Long-term care, care needs and wellbeing of individuals after cancer in childhood or adolescence (VersKiK): study protocol of a large scale multi-methods non-interventional study.

BACKGROUND: It has been shown previously that a relevant proportion of childhood cancer survivors suffers from late effects, which are often directly related to the cancer itself or its therapy, resulting in particular follow-up needs, additionally burdening healthcare systems. Being diagnosed with cancer at a vulnerable stage of development, this group of cancer survivors is at comparatively higher risk of relapse or subsequent cancer. Although national and international follow-up guidelines based on treatment modalities have been developed, their implementation seems to leave room for improvement. Additionally, they lack a sufficient consideration of the survivors' psychosocial needs, affecting their adherence to them. The aim of the VersKiK study is to provide representative information on late effects in childhood and adolescence cancer survivors in Germany. The main research objectives are: (1) to describe the state of follow-up care among survivors after a cancer diagnosis in childhood or adolescence; (2) to quantify the occurrence of late effects among this group of survivors; (3) to examine the adherence to selected audiological and cardiological follow-up guidelines and to identify factors affecting it; (4) to explore actual follow-up needs of paediatric cancer survivors; (5) to review selected follow-up guidelines with the aim to improve and expand them. METHODS: VersKiK is designed as a mixed-methods non-interventional study. We will use claims data from statutory health insurance companies in combination with individually linked population-based registry data from the German Childhood Cancer Registry (GCCR). This data base will permit us to quantify diagnoses and procedures in comparison to the general population as well as the adherence to existing follow-up guidelines. Additional information will be obtained through interviews with childhood and adolescence cancer survivors and their informal caregivers, as well as in focus groups with healthcare professionals. DISCUSSION: The present study aims to research the actual needs of individuals after cancer diagnosis and treatment in childhood or adolescence - physical, psychological and organisational - in order to improve existing follow-up guidelines. These improvements might further positively affect not only actual care provided to paediatric cancer survivors, but also benefit healthcare systems in general while decreasing consequent medical visits in this group of patients. TRIAL REGISTRATION: Registered at German Clinical Trial Register (ID: DRKS00025960 and DRKS00026092).

Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE).

STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.

Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study.

Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4-11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049.

[Late effects following childhood cancer treatment : A special challenge for transition medicine]. / Spätfolgen einer Krebsbehandlung im Kindes- und Jugendalter : Eine Herausforderung für die Transitionsmedizin.

BACKGROUND: Childhood cancer survivors are at risk of cancer- and treatment-related chronic health conditions. Since these sequelae may occur years after the end of treatment, many patients are already adults and have completed pediatric oncological care. Thus, successful transition is essential in order to ensure long-term surveillance. OBJECTIVES: The present review outlines the most frequent late effects of childhood cancer treatment. Moreover, difficulties in transition of these patients are discussed and interdisciplinary models of care are presented. RESULTS: Late effects following childhood cancer treatment occur in over two thirds of patients 30 years after the end of the oncological treatment and can affect different organs. The most frequent sequelae are endocrine disturbances, cardiac conditions, and subsequent neoplasms. Many late effects are effectively manageable if detected early. This necessitates an interdisciplinary approach as well as life-long surveillance. CONCLUSIONS: Transition from pediatric to internal medicine care as well as a change in the focus of care, shifting from relapse centered follow-up to late-effects centered surveillance, constitute a special challenge for a successful transition of long-term childhood cancer survivors. Specialized late-effects survivorship clinics offering interdisciplinary care from pediatric oncologists, specialists of internal medicine, and further disciplines enable the early diagnosis and treatment of late-effects.

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.

Risk of cancer incidence before the age of 15 years after exposure to ionising radiation from computed tomography: results from a German cohort study.

The aim of this cohort study was to assess the risk of developing cancer, specifically leukaemia, tumours of the central nervous system and lymphoma, before the age of 15 years in children previously exposed to computed tomography (CT) in Germany. Data for children with at least one CT between 1980 and 2010 were abstracted from 20 hospitals. Cancer cases occurring between 1980 and 2010 were identified by stochastic linkage with the German Childhood Cancer Registry (GCCR). For all cases and a sample of non-cases, radiology reports were reviewed to assess the underlying medical conditions at time of the CT. Cases were only included if diagnosis occurred at least 2 years after the first CT and no signs of cancer were recorded in the radiology reports. Standardised incidence ratios (SIR) using incidence rates from the general population were estimated. The cohort included information on 71,073 CT examinations in 44,584 children contributing 161,407 person-years at risk with 46 cases initially identified through linkage with the GCCR. Seven cases had to be excluded due to signs possibly suggestive of cancer at the time of first CT. Overall, more cancer cases were observed (O) than expected (E), but this was mainly driven by unexpected and possibly biased results for lymphomas. For leukaemia, the SIR (SIR = O/E) was 1.72 (95 % CI 0.89-3.01, O = 12), and for CNS tumours, the SIR was 1.35 (95 % CI 0.54-2.78, O = 7). Despite careful examination of the medical information, confounding by indication or reverse causation cannot be ruled out completely and may explain parts of the excess. Furthermore, the CT exposure may have been underestimated as only data from the participating clinics were available. This should be taken into account when interpreting risk estimates.

[Principles and fields of application of screening procedures]. / Prinzipien und Einsatzbereiche von Screeningverfahren.

This article explains some important concepts of screening and early detection. It also discusses under which circumstances screening is useful, who can profit from screening and which persons may be at risk from screening procedures. Before the introduction of a screening program, empirical studies on the effectiveness are necessary to evaluate whether a screening program could be successful.

VersKiK: Study protocol of an observational registry-based study on the current state of follow-up care and adherence to follow-up guidelines after cancer in childhood or adolescence.

BACKGROUND: This article describes the study design of the quantitative part of the VersKiK study, The primary objectives of this study are to examine the occurrence of late effects in survivors of childhood or adolescent cancer (module 1), investigate health-related vulnerabilities and medical service utilization within this survivor group (modules 1 and 3), and assess the alignment between documented follow-up care for cardiological and audiological late effects with guideline recommendations, along with evaluating the extent of adherence among paediatric cancer survivors (module 3). METHODS: This is a non-interventional retrospective observational cohort study. It is based on stochastically linked insurance claims data from approximately 150,000 statutory insured persons with information concerning around 25,000-30,000 cancer survivors recorded in the German Childhood Cancer Register (GCCR). To explore adherence to selected follow-up guidelines, intention to treat treatment data from clinical study groups for particular diagnostic entities will be additionally included. DISCUSSION: The growing group of survivors after cancer in childhood and adolescence is representing a special population with an increasing demand for life-long healthcare services through relative high probability of late effects. Currently, there is a limited evidence in Germany on utilization of corresponding medical services and adherence to follow-up guidelines. With this study design, we are aiming to address these gaps and, consequently, suggest improvements to existing follow-up guidelines and follow-up care provision in Germany.

Strategy for long-term surveillance at the German Childhood Cancer Registry - an update.

BACKGROUND: The objective of this paper is to provide information about the quality (e.g. completeness, response) of long-term surveillance in German paediatric oncology and haematology based on the structures implemented by the German Childhood Cancer Registry (GCCR). METHODS: The GCCR contacts parents or patients to collect and update information on a minimal set of follow-up health status data (e.g. late relapses, subsequent neoplasms, current address) and exchanges this information regularly with the appropriate clinical trials. RESULTS: Between 2006 and 2010, GCCR approached a total of about 20,000 patients (contact at the age of 16 years, inquiry concerning the health status) in the context of long-term surveillance. 11,000 addresses of former patients had to be researched via municipal registrar's offices. The response rates ranged from 56% to 68%, the research in municipal offices provided 93-96% valid addresses. Of 46,115 patients diagnosed between 1980 and 2009, 25,283 are in long-term surveillance in 2010. DISCUSSION: Long-term surveillance requires considerable logistic effort at GCCR and requires that thousands of letters be mailed each year in order to ensure regularly updated information. Long-term surveillance is indispensable for a better understanding of late effects, subsequent neoplasms and quality of life of former childhood cancer patients.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Case-control study on risk factors for leukaemia and brain tumours in children under 5 years in Germany.

In the context of a case control study on the cancer risk for children under five by distance to the nearest nuclear power plant, we collected information on other risk factors in a subset. We present the interview study as if it had been an independent study. Parents of 471 cases with Leukaemia, Lymphoma or CNS (Central Nervous System)-tumour from the German Childhood Cancer Registry, diagnosed at age under 5 in the years 1993-2003, and 1,457 matched controls were to be interviewed. For Leukaemia, 243 cases/604 controls, and for CNS 102 cases/246 controls participated, lymphoma cases were too few. Questions related to social status, ionizing radiation, pregnancy and birth, immune system, and selected toxins. The analysis is exploratory in nature; variables were selected by backward elimination. For leukaemia we found a significant protective effect of social contacts (OR=0.50, 95% CI [0.29;0.87]) and a risk for high birth weight (OR=1.96 95% CI [1.12;3.41] comparing >4,000 g to "normal"). We could not reproduce other associations reported in the literature such as a negative association with allergies. For CNS tumours we found a significant protective effect of social contacts (OR=0.30 95% CI [0.13;0.72]), of pesticides and herbicides (OR=0.39 95% CI [0.18;0.83]) and an increased risk for low birth weight (p=0.0232). This study on risk factors for childhood leukaemia and brain tumours is relatively small and exploratory. We could reproduce some major associations reported in the literature (leukaemia: social contacts and high birth weight) but not others. Some observations may be reporting artefacts or self selection artefacts.

Incidence of childhood cancer of the head and neck in Germany.

BACKGROUND: Only very limited data are available in the literature on the incidence of childhood cancer of the head and neck worldwide. METHODS: Based on data obtained from the national German Childhood Cancer Registry, a total of 370 malignancies of the head and neck in children under the age of 15 (199 boys and 171 girls), which were reported to this institution between 1994 and 2003, were analysed in this study. RESULTS: The overall incidence of malignancies of specific sites of the head and neck in Germany is 4.48 per 100000 children. The most frequently observed entities, representing primary tumours, are soft tissue sarcomas (0.39/100000), lymphomas (0.09/100000) and thyroid carcinoma (0.07/100000). The most commonly affected organs are the thyroid (1.21/100000), orbita (0.91/100000), nasopharynx (0.66/100000), tonsils (0.43/100000) and paranasal sinuses (0.14/100000). Overall, boys are more frequently affected than girls; however, incidence increases in girls with age and exceeds that of boys in the age group between 10 and 14 years. CONCLUSIONS: This is a first statistical evaluation detailing cumulative incidences of various histologic types of malignancies of the head and neck including age and gender distribution as well as organ-specific localization in children below the age of 15 in Germany.

Up-to-date monitoring of childhood cancer long-term survival in Europe: tumours of the sympathetic nervous system, retinoblastoma, renal and bone tumours, and soft tissue sarcomas.

BACKGROUND: Prognosis for most types of childhood tumours has improved during the last few decades. In this article we estimate up-to-date period survival for less common, but important childhood malignancies in Europe. METHODS: Using the database of the Automated Childhood Cancer Information System we calculated period estimates of 10-year survival for the 1995-1999 period for children aged 0-14 years diagnosed during 1985-1999 with tumours of the sympathetic nervous system (NS), retinoblastoma, renal tumours, bone tumours and soft tissue sarcomas in four European regions. RESULTS: Ten-year period survival for 1995-1999 was 66% in children with tumours of the sympathetic NS, 96% for retinoblastoma, 87% for renal tumours, 58% for bone tumours and 61% for soft tissue sarcomas. The higher period estimates, as compared with cohort and complete estimates indicate recent improvement in survival for tumours of the sympathetic NS and to a lesser extent for retinoblastoma and renal tumours. Region-specific period survival estimates were lowest for Eastern Europe for renal, bone and soft tissue tumours, but not for the other two tumour groups. CONCLUSION: There have been further improvements in the 1990s in long-term survival of children diagnosed with several malignancies, albeit to a different extent in different European regions.

[Name-based identification of cases of Turkish origin in the childhood cancer registry in Mainz]. / Namensbasierte Identifizierung von Fällen mit türkischer Herkunft im Kinderkrebsregister Mainz.

Until now few analyses of routine data relating to the health of migrants have been conducted in Germany. A major obstacle is that most data sources do not provide reliable information on the origin of migrants. While some sources contain the nationality of persons registered, this information does not allow one to identify migrants who have taken up German citizenship, i.e., a substantial part of second-generation migrants. In this paper we demonstrate how a computer-aided, name-based algorithm can be used to identify persons of Turkish origin in the German Childhood Cancer Registry in Mainz, Germany. The performance of the algorithm, as assessed against the gold standard of assessing names manually, was very good (sensitivity and specificity > or = 0.975). In total, we identified 1774 of the 37,259 cases in the registry as being of Turkish origin. The name algorithm proved to be a useful tool to identify Turkish migrants in routine data sources, thus avoiding potential bias due to changes in citizenship. This approach aims at improving migrant-sensitive health reporting and research in Germany. In future, additional information on migrant status should be obtained already during primary data collection so that health data for all migrant groups can be provided.

Incidence, Trends, and Survival of Children With Embryonal Tumors.

BACKGROUND: Central nervous system (CNS) and non-CNS embryonal tumors occur principally in children and are rarely seen in adults. The incidence rates for rare entities such as atypical teratoid/rhabdoid tumors (AT/RT) or primitive neuroectodermal tumors in the CNS are rarely published. Incidence rates for certain subgroups, such as hepatoblastomas, have been increasing in some countries. METHODS: Data of 8337 embryonal tumors, registered in children (0-14 years) between 1991 and 2012 (for AT/RT 2000-2012) in the population-based German Childhood Cancer Registry with complete national coverage were analyzed for incidence rates, time trends, and survival. RESULTS: For most entities, the incidence rates were the highest for children <1 year. An important exception was medulloblastomas, which occurred mainly in 1- to 9-year-olds. Neuroblastomas and ganglioneuroblastomas as well as Wilms tumors (nephroblastomas) had the highest age standardized incidence rates (13.7 and 9.4 per million, respectively). A statistically significant increasing trend for hepatoblastomas (annual average percent change 4.6%) was detected. The survival probabilities varied between the diagnostic groups: primitive neuroectodermal tumors and AT/RT had the lowest and retinoblastomas the highest. The survival was dependent on the age at diagnosis, the most extreme examples being neuroblastomas, for which the survival probability declined steeply for children ≥1 year and medulloblastomas, for which the highest survival was seen for 10- to 14-year-olds. CONCLUSIONS: This study presents a comprehensive overview of pediatric embryonal tumors from a well-established, complete nationwide cancer registry. Significant increasing trend for hepatoblastomas was detected for the first time in Europe.

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.

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.

Long-term results and risk profiles of patients in five consecutive trials (1979-1997) with stage 4 neuroblastoma over 1 year of age.

During the last two decades new diagnostic and therapeutic tools have been utilized to improve the poor survival chances of children with stage 4 neuroblastoma. This study reviews the risk profiles and the long-term outcome of patients from five consecutive German neuroblastoma trials. A total of 96% of all German patients registered at the German childhood cancer registry with neuroblastoma stage 4 over 1 year of age at diagnosis entered one of the trials during 1979-2001. Eight hundred and twenty-eight consecutive children were analyzed retrospectively. In spite of having significantly improved diagnostic tools like bone marrow superstaging and mIBG scintigraphy the stage 4 incidence did not increase after reaching completeness of the registry (5.4 cases/100,000 children at 1-14 years of age; P=0.52). The distribution of the primary tumors and of metastases was constant over the periods. The amount of bone marrow infiltration did not change with time. The risk factors lactate dehydrogenase, ferritin and MYCN, and the clinical risk groups 4A, 4B, 4C also remained constant over the trials with a few exceptions for NB97. The 5-year event free survival increased from 0.01+/-0.01 (NB79) to 0.14+/-0.03 (NB85), 0.16+/-0.04 (NB82), 0.27+/-0.02 (NB90), and 0.33+/-0.04 (NB97). The overall survival rates improved similarly from 0.04 (NB79) to 0.44 (NB97). In conclusion, the improved survival was associated with better treatment and not caused by lower risk profiles in stage 4 neuroblastoma patients.

Associations between mortality and air pollution in central Europe.

Increased mortality has been observed in association with elevated concentrations of air pollutants in European cities and in the United States. We reassessed the effects of particulate matter in Central Europe. Mortality and air pollution data were obtained for a highly polluted region of the Czech Republic and a rural region in Germany. Poisson regression analyses were conducted considering trend, season, meteorology, and influenza epidemics as confounders in both a parametric and a nonparametric approach. The Czech Republic had a 3.8% increase in mortality [95% confidence interval (CI), 0.8-6.9%] in association with 100 microg/m(3) total suspended particles (TSP) (lagged 2 days) for the time period 1982-1994. During the last 2 years of study, 68% of the TSP consisted of particulate matter [less than/equal to] 10 microm in aerodynamic diameter (PM(10)). An increase of 100 microg/m(3) TSP (lagged 1 day) was associated with a 9.5% increase in mortality (CI, 1.2-18.5%) and 100 microg/m(3) PM(10 )(lagged 1 day) showed a 9.8% increase in mortality (CI, 0.7-19.7%). We found no evidence for an association between mortality and particulate matter in the rural area in Germany at the Czech border. Data from the coal basin in the Czech Republic suggested an increase in mortality associated with the concentration of particulate matter in a highly polluted setting in Central Europe that is consistent with the associations observed in other western European cities and in the United States.