Durchführung eines neuen Therapiekonzepts für Nephroblastome im Bereich der Gesellschaft für Pädiatrische Onkologie und Hämatologie SIOP 9/GPOH

Ludwig, R.; Weirich, A.; Bürger, D.; Graf, Norbert; Harms, D.; Kaatsch, Peter; Pötter, Richard; Rieden, K.; Tröger, J.; Zimmermann, H.

doi:10.1007/s001120050114

Cited by 7 publications

(5 citation statements)

References 13 publications

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“…The higher toxicity rates in our patients, with 10% of all patients fulfilling the NWTS criteria for severe hepatotoxicity compared to the nonirradiated NWTS patients with standard chemotherapy and the UKW patients, may result from the fact that we used a sample representing 95% of all nephroblastomas registered by the German Childhood Cancer Registry [12]. Also, the GPOH centers joined the SIOP-9 trial 11 months after it had started, and by that time some SIOP centers had already reported their experience with increased hepatotoxicity [7].…”

Section: Discussionmentioning

confidence: 96%

“…A higher percentage of patients with VOD in the report on SIOP-9 trial patients (8%) in comparison to 4.8% in our analysis may also be due to sample differ-ences. Because we included all patients with unfavorable histology and stage IV, as well as nonresponders to preoperative treatment, we had a higher rate of patients treated with AMD at double dose on 1 day [12,19]. This group developed no hepatotoxicity (Table V).…”

Section: Discussionmentioning

confidence: 99%

“…The GPOH joined the SIOP-9 in January, 1989, and treated patients according to its protocol until the end of March, 1994 [11,12]. In total, 505 trial and study patients were registered by the GPOH, including all patients with bilateral tumors, initial metastases, and primarily operated WT.…”

Section: Materials and Methods Patientsmentioning

confidence: 99%

“…All 481 patients treated with pre-and/or postoperative chemotherapy according to the SIOP-9 constituted the basic sample for the analysis, including 398 patients who received preoperative and 455 patients who received postoperative chemotherapy. Eighteen patients with a diagnosis of WT on imaging studies who received preoperative chemotherapy eventually turned out to have another malignancy or benign tumor and were only preoperatively treated according to SIOP-9 [12].…”

Section: Materials and Methods Patientsmentioning

confidence: 99%

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Hepatotoxicity in patients treated according to the Nephroblastoma Trial and Study SIOP-9/GPOH

Ludwig

Weirich

Abel

et al. 1999

Med. Pediatr. Oncol.

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Background A major problem for children receiving Wilms tumor (WT) chemotherapy is hepatotoxicity, which may even be life‐threatening. Dactinomycin (AMD) has been shown to be an important factor, as has abdominal irradiation. Procedure In the nephroblastoma trial and study SIOP‐9 (SIOP‐9) two different regimens for the application of AMD were used (standard dose over 3–5 days vs. double dose on a single day). In children at increased risk for local relapse, postoperative abdominal irradiation was given. We analyzed the influence of AMD and radiotherapy on the development of hepatotoxicity in 481 children treated in centers of the German Paediatric Oncology and Haematology Society (GPOH). A special questionaire was sent out for all patients with reduced treatment or delay of more than 1 week because of hepatotoxicity. Because SIOP and the National Wilms Tumor Study (NWTS) used different criteria to asses hepatotoxicity,we applied both definitions. Results All 72 cases of mild or severe hepatotoxicity occurred during treatment with AMD over 3–5 days with the standard dose (9.4–22.5 μg/kg/week) compared to none in the group receiving a double dose on 1 day (3.75–8 μg/kg/week; P < 0.001). Irradiation of the right abdomen, including parts of the liver, enhanced liver toxicity significantly, with a relative risk (RR) of 2.6 (P < 0.003). Preoperative liver toxicity was more frequent in smaller children (P = 0.02) and especially if no dose reduction was done in children with body weight of less than 12 kg (RR 5.3, P = 0.01). If severe liver toxicity was defined according to NWTS criteria, 10% of all treated patients were affected compared to 4.8% if McDonald's criteria for hepatic veno‐occlusive disease (VOD) were applied. Conclusions To diminish the hepatotoxicity of WT treatment, AMD dose intensity should be reduced (below 10 μg/kg per week), especially in smaller children or when the liver is irradiated. Med. Pediatr. Oncol. 33:462–469, 1999. © 1999 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Materials and Methods Patientsmentioning

confidence: 99%

Section: Materials and Methods Patientsmentioning

confidence: 99%

See 2 more Smart Citations

Hepatotoxicity in patients treated according to the Nephroblastoma Trial and Study SIOP-9/GPOH

Ludwig

Weirich

Abel

et al. 1999

Med. Pediatr. Oncol.

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“…We analyzed the status of the entire WT1 gene in 64 cases of WTs predominantly from patients with preoperative chemother-apy and ascertained through the German SIOP9͞GPO study (46). First we studied 32 consecutive cases, followed by patients selected for GU anomalies and bilateral tumors.…”

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confidence: 99%

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Schumacher

Schneider

Figge

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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119

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The WT1 gene, located on chromosome 11p13, is mutated in a low number of Wilms tumors (WTs). Germ-line mutations in the WT1 gene are found in patients with bilateral WT and͞or associated genital tract malformations (GU). We have identified 19 hemizygous WT1 gene mutations͞deletions in 64 patient samples. The histology of the tumors with mutations was stromal-predominant in 13, triphasic in 3, blastemal-predominant in 1, and unknown in 2 cases. Thirteen of 21 patients with stromal-predominant tumors had WT1 mutations and 10 of these were present in the germ line. Of the patients with germ-line alterations, six had GU and a unilateral tumor, two had a bilateral tumor and normal GU tracts, and two had a unilateral tumor and normal GU. Three mutations were tumor-specific and were found in patients with unilateral tumors without GU. These data demonstrate a correlation of WT1 mutations with stromalpredominant histology, suggesting that a germ-line mutation in WT1 predisposes to the development of tumors with this histology. Twelve mutations are nonsense mutations resulting in truncations at different positions in the WT1 protein and only two are missense mutations. Of the stromal-predominant tumors, 67% showed loss of heterozygosity, and in one tumor a different somatic mutation in addition to the germline mutation was identified. These data show that in a large proportion of a histopathologically distinct subset of WTs the classical two-hit inactivation model, with loss of a functional WT1 protein, is the underlying cause of tumor development.The WT1 gene was isolated by positional cloning from chromosome 11p13 (1, 2) and encodes a transcription factor of the zinc finger (ZF) family. Loss of heterozygosity (LOH) studies showed that tumors frequently have lost markers from chromosome 11p. Subsequently, it was found that this loss is often limited to the region 11p15, where a second locus, WT2, involved in the development of Wilms tumor (WT) has been assumed to exist. Further LOH studies revealed loss of chromosome 16q in about 20% of WTs, suggesting that a third locus is located at this site. Susceptibility for the rare form of familial WT in several generations does not show linkage to either of these regions; therefore, another WT locus must exist in these cases (3-5). The WT1 gene encodes four transcripts produced by alternative splicing (6, 7) and encodes a protein with a predicted size of 45-49 kDa. DNA binding to a GC-rich motif identical to the early growth response-binding site was demonstrated for the WT1 protein lacking splice II in the ZF (WT͞ϪKTS), whereas the WT1 protein containing these amino acids (WT͞ϩKTS) does not bind to this sequence (8). Recently it was shown that WT1͞ϩKTS can also bind to a similar GC-rich DNA motif (9). More recent studies have established that the proline-glutamine rich amino terminus has transcriptional regulatory properties. It was shown that WT1 containing splice I (WT͞ϩ17aa) is a repressor, whereas WT1͞Ϫ17aa can be either a repressor or activator depending on the ar...

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Wilms-Tumor

Royer‐Pokora

Schumacher

2001

Molekularmedizinische Grundlagen Von Hereditären Tumorerkrankungen

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Durchführung eines neuen Therapiekonzepts für Nephroblastome im Bereich der Gesellschaft für Pädiatrische Onkologie und Hämatologie SIOP 9/GPOH

Cited by 7 publications

References 13 publications

Hepatotoxicity in patients treated according to the Nephroblastoma Trial and Study SIOP-9/GPOH

Hepatotoxicity in patients treated according to the Nephroblastoma Trial and Study SIOP-9/GPOH

Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal–predominant histology

Wilms-Tumor

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