Claudia Spix

Leukaemia in young children living in the vicinity of German nuclear power plants.

A case control study was conducted where cases were children younger than 5 years (diseased between 1980 and 2003) registered at the german childhood cancer registry (GCCR). Population‐based matched controls (1:3) were selected from the corresponding registrars office. Residential proximity to the nearest nuclear power plant was determined for each subject individually (with a precision of about 25 m). The report is focused on leukaemia and mainly on cases in the inner 5‐km zone around the plants. The study includes 593 leukaemia cases and 1,766 matched controls. All leukaemia combined show a statistically significant trend for 1/distance with a positive regression coefficient of 1.75 [lower 95%‐confidence limit (CL): 0.65]; for acute lymphoid leukaemia 1.63 (lower 95%‐CL: 0.39), for acute nonlymphocytic leukaemia 1.99 (lower 95%‐CL: −0.41). This indicates a negative trend for distance. Cases live closer to nuclear power plants than the randomly selected controls. A categorical analysis shows a statistically significant odds ratio of 2.19 (lower 95%‐CL: 1.51) for residential proximity within 5 km compared to residence outside this area. This result is largely attributed to cases in previous studies of the GCCR (especially in the inner zone) as there is clearly some overlap between those studies. The result was not to be expected under current radiation‐epidemiological knowledge. Considering that there is no evidence of relevant accidents and that possible confounders could not be identified, the observed positive distance trend remains unexplained.

Complementary and alternative treatment methods in children with cancer: A population-based retrospective survey on the prevalence of use in Germany

INTRODUCTION Few studies have been conducted to date on the prevalence of use of complementary and alternative treatment methods (CAMs) in paediatric oncology, and those that have been conducted are often not representative. We therefore decided to study a representative sample of children with cancer in the German population. PATIENTS AND METHODS The study took the form of a retrospective survey amongst all parents whose children were first diagnosed with a disease covered by the German Childhood Cancer Registry in 2001. The primary objectives of the survey were to establish the prevalence of use of CAM and the factors related to its use. RESULTS Of the 1595 questionnaires sent out, 1063 (67%) could be evaluated. 35% of the responders had used CAM. The most frequently used methods were homeopathy, dietary supplements and anthroposophic medicine including mistletoe therapy. Factors which increased the probability of using CAM were the previous use of CAM, higher social status and poor prognosis of the childs disease. The most frequently named reasons for use of CAM were physical stabilisation, strengthening the immune system and improving the chance of cure. Whilst the sources of information about CAM were in most cases not doctors, 71% of users had nevertheless spoken to a doctor about using CAM. The effects of the CAM perceived by the parents were for the most part positive. 89% of the users reported that they would recommend CAM to other parents. CONCLUSIONS CAMs are administered alongside standard therapy to 35% of children with cancer in Germany, usually by the parents. Prospective studies on the effects and side-effects of the most frequently used methods are urgently needed, and paediatric oncologists should have sufficient knowledge of CAM to enable them to advise parents professionally and competently about these treatments, too.

Nephron-sparing surgery of renal cell carcinoma with a normal opposite kidney: long-term outcome in 180 patients

OBJECTIVES To investigate the long-term outcome of an organ-saving approach for renal cell carcinoma (RCC) with a normal opposite kidney (elective indication). METHODS Since 1979, 180 patients have undergone nephron-sparing surgery at our institution for RCC in the presence of a normal contralateral kidney. The mean age was 56 years (range 23 to 83), and the mean follow-up was 4.7 years (maximum 14. 8). Most of these tumors were found incidentally, with a mean tumor diameter on ultrasound of 3.3 cm (range 1.0 to 8.6). RESULTS The postoperative course was unremarkable in 173 patients. Postoperative bleeding was encountered in 4 patients and urinary extravasation in an additional 3 patients. No surgical reintervention was necessary. One hundred seventy-five RCCs were pT1 and 5 were pT3a; 73 were grade 1, 100 grade 2, and 7 were grade 3. The mean tumor diameter (surgical specimen) was 3.2 cm (range 0.5 to 7). In 132 cases, the tumor was less than 4 cm and in 48 cases, greater than 4 cm. Three patients experienced local tumor recurrence (1.6%) during follow-up, and two others developed distant metastases. The 5-year tumor-specific survival rate was 98.0%. CONCLUSIONS Nephron-sparing surgery for RCC under an elective indication in selected patients offers excellent long-term survival and an acceptably low local tumor recurrence rate. These results support the concept of nephron-sparing surgery in the presence of a normal contralateral kidney.

Second malignant neoplasms after treatment of childhood cancer

The aim of this study was to determine therapy-related risk factors for the development of second malignant neoplasm (SMN) after childhood cancer. The German Childhood Cancer Registry (GCCR) registers all childhood malignancies since 1980 including SMN. A nested case-control study with 238 SMN cases and 450 controls was conducted. A confirmatory, as well as an explorative, analysis was performed. Radiotherapy showed a small effect on the risk of SMN for doses >or=65 Gy. Regarding the chemotherapeutical agents, we saw increased Odds Ratios (OR) for high doses of cyclophosphamide (CP >8000 mg/m(2) OR=6.3 (95% Confidence Interval (CI): 1.3-30.2)), cisplatinum (DDP >435 mg/m(2) OR=2.8 (95% CI: 1.1-6.7)) and mercaptopurine (MP >5000 mg/m(2) OR=4.5 (95% CI: 1.1-18.9)). Patients jointly receiving high doses of MP (>5000 mg/m(2)) and dexamethasone (DEXA >or=1200 mg/m(2)) had an OR=6.9 (95% CI: 1.2-40.3). Our results could be added to those of other investigations to give indications for modifying future therapeutic strategies for childhood cancer.

Temporal trends in the incidence rate of childhood cancer in Germany 1987–2004

The German Childhood Cancer Registry regularly presents graphs of childhood cancer incidence rates by period, but no systematic analysis. The Automated Childhood Cancer Information System‐project found an increasing trend in Europe. Against this background we present the first detailed trend analysis of childhood (aged under 15) malignancies in Germany. We examined incidence rates separately in western Germany 1987–2004 and eastern Germany 1991–2004. We analyzed all malignancies, all main diagnostic groups and relevant subsets using an age‐period‐cohort model. Additionally we fitted fractional polynomials to assess the linearity of the drift. All malignancies combined (excluding Central Nervous System‐tumors and neuroblastoma) show a significant trend: +0.7% in western and +1.1% per year in eastern Germany. The overall trend in Germany is mostly due to the significant increase in lymphoid leukemia, which increased significantly in western Germany (+0.7% per year) and significantly nonlinearly in eastern Germany (+3.3% per year until 1998, +0.8% since 1998), catching up from a level 20% below western Germany. This could be due to life style changes since the reunification in eastern Germany influencing early immune system training. We found no trends for acute non‐lymphocytic leukemia and non‐Hodgkin lymphoma. Hodgkins disease shows a cohort effect in western Germany after reunification. Improved registration of CNS tumors led to an increase. Neuroblastoma yielded a period effect in western Germany due to screening. With the exception of germ cell tumors, further observations for solid tumor entities are in agreement with those reported for Europe.

Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes

Background:Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These ‘RASopathies’ also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.Methods:We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.Results:We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4–18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.Conclusions:These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Survival of children with neuroblastoma: time trends and regional differences in Europe, 1978–1992

Neuroblastoma is one of the most common solid cancers in children. We present the data collected for the EUROCARE II study, describing survival patterns for children diagnosed in Europe 1985--1989 in detail, and exploring time trends from 1978 to 1992. On average, the mean 5-year survival rate was considerably higher in infants (79%) compared with older children (30--33%). The risk of death has dropped by 37% from 1978--1981 to 1990--1992. There is a pronounced difference between countries, with Scotland and England and Wales having two of the lowest survival rates (28% (95% confidence interval (CI) 14--48) and 36% (95% CI 31--41) 5-year survival rates, respectively). The survival rates in France, Germany and Italy (48--66% 5-year survival rate) were among the highest. This pattern corresponds to the incidence rates for these countries. It can be assumed that in neuroblastoma, both incidence and survival are related to the frequency of diagnosing asymptomatic cases with good prognosis among infants. However, one cannot ignore possible intercountry differences in the effectiveness of therapy.

Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany

Neuroblastoma is one of the childhood cancers included in two recent population-based case-control studies in West Germany. Altogether, 183 children under the age of 8 with neuroblastoma diagnosed in 1988-1994 and 1785 control children sampled from population registration files participated. Information on potential risk factors was obtained from the childrens parents by a self-administered questionnaire and subsequent telephone interview. We observed positive associations with the use of oral contraceptives or other sex hormones during pregnancy (particularly with male offspring), a shorter gestational duration, lower birth weight, and maternal alcohol consumption during pregnancy. While the association with maternal use of oral contraceptives or sex hormones was strong for stages I/II (odds ratio 4.5, 95% confidence interval 1.2-16.5), the associations with shorter gestation duration (odds ratio 3.4, 95% confidence interval 1.7-6.7) as well as maternal alcohol consumption during pregnancy (>7 glasses/week odds ratio 5.2, 95% confidence interval 1.3-20.6) were observed only for the unfavourable advanced stages. It is notable that the associations in our study were either observed only for the advanced stages of disease or only for the less advanced stages, but not for both subgroups. This adds to evidence for the hypothesis that neuroblastoma consists of at least two distinct disease entities, which differ in clinical stage at the time of diagnosis.

Childhood Leukemia in the Vicinity of Nuclear Power Plants in Germany

INTRODUCTION The causes of leukemia are largely unclear. The question whether leukemia rates are increased near nuclear power plants is controversial. The German Childhood Cancer Registry has published an epidemiological case-control study on childhood cancer and nuclear power plants. METHOD The study was based on the distance of childrens residences from nuclear power plants and addressed the question whether children under age 5 with cancer live closer, on average, to nuclear power plants than randomly selected controls. Odds Ratios (OR) for distance categories and standardized incidence ratios (SIR) were calculated. RESULTS An association was found between the nearness of residence to nuclear power plants and the risk of leukemia (593 cases, 1766 controls). Within the 5-km zone, the OR for the development of leukemia in children under 5 years of age was 2.19 compared to the rest of the region, and this elevation of the OR was statistically significant. The incidence of leukemia in the overall study region was the same as that in Germany as a whole (SIR=0.99; 95% confidence interval 0.92-1.07). DISCUSSION Based on the available information about radiation emissions from German nuclear power plants, a direct relation to radiation seems implausible. Many factors may conceivably cause leukemia, possibly operating in combination, and these factors may be present to a greater extent in the vicinity of German nuclear power plants.

Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer

We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12%), compared with her sister (3%). Subsequent bisulfite plasmid sequencing demonstrated that 13% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.