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ABSTRACT: Die Behandlung krebskranker Kinder und Jugendlicher wurde innerhalb der letzten 50 Jahre stetig verbessert, mit dem Ergebnis,
dass heute Überlebensraten von etwa 75% erreicht werden. Chemo- und/oder Radiotherapien können allerdings bei bis zu 2/3 der
Patienten Folgeerkrankungen (Spätfolgen) verursachen. Anthrazyklininduzierte Kardiotoxizität, Hörminderungen, verursacht durch
platinhaltige Chemotherapeutika, und endokrine Störungen nach Strahlentherapie sind nur drei der häufig beobachteten Spätfolgen,
von denen die Überlebenden betroffen sind. Eine gezielte prospektive Nachsorge der Patienten ist somit von großer Bedeutung
und soll sicherstellen, dass Organschäden dieser Art frühzeitig erkannt und behandelt werden. Das Late Effects Surveillance
System (LESS), ein nationales Nachsorgenetzwerk, das im Auftrag der Gesellschaft für Pädiatrische Onkologie und Hämatologie
(GPOH) gegründet wurde, gibt in Zusammenarbeit mit den Therapieoptimierungsstudien und weiteren GPOH-Arbeitsgruppen Empfehlungen
für eine strukturierte Nachsorge und erfüllt darüber hinaus eine beratende Funktion. Wenn möglich, sollen die Krebsbehandlungen
in Zukunft nebenwirkungsärmer werden.
Over the last 50 years, improvements in treatments for childhood cancer have led to the extremely gratifying result of survival
rates that now exceed 75%. However, about two-thirds of the patients will suffer from late effects of chemotherapy and/or
radiotherapy. Anthracycline-induced cardiotoxicity, hearing impairment caused by platinum compounds, and endocrine disturbances
related to radiation therapy are three commonly observed sequelae that afflict childhood cancer survivors. Systematic prospective
aftercare of these patients is particularly important and is necessary in order to detect and treat organ impairment as soon
as possible. The Late Effects Surveillance System (LESS) is a national aftercare network established by the German Association
of Paediatric Oncology and Haematology (GPOH). In collaboration with therapy optimisation studies and other working groups
of the GPOH, LESS gives recommendations for follow-up and fulfils advisory functions. A future aim is to develop treatments
that will avoid major late effects.
Monatsschrift Kinderheilkunde 04/2012; 157(4):329-338. · 0.27 Impact Factor
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ABSTRACT: Irradiation of brain tumors (BT) in children can lead to the loss of pituitary function, predominantly manifesting as deficiencies in GH and ACTH.
To assess the incidence and nature of pituitary deficiency in relation to initial tumor location in children after radiotherapy of BT.
Twenty survivors (16 males and 4 females) of radiation-treated BT aged 1.4-10.9 (median 3.6) yr at diagnosis were studied, 10 with supratentorial and 10 with infratentorial BT. Radiation doses to the hypothalamus- pituitary (HP) area ranged from 30 to 54 (median 45) Gray. Follow-up was 9.4-16.9 (median 12.2) yr. Basal pituitary hormone levels were measured every 6 months. When growth failure became evident or pituitary deficiency was suspected, provocation tests of the HP axis were performed to assess GH, ACTH, and TSH function.
GH deficiency (GHD) developed in 17/20 (85%) children. In 10 patients, it occurred 4 yr after radiotherapy and in 2, 11 and 12 yr after radiotherapy. Six (30%) patients developed secondary hypothyroidism and 4 (20%) developed ACTH deficiency. Precocious puberty occurred in 2 girls. The course of development and the severity of hormone deficiencies were similar for supratentorial and infratentorial tumors.
The major hormonal effect of BT irradiation in children is GHD, which may sometimes take more than 10 yr to manifest. We confirm findings by others that ACTH insufficiency occurs less frequently in children than reported for adults. Tumor location has no prognostic significance regarding the loss of HP function.
Journal of endocrinological investigation 05/2009; 32(4):294-7. · 1.57 Impact Factor
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M Schwemmlein,
J Stieglmaier,
C Kellner,
M Peipp,
D Saul,
F Oduncu,
B Emmerich,
B Stockmeyer,
P Lang, J D Beck,
G H Fey
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ABSTRACT: CD19 is a B-lineage-specific transmembrane signaling protein participating in the control of proliferation and differentiation. It is present at high surface density on chronic B-lymphocytic leukemia (B-CLL) cells and cells of other B-cell malignancies, and is a prime target for therapy with antibody-derived agents. Many attempts have been made to target malignant cells via CD19, but to date none of these agents have received drug approval. Here we report the design of a monovalent immunotoxin consisting of a CD19-specific single-chain Fv antibody fragment fused to a derivative of Pseudomonas Exotoxin A. This fusion protein induced efficient antigen-restricted apoptosis of several human leukemia- and lymphoma-derived cell lines including Nalm-6, which it eliminated at an effective concentration (EC(50)) of 2.5 nM. The agent displayed synergistic toxicity when used in combination with valproic acid and cyclosporin A in cell-culture assays. It induced apoptosis of primary malignant cells in 12/12 samples from B-CLL patients, including patients responding poorly to fludarabine, and of cells from one pediatric acute lymphoblastic leukemia patient. In NOD/SCID mice transplanted with Nalm-6 cells, the toxin prevented engraftment and significantly prolonged survival of treated mice. Owing to its efficient antigen-restricted antileukemic activity, the agent deserves further development towards clinical testing.
Leukemia 08/2007; 21(7):1405-12. · 9.56 Impact Factor
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Pediatric Blood & Cancer 08/2007; 49(1):113-4; discussion 112. · 1.89 Impact Factor
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M Paulides,
H G Dörr,
W Stöhr,
S Bielack,
E Koscielniak,
T Klingebiel,
H Jürgens,
T Bölling,
N Willich,
R Sauer,
T Langer, J D Beck
[show abstract]
[hide abstract]
ABSTRACT: The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients.
Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998.
We studied 340 relapse-free paediatric patients (median age at diagnosis 12.2 [interquartile range (IQR) = 7.3-15.6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 +/- 9.7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24.6 (IQR = 11.9-44.9) months.
We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations.
The incidence of thyroid disorders was 37% (19/51, 95% CI 24-52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8-15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0.027) and trofosfamide (P = 0.016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0.008) or idarubicin (P = 0.037) (n = 250).
The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.
Clinical Endocrinology 06/2007; 66(5):727-31. · 3.17 Impact Factor
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ABSTRACT: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far.
Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria.
After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence.
Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.
Pediatric Blood & Cancer 04/2007; 48(4):447-52. · 1.89 Impact Factor
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ABSTRACT: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents.
Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments.
There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period.
Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.
Pediatric Blood & Cancer 02/2007; 48(2):140-7. · 1.89 Impact Factor
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ABSTRACT: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland.
The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2).
In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval.
After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.
Pediatric Blood & Cancer 05/2006; 46(4):489-95. · 1.89 Impact Factor
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ABSTRACT: Up to now, cardiotoxicity of epirubicin has been studied almost exclusively in adult cancer patients. The aim of this study was to investigate epirubicin in children and adolescents, in comparison with doxorubicin.
About 172 soft tissue sarcoma patients (mean age at diagnosis: 8.3 years), treated with epirubicin (median cumulative dose: 450 mg/m2) or doxorubicin (median cumulative dose: 240 mg/m2) within the high-risk group of the CWS-96 study, were examined in a prospective multicentre study. Heart function was analysed by echocardiography, measuring left-ventricular fractional shortening (FS). The median follow up was 27.7 months.
Incidence of clinically manifest cardiomyopathy was 0% (0/60; 95% CI: 0-6.0%) in patients treated with epirubicin, and 0.9% (1/108; 95% CI: 0-5.1%) in patients treated with doxorubicin. A further three patients showed subclinical cardiomyopathy. There was no difference in FS between the two treatment arms.
Cardiotoxicity was low in our study. For the short term, cardiotoxicity seems to be only a minor problem in patients treated with epirubicin as applied in this cohort.
Journal of Cancer Research and Clinical Oncology 02/2006; 132(1):35-40. · 2.56 Impact Factor
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ABSTRACT: Mit Hilfe einer multimodalen, interdisziplinär durchgeführten Behandlung können viele krebskranke Kinder und Jugendliche geheilt
werden. Inzwischen leben in Deutschland über 25 000 Geheilte, von denen die Mehrzahl das Erwachsenenalter erreicht haben.
Dabei handelt es sich vor allem um ehemalige Leukämie- und Lymphompatienten, seltener um Überlebende nach einer Hirntumor-
oder Sarkombehandlung.
12/2005: pages 1995-2010;
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ABSTRACT: The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.
Cancer Investigation 01/2005; 23(3):201-7. · 1.85 Impact Factor
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ABSTRACT: The aim of this study was to analyse carboplatin-induced ototoxicity in a recent study trial. Twenty patients who had received carboplatin for the treatment of soft tissue sarcoma were investigated prospectively for ototoxicity in a multi-centre trial. Hearing function was tested by audiometry. All patients but one were treated with a cumulative dose of 1500 mg/m(2), the remaining with 500 mg/m(2). We evaluated the incidence and dependencies of hearing loss, and compared hearing thresholds to those of an untreated control group (n=60). Hearing thresholds in the carboplatin treated group were only marginally poorer compared with those of the control group. After carboplatin therapy no patient (0%; 95%-KI: 0-17%) had a hearing loss >20 dB. Hearing thresholds were not dependent on age, sex or cranial irradiation. We conclude that ototoxicity after carboplatin was low in our group of patients.
Oncology Reports 11/2004; 12(4):767-71. · 1.84 Impact Factor
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M Metzler,
U Brehm,
T Langer,
S Viehmann,
A Borkhardt,
M Stanulla,
M Schrappe,
J Harbott, J D Beck,
W Rascher,
R Repp
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ABSTRACT: Chromosomal translocations are a characteristic feature of leukaemia and other malignant diseases. As clonal markers, they can be applied to identify and quantify the number of malignant cells by polymerase chain reaction (PCR) methods. The translocation t(4;11) is present in >60% of infant leukaemia. In order to facilitate the sequencing of chromosomal breakpoints, we developed an optimized set of 30 PCR primers and a new approach, designated as asymmetric multiplex PCR (am-PCR). Due to the high number of primers, small breakpoint-spanning DNA fragments are obtained in one nested multiplex PCR reaction. All PCR products contain an identical binding site for the initiation of direct sequencing. By using am-PCR, the translocation t(4;11) was examined in bone marrow and blood samples from children with acute leukaemia. Compared with previously described methods for the determination of genomic breakpoints, am-PCR may be advantageous with regard to its simplicity and rapidity. Breakpoint-spanning sequences were also evaluated with regard to their applicability as unique clonal markers to design primers and probes for minimal residual disease quantification by real-time PCR. This approach can easily be adapted to other chromosomal translocations in malignant diseases for the detection and analysis of clone-specific DNA markers.
British Journal of Haematology 02/2004; 124(1):47-54. · 4.94 Impact Factor
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ABSTRACT: Children with metastatic retinoblastoma are considered to have a poor prognosis after conventional chemotherapy. We used high-dose chemotherapy (HDC) with peripheral hematopoietic stem cell transplantation in such patients in an attempt to improve their survival. Four patients with bone marrow metastases and one child with extraorbital disease were treated with HDC after achieving complete remission by enucleation and conventional chemotherapy. The child with extraorbital tumor was the only one to receive local irradiation. The conditioning regimen included thiotepa (900 mg/m(2)), etoposide (40 mg/kg) and carboplatin (1.5 g/m(2)) in four patients, and BCNU (300 mg/m(2)), cyclophosphamide (6.8 g/m(2)) and etoposide (1.6 g/m(2)) in one child. Hematologic recovery occurred without delay in all patients. The main toxicities were diarrhea, mucositis and infectious complications. No toxic deaths or any major late toxicities were observed. The child treated with the BCNU regimen developed a meningeal relapse 10 months after HDC, which was partially resected and treated with conventional chemotherapy, but not with radiotherapy. He is in complete remission (CR) 105 months off treatment. The other patients are in CCR for 107, 57, 9 and 8 months after HDC. HDC with thiotepa, etoposide and carboplatin may represent a curative option for children with extrabulbar or disseminated retinoblastoma responsive to chemotherapy. It may control occult CNS disease. The necessity to irradiate these children and the curative potential of this strategy for patients with bulky CNS disease remain to be determined.
Bone Marrow Transplantation 03/2003; 31(4):281-4. · 3.75 Impact Factor
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ABSTRACT: To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.
Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients.
Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children.
The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.
Medical and Pediatric Oncology 08/2002; 39(1):18-24.
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ABSTRACT: Durch die Erfolge bei der Behandlung krebskranker Kinder haben die Erkennung, Behandlung und, soweit möglich, auch die Vermeidung
von Spätfolgen nach antineoplastischer Behandlung und die Verbesserung der Nachsorge besondere Bedeutung erlangt. Im Rahmen
des “Late Effects Surveillance Systems (LESS)” der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) werden seit
1995 systematisch wesentliche Spätfolgen bei den Patienten der Therapieoptimierungsstudien erfasst, um so die Fragen nach
Inzidenz, Zeitpunkt des Auftretens und der Prognose zu beantworten. Die wichtigsten bisher näher untersuchten Folgeschäden
sind Kardiotoxizität vor allem nach einer Anthrazyklintherapie, Oto- und Nephrotoxizität nach Platinderivaten, Tubulopathien
nach Ifosfamid und endokrine Störungen mit ihren Auswirkungen auf Wachstum, Pubertätsentwicklung und Fertilität. Darüber hinaus
ist das im Vergleich zur übrigen Bevölkerung deutlich erhöhte Risiko, an einem Zweitmalignom zu erkranken, in der Betreuung
dieser Patienten von besonderer Wichtigkeit. Dieser Frage geht das Deutsche Kinderkrebsregister nach. Die Kenntnis einer strukturierten
Nachsorge im Rahmen einer vertikalen Vernetzung stellt für den Kinderarzt in Klinik und Praxis die Grundlage für die Betreuung
ehemals krebskranker Kinder und Jugendlicher dar.
With increasing success of cancer therapy in childhood detection, treatment and possibly avoidance of long term sequelae after
antineoplastic therapy and the aftercare of these patients are of great importance today. The “Late Effects Surveillance System
(LESS)” of the GPOH, established in 1995, collects systematically data on major late effects of patients treated according
to the therapy optimising studies to answer the questions about incidence and latency after first line treatment as well as
prognosis. The most significant late effects known today are cardiotoxicity mainly after therapy with anthracyclines, oto-
and nephrotoxicity after platinum derivatives, tubulopathy after ifosfamide and endocrine dysfunctions causing deficiencies
in growth, pubertal development and fertility. Furthermore the risk of secondary neoplasia is an important issue in the management
of these patients. This is investigated by the German Childhood Cancer Registry. Knowledge of a structured aftercare in the
frame work of a vertical network provides the basis of efficient care and counselling of cancer survivors in childhood and
adolescence.
Monatsschrift Kinderheilkunde 07/2002; 150(8):942-953. · 0.27 Impact Factor
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M Jankovic,
A Reciputo,
R Haupt,
C Micalizzi,
C Manganini,
E Frey,
H Lackner,
R Maurus, J D Beck,
T Langer,
M Marx,
P Krappmann,
E Magyarosy,
A Feldges,
M van Weel-Sipman
Medical and Pediatric Oncology 03/2002; 38(2):124.
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Medical and Pediatric Oncology 08/2001; 37(1):73-4.
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M Reichel,
E Gillert,
S Angermüller,
J P Hensel,
F Heidel,
M Lode,
T Leis,
A Biondi,
O A Haas,
S Strehl,
E R Panzer-Grümayer,
F Griesinger, J D Beck,
J Greil,
G H Fey,
F M Uckun,
R Marschalek
[show abstract]
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ABSTRACT: Derivative chromosomes of 40 patients diagnosed with t(4;11) acute lymphoblastic leukemia (ALL) were analysed on the genomic DNA level. Chromosomal breakpoints were identified in most cases within the known breakpoint cluster regions of the involved MLL and AF4 genes. Due to our current knowledge of the primary DNA sequences of both breakpoint cluster regions, specific features were identified at the chromosomal fusion sites, including deletions, inversions and duplications of parental DNA sequences. After separation of all t(4;11) leukemia patients into two age classes (below and above 1 year of age), the analysis of chromosomal fusion sites revealed significant differences in the distribution of chromosomal breakpoints and led to the definition of two hotspot areas within the MLL breakpoint cluster region. This may point to the possibility of different age-linked mechanisms that were leading to t(4;11) chromosomal translocations.
Oncogene 06/2001; 20(23):2900-7. · 6.37 Impact Factor
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Medical and Pediatric Oncology 05/2001; 36(4):494-6.
