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Autor(en)	Titel	Quelle
Cairo MS, Gerrard M, Sposto R, Auperin A, Pinkerton CR, Michon J, Weston C, Perkins SL, Raphael M, McCarthy K, Patte C, FAB LMB96 International Study Committee	Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents.	Blood 2007, 109: 2736
Cairo MS, Coiffier B, Reiter A, Younes A, TLS Expert Panel	Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.	British journal of haematology 2010, 149: 578
Tumour lysis syndrome (TLS) is a life-threatening oncological emergency characterized by metabolic abnormalities including hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia. These metabolic complications predispose the cancer patient to clinical toxicities including renal insufficiency, cardiac arrhythmias, seizures, neurological complications and potentially sudden death. With the increased availability of newer therapeutic targeted agents, such as rasburicase (recombinant urate oxidase), there are no published guidelines on the risk classification of TLS for individual patients at risk of developing this syndrome. We convened an international TLS expert consensus panel to develop guidelines for a medical decision tree to assign low, intermediate and high risk to patients with cancer at risk for TLS. Risk factors included biological evidence of laboratory TLS (LTLS), proliferation, bulk and stage of malignant tumour and renal impairment and/or involvement at the time of TLS diagnosis. An international TLS consensus expert panel of paediatric and adult oncologists, experts in TLS pathophysiology and experts in TLS prophylaxis and management, developed a final model of low, intermediate and high risk TLS classification and associated TLS prophylaxis recommendations.
Cairo S, Armengol C, Maibach R, Häberle B, Becker K, Carrillo-Reixach J, Guettier C, Vokuhl C, Schmid I, Buendia MA, Branchereau S, von Schweinitz D, Kappler R	A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients.	European journal of cancer (Oxford, England : 1990) 2020, 141: 30
Stratification of hepatoblastoma (HB) patients is based on clinical and imaging characteristics obtained at the time of diagnosis. We aim to integrate biomarkers into a tool that accurately predicts survival of HB patients.
Calaminus G, Vesterling-Hörner D, Bokkerink J, Gadner H, Günther G, Haas H, Jürgens H, Teske C, Göbel U	The prognostic significance of serum alpha 1-fetoprotein in children and adolescents with malignant extracranial non-testicular germ cell tumors.	Klin Pädiatr 1991, 203: 246
Calaminus G, Teske C, Göbel U	Improved prognosis of intracranial germ cell tumors (GCTs), Results of the MAKEI 89 Study. VII European Conference on Clinical Oncology and Cancer Nursing (ECCO).	The European Journal of Cancer 1993, 29A
Calaminus G, Teske C, Göbel U	Chemotherapy associated toxicity in patients with malignant nontesticular germ cell tumors (MNGCT). Comparison of MAKEI 83/86 and MAKEI 89.	Advances in the Bioscience 1994, 91, 67
Calaminus G, Andreussi L, Garré ML, Kortmann RD, Schober R, Göbel U	Secreting germ cell tumors of the central nervous system (CNS). First results of the cooperative German/Italian pilot study (CNS sGCT).	Klinische Padiatrie 1997, 209: 222
BACKGROUND: Secreting germ cell tumors are an invariably fatal subgroup within the malignant pediatric brain tumors. Thus in 1993, an international working group was initiated to establish a cooperative study for diagnostic and treatment of intracranial secreting germ cell tumors of the CNS. To pilot this protocol, since 1994 German and Italian patients are treated in accordance with the established guidelines. METHODS: Regarding to the achieved consensus within the international protocol committee a characteristical diagnostic imaging (CT/MRI scan) of head and spine and a significant increase of tumor markers beta-HCG (> 50 IU/l) and/or AFP (> 25 ng/ml) are defined as sufficient diagnostic criteria. Additionally staging procedures include an initial CSF cytology. Treatment consists of 4 courses PEI: platinum (20 mg/m2 day 1-5), VP16 (100 mg/ m2 day 1-3), and ifosfamide (1.5 g/m2 day 1-5). Surgery of the residual tumor is administered after chemotherapy, if resection is possible, followed by craniospinal irradiation (30 Gy with tumor boost 24 Gy). RESULTS: Until September 96, 19 patients (16 boys and 3 girls) aged 8 to 19 years are registered and have finished their treatment. Seven children are diagnosed by elevated tumor markers. Six of 7 children with stereotactic fine needle biopsy and histology of germinoma have a significant marker increase as a specific characteristic for secreting non-germinomatous germ cell tumors. In 6 patients, the tumor is primarily resected, 2 children are biopsied. In 2 children spinal metastases are diagnosed initially. Tumor marker response is evaluated in 16 children. Thirteen of 16 patients show a clear marker normalization after 2 courses of PEI. One boy with a slight increase of the tumor marker after the 4th course developed an early spinal relapse and died. One girl showed a spinal recurrence during focal radiotherapy. She is still under relapse treatment. A significant decrease of tumor volume after chemotherapy is documented in 10/13 children, who have a definite signal tumor at start of therapy. In 3 children tumor volume does not change despite of marker normalization. Histology of these tumors is teratoma. One of these children died postoperatively because of tumor bleeding. 17/19 patients are alive, 16 of them are in complete remission with a median follow-up of 11 months. CONCLUSION: These results show a further significant increase of event-free survival (EFS 81%). The piloted chemotherapy is proven to be effective and the protocol is now open as an international SIOP CNS GCT study that is started in October 1996.
Calaminus G, Wessalowski R, Harms D, Göbel U	Juvenile granulosa cell tumors of the ovary in children and adolescents: results from 33 patients registered in a prospective cooperative study.	Gynecologic oncology 1997, 65: 447
Clinical and pathological data from 33 prospective registered patients who suffered from juvenile granulosa cell tumors (JGCT) were evaluated according to treatment and outcome. The median age at the time of diagnosis was 7.6 years (range, 6 months to 17.5 years). Fourteen patients showed signs of a pseudo-precocious puberty. In 1 patient premenarcheal bleeding was the only clinical symptom of the disease. A pelvic tumor or an abdominal distention was found in 6 children, revealing signs of an acute abdomen in 3 children. Tumor staging was performed according to the FIGO (International Federation of Gynecology and Obstetrics) classification for ovarian tumors. Twenty children and adolescents were classified as FIGO stage Ia; 8 children had stage Ic tumors. In 4 patients stage IIc and in 1 patient stage IIIc tumors were observed. For local tumor control all 33 patients underwent tumor resection and oophorectomy, which was complete in 28 patients. Adjuvant combination chemotherapy was used in 1 girl who presented with high mitotic pathological index features in FIGO stage Ia. In 8 other children between FIGO stage Ic and IIIc, treatment was also intensified by multidrug chemotherapy. After a follow-up period of 168 months, an event-free survival of 0.75 +/- 0.07 was observed. From our data we conclude that multidrug chemotherapy including cisplatin-based regimens may be useful to enhance treatment results of JGCT, especially in advanced FIGO stages.
Calaminus G, Garre M, Kortmann R, Mann J, Göbel U	CNS germ cell tumors in children. Results of the German MAKEI89 protocols and SIOP CNS GCT 93P/96 study.	Germ Cell Tumors 1998,IV: 247
Calaminus G	Measuring Quality of Life in Children with Cancer.	Med Pediat Oncol 1999, 33
Calaminus G	Health-related quality of life in children with cancer. First results of the PEDQOL Core Questionnaire in German children.	Med Pediatr Oncol 1999, 33
Calaminus G, Haas R, Göbel U	Keimzelltumoren.	Leitlinien der GPOH, in Reinhardt,D , Creutzig,U , Kiess,W , Luthardt,T , Michalk,D , Schmidt,E , Ulmer,H (eds ) Leitlinien Kinderheilkunde und Jugendmedizin München, Jena: Urban & Fischer 1999
Calaminus G, Kiebert G	Studies on health-related Quality of Life in childhood cancer in the European setting.	Int J Cancer 1999, 12: 83
Calaminus G, Bernbeck B, Weinspach S, Wiener A	Spätfolgen bei Kindern und Jugendlichen mit malignen Hirntumoren und ihre Auswirkungen auf die Lebensqualität	Monatsschr Kinderheilkunde 2000, 148
Calaminus G, Langer T, Willich N, Beck J	Lebensqualität und Spätfolgen bei Kindern und Jugendlichen mit Krebserkrankungen.	Der Onkologe 2000, 6: 868
Calaminus G, Weinspach S, Janssen G, Wiener A, Göbel U	Quality of life (QoL) of survivors of medulloblastoma in childhood and adolescence.	Med Pediatr Oncol 2000, 35
Calaminus G, Weinspach S, Teske C, Göbel U	Quality of Life in children and adolescents with cancer.	Klin Pädiatrie 2000, 212: 211
Calaminus G, Weinspach S, Teske C, Göbel U	Quality of life in children and adolescents with cancer. First results of an evaluation of 49 patients with the PEDQOL questionnaire.	Klinische Padiatrie 2000, 212: 211
BACKGROUND: The assessment of Quality of Life (QoL) in childhood cancer survivors is a new field of research, which is important for a better understanding of how children with cancer feel and how treatment can be optimized. The purpose of our examination in a sample of patients treated in our institution was the evaluation of the questions: How do children with cancer reflect on their QoL in comparison to healthy children of the same age? Are there any significant differences in QoL between children with hematological disorders and children with solid tumors and if that is so, which domains are affected? PATIENTS AND METHODS: We used for the evaluation a pilotversion of a self-rating QoL questionnaire for children between 8 and 18 years (PEDQOL), who was developed for pediatric oncology. 49 children off treatment of whom 51% had leukemia/lymphoma and 49% had solid tumors compared to 62 healthy school children were examined. RESULTS: The PEDQOL questionnaire was a good accepted measure among the examined children. The reliability scores of the pilotform for the evaluated domains were also satisfactory (Cronbach's-Alpha > 0.60). In general QoL was scored good by healthy as well as by ill children. In the group of children with leukemia/lymphoma impairment of QoL was more apparent than in children with solid tumors (domains autonomy, emotional functioning, cognition and familial interactions). Survivors of solid tumors reported less impairment of QoL which was mainly seen in physical functioning and body image. CONCLUSION: In general QoL scored with the PEDQOL pilotquestionnaire was good for most of the childhood cancer survivors. Children with solid tumors show less impairment than children with leukemia/lymphoma. Therefore it could be suggested, that young age at diagnosis and the following longer period of being dependent on familial support, the isolation from peer groups and the longer way to become independent may be reflected by these results. To obtain reliable results how children with cancer express their QoL and what consequences illness, treatment and long term effects of therapy have on the childrens' QoL a multicenter prospective study is needed. This will be realized in the near future in a project on
Calaminus G	Lebensqualität bei Kindern und Jugendlichen mit Krebserkrankungen.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2003, 3
Calaminus G, Schneider DT, Bökkerink JP, Gadner H, Harms D, Willers R, Göbel U	Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003, 21: 781
PURPOSE: To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89). PATIENTS AND METHODS: Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed. RESULTS: The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 +/- 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P =.52). CONCLUSION: In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.
Calaminus G	Früher erkennen, ob der Krebs zurückkehrt.	Newsletter Thema Kinder und Jugendliche Gesundheitsforschung: Forschung für den Menschen Hrsg: Bundesministerium für Bildung und Forschung (BMBF) 2004, 7
Calaminus G	Krebskranke Kinder brauchen mehr als Medikamente.	Newsletter Thema Kinder und Jugendliche Gesundheitsforschung: Forschung für den Menschen Hrsg: Bundesministerium für Bildung und Forschung (BMBF) 2004, 7
Calaminus G	Lebensqualität bei Kindern und Jugendlichen mit Hirntumoren.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2004, 2: 6
Calaminus G, Bamberg M, Jürgens H, Kortmann RD, Sörensen N, Wiestler OD, Göbel U	Impact of surgery, chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89.	Klinische Padiatrie 2004, 216: 141
Malignant non-germinomatous intracranial germ cell tumors (MNGGCTs) are a heterogenous group of neoplastic lesions. Their treatment concept follows a multimodal concept that may include tumor resection for local tumor control, craniospinal irradiation to cover leptomenigeal tumor spread and chemotherapy to eliminate systemic tumor dissemination. A Platinum-based chemotherapy proven to be highly effective in testicular and non-testicular malignant germ cell tumors in adults as well as in children has also been chosen for intracranial sites. While therapeutic concepts have been thoroughly evaluated for children and adolescents with extracranial nongonadal GCTs, no such detailed long term follow-up data are available for intracranial MNGGCTs. This paper reports on the long-term outcome of 41 patients with intracranial malignant non-germinomatous GCTs enrolled into the German prospective protocol MAKEI 89. The analysis focuses on the impact of surgery, radio- and chemotherapy. PATIENTS AND METHODS: Between January 1989 and January 1994, 41 patients with malignant intracranial non-germinomatous GCTs were registered. Patients were compared in respect to protocol (n = 27) and non-protocol treatment (n = 14). Estimated were with chi (2) and Fisher exact test the impact of surgery, chemotherapy and irradiation on outcome. RESULTS: The estimated (Kaplan-Meier) 5-year event free survival (EFS) of patients treated according to protocol recommendations was 0.59 +/- 0.06 (n = 27), compared to an EFS of 0.37 +/- 0.33 for patients with different treatments (n = 14) (p = 0.70, log-rank). The 5-year relapse-free survival rate (RFS) was 0.74 +/- 0.06 in protocol patients and 0.38 +/- 0.33 in non-protocol patients (median observation time of 112 months after diagnosis for surviving patients) (p = 0.14, log-rank). Surgery, complete or incomplete had no significant impact on survival (p = 0.12). Radiotherapy, in terms of craniospinal irradiation had a significant influence on survival (p = 0.035) as well as a cumulative cisplatin dose >/= 400 mg/m (2) (p = 0.002). CONCLUSION: Cisplatin chemotherapy and craniospinal irradiation with tumor boost are of significant influence on long term survival in patients with MNGGCTs. The exclusion of major surgery at diagnosis using modern advances in neurosurgery or related tumor resection after neoadjuvant chemotherapy will allow a further reduction of treatment related mortality and long lasting morbidity. The analysis reveals that, given effective treatment, intracranial malignant non-germinomatous GCTs should not longer carry a poor prognosis.
Calaminus G, Bamberg M, Harms D, Jürgens H, Kortmann RD, Sörensen N, Wiestler OD, Göbel U	AFP/beta-HCG secreting CNS germ cell tumors: long-term outcome with respect to initial symptoms and primary tumor resection. Results of the cooperative trial MAKEI 89.	Neuropediatrics 2005, 36: 71
PURPOSE: The aim of the present study was to evaluate survival and factors influencing long-term outcome of patients with AFP/beta-HCG secreting (non-seminomatous) central nervous system germ cell tumors (secCNSGCT), who were prospectively collected in the cooperative MAKEI (German: maligne Keimzelltumoren) 89 protocol. PATIENTS AND METHODS: Between January 1989 and January 1994, 28 patients with secCNS GCT were registered and treated according to the MAKEI 89 protocol. The protocol recommended, after a clinically or histologically proven diagnosis and cisplatin-based chemotherapy, a resection of residual tumor and craniospinal irradiation (30 Gy) with a tumor boost (20 Gy). RESULTS: The estimated (Kaplan-Meier) event-free survival (EFS) of protocol patients is 0.57 +/- 0.09 (n = 28) and the relapse-free survival (RFS) is 0.67 +/- 0.10 (at five and ten years). With respect to long-term survival, the combination of marked neurological symptoms at diagnosis along with primary tumor resection seem to be the main negative prognostic risk factors (Fisher exact test p < 0.05). CNS dissemination at diagnosis can also be considered as a negative risk factor as 3 of 5 patients with primary dissemination died of the disease. CONCLUSION: Cisplatin-based three agent chemotherapy followed by resection of the residual tumor and craniospinal irradiation (CSI) with tumor boost is a successful and well-tolerated treatment for secCNSGCTs. The possibility of a clinical diagnosis based on MRI and tumor markers together with the use of modern neurosurgical techniques gives us the chance to postpone or even avoid major surgery. This gives an additional chance to reduce acute morbidity and further decrease late effects.
Calaminus G, Weinspach S, Teske C, Göbel U	Quality of survival in children and adolescents after treatment for childhood cancer: the influence of reported late effects on health related quality of life.	Klinische Padiatrie 2007 May-Jun; 219: 152
Considering the high survival rates of childhood cancer physical and psychosocial long term effects (LF) as well as the estimation of Quality of Life (QoL) are becoming a new focus of clinical research. Thus, disease related as well as age related variables have to be taken into account. This paper evaluates the physical long term effects of childhood cancer survivors. In addition differences of QoL of the survivors in comparison to children and adolescents of the same age are estimated if present and correlated to somatic late effects.
Calaminus G	Intrakraniale Keimzelltumoren.	Monatsschr Kinderheilkd 2008, 156: 1181–1186
Die histologisch heterogenen Keimzelltumoren des Zentralnervensystems stammen von primordialen totipotenten Keimzellen ab und können eine embryonale oder extraembryonale Entwicklung durchlaufen. Besonderheiten sind der mittellinienorientierte Sitz sowie die Produktion von Tumormarkern. Bei einer Inzidenz von 2,2/106 Kindern/Jahr werden 50% der Tumoren im Jugendalter manifest. Die Anamnese ist je nach Lokalisation unterschiedlich, bei den bevorzugt suprasellär liegenden Germinomen sind Verläufe von mehreren Monaten bis Jahren bekannt, Pinealistumoren werden aufgrund des erhöhten Hirndrucks oft früher diagnostiziert. Etwa 50% der Patienten weisen bei der Diagnose Hormonausfälle als Hinweis auf eine Mitbeteiligung der Hypophyse auf. Bei etwa 1/4 der Patienten liegt eine Disseminierung vor. Die Therapie richtet sich nach Histologie und Ausbreitung und besteht bei sezernierenden Tumoren, embryonalem Karzinom sowie lokalisiertem Germinom aus Chemotherapie und Bestrahlung. Disseminierte Germinome werden nur bestrahlt. Residuales Tumorgewebe nach Chemotherapie bzw. Bestrahlung wird operativ entfernt, eine initiale Resektion maligner Formen bringt keinen Vorteil und erhöht die Morbidität. 2/3 aller betroffenen Kinder und Jugendlichen können geheilt werden. Germ cell tumors (GCT) of the central nervous system (CNS) derive from primordial totipotent germ cells, which are capable of embryonic and extraembryonic differentiation. The specific feature of GCTs is their midline appearance in respect to the embryonic migration of germ cells and their ability to produce tumor markers. With an annual incidence of 2.2/106 in children, 50% of tumors occur during adolescence. Medical history depends on tumor site. In germinoma, which predominantly appear in the suprasellar region, the time to diagnosis can be several months to years. Tumors of the pineal region are diagnosed earlier because of the appearance of raised intracranial pressure. About 50% of patients show hormone failure at diagnosis due to pituitary involvement. Approximately 25% of patients present with tumor spread at diagnosis. Treatment is stratified according to histology and stage. In yolk sac tumors, chorioncarcinoma, embryonal carcinoma and localized germinoma, treatment consists of chemotherapy and radiotherapy. Disseminated germinoma receive craniospinal irradiation alone. Surgery plays a role in the resection of residual disease following chemotherapy or irradiation. Initial tumor resection is not beneficial to patients with malignant CNS GCT and leads to increased morbidity. Two thirds of all children and adolescents diagnosed with this disease can be cured.
Calaminus G, Barr R	Economic evaluation and health-related quality of life.	Pediatric blood & cancer 2008, 50(5 Suppl): 1112
Health-related quality of life (HRQL) is concerned with the opportunities that a person's health status affords, the constraints that it places upon the person and the value that a person places on his or her health status. The rationale for measuring HRQL falls into three categories: discrimination, evaluation, and prediction. Measures have to meet generally accepted psychometric criteria such as acceptability, reliability/reproducibility, responsiveness, validity, interpretability, and usefulness. HRQL instruments have been designed for self-administration or administration by interviews and some have been adapted to multiple cultural/linguistic needs. For adolescents and young adults with cancer several instruments are available. Overall HRQL is compromised, to varying degrees, in such survivors by comparison with peers in the general population; and the burden of morbidity is greatest after brain and bone tumors. As there is a burden of treatment-related morbidity and as the number of survivors within the health care system is growing, the economic dimension of care and cure has to be taken into consideration. Economic evaluation affords a comparison of the costs and consequences (effects) of relevant therapeutic alternatives. The future research activities with respect to HRQL have to consider these new dimensions of care.
Calaminus G, Schneider DT, Weissbach L, Schönberger S, Okpanyi V, Leuschner I, Poremba C, Göbel U	Survival after an antiangiogenetic therapy and surgery in a wide spread growing teratoma originating from a testicular mixed malignant germ cell tumor.	Klinische Padiatrie 2009, 221: 136
Growing teratoma is still an often unsolved problem especially in male with mixed malignant GCTs of the testis or the mediastinum. This specific situation with progressive tumor growth and simultaneous normalization of tumor markers during or after treatment of malignant GCTs with teratomatous elements is judged as a fatal situation if this situation can not be controlled by extensive surgery, as teratoma are not sensible to chemotherapy or irradiation. Here, we report the case history of a 17-year old male patient with a testicular malignant GCT and wide spread lymph node metastases, who developed a rapidly progressive growing teratoma within the lymph node metastases. Within the molecular profile of the tumor we could find a cytogenetic picture typically found in malignant adult GCTs. In view of the bulky abdominal, thoracic and cervical metastases and the uncontrolled tumor progression, the situation was considered incurable. However, following an individual treatment attempt, this patient was treated with a four-agent combination of drugs with antiangiogenetic potential as well as low-dose cyclic chemotherapy. This approach resulted in a sustained disease stabilization followed by extensive surgical resection of the metastases. We therefore would like to highlight this treatment approach in unresectable growing teratoma and would like to stimulate further research and collaboration to come to an optimized treatment suggestion for this group of poor prognostic patients.
Calaminus G, Göbel U, Schrum J, Wittkugel O, Westphal M, Timmermann B	Proton beam therapy for loco-regional control of a recurrent mixed malignant germ cell tumor of the skull in a 22-month-old girl.	Klinische Padiatrie 2010, 222: 175
BACKGROUND: Germ cell tumors (GCT) situated in the head and neck region are very rare and occur predominantely in newborns or young infants. Recurrent CTs are often resectable only by mutilating surgery and the need for alternative treatment strategies is obvious. In this situation radiation therapy is the most important treatment option for loco-regional tumor control, but bear in this area the risk of possible impairment of brain function and face deformation as long term effects. CASE REPORT: In a girl with a connatal expansive growing teratoma of the skull the tumor recurred in spite of repeated surgery as mixed malignant GCT at the age of 15 months. Tumor control could not be achieved with chemotherapy and additional surgery seemed not promising. Therefore high dose proton beam therapy (PT) (54 Gy) has been administered to the child at the age of 22 months and led to local tumor control with only mild side effects. CONCLUSION: PT treatment may be an option for specific clinical conditions in germ cell tumors where local tumor control cannot be achieved by chemotherapy and/or surgery and long lasting side effects of conventional radiotherapy due to tumor localization and age have to be considered. However, PT should be implemented in treatment protocols for specific situations to guarantee supervised application, central documentation and follow-up.
Calaminus G, Kortmann R, Worch J, Nicholson JC, Alapetite C, Garrè ML, Patte C, Ricardi U, Saran F, Frappaz D	SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease.	Neuro-oncology 2013, 15: 788
Background We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). Methods Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. Results Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. Conclusions Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.
Calaminus G, Birch JR, Hollis R, Pau B, Kruger M	The role of SIOP as a platform for communication in the global response to childhood cancer.	Pediatric blood & cancer 2013, epub ahead of print
Since the year 2000, there has been a 35% annual decrease in mortality among children under the age of five worldwide. The decrease is mainly attributed to the decrease in childhood epidemic infections, for example, due to vaccination programs. In the near future, this decrease will draw attention to paediatric non-communicable diseases (NCDs), and cancer is one of the most common. Access to care for children with cancer and survival rates have improved dramatically in high-income countries. However, it is important that a global perspective addresses problems in developing countries in particular. To meet this challenge, it is critical that emphasis is placed on demands such as access to care and drugs that are known to be effective, and which can be safely administered in resource-limited settings. Additionally, cancer registries and improved health care structures that include care for children with cancer, are paramount for further progress to increase awareness and the survival of children with cancer. The purpose of this paper is to describe current worldwide interventions to improve childhood cancer from the perspective of the International Society of Paediatric Oncology (SIOP). This global perspective will serve as an introduction to a series of papers from six SIOP continental branches, which will highlight the specific and/or common issues related to children with cancer worldwide. To strengthen the communication among and synergistic effects of various paediatric cancer stakeholders, SIOP could serve as a global platform for a proposed Global Paediatric Cancer Network through the interaction of its continental branches and partner collaborations. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
Calaminus G, Dörffel W, Baust K, Teske C, Riepenhausen M, Brämswig J, Flechtner HH, Singer S, Hinz A, Schellong G	Quality of life in long-term survivors following treatment for Hodgkin's disease during childhood and adolescence in the German multicentre studies between 1978 and 2002.	Supportive care in cancer 2014, 22: 1519
The purpose of this study was to cross-sectionally assess quality of life (QoL) in survivors of childhood Hodgkin's disease (HD) in a cohort treated for HD in the successive German-Austrian therapy studies HD-78, HD-82, HD-85, HD-87, HD-90, HD-95, respectively, in accordance with the HD-Interval-Treatment recommendation between 1978 and 2002.
Calaminus G, Frappaz D, Kortmann RD, Krefeld B, Saran F, Pietsch T, Vasiljevic A, Garre ML, Ricardi U, Mann JR, Göbel U, Alapetite C, Murray MJ, Nicholson JC	Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial.	Neuro-oncology 2017, 19: 1661
Calaminus G, Jenney M, Hjorth L, Baust K, Bernstein M, Bielack S, Vos P, Hogendoorn PCW, Jovic G, Krailo M, Kreitz K, Marina N, Popoola BO, Sauerland C, Smeland S, Teske C, Schweinitz CV, Whelan J, Wiener A, Sydes MR, Nagarajan R	Quality of Life of Patients With Osteosarcoma in the European American Osteosarcoma Study-1 (EURAMOS-1): Development and Implementation of a Questionnaire Substudy.	JMIR research protocols 2019, 8:e14406
The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups.
Calaminus G, Schneider DT, von Schweinitz D, Jürgens H, Infed N, Schönberger S, Olson TA, Albers P, Vokuhl C, Stein R, Looijenga L, Sehouli J, Metzelder M, Claviez A, Dworzak M, Eggert A, Fröhlich B, Gerber NU, Kratz CP, Faber J, Klingebiel T, Harms D, Göbel U	Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology.	Cancers 2020, 12
To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT).
Calaminus G, Baust K, Berger C, Byrne J, Binder H, Casagranda L, Grabow D, Grootenhuis M, Kaatsch P, Kaiser M, Kepak T, Kepáková K, Kremer LCM, Kruseova J, Luks A, Spix C, van den Berg M, van den Heuvel-Eibrink MMM, van Dulmen-den Broeder E, Kuonen R, Sommer G, Kuehni C	Health-Related Quality of Life in European Childhood Cancer Survivors: Protocol for a Study Within PanCareLIFE.	JMIR research protocols 2021, 10:e21851
Survival after childhood cancer has improved to more than 80% during the last few years, leading to an increased number of childhood cancer survivors. Cancer itself, or its treatment, may cause chronic health conditions, including somatic and mental sequelae, which may affect survivors' health-related quality of life (HRQoL).
Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES	The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications.	Blood 2011 May 12; 117: 5019
The World Health Organization classification of lymphoid neoplasms updated in 2008 represents a worldwide consensus on the diagnosis of these tumors and is based on the recognition of distinct diseases, using a multidisciplinary approach. The updated classification refined the definitions of well-recognized diseases, identified new entities and variants, and incorporated emerging concepts in the understanding of lymphoid neoplasms. However, some questions were unresolved, such as the extent to which specific genetic or molecular alterations define certain tumors, and the status of provisional entities, categories for which the World Health Organization working groups felt there was insufficient evidence to recognize as distinct diseases at this time. In addition, since its publication, new findings and ideas have been generated. This review summarizes the scientific rationale for the classification, emphasizing changes that have had an effect on practice guidelines. The authors address the criteria and significance of early or precursor lesions and the identification of certain lymphoid neoplasms largely associated with particular age groups, such as children and the elderly. The issue of borderline categories having overlapping features with large B-cell lymphomas, as well as several provisional entities, is reviewed. These new observations chart a course for future research in the field.
Campen CJ, Kranick SM, Kasner SE, Kessler SK, Zimmerman RA, Lustig R, Phillips PC, Storm PB, Smith SE, Ichord R, Fisher MJ	Cranial irradiation increases risk of stroke in pediatric brain tumor survivors.	Stroke; a journal of cerebral circulation 2012, 43: 3035
The purposes of this study were to determine the incidence of neurovascular events as late complications in pediatric patients with brain tumor and to evaluate radiation as a risk factor.
Cantu-Rajnoldi A, Biondi A, Jankovic M, Masera G, Rovelli A, Uderzo C, Head D, Raimondi S, Creutzig U, Ritter J	Diagnosis and incidence of acute promyelocytic leukemia (FAB M3 and M3 variant) in childhood.	Blood 1993, 81: 2209
Cantu Rajnoldi A, Fenu S, Kerndrup G, van Wering ER, Niemeyer CM, Baumann I, European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS)	Evaluation of dysplastic features in myelodysplastic syndromes: experience from the morphology group of the European Working Group of MDS in Childhood (EWOG-MDS).	Annals of hematology 2005, 84: 429
In the absence of genetic abnormalities, the diagnoses of myelodysplastic syndromes (MDS) is primarily based on the presence of dysplasia in blood and marrow cells. Currently, there is no standardized approach to evaluate dysplasia. International cooperative study groups like the European Working Group on MDS in Childhood (EWOG-MDS) depend, however, on a concordance in diagnoses by their national reference centres for morphology. In EWOG-MDS, the morphological diagnoses of all cases enrolled from Scandinavia, the Netherlands, Germany, the Czech Republic, Austria and Italy are established by five experienced pathologists or hematologists cooperating in a morphology board. To study their concordance in evaluating myelodysplastic disorders, members of the morphology board initiated blinded reviews of smears of blood and bone marrow aspirates of known cases. Four features of dysplasia in granulopoiesis, erythropoiesis and megakaryopoiesis were assessed on May-Grünwald-Giemsa stained smears. In a final review of six blinded cases, good concordance for these features was achieved among the five observers. Accurately defined and restrictively applied cellular features of dysplasia are an important tool to improve and ensure the concordance in the diagnosis of MDS among investigators. For cooperative groups, agreement on the evaluation of the morphological assessment of dysplasia is a prerequisite.
Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V	Guidelines for the Management of Transfusion Dependent Thalassaemia.	Thalassemia International Federation 3rd Edition
Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE, Kratz A, Wefers AK, Huang K, Pajtler KW, Schweizer L, Stichel D, Olar A, Engel NW, Lindenberg K, Harter PN, Braczynski AK, Plate KH, Dohmen H, Garvalov BK, Coras R, HÃ¶lsken A, Hewer E, Bewerunge-Hudler M, Schick M, Fischer R, Beschorner R, Schittenhelm J, Staszewski O, Wani K, Varlet P, Pages M, Temming P, Lohmann D, Selt F, Witt H, Milde T, Witt O, Aronica E, Giangaspero F, Rushing E, Scheurlen W, Geisenberger C, Rodriguez FJ, Becker A, Preusser M, Haberler C, Bjerkvig R, Cryan J, Farrell M, Deckert M, Hench J, Frank S, Serrano J, Kannan K, Tsirigos A, BrÃ¼ck W, Hofer S, Brehmer S, Seiz-Rosenhagen M, HÃ¤nggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kristensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, MÃ¼hleisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M, Gottardo NG, Driever PH, Kramm CM, MÃ¼ller HL, Rutkowski S, von Hoff K, FrÃ¼hwald MC, Gnekow A, Fleischhack G, Tippelt S, Calaminus G, Monoranu CM, Perry A, Jones C, Jacques TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert G, Westphal M, Reifenberger G, Wesseling P, Weller M, Collins VP, BlÃ¼mcke I, Bendszus M, Debus J, Huang A, Jabado N, Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD, Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W, Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape K, SchÃ¼ller U, Buslei R, Lichter P, Kool M, Herold-Mende C, Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshunov A, von Deimling A, Pfister SM	DNA methylation-based classification of central nervous system tumours.	Nature 2018, 555: 469
Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, Voskaridou E, Liew HK, Pazgal-Kobrowski I, Forni GL, Perrotta S, Khelif A, Lal A, Kattamis A, Vlachaki E, Origa R, Aydinok Y, Bejaoui M, Ho PJ, Chew LP, Bee PC, Lim SM, Lu MY, Tantiworawit A, Ganeva P, Gercheva L, Shah F, Neufeld EJ, Thompson A, Laadem A, Shetty JK, Zou J, Zhang J, Miteva D, Zinger T, Linde PG, Sherman ML, Hermine O, Porter J, Piga A, BELIEVE Investigators	A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent Î²-Thalassemia.	N Engl journal of Med 2020, 26; 382: 1219
Patients with transfusion-dependent ÃÂ²-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor ÃÂ² superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients.
Carli M, Colombatti R, Oberlin O, Stevens M, Masiero L, Frascella E, Koscielniak E, Treuner J, Pinkerton C	High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma.	J Clin Oncol 1999, 17: 2796
Cario G, Stadt U, Reiter A, Welte K, Sykora K	Variant translocations in sporadic Burkitt's lymphoma detected in fresh tumour material.	Br J Haematol 2000, 110: 537
Cario H, Stahnke K, Sander S, Kohne E	Epidemiological situation and treatment of patients with thalassemia major in Germany: results of the German multicenter beta-thalassemia study.	Annals of hematology 2000, 79: 7
At present, about 300 patients in Germany suffer from thalassemia major. In 1990, a multicenter study was introduced to identify all thalassemic patients in Germany as well as to establish a uniform therapy protocol, including follow-up diagnostic procedures. After 6 years of study, the data of 203 patients were analyzed. The majority originate from endemic regions around the Mediterranean Sea. The median age of the patients is 13.8 years (range 1-37.5 years). At present, about 20% of the patients are older than 21 years. Regarding transfusion therapy, a shortening of the average transfusion interval to 3 weeks in most cases occurred. Throughout the entire period, median baseline hemoglobin concentrations of 10.0 g/dl were observed. The evaluation of serum ferritin levels revealed considerable differences, depending on the patients' age. Thalassemic patients in the first decade of life generally presented with good therapeutic results; serum ferritin levels were below 1800 ng/ml in 76/102 patients (75%) upon entry into the study. In contrast, 51/98 patients (52%) older than 10 years had ferritin levels above 2500 ng/ml. More than half of all treated patients presented with siderotic complications such as cardiac disease in 20/157 (13%), liver disease in 32/157 (21%), impaired glucose metabolism in 22/157 (14%), hypogonadism in 39/66 (59%), and hypothyroidism in 38/157 (24%) who were under treatment at the time of first survey. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult with adolescent patients, further efforts should concentrate on this age-group.
Carlsson G, Fasth A	Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original .	Acta paediatrica (Oslo, Norway : 1992) 2001, 90: 757
In 1956 Rolf Kostmann reported on six children with severe neutropenia associated with a block in myelopoiesis at the promyelocyte/myelocyte stage and an autosomal recessive inheritance. He named the new syndrome infantile genetic agranulocytosis. Today it is known as Kostmann's syndrome or severe congenital neutropenia. In 1975 an additional 10 cases from northern Sweden were published. This article reports on the only long-term survivor from the 1975 report plus another five patients born after 1975 who belong to the original
Cario G, Stanulla M, Fine B, Teuffel O, Neuhoff V, Schrauder A, Flohr T, Schafer B, Bartram C, Welte K, Schlegelberger B, Schrappe M	Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia.	Blood 2005, 105: 821
Cario G, Izraeli S, Teichert A, Rhein P, Skokowa J, Möricke A, Zimmermann M, Schrauder A, Karawajew L, Ludwig WD, Welte K, Schünemann HJ, Schlegelberger B, Schrappe M, Stanulla M	High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS.	Journal of clinical oncology 2007, 25: 4813
PURPOSE: Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients. PATIENTS AND METHODS: We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples. RESULTS: Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31). CONCLUSION: Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.
Cario G, Fetz A, Bretscher C, Möricke A, Schrauder A, Stanulla M, Schrappe M	Initial leukemic gene expression profiles of patients with poor in vivo prednisone response are similar to those of blasts persisting under prednisone treatment in childhood acute lymphoblastic leukemia.	Annals of hematology 2008, 87: 709
Response to initial glucocorticoid (GC) treatment is a strong prognostic factor in childhood acute lymphoblastic leukemia (ALL). Patients with a poor prednisone response (PPR) have a poor event-free survival as compared to those with a good prednisone response (PGR). Causes of prednisone resistance are still not well understood. We hypothesized that GC resistance is an intrinsic feature of ALL cells which is reflected in the gene expression pattern and analyzed genome-wide gene expression using microarrays. A case-control study was performed comparing gene expression profiles from initial ALL samples of 20 patients with PPR and those of 20 patients with PGR. Differential gene expression of a subset of genes was confirmed by real-time quantitative polymerase chain reaction analysis and validation was performed in a second independent patient sample (n=20). We identified 121 genes that clearly distinguished prednisone-resistant from sensitive ALL samples (FDR<5%, fold change>or=1.5). Differential gene expression of 21 of these genes could be validated in a second independent set. Of importance, there was a remarkable concordance of genes identified by comparing expression signatures of PPR and PGR cells at diagnosis and those previously described to be up- or downregulated in leukemic cells persisting under GC treatment. Thus, GC resistance seems at least in part to be an intrinsic feature of leukemic cells. Leukemic cells of patients with PPR are characterized by gene expression pattern which are similar to those of resistant cells persisting under glucocorticoid treatment.
Cario G, Zimmermann M, Romey R, Gesk S, Vater I, Harbott J, Schrauder A, Moericke A, Izraeli S, Akasaka T, Dyer MJ, Siebert R, Schrappe M, Stanulla M	Presence of the P2RY8-CRLF2 rearrangement is associated with a poor prognosis in non-high-risk precursor B-cell acute lymphoblastic leukemia in children treated according to the ALL-BFM 2000 protocol.	Blood 2010,
High-level expression of the cytokine receptor-like factor 2 gene, CRLF2, in precursor B-cell acute lymphoblastic leukemia (pB-ALL) was shown to be caused by a translocation involving the IGH@ locus or a deletion juxtaposing CRLF2 with the P2RY8 promoter. To assess its possible prognostic value, CRLF2 expression was analyzed in 555 childhood pB-ALL patients treated according to the ALL-BFM-2000 protocol. Besides CRLF2-rearrangements high-level CRLF2 expression was seen in cases with supernumerary copies of the CRLF2 locus. Based on the detection of CRLF2-rearrangements, a CRLF2-high-expression group (n=49) was defined. This group had a 6-year relapse incidence of 31+/-8% compared to 11+/-1% in the CRLF2-low-expression group (P=0.006). This difference was mainly attributable to an extremely high relapse incidence (71+/-19%) in non-high-risk patients with P2RY8-CRLF2 rearrangement. The assessment of CRLF2-aberrations may therefore serve as new stratification tool in BFM-based protocols by identifying additional high-risk patients who may benefit from an intensified and/or targeted treatment.
Cario H, Grosse R, Janssen G, Jarisch A, Meerpohl J, Strauss G, German hematology societies (GPOH and DGHO)	[Guidelines for diagnosis and treatment of secondary iron overload in patients with congenital anemia].	Klinische Padiatrie 2010, 222: 399
In Germany and Central Europe, congenital disorders leading to secondary hemochromatosis are rare. The majority of these patients are treated in peripheral medical institutions. As a consequence, the experience of each institution in the treatment of secondary hemochromatosis in patients with congenital anemia is limited. Recent developments concerning new chelating agents, their combination for intensified chelation and new possibilities to diagnose and monitor iron overload have important consequences for the management of patients with secondary hemochromatosis and increase its complexity enormously. Therefore, the development of a guideline for rational and efficient diagnostics and treatment was necessary. The new guideline was developed within a formal consensus process and finally approved by a consensus conference with participants from both the pediatric and adult German hematology societies (GPOH and DGHO). Apart from general information and recommendations, the guideline contains 9 consensus statements on diagnostics (iron status, siderotic complications, chelator side-effects), the start of chelation, indications for intensified chelation, iron elimination in specific disorders, and iron elimination after stem cell transplantation. Here, these consensus statements are presented and discussed in detail. For the complete text of the guideline, please visit the AWMF homepage at http://www.leitlinien.net .
Carlsson G, Winiarski J, Ljungman P, Ringdén O, Mattsson J, Nordenskjöld M, Touw I, Henter JI, Palmblad J, Fadeel B, Hägglund H	Hematopoietic stem cell transplantation in severe congenital neutropenia.	Pediatric blood & cancer 2011, 56: 444
Severe congenital neutropenia (SCN) is an immunodeficiency characterized by disturbed myelopoiesis and an absolute neutrophil count (ANC) <0.5 × 10(9)/L. SCN is also a premalignant condition; a significant proportion of patients develop myelodysplastic syndrome or leukemia (MDS/L). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCN.
Cario H, Kohne, E	Thalassämie, Leitlinie der Gesellschäft für Pädiatrische Onkologie und Hämatologie.	AWMF online
Cario H, Grosse R, Janssen G et al.	Leitlinie (S2k) zur Diagnostik und Therapie der sekundären Eisenüberladung bei Patienten mit angeborenen Anämien.	AWMF online 2015
Cario G, Rhein P, Mitloehner R, Zimmermann M, Bandapalli OR, Romey R, Moericke A, Ludwig WD, Ratei R, Muckenthaler MU, Kulozik AE, Schrappe M, Stanulla M, Karawajew L	High CD45 surface expression determines relapse risk in children with precursor B-cell and T-cell acute lymphoblastic leukemia treated according to the ALL-BFM 2000 protocol.	Haematologica 2013 Aug 2; E-pub ahead of print
Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from an intensified treatment. We earlier identified PTPRC (CD45) gene expression as potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75th percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia compared to B-cell-precursor acute lymphoblastic leukemia (P<0.0001) analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event free survival (B-cell-precursor acute lymphoblastic leukemia: 72+/-3% vs. 86+/-1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60+/-8% vs. 78+/-4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22+/-3% vs. 11+/-1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31+/-8% vs. 11+/-3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor- and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as additional stratification tool in BFM-based protocols. Clinicaltrials.gov identifier: NCT00430118.
Carroll C, Watson P, Spoudeas HA, Hawkins MM, Walker DA, Clare IC, Holland AJ, Ring HA	Prevalence, associations, and predictors of apathy in adult survivors of infantile (<5 years of age) posterior fossa brain tumors.	Neuro-oncology 2013, 15: 497
Apathy is associated with pervasive and disadvantageous effects on daily functioning. It has been observed transiently in some children after surgery for posterior fossa tumors. In this study, our objective was to examine prevalence, associations, and predictors of apathy in adult survivors of an infantile posterior fossa brain tumor (PFT).
Cario H, Grosse R, Jarisch A, et al.	Leitlinie Sichelzellkrankheit (S2k).	AWMF online 2014
Cario H, Gattermann N	Tischatlas Eisenüberladung bei polytransfundierten Patienten.	Georg-Thieme-Verlag Stuttgart 2018
Cario H, Hoferer A, Schmugge M, Sillaber C, Wörmann B	Onkopedia Leitline: Beta-Thalassämie.	DGHO 2018
Cario G, Leoni V, Conter V, Attarbaschi A, Zaliova M, Sramkova L, Cazzaniga G, Fazio G, Sutton R, Elitzur S, Izraeli S, Lauten M, Locatelli F, Basso G, Buldini B, Bergmann AK, Lentes J, Steinemann D, Goehring G, Schlegelberger B, Haas OA, Schewe D, Buchmann S, Moericke A, White D, Revesz T, Stanulla M, Mann G, Bodmer N, Arad-Cohen N, Zuna J, Valsecchi MG, Zimmermann M, Schrappe M, Biondi A	Relapses and treatment-related events contributed equally to poor prognosis in children with ABL-class fusion positive B-cell acute lymphoblastic leukemia treated according to AIEOP-BFM protocols.	Haematologica 2019,
ABL-class fusions other than BCR-ABL1 characterize about 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of >5x10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality 20.8+6.8%. One out of 13 cases with tyrosine kinase inhibitor added to chemotherapy relapsed while eight of 33 cases without tyrosine kinase inhibitor treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high treatment-related mortality (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of tyrosine kinase inhibitors, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (ClinicalTrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).
Cario G, Leoni V, Conter V, Baruchel A, Schrappe M, Biondi A	BCR-ABL1-like acute lymphoblastic leukemia in childhood and targeted therapy.	Haematologica 2020, Epup ahead of print
Castleberry R, Pritchard J, Ambros P, Berthold F, Brodeur G, Castel V, Cohn S, De Bernardi B, Dicks-Mireaux C, Frappaz D, Haase G, Haber M, Jones D, Joshi V, Kaneko M, Kemshead J, Kogner P, Lee R, Matthay K, Michon J, Monclair R, Roald B, Seeger R, Shaw P, Shuster J,	The International Neuroblastoma Risk Groups (INRG).	Eur J Cancer 1997, 33: 2113
Castiello MC, Scaramuzza S, Pala F, Ferrua F, Uva P, Brigida I, Sereni L, van der Burg M, Ottaviano G, Albert MH, Grazia Roncarolo M, Naldini L, Aiuti A, Villa A, Bosticardo M	B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome.	The Journal of allergy and clinical immunology 2015, 136: 692-702.e2
Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene-corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach.
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, Bonvalot S, Boukovinas I, Bovee JVMG, Brennan B, Brodowicz T, Broto JM, Brugières L, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dileo P, Dhooge C, Eriksson M, Fagioli F, Fedenko A, Ferraresi V, Ferrari A, Ferrari S, Frezza AM, Gaspar N, Gasperoni S, Gelderblom H, Gil T, Grignani G, Gronchi A, Haas RL, Hassan B, Hecker-Nolting S, Hohenberger P, Issels R, Joensuu H, Jones RL, Judson I, Jutte P, Kaal S, Kager L, Kasper B, Kopeckova K, Krákorová DA, Ladenstein R, Le Cesne A, Lugowska I, Merimsky O, Montemurro M, Morland B, Pantaleo MA, Piana R, Picci P, Piperno-Neumann S, Pousa AL, Reichardt P, Robinson MH, Rutkowski P, Safwat AA, Schöffski P, Sleijfer S, Stacchiotti S, Strauss SJ, Sundby Hall K, Unk M, Van Coevorden F, van der Graaf WTA, Whelan J, Wardelmann E, Zaikova O, Blay JY, ESMO Guidelines Committee, PaedCan and ERN EURACAN	Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up.	Annals of oncology : official journal of the European Society for Medical Oncology 2018 Oct 1; 29:iv79-iv95
Castel D, Philippe C, Kergrohen T, Sill M, Merlevede J, Barret E, Puget S, Sainte-Rose C, Kramm CM, Jones C, Varlet P, Pfister SM, Grill J, Jones DTW, Debily MA	Transcriptomic and epigenetic profiling of 'diffuse midline gliomas, H3 K27M-mutant' discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location.	Acta neuropathologica communications 2018 Nov 5; 6: 117
Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18ÃÂ years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (nÃ¢ÂÂ=Ã¢ÂÂ140) and methylation (nÃ¢ÂÂ=Ã¢ÂÂ80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8ÃÂ months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.
Cattaneo M, Cerletti C, Harrison P, Hayward CP, Kenny D, Nugent D, Nurden P, Rao AK, Schmaier AH, Watson SP, Lussana F, Pugliano MT, Michelson AD	Recommendations for the Standardization of Light Transmission Aggregometry: A Consensus of the Working Party from the Platelet Physiology Subcommittee of SSC/ISTH.	Journal of thrombosis and haemostasis : JTH 2013, 11: 1183
Cavazzana A, Schmidt D, Ninfo V, Harms D, Tollot M, Carli M, Treuner J, Betto R, Salviati G	Spindle cell rhabdomyosarcoma. A prognostically favorable variant of rhabdomyosarcoma.	Am J Surg Pathol 1992, 16: 229
Cavazzana-Calvo M, Payen E, Negre O, et al.	Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.	Nature 2010, 467, 18–322
The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become trans-fusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl–1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochasticor resultfrom a hithertobenign cellexpansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.
Cazzaniga G, De Lorenzo P, Alten J, Röttgers S, Hancock J, Saha V, Castor A, Madsen HO, Gandemer V, Cavé H, Leoni V, Köhler R, Ferrari GM, Bleckmann K, Pieters R, van der Velden V, Stary J, Zuna J, Escherich G, Stadt UZ, Ariò M, Conter V, Schrappe M, Valsecchi MG, Biondi A	Predictive value of minimal residual disease in Philadelphia-chromosome-positive acute lymphoblastic leukemia treated with imatinib in the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia, based on immunoglobulin/T-cell receptor and BCR/ABL1 methodologies.	Haematologica 2018, 103: 107
The prognostic value of minimal residual disease (MRD) in Philadelphia-chromosome-positive (Ph+) childhood acute lymphoblastic leukemia (ALL) treated with tyrosine kinase inhibitors is not fully established. We detected MRD by real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes (IG/TR) and/or BCR/ABL1 fusion transcript to investigate its predictive value in patients receiving Berlin-Frankfurt-Münster (BFM) high-risk (HR) therapy and post-induction intermittent imatinib (the European intergroup study of post-induction treatment of Philadelphia-chromosome-positive acute lymphoblastic leukemia (EsPhALL) study). MRD was monitored after induction (time point (TP)1), consolidation Phase IB (TP2), HR Blocks, reinductions, and at the end of therapy. MRD negativity progressively increased over time, both by IG/TR and BCR/ABL1. Of 90 patients with IG/TR MRD at TP1, nine were negative and none relapsed, while 11 with MRD<5×10-4 and 70 with MRD≥5×10-4 had a comparable 5-year cumulative incidence of relapse of 36.4 (15.4) and 35.2 (5.9), respectively. Patients who achieved MRD negativity at TP2 had a low relapse risk (5-yr cumulative incidence of relapse (CIR)=14.3[9.8]), whereas those who attained MRD negativity at a later date showed higher CIR, comparable to patients with positive MRD at any level. BCR/ABL1 MRD negative patients at TP1 had a relapse risk similar to those who were IG/TR MRD negative (1/8 relapses). The overall concordance between the two methods is 69%, with significantly higher positivity by BCR/ABL1. In conclusion, MRD monitoring by both methods may be functional not only for measuring response but also for guiding biological studies aimed at investigating causes for discrepancies, although from our data IG/TR MRD monitoring appears to be more reliable. Early MRD negativity is highly predictive of favorable outcome. The earlier MRD negativity is achieved, the better the prognosis.
Cecchetto G, Bisogno G, Treuner J, Ferrari A, Mattke A, Casanova M, Dall'Igna P, Zanetti I, Volpato S, Siracusa F, Scarzello G, Boglino C, Carli M	Role of surgery for nonmetastatic abdominal rhabdomyosarcomas.	Cancer 2003, 97: 1974
Chang CH, Housepian EM, Herbert C Jr	An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas.	Radiology 1969, 93: 1351
del Charco JO, Bolek TW, McCollough WM, Maria BL, Kedar A, Braylan RC, Mickle JP, Buatti JM, Mendenhall NP, Marcus RB	Medulloblastoma: time-dose relationship based on a 30-year review.	Int J Radiat Oncol Biol Phys 1998, 42: 147
PURPOSE: Time-dose relationships have proven important in many cancer sites. This study evaluates the time factors involved in the successful postoperative radiotherapy of medulloblastoma, based on a 30-year experience in a single institution. METHODS AND MATERIALS: Fifty-three patients with medulloblastoma received postoperative craniospinal radiotherapy with curative intent between 1963 and 1993. Seven patients (13%) underwent biopsy alone, 28 patients (53%) had subtotal excision, and 18 patients (34%) had gross total excision. Eleven patients received adjuvant chemotherapy. The mean posterior fossa dose was 53.1 Gy; most patients received 54.0 Gy (range, 34.3 to 69.6 Gy). For 41 patients receiving once-a-day therapy, the mean dose was 50.6 Gy (range, 34.3 to 56.0 Gy). For 12 patients receiving twice-a-day therapy, the mean dose was 61.8 Gy (range, 52.6 to 69.6 Gy). Minimum follow-up was 2 years, and median follow-up was 10.7 years. Survival, freedom from relapse, and disease control in the posterior fossa were calculated using the Kaplan-Meier method, and multivariate analysis was performed for prognostic factors. Variables related to radiotherapy were examined, including dose to the craniospinal axis, dose to the posterior fossa, fractionation (once-a-day vs. twice-a-day), use of adjuvant chemotherapy, risk group [high (> or =T3b or > or =M1) or low (< or =T3a and M0-MX)], interval between surgery and radiotherapy (excluding patients receiving chemotherapy before radiotherapy), and duration of radiotherapy. RESULTS: At 5 and 10 years, overall survival rates were 68 and 64%, respectively, and freedom-from-relapse rates were 61 and 52%, respectively. Rates of disease control in the posterior fossa at 5 and 10 years were 79 and 68%, respectively. At 5 years, absolute survival rates after biopsy alone, subtotal excision, and gross total excision were 43, 67, and 78%, respectively (p=0.04), and posterior fossa control rates were 27, 89, and 83%, respectively (p=0.004). Duration of the treatment course was the only radiotherapy-related variable with a significant impact on freedom from relapse and posterior fossa control. For patients whose radiation treatment duration was < or =45 days, posterior fossa control was 89% at 5 years, compared with 68% for those treated for >45 days (p=0.01). Duration of treatment also affected freedom from relapse at 5 years: < or =45 days (76%) compared with >45 days (43%), p=0.004. CONCLUSION: Our study demonstrates that if adequate doses are used, then radiotherapy treatment duration will significantly affect the outcome in terms of control of disease in the posterior fossa and freedom from relapse. Fractions of at least 1.75 Gy given once a day, or a twice-a-day regimen should yield optimal local control results.
Cham B, Bonilla MA, Winkelstein J	Neutropenia associated with primary immunodeficiency syndromes.	Seminars in hematology 2002, 39: 107
The primary immunodeficiency diseases are a heterogeneous group of more than 75 disorders characterized by intrinsic defects in the functions of the immune system. Many are associated with abnormalities of hematopoiesis as well. This article will review those primary immunodeficiency syndromes in which neutropenia is a prominent finding, including X-linked agammaglobulinemia (XLA), hyper IgM syndrome, common variable immunodeficiency (CVID), IgA deficiency, cartilage-hair hypoplasia (CHH), and reticular dysgenesis, with regards to pathophysiologic findings and treatment.
Chantada G, Fandino A, Davila MT, Manzitti J, Raslawski E, Casak S, Schvartzman E	Results of a prospective study for the treatment of retinoblastoma.	Cancer 2004, 100: 834
BACKGROUND: The objectives of this prospective study were to avoid adjuvant treatment for patients with intraocular disease and patients with postlaminar optic nerve invasion (PL-ONI) without full choroidal or scleral invasion. Adjuvant chemotherapy (Regimen 1) was given to patients with scleral invasion, PL-ONI without cut section, and full choroidal and/or scleral invasion. A more intensive regimen of higher dose intravenous chemotherapy (Regimen 2) and local radiotherapy was given to patients with PL-ONI and compromise at the cut end and to patients with overt extraocular disease. METHODS: Six-month intravenous chemotherapy included carboplatin plus etoposide alternating with cyclophosphamide plus vincristine (Regimen 1) and the same drugs at higher dosage plus idarubicin (Regimen 2). Chemoreduction with carboplatin and vincristine with or without etoposide was given to selected patients (n = 39 patients). RESULTS: From 1994 to 2001, 169 patients were evaluable at the Hospital Garrahan (Buenos Aires, Argentina). One hundred eighteen patients with intraocular disease had a 5-year disease free survival (DFS) rate of 0.98, including 54 patients with choroidal invasion. None of 22 patients with isolated PL-ONI developed recurrent disease, whereas 2 of 8 patients with concomitant risk factors had tumor recurrences and died. Three of 5 patients with scleral invasion survived, and 7 of 10 patients with cut-end ONI survived. The only patient with metastatic disease that survived (n = 6) had only lymph node invasion. CONCLUSIONS: Adjuvant therapy can be avoided in patients with intraocular and isolated PL-ONI. Patients with PL-ONI who also had other risk factors required intensive adjuvant therapy, such as patients with cut-end and overt extraocular disease. Metastatic disease was not found to be curable with this approach.
Chang ET, Smedby KE, Hjalgrim H, Porwit-MacDonald A, Roos G, Glimelius B, Adami HO	Family history of hematopoietic malignancy and risk of lymphoma.	J Natl Cancer Inst 2005, 97: 1466
Chantada G, Doz F, Antoneli CB, Grundy R, Clare Stannard FF, Dunkel IJ, Grabowski E, Leal-Leal C, Rodríguez-Galindo C, Schvartzman E, Popovic MB, Kremens B, Meadows AT, Zucker JM	A proposal for an international retinoblastoma staging system.	Pediatric blood & cancer 2006, 47: 801
Although intra-retinal tumor has long been staged presurgically according to the Reese-Ellsworth (R-E) system, retinoblastoma differs from other pediatric neoplasms in never having had a widely accepted classification system that encompasses the entire spectrum of the disease. Comparisons among studies that consider disease extension, risk factors for extra-ocular relapse, and response to therapy require a universally accepted staging system for extra-ocular disease.
Chadi M El Saleeby, MD, Brian E Grottkau, MD, Alison M Friedmann, MD, Sjirk J Westra, MD, and Aliyah R Sohani, MD	Case 4-2011 — A 4-Year-Old Boy with Back Pain and Hypercalcemia.	N Engl J Med 2011 364: 552
Chao MM, Kuehl JS, Strauss G, Hanenberg H, Schindler D, Neitzel H, Niemeyer C, Baumann I, von Bernuth H, Rascon J, Nagy M, Zimmermann M, Kratz CP, Ebell W	Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only.	Annals of hematology 2015, 94: 1311
Fanconi anemia (FA) is a genomic instability syndrome associated with bone marrow failure, myelodysplastic syndrome (MDS), and/or acute myeloid leukemia (AML) requiring hematopoietic stem cell transplantation (HSCT) to restore normal hematopoiesis. Although low-intensity fludarabine-based preparative regimens without radiation confer excellent outcomes in FA HSCTs with HLA-matched sibling donors, outcomes for FA patients with alternative donors are less encouraging, albeit improving. We present our experience with 17 FA patients who completed mismatched related or unrelated donor HSCT using a non-radiation fludarabine-based preparative regimen at Charité University Medicine Berlin. All patients engrafted; however, one patient had unstable chimerism in the setting of multi-viral infections that necessitated a stem cell boost to revert to full donor chimerism. Forty-seven percent of patients developed grade I acute graft-verus-host disease (aGVHD). No grade II-IV aGVHD or chronic graft-versus-host disease of any severity occurred. At a median follow-up of 30 months, 88 % of patients are alive with normal hematopoiesis. Two patients died of infections 4 months post-transplantation. These results demonstrate that short-term outcomes for FA patients with mismatched and unrelated donor HSCTs can be excellent using chemotherapy only conditioning. Viral reactivation, however, was a major treatment-related complication.
Chagtai T, Zill C, Dainese L, Wegert J, Savola S, Popov S, Mifsud W, Vujanic G, Sebire N, Le Bouc Y, Ambros PF, Kager L, O'Sullivan MJ, Blaise A, Bergeron C, Mengelbier LH, Gisselsson D, Kool M, Tytgat GA, van den Heuvel-Eibrink MM, Graf N, van Tinteren H, Coulomb A, Gessler M, Williams RD, Pritchard-Jones K	Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: A SIOP Renal Tumours Biology Consortium Study.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2016 Sep 10; 34: 3195
PURPOSE: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. MATERIALS AND METHODS: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. RESULTS: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. CONCLUSION: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage. © 2016 by American Society of Clinical Oncology.
Chao MM, Thomay K, Goehring G, Wlodarski M, Pastor V, Schlegelberger B, Schindler D, Kratz CP, Niemeyer C	Mutational Spectrum of Fanconi Anemia Associated Myeloid Neoplasms.	Klinische Padiatrie 2017, 229: 329
Individuals with Fanconi anemia (FA) have a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), yet the secondary somatic mutations lending to these malignancies remain to be further elucidated. We employed a next-generation sequencing myeloid neoplasia gene panel to determine the mutational spectrum of FA-related MDS/AML. Ten of 16 patients showed missense, nonsense, insertion or duplication mutations in 13 genes. In contrast to findings in MDS in the general population, mutations in genes involved in RNA splicing were rarely affected. Mutations in RUNX1 and genes of the RAS pathway appeared more instrumental in the pathogenesis of FA myeloid malignancies. RUNX1 mutations were associated with more advanced disease. Interestingly, one patient with refractory anemia with ring sideroblasts harbored the SF3B1 p.K700E mutation highlighting the mutation's causative role in MDS with ring sideroblasts even in the context of FA. On the whole, our findings implicate a different genetic architecture of FA MDS/AML from adult sporadic MDS. Notably, the genetic events resemble those described in pediatric MDS
Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ, et al.	Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.	J Clin Oncol 1990, 8: 813
Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O, Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL	Integrative Genomic Analysis of Medulloblastoma Identifies a Molecular Subgroup That Drives Poor Clinical Outcome.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010 Dec 6;
PURPOSE Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. PATIENTS AND METHODS We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets. Results Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals. CONCLUSION Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
Christiansen N, Christiansen H, Berthold F, Lampert F	Transcriptional activity of N-myc and ngf-r in 50 primary human neuroblastomas as predictor for clinical outcome.	Int J Oncol 1993, 3: 853
Christiansen H, Delattre O, Fuchs S, Theobald M, Christiansen N, Berthold F, Lampert F	Loss of the putative tumor suppressor-gene locus 1p36 as investigated by a PCR-assay and N-myc amplification in 48 neuroblastomas.	Prog Clin Biol Res 1994, 385: 19
Christiansen H, Sahin K, Berthold F, Hero B, Terpe H, Lampert F	Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma.	Eur J Cancer 1995, 31A: 541
Christiansen H, Terpe H, Gonzales M, Wenderhold S, Berthold F, Lampert F	Expression of CD44-standard in 182 primary neuroblastomas.	Klin Pädiatr 1995, 207: 219
Christiansen S, Semik M, Dockhorn-Dworniczak B, Rötker J, Thomas M, Schmidt C, Jürgens H, Winkelmann W, Scheld H	Diagnosis, treatment and outcome of patients with Askin-tumors.	Thorac Cardiov Surg 2000, 48: 311
Claviez A, Hero B, Schneppenheim R, Berthold F	Hepatopathy in patients with stage 4S neuroblastoma.	Klin Pädiatr 1996, 208: 221
Classen C, Fulda S, Friesen C, Debatin K	Decreased sensitivity of drug-resistant cells towards T cell cytotoxicity.	Leukemia 1999, 13: 410
Claviez A, Klingebiel T, Beyer J, Nurnberger W, Ehninger G, Suttorp M, Dreger P, Dörffel W, Schmitz N	Allogeneic peripheral blood stem cell transplantation following fludarabine-based conditioning in six children with advanced Hodgkin's disease.	Annals Hematology 2004, 83: 237
Claviez A, Tiemann M, Lüders H, Krams M, Parwaresch R, Schellong G, Dörffel W	The impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma.	haematologica 2004
Claviez A	Morbus Hodgkin.	in: Gutjahr P (Hrsg.): Krebs bei Kindern und Jugendlichen Deutscher Ärzte-Verlag Köln, 5. Aufl. 2004, 347
Claviez A, Lakomek M, Ritter J, Suttorp M, Kremens B, Dickerhoff R, Harms D, Berthold F, Hero B	Low occurrence of familial neuroblastomas and ganglioneuromas in five consecutive GPOH neuroblastoma treatment studies.	European journal of cancer (Oxford, England : 1990) 2004, 40: 2760
Familial neuroblastoma is of special interest in view of the oncogenesis of this tumour with its early manifestation in childhood. The inheritance seems to follow an autosomal-dominant mendelian trait with incomplete penetrance. Familial neuroblastomas and ganglioneuromas have not been reported in detail within large treatment studies. A retrospective clinicopathological survey of patients reported to the German neuroblastoma treatment studies over 24 years was performed. Among 2863 patients (2752 neuroblastomas, 111 ganglioneuromas) included in five consecutive trials, only 22 hereditary cases in ten families were observed. Neuroblastomas were found in 18 patients and ganglioneuromas in four, accounting for less than one percent of all cases. Six patients with neuroblastomas had localised disease, seven had stage 4, three had stage 4S, and stage was unknown in two patients. Two families had three affected patients. Contrary to previous reports, age distribution and number of primary tumours in patients with familial data confirm the low prevalence of familial neuroblastoma and may help in counselling the affected families.
Claviez A	Rhabdomyosarkome.	in Gutjahr P (Hrsg.): Krebs bei Kindern und Jugendlichen Deutscher Ärzte-Verlag Köln, 5. Aufl. 2004, 461
Claviez A, Tiemann M, Lüders H, Krams M, Parwaresch R, Schellong G, Dörffel W	Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma.	J Clin Oncol 2005, 23: 4048
Classen CF, Teigler-Schlegel A, Rottgers S, Reinhardt D, Dohner K, Debatin KM	AML bearing the translocation t(11;17)(q23;q21): involvement of MLL and a region close to RARA, with no differentiation response to retinoic acid.	Annals of hematology 2005, 84: 774
We describe a case of acute myeloid leukemia (AML) bearing the translocation t(11;17)(q23;q21). The morphological phenotype represented a monoblastic leukemia, AML French-American-British (FAB) M5a. Further analysis of the translocation revealed an involvement of the mixed-lineage leukemia (MLL) gene and a region closely proximal to the retinoic acid (RA) receptor alpha (RARA) gene. AMLs involving both a rearranged MLL and the 17q21 region, in which the RARA gene is located, have only been described in some individual cases. The functional role of this translocation is still unknown. Rearrangements of the MLL (11q23) gene in AML are usually related to the morphological phenotype FAB M5. In general, they are associated with an adverse prognosis. In acute promyelocytic leukemia, the translocation (15;17)(q22;q11-21) involving the RARA leads to a maturation arrest that can be overcome by RA, often inducing remission. In other forms of AML, however, the effects of RA are limited and diverse. To study whether RA might have a therapeutical potential in our case, we performed an in vitro analysis of RA effects on AML cells. We found that RA leads to enhanced cell death and up-regulation of CD38 and CD117. However, no hints of RA-induced in vitro differentiation were visible. Our data indicate that in AML cells bearing the t(11;17)(q23;q21), a differentiation arrest that is overcome by RA is not present. On the contrary, RA induces alterations in cellular regulation that are similar to the RA-induced changes observed in early hematogenic progenitors; thus, a possible therapeutical benefit of RA in such cases remains open.
Claviez A	Hodgkin-Lymphom.	Interdisziplinäre Leitlinie der Deutschen Krebsgesellschaft und der Deutschen Gesellschaft für Pädiatrische Onkologie und Hämatologie 2007
Claviez A, Canals C, Dierickx D, Stein J, Badell I, Pession A, Mackinnon S, Slavin S, Dalle JH, Chacón MJ, Sarhan M, Wynn RF, Suttorp M, Dini G, Sureda A, Schmitz N, Lymphoma and Pediatric Diseases Working Parties	Allogeneic hematopoietic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin lymphoma: an analysis of the European Group for Blood and Marrow Transplantation.	Blood 2009, 114: 2060
Ninety-one children and adolescents 18 years or younger after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed or refractory Hodgkin lymphoma (HL) were analyzed. Fifty-one patients received reduced intensity conditioning (RIC); 40 patients received myeloablative conditioning (MAC). Nonrelapse mortality (NRM) at 1 year was 21% (+/- 4%), with comparable results after RIC or MAC. Probabilities of relapse at 2 and 5 years were 36% (+/- 5%) and 44% (+/- 6%), respectively. RIC was associated with an increased relapse risk compared with MAC; most apparent beginning 9 months after HSCT (P = .01). Progression-free survival (PFS) was 40% (+/- 6%) and 30% (+/- 6%) and overall survival (OS) was 54% (+/- 6%) and 45% (+/- 6%) at 2 and 5 years, respectively. Disease status at HSCT was predictive of PFS in multivariate analysis (P < .001). Beyond 9 months, PFS after RIC was lower compared with MAC (P = .02). Graft-versus-host disease did not affect relapse rate and PFS. In conclusion, children and adolescents with recurring HL show reasonable results with allogeneic HSCT. Especially patients allografted in recent years with good performance status and chemosensitive disease show highly encouraging results (PFS: 60% +/- 27%, OS: 83% +/- 15% at 3 years). Because relapse remains the major cause of treatment failure, additional efforts to improve disease control are necessary.
Claus RA, Bockmeyer CL, Budde U, Kentouche K, Sossdorf M, Hilberg T, Schneppenheim R, Reinhart K, Bauer M, Brunkhorst FM, Lösche W	Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure.	Thrombosis and haemostasis 2009, 101: 239
Von Willebrand factor (VWF) and related parameters as well as the protease activity regulating its biological activity were measured in plasma of healthy controls and patients with different cause and severity of systemic inflammation to examine the efficacy of the measures to detect highly prothrombotic states including thrombotic microangiopathy (TMA), one of the sequelae of sepsis. Plasma levels of VWF increased with increasing severity of systemic inflammation, probably due to activation of the endothelium. In parallel, the proteolytic activity of VWF inactivating protease, ADAMTS13, stepwise declined with the severity of inflammation, emphasizing the role of VWF-triggered platelet aggregation on the endothelium subsequently followed by development of TMA. As a consequence, the ratio of VWF antigen level and ADAMTS13 activity was significantly higher in patients with inflammation and sepsis, suggesting that this ratio might be more useful for the diagnosis of highly prothrombotic states including TMA than VWF multimer analysis alone. These findings suggest that ADAMTS13, VWF and related parameters, even in a combined approach, might be useful for the diagnosis and the therapeutic monitoring of patients with sepsis associated thrombotic microangiopathy.
Claviez A	Hodgkin-Lymphom.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) AWMF 2018
Claus K	Was ist eigentlich CAR-T-Zelltherapie?	WIR 2020/01
Clinton C, Gazda HT: Hrsg: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K	Diamond-Blackfan Anemia.	GeneRevievs 2014
Disease characteristics. Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in approximately 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life (median age of onset: 2 months). Eventually, 40% of affected individuals are corticosteroid dependent, 40% are transfusion dependent, and 20% go into remission. The phenotypic spectrum ranges from a mild form (e.g., mild anemia; no anemia with only subtle erythroid abnormalities; physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma. Diagnosis/testing. The diagnosis is based on the presence of: normochromic (usually macrocytic) anemia, reticulocytopenia, normal or slightly decreased leukocyte counts, normal or increased platelet counts, and normocellular bone marrow with selective deficiency of red cell precursors. Other genetic forms of anemia, such as Fanconi anemia, need to be considered and ruled out as appropriate. DBA has been associated with mutations in eleven genes that encode ribosomal proteins and in GATA1. A mutation in one of these twelve genes is identified in approximately 55% of individuals with DBA. Management. Treatment of manifestations: Corticosteroid treatment, recommended in children over age twelve months, can initially improve the red blood count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is initially necessary while the diagnosis is made and in those not responsive to corticosteroids. Hematopoietic stem cell transplantation (HSCT), the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities. Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after 10-20 transfusions. Steroid-related side effects must also be closely monitored, especially as related to risk for infection, growth retardation, and loss of bone density in growing children. Often patients will be placed on transfusion therapy if these side effects are intolerable. Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy to evaluate morphology and cellularity in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and growth (in children). Agents/circumstances to avoid: Infection (especially those on corticosteroids); deferiprone for the treatment of iron overload has lead to severe neutropenia in a few individuals with DBA. Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives of a proband with a known pathogenic mutation allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. Genetic counseling. DBA is most often inherited in an autosomal dominant manner; GATA1 mutations are inherited in an X-linked manner. Approximately 40% to 45% of individuals with autosomal dominant DBA have inherited the mutation from a parent; approximately 55% to 60% have a de novo mutation. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the mutation. Males with a GATA1 mutation pass the disease-causing mutation to all of their daughters and none of their sons. Women who are carriers of a GATA1 mutation have a 50% chance of transmitting the mutation in each pregnancy: males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family. If the disease-causing mutation has been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.
Cloos J, Zwaan CM, Corthals SL, Goemans BF, Waisfisz Q, Creutzig U, Reinhardt D, Hählen K, Kaspers GJL	FLT3/Internal Tandem Duplication in Paired Presentation and Relapse Pediatric AML Samples.	Blood 2004, 104[11], 30a.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U, Gruppo Italiano Malattie Ematologiche dell'Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance Leukemia	Retinoic acid and arsenic trioxide for acute promyelocytic leukemia.	N Engl J Med 2013, 369: 111
All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.
Children's Oncology Group	Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers.	2014
Children´s Oncology Group	Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers.	2018, Version 5.0
Cohena Y, Nagler A	Hematopoietic stem-cell transplantation using umbilical-cord blood.	Leukemia & lymphoma 2003, 44: 1287
In the recent years, umbilical cord blood (UCB) has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients lacking an HLA-matched marrow donor. Since 1998, about 2500 patients have received UCB transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20kg, however, more than 500 UCB transplantations (UCBT) have already been performed in adults. The
Cohen Y, Nagler A	Umbilical cord blood transplantation--how, when and for whom?	Blood reviews 2004, 18: 167
In recent years, umbilical cord blood (UCB) has emerged as a feasible alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack HLA-matched marrow donors. Since the first case reported in 1998, more than 3500 patients have received UCB transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg; however, more than 500 UCB transplantations (UCBTs) have already been performed in adults. The
Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, Faldum A, Hero B, Iehara T, Machin D, Mosseri V, Simon T, Garaventa A, Castel V, Matthay KK, INRG Task Force	The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.	Journal of clinical oncology 2009, 27: 289
PURPOSE: Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. PATIENTS AND METHODS: The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors. RESULTS: Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to < or = 85%, > or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively. CONCLUSION: By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.
Cohen KJ, Pollack IF, Zhou T, Buxton A, Holmes EJ, Burger PC, Brat DJ, Rosenblum MK, Hamilton RL, Lavey RS, Heideman RL	Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group.	Neuro-oncology 2011, 13: 317
Conter V, Schrappe M, Arico M, Reiter A, Rizzari C, Dordelmann M, Valsecchi M, Zimmermann M, Ludwig W, Basso G, Masera G, Riehm H	Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster groups.	J Clin Oncol 1997, 15: 2786
Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, Reiter A, Riehm H, Masera G, Schrappe M	Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial.	Lancet 2007, 369: 123
BACKGROUND: Studies in the 1970s and 1980s suggested that the outcome of childhood acute lymphoblastic leukaemia (ALL) could be improved by intensification of conventional continuation chemotherapy with pulses of vincristine sulfate and steroids. We aimed to investigate the efficacy and toxic effects of vincristine-dexamethasone pulses as an addition to the continuation-therapy phase in a large cohort of children with intermediate-risk disease who were treated with the Berlin-Frankfurt-Münster (BFM) treatment strategy. METHODS: 3109 children, diagnosed with ALL and intermediate-risk features, were enrolled by eight participating organisations in eleven countries. All were treated with very similar protocols based on the BFM treatment strategy, which included induction, consolidation, reinduction, and continuation-therapy phases. At the beginning of the continuation-therapy phase, those patients in complete remission were randomly assigned to either a treatment or a control group. Control patients were given conventional mercaptopurine and methotrexate chemotherapy only. Patients in the treatment arm were also given pulses of vincristine (1.5 mg/m2 weekly for 2 weeks) and dexamethasone (6 mg/m2 daily for 7 days) every 10 weeks for six cycles. The primary outcome measure was disease-free survival. Analysis was by intention to treat. The study is registered at http://www.clinicaltrials.gov with the identifier NCT00411541. FINDINGS: 174 patients (5.6%) relapsed or died in complete remission before randomisation. Of the remaining 2935 patients, 2618 (89.2%) were randomly assigned: 1325 to the treatment group and 1293 to the control group. With median follow-up of 4.8 years, 240 children in the treatment group and 241 in the control group had relapses; 15 in the treatment group and 14 controls died in complete remission or developed second malignant neoplasms. The 5-year and 7-year disease-free survival estimates were 79.8% (SE 1.2) and 77.5% (1.5) in the treatment group and 79.2% (1.2) and 78.4% (1.3) in the control group, respectively. Treatment with pulses of vincristine and dexamethasone was associated with a non-significant 3% relative-risk reduction (hazard ratio 0.97; 95% CI 0.81-1.15; p=0.70). INTERPRETATION: Children with intermediate-risk ALL who received intensive chemotherapy based on BFM protocols did not benefit from intensification of the continuation-therapy phase with a schedule of pulses of vincristine and dexamethasone.
Conklin HM, Li C, Xiong X, Ogg RJ, Merchant TE	Predicting change in academic abilities after conformal radiation therapy for localized ependymoma.	Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 Aug 20; 26: 3965
Conformal radiation therapy (CRT) aims to limit the highest radiation dose to the tissue volume at risk while sparing surrounding normal tissues. This study investigated whether treatment of childhood ependymoma with CRT would preserve cognitive function. Academic competence was chosen as the primary outcome measure given it is a measure of applied cognitive abilities in a child's natural setting.
Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke A, Aricò M, Zimmermann M, Mann G, De Rossi G, Stanulla M, Locatelli F, Basso G, Niggli F, Barisone E, Henze G, Ludwig WD, Haas OA, Cazzaniga G, Koehler R, Silvestri D, Bradtke J, Parasole R, Beier R, van Dongen JJ, Biondi A, Schrappe M	Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study.	Blood 2010, 115: 3206
The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10(-4)); MRD high risk (MRD-HR) if 10(-3) or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP.
Conran N	High Foetal Haemoglobin in Sickle Cell Disease: Not so Protective?	EBioMedicine 2015, 2: 102
Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A, Boelens JJ, Hewitt A, Schrum J, Schulz AS, Müller I, Stein J, Wynn R, Greil J, Sykora KW, Matthes-Martin S, Führer M, O'Meara A, Toporski J, Sedlacek P, Schlegel PG, Ehlert K, Fasth A, Winiarski J, Arvidson J, Mauz-Körholz C, Ozsahin H, Schrauder A, Bader P, Massaro J, D'Agostino R, Hoyle M, Iacobelli M, Debatin KM, Peters C, Dini G	Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial.	Lancet 2012, 379: 1301
Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting.
Corbacioglu S	Early phase clinical trials in pediatric hematology and oncology.	Klinische Padiatrie 2012, 224: 197
Pediatric oncology is an unrivaled success story in the recent history of medicine. This success is mostly based on a persistent refinement of evidence based therapeutic concepts. With that regard physicians and their staff are highly experience in the conduct of prospective evidence based trials and are therefore competent partners for the pharmaceutical industry. In times of personalized medicine the individual target population is diminishing and the borders of indications are not more disease based. A situation that requires new concepts from the industry. Therefore children with cancer could benefit early from the current developments as well as the pharmaceutical industry could benefit from the legislative incentives through highly recruiting and well conducted prospective trials. Pivotal is a functional platform of communication in order to maintain a close dialogue between academia and pharmaceutical companies.
Cotterill S, Ahrens S, Paulussen M, Jürgens H, Voute P, Gadner H, Craft A	Prognostic factors in Ewing's tumor of bone.	J Clin Oncol 2000, 18: 3108
Cottle TE, Fier CJ, Donadieu J, Kinsey SE	Risk and benefit of treatment of severe chronic neutropenia with granulocyte colony-stimulating factor.	Seminars in hematology 2002, 39: 134
The Severe Chronic Neutropenia International Registry (SCNIR) was established in 1994 following four phase I/II and one phase III clinical trial on the use of filgrastim (recombinant human granulocyte colony-stimulating factor [r-metHuG-CSF]) as a treatment for severe chronic neutropenia (SCN). A primary purpose of the SCNIR is to monitor SCN patients treated with filgrastim for adverse events that might occur over time. As of December 31, 2000, 832 patients with SCN (384 congenital, 160 cyclic, 288 idiopathic) were enrolled. Clinical trial and Registry data show that filgrastim is an effective treatment for SCN; more than 90% of patients treated respond with normalization of blood neutrophil counts. The SCNIR has collected data on bone pain, splenomegaly, hepatomegaly, thrombocytopenia, osteopenia/osteoporosis, vasculitis, glomerulonephritis, growth and development, pregnancy and fertility, leukemic transformation, and mortality. Analysis of data from patients who received filgrastim for up to 11 years did not identify any adverse events associated with increased duration of treatment.
Cotter M, Gulmann C, Jeffers M, Smith OP	Increased bone marrow angiogenesis in children with severe chronic neutropenia treated with granulocyte colony-stimulating factor.	Journal of pediatric hematology/oncology 2004, 26: 504
Severe chronic neutropenia (SCN) is a heterogeneous group of conditions characterized by chronically low neutrophil counts and recurrent infections. Granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, and evidence exists that G-CSF may promote angiogenesis. To evaluate the effects of G-CSF on angiogenesis in children with SCN, the authors assessed microvessel density in bone marrow biopsies from nine children with SCN before starting G-CSF treatment and while receiving G-CSF. In all patients, microvessel density was greater in the on-treatment biopsy. Increased angiogenesis may result from a direct effect of G-CSF on endothelial cells or may be an indirect effect from increased neutrophils.
Cox K, Price V, Kahr WH	Inherited platelet disorders: a clinical approach to diagnosis and management.	Expert review of hematology 2011, 4: 455
Inherited platelet disorders encompass a heterogeneous group of bleeding disorders where a variety of molecular defects can affect platelet number, function or both. The defects involve deficiencies or dysfunction of platelet receptors, signaling pathways, cytoskeletal proteins, granule contents and abnormalities in procoagulant activity. These disorders can be difficult to distinguish clinically as they present with the common symptom of mucocutaneous bleeding. Inherited thrombocytopenia needs to be considered in all patients suspected of having primary immune thrombocytopenia, where platelets may also have functional defects. After a careful history and physical examination, initial investigations include a complete blood count with a peripheral smear, followed by appropriate specific investigations that often require specialized referral centers. This article is a summary of the current data on clinical presentation, pathogenesis, diagnosis and management of inherited platelet disorders.
Craig F, Abu-Saad Huijer H, Benini F, Kuttner L, Wood C, Feraris PC, Zernikow B	IMPaCCT: standards of paediatric palliative care.	Schmerz 2008, 22: 401
The needs of children and families living with life-limiting and life-threatening illness are similar across all European countries. Meeting these needs requires a comprehensive and integrative approach, with the input of a skilled multidisciplinary paediatric team. It is essential that the core standards for paediatric palliative care recommended in this document of the European Association for Palliative Care (EAPC) now be implemented across Europe.
Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtułowicz K, Reshef A, Ritchie B, Moldovan D, Shirov T, Grivcheva-Panovska V, Kiessling PC, Keinecke HO, Bernstein JA	Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks.	The Journal of allergy and clinical immunology 2009, 124: 801
Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder.
Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke HO, Wasserman RL	C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I. M.P. A.C. T.2 study.	Allergy 2011, 66: 1604
BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.
Creutzig U, Eschenbach C, Ritter J, Schellong G	Akute Leukämie bei einem 13jährigen Jungen mit gleichzeitigem Auftreten von Lymphoblasten und Monoblasten.	Klinische Pädiatrie 1981, 193: 162
Creutzig U, Schellong G	Differenzierung der akuten Leukämien.	Dtsch Med Wochenschr 1981, 106: 1303
Creutzig U, Ritter J, Langermann H, Riehm H, Henze G, Niethammer D, Jürgens J, Stollmann B, Lasson U, Kabisch H, Wahlen W, Löffler H, Schellong G	Akute myeloische Leukämie bei Kindern.	Klinische Pädiatrie 1983, 195: 152
Creutzig U, Schellong G, Ritter J, Sutor A, Riehm H, Langermann H, Jobke A, Kabisch H	Improved results in treatment of acute myelogenous leukemia in children - report of the German cooperative AML study BFM-78.	Haematology and Blood Transfusion 1983, 28: 46
Creutzig U, Schellong G, Ritter J, Sutor A, Riehm H, Langermann H, Niethammer D, Löffler H	Ergebnisse und Risikoanalyse bei 130 Patienten der kooperativen Studie BFM-78 zur Behandlung der akuten myeloischen Leukämie im Kindesalter.	Verhandlungsband Deutsche Krebsgesellschaft 1983, 4: 207
Creutzig U, Schaaff A, Ritter J, Jobke A, Kaufmann U, Schellong G	Akute myeloische Leukemia bei Kindern unter 2 Jahren.	Klinische Pädiatrie 1984, 196: 130
Creutzig U, Ritter J, Riehm H, Langermann H, Henze G, Kabisch H, Niethammer D, Jürgens J, Stollmann B, Lasson U, Kaufmann U, Löffler H, Schellong G	Improved treatment results in childhood acute myelogenous leukemia.	Blood 1985, 65: 298
Creutzig U, Ritter J, Budde M, Riehm H, Henze G, Lampert F, Gerein V, Müller-Weihrich S, Niethammer D, Spaar H, Schellong G	Aktuelle Ergebnisse der kooperativen AML-Therapiestudien bei Kindern.	Klinische Pädiatrie 1986, 198: 183
Creutzig U, Ritter J, Riehm H, Schellong G	Therapy of acute nonlymphoblastic leukemias.	Monogr in Paediat 1986, 18: 136
Creutzig U, Cantu-Rajnoldi A, Ritter J, Romitti L, Odenwald E, Conter V, Riehm H, Masera G	Myelodysplastic syndromes in childhood.	American Journal Pediatric Hematology Oncology 1987, 9: 324
Creutzig U, Hoelzer D	Myelodysplastische Syndrome.	Klinische Pädiatrie 1987, 199: 169
Creutzig U, Ritter J, Budde M, Jürgens H, Riehm H, Schellong G	Treatment results in childhood AML, with special reference to the German studies BFM-78 and BFM-83.	Haematology and Blood Transfusion 1987, 31: 30
Creutzig U, Ritter J, Budde M, Sutor A, Schellong G	Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia.	Cancer 1987, 60: 3071
Creutzig U, Ritter J, Riehm H, Budde M, Schellong G	The childhood AML-studies BFM-78 and -83.	Haematology and Blood Transfusion 1987, 30: 71
Creutzig U, Stahnke K, Pollmann H, Sutor A, Ritter J, Budde M, Schellong G	The problem of early death in childhood AML.	Haematology and Blood Transfusion 1987, 30: 524
Creutzig U	Therapiestudien bei bösartigen Neubildungen.	1988, 9
Creutzig U, Hofmann J, Ritter J, Schellong G	Therapierealisierung und Komplikationen in der Therapiestudie BFM-83 für die akute myeloische Leukämie.	Klinische Pädiatrie 1988, 200: 190
Creutzig U, Ritter J, Niederbierbaum-Koczy G, Harbott J, Schellong G	Prognostische Bedeutung der Eosinophilie bei Kindern mit akuter myeloischer Leukämie in den Studien AML-BFM-78 und -83.	Klinische Pädiatrie 1989, 201: 220
Creutzig U, Niederbiermann G, Ritter J, Harbott J, Löffler H, Schellong G	Prognostic significance of eosinophilia in acute myelomonocytic leukemia in relation to induction treatment.	Haematology and Blood Transfusion 1990, 33: 226
Creutzig U, Ritter J, Schellong G	Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in the study AML-BFM-83 as compared with study AML-BFM-78.	Blood 1990, 75: 1932
Creutzig U, Ritter J, Vormoor J, Eschenbach C, Dickerhoff R, Burdach S, Scheel-Walter H, Kühl J, Schellong G	Transiente Myeloproliferation und akute myeloische Leukämie bei Säuglingen mit Morbus Down.	Klinische Pädiatrie 1990, 202: 253
Creutzig U, Ritter J, Vormoor J, Eschenbach C, Dickerhoff R, Burdach S, Scheel-Walter H, Kühl J, Schellong G	Transient myeloproliferative disorders and acute leukaemias in infants with Down's syndrome.	Contrib Oncol 1990, 41: 75
Creutzig U, Ritter J, Schellong G	Intensification of chemotherapy in children with acute myeloid leukemia.	Gematol Transfuziol 1991, 36: 16
Creutzig U, Bender-Götze C, Klingebiel T, Ebell W, Friedrich W, Stollmann-Gibbels B, Schmid H, Suttorp M, Gratwohl A, Heyen P, Ritter J, Schellong G	Vergleich der alleinigen Chemotherapie mit der allogenen Knochenmarktransplantation in erster Vollremission bei Kindern mit akuter myeloischer Leukämie in den Studien AML-BFM-83 und AML- BFM-87 - Matched Pair Analyse.	Klinische Pädiatrie 1992, 204: 246
Creutzig U, Ritter J, Heyen P, Berthold F, Henze G, Kabisch H, Lampert F, Niethammer D, Riehm H, Schellong G	Effect of cranial irradiation on rate of recurrence in children with acute myeloid leukemia. Initial results of the AML-BFM-87 study. The AML-BFM Study Group.	Klin Pädiatr 1992, 204: 236
Creutzig U, Ritter J, Schellong G, Group for	Involvement of the CNS in childhood AML.	Haematology and Blood Transfusion 1992, 34: 491
Creutzig U, Ritter J, Ludwig W, Harbott J, Löffler H, Schellong G	Klassifikation der AML nach morphologischen, immunologischen und zytogenetischen Kriterien - Übersicht unter Berücksichtigung der Subtypen in der Studie AML-BFM-87.	Klinische Pädiatrie 1993, 205: 272
Creutzig U, Ritter J, Schellong G, Group for	Cranial irradiation is essential in the treatment of childhood acute myelogenous leukemia.	Haematology and Blood Transfusion 1993, 36: 468
Creutzig U, Ritter J, Zimmermann M, Schellong G	Does cranial irradiation reduce the risk for bone marrow relapse in acute myelogenous leukemia?	J Clin Oncol 1993, 11: 279
Creutzig U, Ritter J, Zimmermann M, Schellong G	Superior results by cranial irradiation in children with acute myelogenous leukemia.	Onkologie 1994, 17: 66
Creutzig U	Therapie von Tumoren und malignen Systemerkrankungen des Kindes, in Zeller WJ, zur Hausen H: Onkologie.	Ecomed Verlagsgesellschaft Landsberg 1995
Creutzig U, Graf N	Früherkennung von Neoplasien im Kindesalter. (Sonderheft Früherkennung).	Onkologie 1995, 18: 24
Creutzig U, Ritter J, Ludwig W, Niemeyer C, Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J	Acute myeloid leukemia in children with Down syndrome.	Klin Pädiatr 1995, 207: 136
Creutzig U, Ritter J, Zimmermann M, Bender-Götze C, Schellong G	Bone-marrow transplantation.	Lancet 1995, 346: 60
Creutzig U, Ritter J, Zimmermann M, Bender-Götze C, Schellong G	Seven-year survival exceeding 70% without bone-marrow transplantation in first remission in standard risk children with acute myelogenous leukemia.	Blood 1995, 86
Creutzig U, Sperling Ch, Harbott J, Ritter J, Zimmermann M, Löffler H, Riehm H, Schellong G, Ludwig W	Clinical significance of surface antigen expression in children with acute myeloid leukemia.	Blood 1995, 86: 3097
Creutzig U	Cancer in the children of survivors of acute leukemia or non- Hodgkin's lymphomas in childhood.	Strahlenther Onkol 1996, 172: 690
Creutzig U	Diagnosis and treatment of acute myelogenous leukemia in childhood.	Cricial Revue Oncology Hematology 1996, 22: 183
Creutzig U, Ritter J, Harbott J, Zimmermann M, Löffler H, Schwartz S, Lampert F	Biological entities in acute myelogenous leukemia according to morphological, cytogenetic and immunological criteria.	Haematol Blood Transfus 1996,V: 524
Creutzig U, Ritter J, Niemeyer C, Stollmann-Gibbels B, Zimmermann M, Reinisch I, Harbott J	Down's syndrome and megakaryoblastic leukemia.	Haematology and Blood Transfusion 1996, 38: 754
Creutzig U, Ritter J, Vormoor J, Ludwig W, Niemeyer C, Reinisch I, Stollmann-Gibbels B, Zimmermann M, Harbott J	Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group.	Leukemia 1996, 10: 1677
Creutzig U, Ritter J, Zimmermann M, Klingebiel T	Prognose von Kindern mit chronischer myeloischer Leukämie.	Klinische Pädiatrie 1996, 208: 236
Creutzig U, Schrappe M	Akute Leukämien im Kindesalter.	Internist 1996, 37: 982
Creutzig U, Schrappe M	Acute leukemia in childhood. Classification--diagnosis--therapy--prognosis.	Internist (Berl) 1996, 37: 982
Creutzig U, Hermann J, Gadner H, Zimmermann M, Jürgens H, Ritter J	Comparison of equipotential doses of daunorubicin and idarubicin during induction.	Blood 1997, 90, suppl. 1
Creutzig U, Ritter J, Zimmermann M, Boos J, Bender-Götze C, Stahnke K	Risk factors for survival in children with refractory AML treated according to AML relapse strategies.	Haematology and Blood Transfusion 1997, 39: 810
Creutzig U, Baumann M	Spontaneous remission in neonates with Down's syndrome and acute myelogenous leukemia - transient myeloproliferative disease.	Onkologie 1998, 21: 184
Creutzig U, Bender-Götze C, Ritter J, Zimmermann M, Stollmann-Gibbels B, Körholz D, Niemeyer C	The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t	Leukemia 1998, 12: 652
Creutzig U, Kallage V, Zimmermann M, Müller J, Beck J, Kohne E, Ritter J, Group for	Therapy and outcome in children with AML classified as nonresponders.	Blood 1998, 92 suppl :
Creutzig U, Ritter J, Boos J, Zimmermann M, Bender-Gotze C, Stahnke K	Prognosis of children with acute myelocytic leukemia after first relapse.	Klin Pädiatr 1998, 210: 207
Creutzig U, Ritter J, Boos J, Zimmermann M, Bender-Götze C, Stahnke K	Prognose von Kindern mit AML nach dem ersten Rezidiv.	Klin Pädiatr 1998, 210: 207
Creutzig U	Grundlagenforschung.	Monatsschr Kinderheilk 1999, 147
Creutzig U, Jürgens H, Henze G	Kompetenznetzwerk Pädiatrische Onkologie und Hämatologie (Editorial).	Klin Pädiatrie 1999, 211: 187
Creutzig U, Ritter J, Zimmermann M, Hermann J, Bender-Götze C, Berthold F, Henze G, Jürgens H, Kabisch H, Niemeyer C, Reiter A, Feldges A, Gadner H, Group for	Improved treatment results after risk-adapted intensification of chemotherapy in children with AML.	Blood 1999, 94
Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Löffler H, Schellong G	Definition of a standard-risk group in children with AML.	Br J Haematol 1999, 104: 630
Creutzig U, Calaminus G	Vertikale Vernetzung in der Pädiatrischen Onkologie. Von der Diagnose bis zur Nachsorge.	Onkologe 2000, 6: 814
Creutzig U, Körholz D, Niemeyer C, Kabisch H, Graf N, Reiter A, Scheel-Walter H, Bender-Gotze C, Behnisch W, Hermann J, Mann G, Ritter J, Zimmermann M	Toxicity and effectiveness of high-dose idarubicin during AML induction therapy.	Klin Pädiatr 2000, 212: 163
Creutzig U, Körholz D, Niemeyer C, Kabisch H, Graf N, Reiter A, Scheel-Walter H, Bender-Götze C, Behnisch W, Hermann J, Mann G, Ritter J, Zimmermann M	3 x14 mg idarubicin during induction. Results of a pilot study in children with AML.	Leukemia 2000, 14: 340
Creutzig U, Schwager W, Reinhardt D, Klein G, Harbott J, Zimmermann M, Ritter J	Secondary acute myeloid leukemia following primary malignancies in Childhood [Abstract].	Blood 2000, 96: 1365
Creutzig U, Berthold F, Boos J, Fleischhack G, Gadner H, Gnekow A, Graubner U, Henze G, Hermann J, Imbach P, Jürgens H, Kabisch H, Körholz D, Niemeyer C, Reinhardt D, Reiter A, Ritter J, Spaar H, Zimmermann M	Improved treatment results in children with AML.	Klin Pädiatr 2001, 213: 175
Creutzig U, Reinhardt D, Ritter J, Schrappe M, Teigler-Schlegel A, Zimmermann M	Extramedullary leukemia predicts unfavorable prognosis in children with AML.	Blood (suppl) 2001, 98: 3001
Creutzig U, Reinhardt D, Zimmermann M, Klingebiel T, Gadner	Intensive chemotherapy versus bone marrow transplantation in pediatric acute myeloid leukemia.	Blood 2001, 97: 3671
Creutzig U, Ritter J, Zimmermann M, Hermann J, Gadner H, Group for	Risk-Adapted Therapy and Randomization in Children with AML.	Haematology and Blood Transfusion 2001, 40: 519
Creutzig U, Ritter J, Zimmermann M, Hermann J, Gadner H, Sawatzki D, Niemeyer C, Schwabe D, Selle B, Boos J, Kühl J, Feldges A	Idarubicin improves blast cell clearance during induction therapy in children with AML.	Leukemia 2001, 15: 348
Creutzig U, Ritter J, Zimmermann M, Reinhardt D, Hermann J, Berthold F, Henze G, Jürgens H, Kabisch H, Havers W, Reiter A, Kluba U, Niggli F, Gadner H	Improved treatment results in high-risk pediatric acute myeloid leukemia patients after intensification with high-dose cytarabine and mitoxantrone.	J Clin Oncol 2001, 19: 2705
Creutzig U, Belohradsky BH	Infektionsprophylaxe bei hämatologisch-onkologischen Patienten in der Pädiatrie. Berichte der Qualitätssicherungsgruppe der GPOH in Zusammenarbeit mit der AG „Infektionen bei Neutropenie“ der DGPI.	Klin Pädiatr 2001, 213 [S1]:A1-A114
Creutzig U, Belohradsky B	Infektionsprophylaxe bei hämatologisch-onkologischen Patienten in der Pädiatrie Zusammenfassung aus Sonderband.	Klin Pädiatr 2001 213 S1 A1-A114
Creutzig U, Reinhardt D	Current controversies.	Br J Haematol 2002, 118: 365
Creutzig U, Reinhardt D, Lehrnbecher T, Zimmermann M	Patterns of Failures Related to Intensive Chemotherapy in Childhood AML.	Blood 2002, 100: 258b-258b
Creutzig U, Bielack S, Henze G, Jürgens H, Herold R, Kaatsch P, Klussmann J, Graf N, Reinhardt D, Schrappe M, Zimmermann M	Bedeutung der Therapie-Optimierungs-Studien für die erfolgreiche Behandlung krebskranker Kinder – Ein Rückblick auf 25 Jahre Pädiatrische Onkologie.	WIR Informationsschrift der Aktion für krebskranke Kinder e.V. (Bonn) 2002, 3: 7
Creutzig U	Akute myeloische Leukämien (AML) bei Kindern. Erstellt im Rahmen der Tagung 2003 für Leukämie- und Lymphompatienten in Leipzig.	WIR 2003
Creutzig U	Treatment of acute myeloid leukemia in children, in Pui CH: Treatment of Acute Leukemias, New Directions for Clinical Research.	Totowa, NJ: Humana Press Inc 2003, 237
Creutzig U, Henze G, Bielack S, Herold R, Kaatsch P, Klusmann J, Graf N, Reinhardt D, Schrappe M, Zimmermann M, Jürgens H	Krebserkrankungen bei Kindern. Erfolg durch einheitliche Therapiekonzepte seit 25 Jahren.	Deutsches Ärzteblatt 2003, 100:A842
Creutzig U, Henze G, Jürgens H	APO (Arbeitsgemeinschaft Pädiatrische Onkologie). Fortschritt durch Zusammenarbeit innerhalb von Studien.	Forum DKG 2003, 38
Creutzig U, Reinhardt D, Zimmermann M, Dworzak M, Stary J	Excellent Results In Patients With Downs Syndrome by Standard AML-BFM Therapy with Reduced Drug Intensity.	Blood 2003, 102
Creutzig U, Zimmermann M, Hannemann J, Krämer I, Herold R, Henze G	Qualitätssicherung im Kompetenznetz Pädiatrische Onkologie und Hämatologie.	Klin Pädiatr 2003, 215: 338
Creutzig U, Zimmermann M, Reinhardt D, Lehrnbecher T	Analysis of Causes of Death During Intensive Chemotherapy According to Treatment Protocol AML-BFM 93.	Klin Pädiatr 2003, 215: 151
Creutzig U	Bessere Chancen auf Heilung - Erfolge in der Behandlung von Kindern mit Krebs.	Heilberufe 2004, 38
Creutzig U, Jürgens H, Herold R, Göbel U, Henze G	Konzepte der GPOH und des Kompetenznetzes zur Weiterentwicklung und Qualitätssicherung in der Pädiatrischen Onkologie.	Klin Pädiatr 2004, 216: 379
Creutzig U, Reinhardt D, Zimmermann M: AML-BFM Study Group	Prognostic Relevance of Risk Groups in the Pediatric AML-BFM Trials 93 and 98.	Annals Hematology 2004, 83:S112-S116
Creutzig U, Zimmermann M, Reinhardt D, Dworzak M, Stary J, Lehrnbecher T	Early Deaths and Treatment-Related Mortality in Children Undergoing Therapy for Acute Myeloid Leukemia.	J Clin Oncol 2004, 22: 4384
Creutzig U	Studienprotokoll der Therapieoptimierungsstudie AML-BFM 2004.	2004
Creutzig U und Klusmann JH	Chronik der Gesellschaft für Pädiatrische Onkologie und Hämatologie.	Eigenpublikation GPOH und KPOH 2004
Creutzig U, Reinhardt D, Diekamp S, Dworzak M, Stary J, Zimmermann M	AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity.	Leukemia 2005, 19: 1355
Despite improved prognosis in acute myelogenous leukaemia (AML) children with Down syndrome (DS), therapy-related toxicity remained a problem. We compared 67 DS patients from study AML-BFM 98 with 51 DS patients of the previous study AML-BFM 93, and the non-DS groups of both studies. Compared to non-DS patients, DS patients were treated with reduced anthracycline doses, without high-dose cytarabine/mitoxantrone and without cranial irradiation. AML-DS patients were in median 1.8 years old, and 102/118 (86%) showed the typical morphology of acute megakaryoblastic leukaemia. In study 93, seven DS patients did not receive AML-specific chemotherapy, and treatment modifications were more common. Results improved significantly for patients treated in study 98 with a 3-year survival of 91+/-4 vs 70+/-7% in study 93 (P=0.001). There were no differences in outcome concerning the age groups 0-
Creutzig U, Zimmermann M, Ritter J, Reinhardt D, Hermann J, Henze G, Jürgens H, Kabisch H, Reiter A, Riehm H, Gadner H, Schellong G	Treatment strategies and long-term results in paediatric patients treated in four consecutive AML-BFM trials.	Leukemia 2005, 19: 2030
A total of 1111 children with acute myeloblastic leukaemia (AML) were treated in four consecutive Berlin-Frankfurt-Münster (BFM) studies from 1978 to 1998. The first cooperative trial AML-BFM 78 established intensive chemotherapy with seven drugs, CNS irradiation and 2-year maintenance, achieving a long-term survival (overall survival (OS)) of 40%. Induction intensification in AML-BFM 83 resulted in significant improvement of disease-free survival (DFS). The risk of haemorrhage, especially in children with hyperleukocytosis, proved the high relevance of supportive care. In AML-BFM 87, the benefit of CNS irradiation in preventing CNS/systemic relapses was demonstrated. In AML-BFM 93, the introduction of idarubicin during first induction followed by intensification with HAM increased the 5-year EFS, DFS and OS to 50+/-2, 61+/-3 and 57+/-2%, respectively. Stem cell transplantation (SCT), as applied in high-risk patients with a matched related donor, did not significantly improve the outcome compared to chemotherapy alone. In spite of treatment intensification, the therapy-related death rate decreased from trial to trial, mainly during induction. The future aim is to reduce long-term sequelae, especially cardiotoxicity, by administration of less cardiotoxic drugs, and toxicity of SCT by risk-adapted indications. The AML-BFM studies performed in three European countries with >70 cooperating centres have significantly improved the outcome in AML children; nevertheless, increasing experience with these intensive treatment regimens is of fundamental importance to reduce fatal complications.
Creutzig U, Reinhardt D	Akute myeloische Leukämien.	In: Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors. Pädiatrische Hämatologie und Onkologie Berlin, Heidelberg, New York: Springer Verlag, 2006, 690-714.
Creutzig U	Relapsed acute myeloid leukemia, in Pui CH: Childhood Leukemias.	Cambridge University Press 2006, 2. Aufl.
Creutzig U, Zimmermann M, Lehrnbecher T, Graf N, Hermann J, Niemeyer CM, Reiter A, Ritter J, Dworzak M, Stary J, Reinhardt D	Less toxicity by optimizing chemotherapy, but not by addition of granulocyte colony-stimulating factor in children and adolescents with acute myeloid leukemia: results of AML-BFM 98.	Journal of clinical oncology 2006, 24: 4499
PURPOSE: To improve prognosis in children with acute myeloid leukemia (AML) by randomized comparisons of (1) two short consolidation cycles versus the Berlin-Frankfurt-Muenster (BFM) -type biphasic 6-week consolidation and (2) the prophylactic administration of granulocyte colony-stimulating factor (G-CSF) versus no G-CSF. Further, therapy for standard risk patients was intensified by addition of a second induction, HAM (high-dose cytarabine and mitoxantrone). PATIENTS AND METHODS: Four hundred seventy-three patients younger than 18 years with de novo AML were enrolled in trial AML-BFM 98. Patients received five courses of intensive chemotherapy, cranial irradiation, and 1-year maintenance therapy. RESULTS: Four hundred eighteen patients (88%) achieved remission. Compared with trial AML-BFM 93, early deaths decreased from 7.4 to 3.2% (P = .005), and 5-year overall survival increased from 58% to 62% (log-rank P = .03). Both types of consolidation therapy led to similar outcome (event-free survival, 51% v 50%), but in the two-cycle arm, treatment duration was shorter (median duration, 15 days), and treatment related mortality was lower (five v nine patients). G-CSF shortened neutropenia, but did not reduce the rate of severe infections. Intensification of induction therapy did not improve prognosis of standard-risk patients (event-free survival, 62% v 67%). CONCLUSION: Overall results were improved by neither the administration of G-CSF nor by cycle therapy; however, the latter was easier to perform. Compared with study AML-BFM 93, therapy intensification with HAM in standard-risk patients did not result in improved prognosis. Future treatment designs have to balance intensification of treatment with higher toxicity, improve supportive care, and to consider alternative treatment strategies.
Creutzig U, Zimmermann M	Klinische Studien: Planung, Durchführung und Interpretation.	In: Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors. Pädiatrische Hämatologie und Onkologie Berlin, Heidelberg, New York: Springer Verlag, 2006, 634
Creutzig U, Diekamp S, Zimmermann M, Reinhardt D	Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML.	Pediatric blood & cancer 2007, 48: 651
BACKGROUND: Anthracyclines are effective antineoplastic drugs in acute myelogenous leukemia (AML). However, their use is limited by cardiomyopathy, which occurs in children already at cumulative doses of 300 mg/m(2) (given as daunorubicin equivalent). PROCEDURE: To evaluate anthracycline-associated cardiomyopathy in pediatric AML-patients, the incidence of early and late (>1 year after intensive AML chemotherapy) clinical and subclinical cardiotoxicity was analyzed out of a total of 1,207 patients <18 years treated between 1993 and 2003 in trials AML-BFM93/98: 1,010 protocol patients with de novo AML, 121 with Down syndrome (DS)-AML, and 76 with secondary AML. The cumulative dose of anthracyclines was generally risk-adapted: 300-450 mg/m(2) using 1-4-hr infusions of anthracyclines with the assumed lowest cardiotoxic potential. Eight hundred eighty-five patients (73%) were eligible for the analysis of early and 547 (45%) of late cardiotoxicity (1,399 follow-up data). RESULTS: Thirty-eight patients (4.3%), including 3 DS-AML and 1 secondary AML, suffered from early cardiomyopathy. After 5 years, four patients showed temporarily or persistently a reduced shortening fraction, which led to death in one DS-AML patient. Including these 4 patients, late cardiomyopathy was seen in 16 patients (cumulative incidence after 11 years: 5% +/- 1%). Nine patients (2.5 +/- 1%) showed clinical symptoms, five of them had persistent abnormal shortening fraction. Late subclinical cardiomyopathy occurred temporarily in seven patients. Late clinical cardiomyopathy mainly affected patients with a second anthracycline therapy (secondary malignancy) and those with early cardiotoxicity. CONCLUSION: In spite of a highly intensive and effective treatment, the frequency of anthracycline-associated cardiomyopathy was low in the AML-BFM studies.
Creutzig U, Büchner T, Sauerland MC, Zimmermann M, Reinhardt D, Döhner H, Schlenk RF	Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A.	Cancer 2008, 112: 562
BACKGROUND: Data on the impact of age in acute myeloid leukemia (AML) patients <30 years treated in pediatric and adult trials are scarce. METHODS: In all, 891 patients <18 years were treated in the pediatric trials AML-BFM 93/98 and 290 adolescents and young adults (>16 to <30 years) in the AMLCG 92/99 and AMLSG HD93/98A trials. Treatment schedules and dose intensities were comparable. RESULTS: Initial features and risk factors differed considerably between infants (<2 years) and older age groups and only slightly between children (2 to <13), adolescents (13 to <21) and young adults (21 to <30). Treatment results were most favorable in children (5-year event free survival [EFS]: 54% +/- 3%), slightly inferior in adolescents (46% +/- 4%, P = .03), and unfavorable in young adults (28% +/- 5%, P = .0001). Excluding patients with favorable karyotypes, the results were similar in infants and children (EFS: 44% +/- 4% and 46% +/- 3%, respectively) and inferior in adolescents (35% +/- 4%) and young adults (23% +/- 4%). There was an increased, age-related percentage and inferior outcome in patients with >5% bone marrow blasts after induction. EFS was especially poor in young adults, with blasts >5%. The blast count after induction was of no prognostic value in patients with favorable karyotypes, but a significant risk factor in patients with other cytogenetics. CONCLUSIONS: Biologic data differed mainly between infants and older age groups. When comparing the same age groups, outcome was similar between the trial groups, which differed from reports concerning acute lymphoblastic leukemia. However, the prognosis decreased after childhood independent of other risk factors. This indicates that even in the younger cohorts increasing age may be an additional unfavorable factor.
Creutzig U, Henze G	Abschlusssymposium des Kompetenznetzes Pädiatrische Onkologie und Hämatologie.	Onkologie 2008, 14: 951
1433-0415
Cremer, H	Hämangiome – Klassifizierung und Therapie-Empfehlungen.	pädiatrie hautnah 2009, 2: 133
Hämagiome treten in sehr unterschiedlichen Verlaufsformen auf, diese grenzen sich stark in Häufigkeit und Entwicklung voneinander ab. Ersten Erfahrungsberichten zufolge steht mit Propranolol eine neue Option zur Behandlung von Hämangiomen zur Verfügung, die wesentlich besser geeignet ist als Kortikosteroide.
Creutzig U, Zimmermann M, Dworzak M, Urban C, Henze G, Kremens B, Lakomek M, Bourquin JP, Stary J, Reinhardt D	Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses.	British journal of haematology 2010, 149: 399
Summary Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m(2)) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 +/- 4% and event-free survival (pEFS) was 73 +/- 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 +/- 8%, 98: 85 +/- 7% and 2004: 94 +/- 8%, P((logrank)) = 0.63). Seventy-five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long-term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long-term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that - combined with ATRA - a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long-term sequelae, such as cardiotoxicity in APL patients.
Creutzig U, Herold R, Henze G	Results of the Competence Net Pediatric Oncology and Haematology - a View Back.	Klinische Padiatrie 2010, 222: 333
Creutzig U, Tallen G, Bode A, Reinken K, Yiallouros M, Herold R, Henze G	Das Informationsportal www. kinderkrebsinfo. de.	FORUM 2010 25: 49
Creutzig U, Tallen G Dobke J, Grüneberg I, Reinken K, Yiallouros M, Henze G	Das Informationsportal www. kinderkrebsinfo. de - Internet als Ratgeber über Krebs bei Kindern und Jugendlichen.	Onkologische Pharmazie 2010 3: 45
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, von Neuhoff C, Sander A, Schrauder A, von Stackelberg A, Ritter J, Starý J, Reinhardt D	CNS irradiation in pediatric acute myeloid leukemia: Equal results by 12 or 18 Gy in studies AML-BFM98 and 2004.	Pediatr Blood Cancer 2011, [Epub ahead of print]
BACKGROUND: The impact of preventive central nervous system irradiation (CNS-RT) in childhood acute myeloid leukemia (AML) is still discussed. As results of study AML-BFM87 revealed an increased risk for relapse when CNS-RT was not performed, studies AML-BFM98 and -2004 randomized CNS-RT of 18 or 12 Gy in order to evaluate the efficacy of the lower dose and to reduce late effects. PROCEDURES: To achieve a power of 80% for non-inferiority (range 11%) 240 patients per group were required. Out of 722 eligible patients, 486 patients <18 years were randomized to receive 12 Gy (n = 249) or 18 Gy (n = 237). Since this was a non-inferiority study, the analysis was performed for patients as treated (12 Gy: n = 252 and 18 Gy: n = 219). RESULTS: Five-year survival, event-free survival and cumulative incidence of relapse were similar in patients who received 12 or 18 Gy, respectively (82 ± 3% vs. 79 ± 3%, 68 ± 3% vs. 63 ± 3%, and 30 ± 3% vs. 34 ± 3%). The lower limit of the one-sided confidence interval for the -5% difference in 5-years pEFS was 2%. There were six relapses with CNS involvement (one in the 12 Gy, and five in the 18 Gy group). CONCLUSION: Results demonstrate no disadvantage for patients irradiated with a reduced CNS dose of 12 Gy
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, von Neuhoff C, Sander A, Schrauder A, Teigler-Schlegel A, Stary J, Corbacioglu S, Reinhardt D	Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16).	Blood 2011, 118: 5409
Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) or inv(16)/t(16;16) subtypes require intensification remained to be determined. In the two successive studies AML-BFM 98 and -2004, 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study -98 but not in -2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n=78) compared to without HAM (n=53): OS 92%±3% vs. 80%±6%, plogrank0.047, EFS 84%±4% vs. 59%±7%, plogrank0.001, and CIR 14%±4% vs. 34%±7%, p(gray)0.006. These differences were not seen for inv(16) (n=43 and 46, respectively): OS 93%±4% vs. 94%±4%, EFS 75%±7% vs. 71%±9% and CIR 15%±6% vs. 23%±8% (not significant). The subtype t(8;21) but not inv(16) was an independent predictor of worse outcome without HAM reinduction. Based on our data, a five-year OS of more than 90% can be expected for CBF-AML, when stratifying t(8;21) but not inv(16) patients to high risk chemotherapy including HAM reinduction.
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Kremens B, Lehrnbecher T, von Neuhoff C, Sander A, von Stackelberg A, Schmid I, Starý J, Steinbach D, Vormoor J, Reinhardt D	Favorable outcome in infants with AML after intensive first- and second-line treatment: an AML-BFM study group report.	Leukemia 2012, 26: 654
Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia (AML) were treated in studies AML-BFM-98 (n=59) and -2004 (n=66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66±4%, and improved from 61±6% in study-98 to 75±6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44±6% and 51±6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.Leukemia advance online publication, 4 October 2011; doi:10.1038/leu.2011.267.
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, von Neuhoff C, Sander A, Schrauder A, Teigler-Schlegel A, Stary J, Corbacioglu S, Reinhardt D	Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16).	Blood 2011, 118: 5409
Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) or inv(16)/t(16;16) subtypes require intensification remained to be determined. In the two successive studies AML-BFM 98 and -2004, 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study -98 but not in -2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n=78) compared to without HAM (n=53): OS 92%±3% vs. 80%±6%, plogrank0.047, EFS 84%±4% vs. 59%±7%, plogrank0.001, and CIR 14%±4% vs. 34%±7%, p(gray)0.006. These differences were not seen for inv(16) (n=43 and 46, respectively): OS 93%±4% vs. 94%±4%, EFS 75%±7% vs. 71%±9% and CIR 15%±6% vs. 23%±8% (not significant). The subtype t(8;21) but not inv(16) was an independent predictor of worse outcome without HAM reinduction. Based on our data, a five-year OS of more than 90% can be expected for CBF-AML, when stratifying t(8;21) but not inv(16) patients to high risk chemotherapy including HAM reinduction.
Creutzig U	Kommentar: Krebs bei Kindern und Jugendlichen - Versorgung in Zentren.	Dtsch Arztebl 2012; 109(1-2): A-18 / B-15 / C-15
Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN, Adachi S, de Bont E, Harbott J, Hasle H, Johnston D, Kinoshita A, Lehrnbecher T, Leverger G, Mejstrikova E, Meshinchi S, Pession A, Raimondi SC, Sung L, Stary J, Zwaan CM, Kaspers GJ, Reinhardt D, AML Committee of the International BFM Study Group	Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel.	Blood 2012, 120: 3187
Despite major improvements in outcome over the past decades, acute myeloid leukemia (AML) remains a life-threatening malignancy in children, with current survival rates of ∼70%. State-of-the-art recommendations in adult AML have recently been published in this journal by Döhner et al. The primary goal of an international expert panel of the International BFM Study Group AML Committee was to set standards for the management, diagnosis, response assessment, and treatment in childhood AML. This paper aims to discuss differences between childhood and adult AML, and to highlight recommendations that are specific to children. The particular relevance of new diagnostic and prognostic molecular markers in pediatric AML is presented. The general management of pediatric AML, the management of specific pediatric AML cohorts (such as infants) or subtypes of the disease occurring in children (such as Down syndrome related AML), as well as new therapeutic approaches, and the role of supportive care are discussed.
Creutzig U	Relapsed acute myeloid leukemia. In: Pui C-H, ed. Childhood Leukemias. Cambridge:.	Cambridge University Press; 2012, 421-428.
Creutzig U, Tallen G	Treatment results for children and adolescents with acute myeloid leukemia in Middle and Eastern European countries.	memo 2013 6: 5
Creutzig U ,Zimmermann M, Dworzak MN, Ritter J, Schellong G, Reinhardt D	Development of a curative treatment within the AML-BFM studies.	Klinische Padiatrie 2013, 225 Suppl 1:S79
The first multicenter treatment study for AML in childhood in Germany was performed from 1978 onwards. The therapy plan was designed similar to that for the acute lymphoblastic leukaemia (ALL). The drugs with the highest efficacy in AML, cytarabine cutting catara-bine and anthracyclines, were combined during induction and consolidation, followed by preventive cranial irradiation and maintenance therapy similar to that in ALL. The remission rate of the initial study was 80%, and the 5-year survival rate increased from less than 10% before 1970 to 40%. 5 subsequent trials have further increased the 5-year survival to now 70% and even 90% in the subgroup of core-binding factor leukaemias by using an intensified and optimised treatment schedule.The AML-BFM studies were the only prospective study sequence testing the benefit of cranial irradiation. Results from study -87 including the non-randomized patients showed an increased risk of CNS and/or bone marrow relapses in non-irradiated patients. Later on there was evidence that 12 Gy resulted in the same relapse rate as 18 Gy. The AML-BFM studies always used the experience from the previous study to optimize the next study. This approach was essential together with improved supportive treatment and experience of the medical staff for the step-wise and considerable increase of longterm survival within the 6 subsequent AML-BFM studies.
Creutzig U, Zimmermann M, Bourquin JP, Dworzak MN, Fleischhack G, Graf N, Klingebiel T, Kremens B, Lehrnbecher T, von Neuhoff C, Ritter J, Sander A, Schrauder A, von Stackelberg A, Stary J, Reinhardt D	Randomized trial comparing liposomal daunorubicin with idarubicin in induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004.	Blood 2013, 122: 37
Outcome of adult and pediatric patients with AML improved significantly by intensification of induction treatment. To further intensify anthracycline-dosage without increasing cardiotoxicity, we compared the potentially less cardiotoxic liposomal daunorubicin (L-DNR) at a higher than equivalent dose (80mg/m(2)/day/x3) to idarubicin (12mg/m(2)/day/x3) during induction. In study AML-BFM 2004, 521/611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival: 76%±3% [L-DNR] vs. 75%±3% [idarubicin], plogrank=.65, event-free survival [pEFS]: 59%±3% vs. 53%±3%, plogrank=.25; cumulative incidence of relapse: 29%±3% vs. 31%±3%, p(Gray)=0.75), as were EFS results for standard (72%±5% vs. 68%±5%, plogrank=.47) and high-risk patients (51%±4% vs. 46%±4%, plogrank=.45). L-DNR resulted in significantly better pEFS in t(8;21) patients. Overall, treatment-related mortality (TRM), was lower in the L-DNR- than in the idarubicin-group (2/257 vs. 10/264 patients, p=.04). Grade III/IV cardiotoxicity was rare after induction (4 L-DNR- vs. 5 idarubicin-patients). Only one L-DNR- and 3 idarubicin-patients presented with subclinical or mild cardiomyopathy during follow-up. We conclude that L-DNR has - at the given dose - an overall anti-leukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less TRM. These results with high survival rates support its use in the forthcoming AML-BFM trial. ClinicalTrials.gov Identifier: NCT00111345.
Creutzig U, Dworzak M, Reinhardt D	Akute myeloische Leukämie im Kindesalter - Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie -	AWMF online 02/2013
Creutzig U, Semmler J, Kaspers GL, Reinhardt D, Zimmermann M	Re-induction with L-DNR/FLAG improves response after AML relapse, but not long-term survival.	Klinische Padiatrie 2014, 226(6-7): 323
According to the results of the international study Relapsed AML 2001/01 response was better after re-induction with L-DNR/FLAG (liposomal daunorubicin, fludarabine, cytarabine, G-CSF) compared to FLAG only but survival rate was not improved. However, the findings might be group-specific.
Creutzig U, Rössig C, Dworzak M, Stary J, von Stackelberg A, Wössmann W, Zimmermann M, Reinhardt D	Exchange Transfusion and Leukapheresis in Pediatric Patients with AML With High Risk of Early Death by Bleeding and Leukostasis.	Pediatr Blood Cancer 2015 [Epub ahead of print]
The risk of early death (ED) by bleeding/leukostasis is high in patients with AML with hyperleukocytosis (>100,000/μl). Within the pediatric AML-BFM (Berlin-Frankfurt-Münster) 98/04 studies, emergency strategies for these children included exchange transfusion (ET) or leukapheresis (LPh). Risk factors for ED and interventions performed were analyzed. PATIENTS: Two hundred thirty-eight of 1,251 (19%) patients with AML presented with hyperleukocytosis; 23 of 1,251 (1.8%) patients died of bleeding/leukostasis. RESULTS: ED due to bleeding/leukostasis was highest at white blood cell (WBC) count >200,000/μl (14.3%). ED rates were even higher (20%) in patients with FAB (French-American-British) M4/M5 and hyperleukocytosis >200,000/μl. Patients with WBC >200,000/μl did slightly better with ET/LPh compared to those without ET/LPh (ED rate 7.5% vs. 21.2%, P = 0.055). Multivariate WBC >200,000/μl was of strongest prognostic significance for ED (P(χ2 ) <0.0001). CONCLUSION: Our data confirm the high risk of bleeding/leukostasis in patients with hyperleukocytosis. ET/LPh shows a trend toward reduced ED rate due to bleeding/leukostasis and is recommended at WBC >200,000/μl, and in FAB M4/M5 even at lower WBC.
Creutzig U, Dworzak M, Zimmermann M, Bourquin JP, Gruhn B, Fleischhack G, Graf N, Klingebiel T, Kremens B, Lehrnbecher T, von Neuhoff C, von Stackelberg A, Stray J, Reinhardt D	Randomised Introduction of 2-CDA as Intensification during Consolidation for Children with High-risk AML--results from Study AML-BFM 2004.	Klin Pädiatr 2015, 227: 116
BACKGROUND: The outcome in children and adolescents with high-risk (HR) acute myeloid leukemia (AML) is still unsatisfactory. Therefore, in study AML-BFM 2004 we aimed to improve outcome of HR-patients by adding moderately dosed 2-Chloro-2-Deoxyadenosine (2-CDA) to the respective consolidation treatment backbone without increasing toxicity. The aim was to improve prognosis especially in FAB M4/M5/MLL patients, who represent the largest subgroup of HR patients. PATIENTS AND METHODS: In total, 343 children and adolescents with HR-AML were randomized to receive or not 2-CDA (6 mg/m²/d, days 1, 3) in combination with cytarabine/idarubicine (AI=500 mg/m² cytarabine 5 days continuous infusion plus 7 mg/m²/d idarubicin, days 3 and 5). RESULTS: RESULTS for patients of the AI/2-CDA arm (n=168) vs. the AI-arm (n=175) were similar: 5-year overall survival 68±4 vs. 72±4%, plogrank=0.38, event-free survival 53±4 vs. 49±4%, plogrank=0.77; cumulative incidence of relapse at 5 years: 35±4 vs. 37±4%, p(Gray)=0.89. RESULTS in patients with MLL rearrangement or FAB M4/M5 were also similar in the treatment groups. In addition, toxicities did not differ between the two arms. CONCLUSION: We conclude that additional, moderate dose 2-CDA does not improve prognosis in HR-patients when given during consolidation treatment. Its effect might be too low in this multidrug regimen, where the strongest effects are achieved during induction, or the chosen dose of 2-CDA might have been too low.
Creutzig U, Dworzak MN, Zimmermann M, Bourquin JP, Gruhn B, Fleischhack G, Graf N, Klingebiel T, Kremens B, Lehrnbecher T, von Neuhoff C, Stackelberg AV, Starý J, Reinhardt D	Additional treatment with 2-Chloro-2-Deoxyadenosine during consolidation in children with high-risk acute myeloid leukemia does not improve survival.	Leukemia 2015, 29: 2260
Creutzig U, Zimmermann M, Reinhardt D, Rasche M, von Neuhoff C, Alpermann T, Dworzak M, Perglerová K, Zemanova Z, Tchinda J, Bradtke J, Thiede C, Haferlach C	Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups.	Cancer 2016, 122: 3821
BACKGROUND: To obtain better insight into the biology of acute myeloid leukemia (AML) in various age groups, this study focused on the genetic changes occurring during a lifetime. METHODS: This study analyzed the relation between age and genetics from birth to 100 years in 5564 patients with de novo AML diagnosed from 1998 to 2012 (1192 patients from nationwide pediatric studies [AML Berlin-Frankfurt-Münster studies 98 and 2004] and 4372 adults registered with the Munich Leukemia Laboratory). RESULTS: The frequencies of cytogenetic subgroups were age-dependent. Favorable subtypes (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased in general from the pediatric age group (2 to < 18 years; 33%) to the oldest groups (<5% for > 70 years; P < .0001). Unfavorable cytogenetics (-7/del(7), -5/del(5q) or 5p, inv(3)/t(3;3), t(6;9), complex karyotype, 12p, 17p, and 11q23/mixed-lineage leukemia aberrations, excluding t(9;11)) were frequent (42%) in infants (<2 years), had a low frequency in children and young adults (<22%), and increased in frequency up to 36% in patients older than 85 years (P = .01). This was even more significant for complex karyotypes (P ≤ .0001), which also showed a strong increase in the absolute age-specific incidence with age. Interestingly, the frequency of 11q23 abnormalities decreased from infants to older patients. The proportion of clinically relevant molecular aberrations of CCAAT/enhancer binding protein α, nucleophosmin (NPM1), and NPM1/fms-related tyrosine kinase 3-internal tandem duplication increased with age. CONCLUSIONS: Altogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016;122:3821-3830. © 2016 American Cancer Society.
Creutzig U, Dworzak MN, Bochennek K, Faber J, Flotho C, Graf N, Kontny U, Rossig C, Schmid I, von Stackelberg A, Mueller JE, von Neuhoff C, Reinhardt D, von Neuhoff N	First experience of the AML-Berlin-Frankfurt-Münster group in pediatric patients with standard-risk acute promyelocytic leukemia treated with arsenic trioxide and all-trans retinoid acid.	Pediatric blood & cancer 2017, Epub ahead of print
Recently, studies in adults with acute promyelocytic leukemia (APL) showed high cure rates in low-risk patients treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO), while toxicities were significantly reduced compared to the standard treatment with ATRA and chemotherapy. Here we report about first experience with 11 pediatric patients with low-risk APL treated with ATRA and ATO. All patients stayed in molecular remission. All suffered from hyperleukocytosis. Two patients experienced reversible severe side effects. One suffered from osteonecroses at both femurs, seizures, as well as posterior reversible encephalopathy syndrome, the other patient had an abducens paresis.
Creutzig U, Reinhardt D	Akute myeloische Leukämien.	in Niemeyer CH, Eggert A (Hrsg.): Pädiatrische Hämatologie und Onkologie 2018
Creutzig U, Dworzak M, von Neuhoff N, Rasche M, Reinhardt D	[Acute Promyelocytic Leukemia: New treatment strategies with ATRA and ATO - AML-BFM-Recommendations].	Klinische Padiatrie 2018, 230: 299
The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children.
Creutzig U, Dworzak M, Reinhardt D	Akute myeloische Leukämie (AML) im Kindes- und Jugendalter.	Leitlinie der Gesellschaft für Pädiatrische Onkologie und Hämatologie AWMF
Niktoreh N, Lerius B, Zimmermann M, Gruhn B, Escherich G, Bourquin JP, Dworzak M, Sramkova L, Rossig C, Creutzig U, Reinhardt D, Rasche M	Gemtuzumab ozogamicin in children with relapsed or refractory acute myeloid leukemia: a report by Berlin-Frankfurt-Münster study group.	Haematologica 2019, 104: 120
Creutzig U, Hiddemann W	Late Effects after Treatment of Acute Myeloid Leukemia in Childhood and Adolescence.	in Beck JD et al. (Hrsg.): Late Treatment Effects and Cancer Survivor Care in the Young, pp 183-188 Springer Nature Switzerland AG 22021
Crosby LE, Shook LM, Ware RE, Brinkman WB	Shared decision making for hydroxyurea treatment initiation in children with sickle cell anemia.	Pediatric blood & cancer 2014, Epub ahead of print
Clinical trials have demonstrated hydroxyurea's efficacy in improving health outcomes for children with sickle cell anemia (SCA) who have medical complications. New NHLBI clinical guidelines will recommend offering hydroxyurea to young patients regardless of clinical severity. Shared decision making may be an effective approach for implementing this practice change. Decision aids that help patients/parents feel empowered to make this decision and help providers feel comfortable in discussing hydroxyurea as a preventive treatment may facilitate shared discussions between families and providers. We recommend six strategies providers can use to facilitate these discussions while decision aids and tools are being developed. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
Cuker A, Neunert CE	How I treat refractory immune thrombocytopenia.	Blood 2016, 128: 1547
cw	Nachsorge ist für alle ein Thema.	Pädiatrische Nachrichten 1999, 4
Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, Rinaldi E, Feng Y, Aronson D, Malogolowkin M, Yoshimura K, Leuschner I, Lopez-Terrada D, Hishiki T, Perilongo G, von Schweinitz D, Schmid I, Watanabe K, Derosa M, Meyers R	The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model.	European journal of cancer 2016, 52: 92
Contemporary state-of-the-art management of cancer is increasingly defined by individualized treatment strategies. For very rare tumors, like hepatoblastoma, the development of biologic markers, and the identification of reliable prognostic risk factors for tailoring treatment, remains very challenging. The Children's Hepatic tumors International Collaboration (CHIC) is a novel international response to this challenge.
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