Treatment of cystic nephroma and cystic partially differentiated nephroblastoma--a report from the SIOP/GPOH study group

PURPOSE: Cystic partially differentiated nephroblastoma is a rare variant of Wilms tumor, and might be confused with cystic nephroma. Definitive diagnosis can only be made by histological examination. Therefore, initiation of therapy, either primary nephrectomy or preoperative chemotherapy, might create a dilemma when radiological diagnosis is doubtful. MATERIALS AND METHODS: To define treatment strategies for these entities, we reviewed the records of 1,245 patients enrolled in SIOP (International Society of Pediatric Oncology) trials 93-01 and 2001 GPOH (German Society of Pediatric Oncology and Hematology) between July 1993 and August 2004. Data were collected retrospectively. Therapy, outcome and preoperative management were evaluated. To confirm diagnosis of cystic nephroma/partially differentiated nephroblastoma, all patients underwent review by the Reference Pathology Center of SIOP/GPOH. RESULTS: A total of 14 patients with diagnoses of cystic nephroma (7) and cystic partially differentiated nephroblastoma (7) were identified. Median patient age at diagnosis was 1 year (0.46 to 3). Two patients received preoperative chemotherapy. Primary nephrectomy was performed in 12 patients. Two patients underwent partial nephrectomy. In 1 child postoperative chemotherapy was administered. None of the patients had progression of disease or recurrence. Overall survival was 100%. Median followup was 2.41 years (0.3 to 9). CONCLUSIONS: In cystic renal tumors radiological findings should always be reviewed by the reference radiologist of the treatment protocol study group. Irrespective of the chosen therapy, outcome of cystic nephroma and cystic partially differentiated nephroblastoma is favorable. Even in large international trials the number of patients with cystic nephroma or cystic partially differentiated nephroblastoma is too small for statistical analysis.     

New insights into the genetics of glioblastoma multiforme by familial exome sequencing

Glioblastoma multiforme (GBM) is the most aggressive and malignant subtype of human brain tumors. While a family clustering of GBM has long been acknowledged, relevant hereditary factors still remained elusive. Exome sequencing of families offers the option to discover respective genetic factors.We sequenced blood samples of one of the rare affected families: while both parents were healthy, both children were diagnosed with GBM. We report 85 homozygous non-synonymous single nucleotide variations (SNVs) in both siblings that were heterozygous in the parents. Beyond known key players for GBM such as ERBB2, PMS2, or CHI3L1, we identified over 50 genes that have not been associated to GBM so far. We also discovered three accumulative effects potentially adding to the tumorigenesis in the siblings: a clustering of multiple variants in single genes (e.g. PTPRB, CROCC), the aggregation of affected genes on specific molecular pathways (e.g. Focal adhesion or ECM receptor interaction) and genomic proximity (e.g. chr22.q12.2, chr1.p36.33). We found a striking accumulation of SNVs in specific genes for the daughter, who developed not only a GBM at the age of 12 years but was subsequently diagnosed with a pilocytic astrocytoma, a common acute lymphatic leukemia and a diffuse pontine glioma.The reported variants underline the relevance of genetic predisposition and cancer development in this family and demonstrate that GBM has a complex and heterogeneous genetic background. Sequencing of other affected families will help to further narrow down the driving genetic causes for this disease.     

An international strategy to determine the role of high dose therapy in recurrent Wilms’ tumour

PurposeTo review event-free (EFS) and overall survival (OS) from publications describing outcome for children with relapsed Wilms’ tumour. Comparisons are made between those receiving myeloablative high dose chemotherapy with autologous stem-cell rescue (HDT) and those not (NoHDT).Materials and methodsRelevant information was extracted from individual patient or summary data and 3-year EFS and OS rates established. These rates were combined in a weighted manner to derive hazard ratios (HRs).ResultsNineteen publications were identified (5 HDT, 6 NoHDT, 8 both). Pooling all studies suggested an advantage to HDT with a hazard ratio (HR) for EFS of 0.87 (95% confidence interval (CI) 0.67–1.12) and 0.94 (0.71–1.24) for OS. A stratified analysis confined to studies that provided individual patient data on both HDT and NoHDT gave HRs of 0.83 (0.56–1.24) and 0.92 (0.59–1.41). Further, analyses of risk groups, defined by treatment and/or histology prior to first relapse, suggested a HR for EFS of 0.90 (95% CI 0.62–1.31) for those of high and 0.50 (CI 0.31–0.82) for the very high risk patients.ConclusionThe evidence suggests, although there are many caveats since the information summarised here is not from randomised trials, a great deal of uncertainty concerning the role of HDT in patients following relapse after treatment for their Wilms’ tumour. For each risk group we propose a randomised trial comparing a standard with a more intensive therapy with specific choice of regimen tailored to the risk group (and co-operative groups) concerned. A synthesis of updated evidence from studies in this overview together with any emerging studies and future trial information will form the basis for future evidence-based clinical decision-making.     

Secondary Neoplasms After Wilms’ Tumor in Germany

Strahlentherapie und Onkologie -     

Multicenter study identified molecular blood-born protein signatures for Wilms Tumor

Wilms Tumor (WT) is the most common renal childhood tumor. Recently, we reported a cDNA microarray expression pattern that varied between WTs with different risk histology. Since the Societé Internationale d'Oncologie Pédiatrique (SIOP) in Europe initiates treatment without a histological confirmation, it is important to identify blood-born markers that indicate WT development. In a multicenter study, we established an autoantibody signature by using an array with 1,827 recombinant E. coli clones. This array was screened with sera of patients with WT recruited by SIOP or the Children's Oncology Group (COG). We report an extended number of antigens that are reactive with autoantibodies present in sera from patients with WT. We established an autoantibody signature that separates untreated patients with WT recruited in SIOP from non-WT controls with a specificity of 0.83 and a sensitivity of 0.82 at standard deviations of 0.02 and 0.04, respectively. Likewise, patients recruited in the COG in the United States were separated from the controls with an accuracy of 0.83 at a standard deviation of 0.02. Proteins that were most significant include zinc finger proteins (e.g., ZFP 346), ribosomal proteins and the protein fascin that has been associated with various types of cancer including renal cell carcinoma. Our study provides first evidence for autoantibody signatures for WTs and suggests that these may be most informative before chemotherapy. We present the first multicenter study of autoantibody signatures in patients with WT. We established an autoantibody signature that separates patients with WT from controls.     

Primary hepatic metastases in nephroblastoma--a report of the SIOP/GPOH Study

Purpose

Remarkable progress could be achieved in the treatment of nephroblastoma within the last decades. In all children with Wilms' tumor, 5-year overall survival rate reaches more than 90% in the SIOP/GPOH Study Group. Despite this fact, there is a small group of patients who have tumor lesions in the liver primarily representing a challenge in treatment. Data of this group are analyzed.

Methods

To define survival and success of treatment in this group of patients, we reviewed the records of 29 of 1365 patients enrolled in the SIOP 93-01/GPOH Study and the SIOP 2001/GPOH Study between April 1, 1994, and September 30, 2004.

Results

Median age at diagnosis was 10.61 years (range, 0.19-34.16 years). All patients but two underwent nephrectomy. Liver metastases were operated in 11 children at time of nephrectomy, in 4 patients secondarily, whereas in 11 patients, liver lesions were treated alone with chemotherapy and radiotherapy, respectively. In 3 children, no treatment could be initiated. Sixteen patients received radiotherapy additionally. Median follow-up was 64 months (range, 3-157 months). Eleven patients died in the course at a median of 13.07 months (range, 0.25-42 months) after initial diagnosis. These included 7 patients who never had surgery for their liver lesions and 4 patients who had incomplete and/or atypical resections of their metastatic liver lesions. All patients who underwent complete resection of hepatic metastases (n = 9) survived. Eight children survived with a nonsurgical treatment. Overall survival was below 60% in the whole group up to now.

Conclusions

Liver metastases are much less frequent than metastases to other sites. Our report suggests that Wilms' tumor complicated by metastases of the liver primarily has a less favorable outcome. Chemotherapy and radiotherapy play an important role in treatment. Radical surgery for nephrectomy as well as surgery of liver lesions cannot be overemphasized to prevent local and distant recurrence.