patients with favorable and adverse prognosis in subsets defined by stage, grade, age, and MYCN status. In a multivariate analysis, the RI emerged as the most important predictor of event-free and disease-specific survival with hazard ratios of 11.7 and 10.5, respectively (both P <.0001). CONCLUSION: It seems that repp86 expression is closely associated with the biologic behavior of neuroblastoma. Assessment of the RI might, therefore, considerably refine prognostic models.
Kratz CP, Rogge T, Kopp M, Baumann I, Niemeyer CM	Myelodysplastic features in an infant with cystic fibrosis presenting with anaemia, oedema and failure to thrive.	European journal of pediatrics 2005, 164: 56
Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M, Loh ML	The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.	Blood 2005, 106: 2183
Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML.
Kramm CM, Wagner S, Van Gool S, Schmid H, Strater R, Gnekow A, Rutkowski S, Wolff JE	Improved survival after gross total resection of malignant gliomas in pediatric patients from the HIT-GBM studies.	Anticancer Res 2006, 26: 3773
Kratz CP, Steinemann D, Niemeyer CM, Schlegelberger B, Koscielniak E, Kontny U, Zenker M	Uniparental disomy at chromosome 11p15. 5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome.	Human molecular genetics 2007, 16: 374
Costello syndrome (CS; MIM 218040) is characterized by short stature, facial dysmorphism, cardiac defects and predisposition to embryonal rhabdomyosarcoma (CS/ERMS) and other neoplasias. CS is caused by germline mutations in the HRAS gene on chromosome 11p15.5, a region showing allelic imbalances in sporadic ERMS and CS/ERMS. The critical gene for ERMS development in this region is unknown. The association of CS and ERMS as well as previous reports illustrating that somatic HRAS mutations are found in a proportion of these tumors prompted us to clarify the significance and a possible correlation of HRAS mutations and genomic rearrangements at 11p15.5 in sporadic ERMS. We screened for somatic HRAS mutations and 11p15.5 imbalances in six sporadic ERMS samples. This analysis uncovered five ERMS samples with uniparental disomy (UPD) at the HRAS locus, two of which harbored HRAS mutations. By analyzing informative genetic variations in or at the HRAS gene locus, we show that one HRAS allele is entirely lost in specimens with UPD at 11p15.5. Notably, in both cases with UPD and HRAS mutations these mutations were heterozygous. Therefore, they must have succeeded the emergence of UPD. In contrast, HRAS germline mutations are the first step in CS/ERMS. Subsequent development of UPD at 11p15.5 may explain previous observations that CS/ERMS express mutant HRAS only. These data implicate that in sporadic ERMS, UPD at 11p15.5 is not driven by HRAS mutations and that imbalances at 11p15.5 and HRAS mutations represent independent but cooperating events during ERMS development.
Krappmann P, Paulides M, Stöhr W, Ittner E, Plattig B, Nickel P, Lackner H, Schrappe M, Janka G, Beck JD, Langer T	Almost normal cognitive function in patients during therapy for childhood acute lymphoblastic leukemia without cranial irradiation according to ALL-BFM 95 and COALL 06-97 protocols: results of an Austrian-German multicenter longitudinal study and implications for follow-up.	Pediatric hematology and oncology 2007, 24: 101
In a multicenter study the authors prospectively investigated neurocognitive function in childhood ALL patients. Sixty-six patients (mean age at diagnosis 7.9 +/- 3.6 years, 34 female), treated with repeated intrathecal and systemical methotrexate administrations without cranial irradiation, underwent psychometric testing for intelligence, concentration, and visual-motor integration postdiagnosis and after reinduction therapy. Although there was a statistically significant decline of intellectual function after reinduction therapy for younger patients and girls (IQ scores still within normative data range), there were no differences in visual-motor performance and concentration over the time of induction therapy. Thus, neurocognitive examination should focus on younger ALL patients and girls.
Kramm C, Wolff JEA	Hochgradig maligne Gliome und Ponsgliome im Kindes- und Jugendalter.	Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Deutschen Gesellschaft für Pädiatrische Onkologie und Hämatologie 2008
Kramm C, Rausche U, Butenhoff S, Kühnöl C, Kunze C, Kortmann R, Wolff J, van Gool S	Hochmaligne Gliome im Kindes- und Jugendalter.	Monatsschr Kinderheilkd 2008, 156: 1201
Kramm C	Die HIT-HGG-Studiengruppe - Beratung und Protokolle für alle Behandlungssituationen bei hochmalignen Gliomen im Kindes- und Jugendalter.	WiR - die Zeitschrift der Deutschen Leukämie-Forschungshilfe e.V. und der Deutschen Kinderkrebsstiftung 1/2010
Kramm CM, Butenhoff S, Rausche U, Warmuth-Metz M, Kortmann RD, Pietsch T, Gnekow A, Jorch N, Janssen G, Berthold F, Wolff JE	Thalamic high-grade gliomas in children: a distinct clinical subset?	Neuro Oncol 2011, 13: 680
Pediatric high-grade gliomas (HGGs) of the thalamic region account for up to 13% of pediatric HGGs and usually result in only anecdotal long-term survival. Because very little is known about these tumors, we aimed to further characterize them. In our series of 99 pediatric thalamic HGGs, there were no significant differences in survival between patients with tumors affecting the thalamus alone (including bithalamic lesions) and patients with tumors affecting the thalamus plus adjacent structures. Tumor resection (event-free survival/overall survival) and an early treatment response to radiotherapy/chemotherapy (event-free survival) had independent prognostic significance, as shown by Kaplan-Meier and multivariate Cox regression analyses. When we compared clinical characteristics and outcomes of pediatric thalamic HGG with those of pediatric (nonthalamic) supratentorial (n = 177) as well as pediatric pontine HGG (including diffuse intrinsic pontine gliomas; n = 234), we found that thalamic HGG shared more similarities with pontine than with supratentorial HGG, but overall, it appeared to represent a clinically distinct subgroup of pediatric HGG. The varying extent of tumor resection in the different tumor localizations may play some role in the observed clinical differences, as shown by multivariate Cox regression analyses, but the tumor site itself was also identified as an independent prognostic parameter. Thus, an additional location-specific effect on survival and/or tumor biology, despite different neurosurgical accessibility, has to be considered. Therefore, future investigations should try to further characterize the obviously site-specific heterogeneity of pediatric HGG on a molecular genetic basis.
Krawczuk-Rybak M, Płonowski M, Solarz E, Sega-Pondel D, Kazanowska B, Zelazowska-Rutkowska B, Wysocka J	Assessment of gonadal function in boys and adolescents at the diagnosis of neoplastic disease.	Journal of pediatric endocrinology & metabolism : JPEM 2012, 25(5-6): 453
We assessed the gonadal function in boys with a newly diagnosed neoplastic disease prior to chemotherapy. Eighty-four boys (48 prepubertal and 36 pubertal) were evaluated, including 50 with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL), 10 with Hodgkin lymphoma (HL), and 24 with solid tumors. The control group consisted of 24 healthy prepubertal and 24 pubertal boys. The levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), inhibin B, and testosterone were determined, and testicular volumes were measured.
Kramm C	Die neue HIT-HGG-2013-Studie.	WIR - Zeitschrift der Deutschen Kinderkrebsstiftung und der Deutschen Leukämie-Forschungshilfe e.V 3/17
Kramm C, Benesch M	Gliome mit hoher Malignität und diffus intrinsische Ponsgliome.	in: Niemeyer C, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie. Springer-Verlag GmbH Deutschland, 2. vollständig überarbeitete Auflage 2018, 388
Kremens B, Klingebiel T, Herrmann F, Bender-Gotze C, Burdach S, Ebell W, Friedrich W, Koscielniak E, Schmid H, Siegert W,	High-dose consolidation with local radiation and bone marrow rescue in patients with advanced neuroblastoma.	Med Pediatr Oncol 1994, 23: 470
Kremens B, Gruhn B, Klingebiel T, Hasan C, Laws H, Koscielniak E, Hero B, Selle B, Niemeyer C, Finckenstein F, Schulz A, Wawer A, Zintl F, Graf N	High-dose chemotherapy with autologous stem cell rescue in children with nephroblastoma.	Bone Marrow Transplant 2002, 30: 893
Kremens B, Hero B, Esser J, Weinel P, Filger-Brillinger J, Fleischhack G, Graf N, Gruttner H, Niemeyer C, Schulz A, Wickmann L, Berthold F	Ocular symptoms in children treated with human-mouse chimeric anti-GD2 mAb ch14. 18 for neuroblastoma.	Cancer Immunol Immunother 2002, 51: 107
Kremens B, Wieland R, Reinhard H, Neubert D, Beck JD, Klingebiel T, Bornfeld N, Havers W	High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma.	Bone marrow transplantation 2003, 31: 281
Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.
Kreuter M, Bieker R, Bielack SS, Auras T, Buerger H, Gosheger G, Jürgens H, Berdel WE, Mesters RM	Prognostic relevance of increased angiogenesis in osteosarcoma.	Clinical cancer research : an official journal of the American Association for Cancer Research 2004, 10: 8531
PURPOSE: The purpose of this work was to evaluate the prognostic relevance of microvessel density (MVD) for response to chemotherapy and long-term outcome in osteosarcoma. EXPERIMENTAL DESIGN: Pretherapeutic tumor biopsies of 60 patients with high-grade central osteosarcoma, who were treated according to multimodal neoadjuvant protocols of the German-Austrian-Swiss Cooperative Osteosarcoma Study Group, were evaluated for intratumoral MVD. MVD was correlated with demographic and tumor-related variables, response, and survival. RESULTS: The median intratumoral MVD was 52 microvessels per 0.26-mm2 field area (interquartile range, 31-77 microvessels per 0.26-mm2 field area). At a median follow-up period of 3.5 years, patients with a high (>median) MVD had significantly higher 5- and 10-year overall survival rates (84%) than patients with low (< or =median) MVD (49%; P = 0.0029). Furthermore, increased relapse-free survival for patients with high MVD (P = 0.0064) was observed. In a subgroup analysis of 44 patients with primary high-grade central osteosarcoma of the extremities without primary metastases and good surgical remission, high MVD was associated with 5- and 10-year overall survival rates of 91% compared with 58% for low MVD (P = 0.034). Cox regression analysis revealed that MVD was an independent prognostic factor for survival. A good response to chemotherapy (histologic grading scale of Salzer-Kuntschik) correlated significantly with a high MVD (P = 0.006). CONCLUSIONS: Increased angiogenesis is a prognostic indicator for higher survival and response rates to chemotherapy in patients with osteosarcoma. Thus, measurement of MVD might be useful in decisions selecting patients for future neoadjuvant treatment.
Kreicbergs U, Valdimarsdóttir U, Steineck G, Henter JI	A population-based nationwide study of parents' perceptions of a questionnaire on their child's death due to cancer.	Lancet (London, England) 2004 Aug 28-Sep 3; 364: 787
A proposed nationwide postal questionnaire to Swedish parents who had lost a child due to cancer between 1992 and 1997 was denied approval by the local ethics committee. However, a pilot study to assess the harm and benefit of the questionnaire was approved. 95% of parents found the pilot study valuable; thus, we were allowed to proceed with the main study, which consisted of 129 questions about the child's care and death and five about the parents' perceptions of the study. 423 (99%) parents found the investigation valuable, 285 (68%) were positively affected, and 123 (28%) were negatively affected (10 [2%] of whom, very much). Although the numerical data cannot be directly translated to ethical conclusions, they can provide guidance for future ethical decisions.
Kreuter M, Paulussen M, Boeckeler J, Gerss J, Buerger H, Liebscher C, Kessler T, Jürgens H, Berdel WE, Mesters RM	Clinical significance of Vascular Endothelial Growth Factor-A expression in Ewing's sarcoma.	European journal of cancer (Oxford, England : 1990) 2006, 42: 1904
The aim of our study was to gain further insight into the role of angiogenesis in Ewing's sarcoma. To this end, expression of Vascular Endothelial Growth Factor-A (VEGF-A), its receptors VEGFR-1 and -2 and microvessel density (MVD) were evaluated by quantitative immunohistochemistry in pretherapeutic biopsies of 40 patients with Ewing's sarcoma treated within standardised neoadjuvant protocols. Median expression levels were 1.5 arbitrary units (AU) for VEGF-A, 8.2 AU for VEGFR-2 and median MVD was 96/0.26 mm(2). VEGFR-1 was expressed in 12.5% of the samples, only. Ten-year relapse free and overall survival rates were significantly higher for patients with high VEGF-A expression (60% versus 29%, p=0.0216 and 65% versus 25%, p=0.013, respectively). Multivariate Cox regression analysis revealed that VEGF-A expression was an independent prognostic factor for survival. In conclusion, these data suggest that the angiogenic mediator VEGF plays an important prognostic role in Ewing's sarcoma.
Krentz S, Hof J, Mendioroz A, Vaggopoulou R, Dörge P, Lottaz C, Engelmann JC, Groeneveld TW, Körner G, Seeger K, Hagemeier C, Henze G, Eckert C, von Stackelberg A, Kirschner-Schwabe R	Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.	Leukemia 2013, 27: 295
Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.Leukemia advance online publication, 3 July 2012; doi:10.1038/leu.2012.155.
Kreuz W, Rusicke E, Martinez-Saguer I, Aygören-Pürsün E, Heller C, Klingebiel T	Home therapy with intravenous human C1-inhibitor in children and adolescents with hereditary angioedema.	Transfusion 2012, 52: 100
C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE).
Kreitler S, Weyl Ben- Arush M, Martin A (eds)	Pediatric Psycho-oncology. Psychosocial Aspects and Clinical Intervention.	Wiley-Blackwell Oxford Second Edition 2012
Krentz S, Hof J, Mendioroz A, Vaggopoulou R, Dörge P, Lottaz C, Engelmann JC, Groeneveld TW, Körner G, Seeger K, Hagemeier C, Henze G, Eckert C, von Stackelberg A, Kirschner-Schwabe R	Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.	Leukemia 2013, 27: 295
Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.
Krell PF, Reuther S, Fischer U, Keller T, Weber S, Gombert M, Schuster FR, Asang C, Stepensky P, Strahm B, Meisel R, Stoye J, Borkhardt A	Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a beta chain CDR3 sequence associated with hepatitis-induced pathogenesis.	Haematologica 2013, Epub ahead of print
Current diagnostic approaches that characterize T-cell deficiency by analyzing diversity of T-cell receptor sequences effectuate limited informational gain about the actual restrictiveness. For deeper insight into T-cell receptor repertoires we developed next-generation-sequencing-spectratyping, which employs high coverage Roche/454 sequencing of T-cell receptor β-chain amplicons. For automated analysis of high-throughput-sequencing data, we developed a freely available software, the TCR profiler. Gene usage, length, encoded amino acid sequence and sequence diversity of the complementarity determining region 3 were determined and comprehensively integrated into a novel complexity score. Repertoires of CD8+ T-cells from children with idiopathic or hepatitis-induced very severe aplastic anemia (n=7), children two months after bone marrow transplantation (n=7) and healthy controls (children n=5, adults n=5) were analyzed. Complexity scores clearly distinguished between healthy and diseased, and even between different immune deficiency states. The repertoire of aplastic anemia patients was dominated by public (i.e. present in more than one person) T-cell receptor clonotypes, whereas only 0.2% or 1.9% were public in normal children and adults, respectively. The CDR3 sequence ASSGVGFSGANVLT was highly prevalent in three cases of hepatitis-induced anemia (15-32% of all sequences), but was only low expressed in idiopathic aplastic anemia (2-5%, n=4) or healthy controls (<1%). 15 high frequent sequences were present exclusively in aplastic anemia patients. Next-generation-sequencing-spectratyping allows in-depth analysis of T-cell receptor repertoires and their restriction in clinical samples. A dominating clonotype was identified in hepatitis-induced anemia that may be associated with disease pathogenesis and several aplastic-anemia-associated, putatively autoreactive clonotypes were sequenced.
Kremeike K, Juergens C, Alz H, Reinhardt D	Patients' Adherence in the Maintenance Therapy of Children and Adolescents with Acute Lymphoblastic Leukemia.	Klin Pädiatr 2015, 227(6-07): 329
Background: Acute lymphoblastic leukemia (ALL) is the most common form of paediatric cancer. Maintenance therapy as last treatment phase includes oral chemotherapy with methotrexate (MTX) and mercaptopurine (6-MP), self- or parent-administered at home, given for about 1 ½ years, and qualified as decisive for an optimum therapy outcome. The aim of our study was to analyze factors influencing the adherence of patients with ALL undergoing maintenance therapy and their families. Methods: A multi-method study was undertaken between 11/2011 and 10/2014 with patients surveyed by the Hannover Medical School outpatient clinic, including a questionnaire survey and qualitative interviews with parents as well as blood samples of the patients. Results: 33 questionnaires, 27 interviews and blood samples of 26 patients could be analyzed. Only one third of the blood samples showed concentrations of the 6-MP active metabolite within the therapeutic reference range. Parents named the clinical doctor as their main advisor on medication intake. 36% (12/33) of the participants stated that medication intake has not always occurred the way medication was prescribed. Drug formulation and drug intake information could be identified as determinants of adherence. Parents' problems to obtain information are partly caused by different study results concerning the correct timing of the drug intake and drug interactions with milk products. Conclusion: Parents' information on drug therapy should be more consistent and the pharmaceutical formulations have to be adapted to patients' needs to improve adherence and thereby the chance of long-term remission.
Kreyer J, Ranft A, Timmermann B, Jürgens H, Jung S, Wiebe K, Boelling T, Schuck A, Vieth V, Streitbuerger A, Hardes J, Heinemann M, Dirksen U	Impact of the Interdisciplinary Tumor Board of the Cooperative Ewing Sarcoma Study Group on local therapy and overall survival of Ewing sarcoma patients after induction therapy.	Pediatric blood & cancer 2018, 65:e27384
The Interdisciplinary Tumor Board (ITB) of the Cooperative Ewing Sarcoma Study (CESS) Group was investigated to assess its impact on the overall survival (OAS) of Ewing sarcoma (EwS) patients. The ITB functions as a reference center for the international institutions participating in the clinical trials of the CESS group, but is also available internationally to patients who have not been treated within an appropriate clinical trial. The value of tumor boards in terms of benefit for the patients and the health care system in general is not well documented and is also the subject of controversial discussions. A review of the representative literature is included.
Kreitz K, Ernst A, Schmidt R, Simon T, Fischer M, Volland R, Hero B, Berthold F	A new risk score for patients after first recurrence of stage 4 neuroblastoma aged ≥18 months at first diagnosis.	Cancer medicine 2019 Oct 20;
The prognosis of patients with recurrences from stage 4 neuroblastoma is not uniformly dismal. The evaluation of new therapies therefore needs to consider the individual risks of the treated patients. This study aims to define clinically useful risk criteria.
Krewer J, Rolle U, Koscielniak E, Vokuhl C, Mentzel T, Seitz G, Feuchtgruber S, von Kalle T, Scheer M, Münter M, Bielack SS, Fuchs J, Niggli F, Hettmer S, Klingebiel T, Sparber-Sauer M, CWS Study Group	Dermatofibrosarcoma protuberans in children and adolescents: Primary and Relapsed disease-Experience of the Cooperative Weichteilsarkomstudiengruppe (CWS).	Journal of surgical oncology 2020, 122: 263
Dermatofibrosarcoma protuberans (DFSP) is a rare low-grade tumor. Little is known about best treatment of primary and relapsed disease (RD).
Kresbach C, Dorostkar MM, Suwala AK, Wefers AK, Schweizer L, Engertsberger L, Bison B, Mynarek M, Kloth-Stachnau K, Spohn M, von Deimling A, Benesch M, Hagel C, Mautner VF, Rutkowski S, Schüller U	Neurofibromatosis type 2 predisposes to ependymomas of various localization, histology, and molecular subtype.	Acta neuropathologica 2021, 141: 971
Krieger D, Moericke A, Oschlies I, Zimmermann M, Schrappe M, Reiter A, Burkhardt B	Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia.	Haematologica 2010, 95: 158
Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.
Krishnamurti L	Should young children with sickle cell disease and an available human leukocyte antigen identical sibling donor be offered hematopoietic cell transplantation?	Hematol Oncol Stem Cell Ther 2020 Mar 12; ePub
Availability of an HLA-identical sibling donor raises the question,
Hrsg: Kroll T, Petermann F, Wiedebusch S	Schmerz im Kindesalter: Verhaltensmedizinische Grundlagen und Anwendungen.	1994
Kroll M, Kaupat-Bleckmann K, Moerickel A, Altenl J, Schewel DM, Stanullal M, Zimmermann M, Schrappe M, Cario G	Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen.	Haematologica 2020, 105: 1013
Children with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) often suffer from severe toxicities during treatment, especially with high-dose methotrexate (HD-MTX). Systematic data on methotrexate (MTX) toxicity in these patients are rare. We analyzed seven MTX-associated toxicities during consolidation therapy in 103 DS- and 1,109 non-DS-patients (NDS) with ALL (NDS-ALL) enrolled in ALL-Berlin-Frankfurt-MÃÂ¼nster (ALL-BFM) trials between 1995-2016 and 1995-2007, respectively. Patients received four courses MTX (5 g/m each) plus intrathecal MTX and 6-mercaptopurine (6-MP). From 2004 onwards, a dose of 0.5 g/m in the first MTX course has been recommended for DS-patients. DS-patients showed higher rates of grade 3/4 toxicities after the first course with 5 g/m MTX compared to NDS-patients (grade 3/4 toxicities 62 in 45 DS-patients 516 in 1,089 NDS-patients, <0.001). The dose reduction (0.5 g/m) in DS-patients has reduced toxicity (39 in 51 patients, <0.001) without increasing the relapse risk (reduced dose, 5-year cumulative relapse incidence = 0.09ÃÂ±0.04 high dose, 0.10ÃÂ±0.05, =0.51). MTX dose escalation to 1.0 g/m for DS-patients who tolerated 0.5 g/m (n= 28 of 51 patients) did not result in an increased rate of grade 3/4 toxicities after the second course (=0.285). Differences in MTX plasma levels at 42 and 48 hours after the start of the first methotrexate infusion did not explain higher toxicity rates in DS-patients treated with 0.5 g/m compared to NDS-patients treated with 5 g/m Within the DS cohort a higher MTX plasma level was associated with increased toxicity. In conclusion, dose reduction in the first MTX course reduced severe toxicities without increasing the risk of relapse. ().
Krull KR, Sabin ND, Reddick WE, Zhu L, Armstrong GT, Green DM, Arevalo AR, Krasin MJ, Srivastava DK, Robison LL, Hudson MM	Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012 Oct 10; 30: 3618
Krull K, Kunstreich M, Bronsema A, Bleckmann K, Classen CF, Erdlenbruch B, Jorch N, Kolb R, Leipold A, Moser O, Prokop A, Scheurlen W, Steinbach D, Klasen-Sansone J, Klee D, Escherich G, Moericke A, Schrappe M, Borkhardt A, Kuhlen M	Osteonecrosis in children with acute lymphoblastic leukemia at initial diagnosis and prior to any chemotherapy.	Leukemia & lymphoma 2019, 60: 78
steonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.
Krzyzankova M, Mertsch S, Koos B, Jeibmann A, Kruse A, Kordes U, Frühwald MC, Wolff JE, Paulus W, Hasselblatt M	Loss of TP53 expression in immortalized choroid plexus epithelial cells results in increased resistance to anticancer agents.	Journal of neuro-oncology 2012, 109: 449
Choroid plexus carcinomas are malignant brain tumors predominantly arising in young children. Because a prognostic role of p53 alterations has been demonstrated, further research into potential underlying mechanisms is essential. Our objective was, therefore, to investigate the role of p53 in the growth-inhibitory potential of a variety of anticancer agents in the rodent choroid plexus epithelial cell line Z310. Furthermore, association of p53 alterations with proliferative activity (Ki67/MIB1) in choroid plexus carcinoma samples (N = 20) was examined by use of immunohistochemistry. Silencing of TP53 expression did not significantly alter metabolic activity in Z310 cells and p53 protein expression status was not associated with increased proliferative activity in choroid plexus carcinomas. However, the growth-inhibitory activity of vincristine, doxorubicin, carboplatin, etoposide, and temozolomide was significantly impaired by silencing of TP53. In conclusion, these results indicate a potential predictive role of p53 in choroid plexus carcinomas. Alterations of p53 should be taken into account when evaluating the effect of anticancer agents in future clinical trials.
Krümpelmann S, Tillmann B, Schulze-Westhoff P, Jürgens H, Boos J	Comparison of oral vs. intravenous etoposide.	Med Pediatr Oncol 1996, 27
Kuçi S, Rettinger E, Voss B, Weber G, Stais M, Kreyenberg H, Willasch A, Kuçi Z, Koscielniak E, Klöss S, von Laer D, Klingebiel T, Bader P	Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells: implications for adoptive immunotherapy after allogeneic stem cell transplantation.	Haematologica 95: 1579
BACKGROUND: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved. DESIGN AND METHODS: Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay. RESULTS: Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRalphabeta molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential. CONCLUSIONS: Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation.
Kühl J	Chemotherapy of brain tumors in childhood. Review of the literature and pilot protocol.	Klin Pädiatr 1988, 200: 214
Kühl J, Rating D, Berthold F, Graf N, Maass E, Gnekow A, Weinl P, Göbel U, Havers W, Lakomek M, Gutjahr P, Urban Ch, Bamberg M, Bode U, Kaatsch P, Kleihues P, Niethammer D, Sörensen N	Ergebnisse der multizentrischen Chemotherapiepilotstudie HIT '88/'89.	Aktuelle Neuropädiatrie 1991 1992, 176
Kühl J, Berthold M, Bode U, Bucsky P, Graf N, Gnekow A, Maass E, Bamberg M, Kaatsch P, Kleihues P, Rating D, Riehm H, Sörensen N	Preradiation chemotherapy of children with poor-prognosis medulloblastoma:response rate and toxicity of the ifosfamide-containing multidrug regimen HIT 88/89.	The Am J Pediatr Hematol Oncol 1993, 15: 67
Kühl J	Interdisziplinäre Behandlung von Medulloblastom und PNET.	Klinische Onkologie 94/95 (Sonderband der Schweizer Rundschau für Medizin) 1994, 16
Kühl J	Ergebnisse der Pädiatrischen Neuro-Onkologie III, Berichte von der Tagung der Arbeitsgruppe für Hirntumoren im Kindesalter der Gesellschaft für Pädiatrische Onkologie und Hämatologie und der Gesellschaft für Neuropädiatrie am 13./14. Juni 1997 in Würzburg.	GPOH 1997
Kühne T, Freedman J, Semple JW, Doyle J, Butchart S, Blanchette VS	Platelet and immune responses to oral cyclic dexamethasone therapy in childhood chronic immune thrombocytopenic purpura.	The Journal of pediatrics 1997, 130: 17
To examine the effectiveness of cyclic oral high-dose (HD) dexamethasone therapy in pediatric patients with chronic immune thrombocytopenic purpura (ITP), which has been reported to cause complete remission in adults with chronic ITP.
Kühl J	Modern treatment strategies in medulloblastoma.	Childs Nerv Syst 1998, 14: 2
Kühl J, Muller H, Berthold F, Kortmann R, Deinlein F, Maass E, Graf N, Gnekow A, Scheurlen W, Göbel U, Wolff J, Bamberg M, Kaatsch P, Kleihues P, Rating D, Sörensen N, Wiestler O	Preradiation chemotherapy of children and young adults with malignant brain tumors.	Klin Pädiatr 1998, 210: 227
Kühl J, Kortmann R, Pietsch T, Sörensen N, Warmuth-Metz M	Medulloblastom.	Hämatologie und Onkologie - ODIN-Kompendium Hannover 2000,Onkologisch-hämatologisches Daten- und Informationsnetz, Berlin: HOS-multimedica Health Online Service
Kühl J	Therapie von Kindern mit einem Medulloblastom.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2001, 4: 8
Kühne T, Imbach P, Bolton-Maggs PH, Berchtold W, Blanchette V, Buchanan GR, Intercontinental Childhood ITP Study Group	Newly diagnosed idiopathic thrombocytopenic purpura in childhood: an observational study.	Lancet 2001, 358: 2122
Diagnosis and management of idiopathic thrombocytopenic purpura (ITP) have been based primarily on expert opinion and practice guidelines rather than on evidence. We have used a registry to prospectively survey the presenting features and the diagnostic evaluation and management practices used for children with ITP worldwide.
Kühl J, Korinthenberg R	ZNS-Tumoren. In: Gadner H, Gaedicke G, Niemeyer CH, Ritter J (Hrsg.): Pädiatrische Hämatologie und Onkologie.	Springer-Verlag 2006, 777
Küper M, Timmann D	Cerebellar mutism.	Brain and language 2013, 127: 327
Cerebellar mutism occurs in about 25% of children following posterior fossa tumor surgery. It is usually accompanied by other neurological and behavioral disturbances. Mutism is transient in nature lasting several days to months and is frequently followed by dysarthria. In addition, impairment of language and other neuropsychological functions can be found after long term follow up in the majority of patients. The pathophysiological background of mutism may be higher speech dysfunction mediated by crossed cerebello-cerebral diaschisis which is frequently found during the mute period. Foremost injury to the bilateral dentatothalamocortical tract appears to be critical for the development of cerebello-cerebral diaschisis and subsequent mutism. Direct cerebellar injury is the likely reason for persisting deficits after the mute period. Minimization of injury to the dentatothalamocortical tract during surgery may be promising in the prevention of mutism. While there is no established treatment of mutism, early speech and rehabilitation therapy is recommended.
Künkele A, Wilm J, Holdt M, Lohmann D, Bornfeld N, Eggert A, Temming P, Schulte JH	Neoadjuvant/adjuvant treatment of high-risk retinoblastoma: a report from the German Retinoblastoma Referral Centre.	The British journal of ophthalmology 2015,Epub ahead of print
Retinoblastoma can extend beyond the structures of the eye, where cells can enter the bloodstream and cause metastases. Various types of protocols for adjuvant treatment risk-adapted according to histopathological risk factors are used worldwide.
Kuhlen M, Bader P, Sauer M, Albert MH, Gruhn B, Güngür T, Kropshofer G, Lang P, Lawitschka A, Metzler M, Pentek F, Rossig C, Schlegel PG, Schrappe M, Schrum J, Schulz A, Schwinger W, von Stackelberg A, Strahm B, Suttorp M, Luettichau IT, Wössmann W, Borkhardt A, Meisel R, Poetschger U, Glogova E, Peters C	Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial.	British journal of haematology 2018, 183: 104
Kuhlen M, Willasch AM, Dalle JH, Wachowiak J, Yaniv I, Ifversen M, Sedlacek P, Guengoer T, Lang P, Bader P, Sufliarska S, Balduzzi A, Strahm B, von Luettichau I, Hoell JI, Borkhardt A, Klingebiel T, Schrappe M, von Stackelberg A, Glogova E, Poetschger U, Meisel R, Peters C	Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL-SCT 2003/2007 trial.	British journal of haematology 2018, 180: 82
Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.
Kuhlen M, Wieczorek D, Siebert R, Frühwald MC	How I approach hereditary cancer predisposition in a child with cancer.	Pediatric blood & cancer 2019, 66:e27916
Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.
Kulozik A	Hemoglobin variants and the rarer hemoglobin disorders.	In: Lilleyman JS, Hann IM, Blanchette VS (Hrsg.): Pediatric hematology, 2nd ed 1999, p. 231.256
Kulozik, AE	Hemoglobin variants and the rarer hemoglobin disorders.	In: Pediatric Hematology, 3rd Edition,Robert J. Arceci (Editor), Ian M. Hann (Editor), Owen P. Smith (Editor), A. Victor Hoffbrand ( 2006
Kulozik, AE	Thalassämien.	In: Gadner, H, Gaedicke, G, Niemeyer, C, Ritter, J (Hrsg.): Pädiatrische Hämatologie und Onkologie, Springer Medizin Verlag 2006
Kulozik AE, Kunz J	Anämiediagnostik im Kindesalter.	AWMF Leitlinien
Für eine rationale und rationelle Diagnostik sind Häufigkeit der Erkrankungen, Bedeutung einer raschen Diagnosestellung und Vermeidung unnötiger Untersuchungen wesentliche Gesichtspunkte. Der abgebildete Algorithmus soll in der klinischen Situation "Kind mit Anämie" helfen, die zugrunde liegende Störung systematisch und schrittweise zu identifizieren und damit eine ungezielte und/oder teure Globaldiagnostik vermeiden. Es muss jedoch betont werden, dass diese Leitlinie ausführlichere Informationsquellen nicht ersetzen will oder kann.
Kulozik E	Hämoglobinopathien nehmen zu.	Dtsch Arztebl Int 2010; 107: 63
Kulozik AE, Kunz J	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie. Anämiediagnostik im Kindesalter.	AWMF online 2012
Kulkarni AV, Piscione J, Shams I, Bouffet E	Long-term quality of life in children treated for posterior fossa brain tumors.	Journal of neurosurgery. Pediatrics 2013, 12: 235
In the face of increasing survival, quality of life (QOL) has become an important indicator of treatment success in children with posterior fossa brain tumors (PFBTs). The authors' objective was to assess the long-term QOL in survivors of PFBT.
Kun LE, Kovnar EH, Sanford RA	Ependymomas in children.	Pediatr Neurosci 1988, 14: 57-63. Review
Kunz JB, Kulozik AE	Differentialdiagnose der kindlichen Anämie.	Monatsschrift Kinderheilkunde 2012, 4
Kunz JB, Rausch T, Bandapalli OR, Eilers J, Pechanska P, Schuessele S, Assenov Y, Stütz AM, Kirschner-Schwabe R, Hof J, Eckert C, von Stackelberg A, Schrappe M, Stanulla M, Koehler R, Avigad S, Elitzur S, Handgretinger R, Benes V, Weischenfeldt J, Korbel JO, Muckenthaler MU, Kulozik AE	Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.	Haematologica 2015, 100: 1442
Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition.
Kunz J, Kulozik A	Sichelzellkrankheit.	In: Niemeyer C, Eggert A. ed. Pädiatrische Hämatologie und Onkologie Springer; 2018, 65
Kunz J, Kulozik A	Hämolytische Anämien.	In: Niemeyer C, Eggert A. ed. Pädiatrische Hämatologie und Onkologie Springer; 2018, 55
Kunz J, Kulozik A	Makrozytäre Anämien.	In: Niemeyer C, Eggert A. ed. Pädiatrische Hämatologie und Onkologie Springer; 2018 54
Kunz JB, Lobitz S, Grosse R, Oevermann L, Hakimeh D, Jarisch A, Cario H, Beier R, Schenk D, Schneider D, Groß-Wieltsch U, Prokop A, Heine S, Khurana C, Erlacher M, Dürken M, Linke C, Frühwald M, Corbacioglu S, Claviez A, Metzler M, Ebinger M, Full H, Wiesel T, Eberl W, Reinhard H, Tagliaferri L, Allard P, Karapanagiotou-Schenkel I, Rother LM, Beck D, Le Cornet L, Kulozik AE, German Sickle Cell Disease Registry	Sickle cell disease in Germany: Results from a national registry.	Pediatric blood & cancer 2020, 67:e28130
Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany.
Kuppers R, Klein U, Hansmann ML, Rajewsky K	Cellular origin of human B-cell lymphomas.	N Engl J Med 1999, 341: 1520
Kurowski C, Berthold F	Presence of classical multidrug resistance and P-glycoprotein expression in human neuroblastoma cells.	Ann Oncol 1998, 9: 1009
Kurth A, Kreuz W, Scharrer I	Die orthopädische Behandlung von muskulo-skelettalen Komplikationen der Hämophilie.	Dtsch Ärztebl 2002, 99: A 2928
Die Gelenkprobleme von Blutern beginnen schon im Säuglings- und Krabbelalter, wenn kleine Verletzungen zu Gelenkeinblutungen führen. Der frühe Beginn einer regelmäßigen Prophylaxe ist von größter Bedeutung, da das wachsende Skelett sehr anfällig für Blutungen und deren Komplikationen ist. Schwerwiegende strukturelle Defizite können sich schnell entwickeln. Wenn eine regelmäßige Prophylaxe nicht durchgeführt werden kann, muss eine konsequente Therapie bei akuten Gelenkeinblutungen erfolgen, um wiederkehrende Einblutungen, ein Fortschreiten der Synovitis, und eine hämophile Arthropathie zu verhindern. Beim Auftreten einer Synovitis muss diese so früh und konsequent wie möglich behandelt werden. Dafür stehen zurzeit konservative und operative Verfahren zur Verfügung. Zwischen der zweiten und vierten Lebensdekade entwickeln sich bei vielen Blutern ausgeprägte Gelenkzerstörungen. In dieser Situation beinhaltet die Therapie Korrekturosteotomien, Gelenkdebridement, Gelenkversteifung und Gelenkersatz. Diese sind heute durch eine konsequente Substitutionstherapie des fehlenden Gerinnungsfaktors mit einer großen Sicherheit erfolgreich durchführbar.
Kurnik K, Bidlingmaier C, Olivieri M	Hämostaseologie in der Pädiatrie.	Hämostaseologie 2016, 36: 109
Kurz L, Miklyaeva A, Skowron MA, Overbeck N, Poschmann G, Becker T, Eul K, Kurz T, Schönberger S, Calaminus G, Stühler K, Dykhuizen E, Albers P, Nettersheim D	ARID1A Regulates Transcription and the Epigenetic Landscape via POLE and DMAP1 while ARID1A Deficiency or Pharmacological Inhibition Sensitizes Germ Cell Tumor Cells to ATR Inhibition.	Cancers 2020, 12
Germ cell tumors (GCTs) are the most common solid malignancies found in young men. Although they generally have high cure rates, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin. Additionally, the loss-of-function mutations re-sensitize different tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated -deficient GCT cells and demonstrate by mass spectrometry that is putatively involved in regulating transcription, DNA repair and the epigenetic landscape via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, deficiency or pharmacological inhibition increased the efficacy of romidepsin and considerably sensitized GCT cells, including cisplatin-resistant subclones, towards ATR inhibition. Thus, targeting ARID1A in combination with romidepsin and ATR inhibitors presents as a new putative option to treat GCTs.
Kurch L, Mauz-Körholz C, Fosså A, Georgi TW, Kluge R, Bartelt JM, Kunze C, Wohlgemuth WA, Pelz T, Vordermark D, Plößl S, Hasenclever D, Sabri O, Landman-Parker J, Wallace WH, Karlen J, Fernández-Teijeiro A, Cepelova M, Klekawka T, Løndalen AM, Steiner D, Krombach G, Attarbaschi A, Hoffmann M, Ceppi F, Pears J, Hraskova A, Uyttebroeck A, Beishuizen A, Dieckmann K, Leblanc T, Daw S, Körholz D, Stoevesandt D	Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.	Pediatric blood & cancer 2021, 68:e28903
In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging.
Kusch M, Labouvie H, Langer T, Winkler von Mohrenfels U, Topf R, Felder-Puig R, Beck J, Gadner H, Bode U	Psychosoziale Folgen von Krebs im Kindes- und Jugendalter.	Versorgungsmanagement in Theorie und Praxis 1999, 4: 1
Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M, Giampietro PF, Hanenberg H, Auerbach AD	A 20-year perspective on the International Fanconi Anemia Registry (IFAR).	Blood 2003, 101: 1249
Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA cross-linking agents and cancer predisposition. Recent evidence for the interactions of ataxia-telangiectasia mutated protein ATM and breast cancer susceptibility proteins BRCA1 and BRCA2 (identified as FANCD1) with other known FA proteins suggests that FA proteins have a significant role in DNA repair/recombination and cell cycle control. The International Fanconi Anemia Registry (IFAR), a prospectively collected database of FA patients, allows us the unique opportunity to analyze the natural history of this rare, clinically heterogeneous disorder in a large number of patients. Of the 754 subjects in this study, 601 (80%) experienced the onset of bone marrow failure (BMF), and 173 (23%) had a total of 199 neoplasms. Of these neoplasms, 120 (60%) were hematologic and 79 (40%) were nonhematologic. The risk of developing BMF and hematologic and nonhematologic neoplasms increased with advancing age with a 90%, 33%, and 28% cumulative incidence, respectively, by 40 years of age. Univariate analysis revealed a significantly earlier onset of BMF and poorer survival for complementation group C compared with groups A and G; however, there was no significant difference in the time to hematologic or nonhematologic neoplasm development between these groups. Multivariate analysis of overall survival time shows that FANCC mutations (P =.007) and hematopoietic stem cell transplantation (P = <.0001) define a poor-risk subgroup. The results of this study of patients registered in the IFAR over a 20-year period provide information that will enable better prediction of outcome and aid clinicians with decisions regarding major therapeutic modalities.
Köller U, Haas O, Ludwig W, Bartram C, Harbott J, Panzer-Grümayer R, Hansen-Hagge T, Ritter J, Creutzig U, Knapp W, Gadner H	Phenotypic and genotypic heterogeneity in infant acute leukemia II. Acute non-lymphoblastic leukemia.	Leukemia 1989, 3: 708
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