Scientific opinion on the tolerable upper intake level for folate.

Following a request from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for folic acid/folate. Systematic reviews of the literature were conducted to assess evidence on priority adverse health effects of excess intake of folate (including folic acid and the other authorised forms, (6S)-5-methyltetrahydrofolic acid glucosamine and l-5-methyltetrahydrofolic acid calcium salts), namely risk of cobalamin-dependent neuropathy, cognitive decline among people with low cobalamin status, and colorectal cancer and prostate cancer. The evidence is insufficient to conclude on a positive and causal relationship between the dietary intake of folate and impaired cognitive function, risk of colorectal and prostate cancer. The risk of progression of neurological symptoms in cobalamin-deficient patients is considered as the critical effect to establish an UL for folic acid. No new evidence has been published that could improve the characterisation of the dose-response between folic acid intake and resolution of megaloblastic anaemia in cobalamin-deficient individuals. The ULs for folic acid previously established by the Scientific Committee on Food are retained for all population groups, i.e. 1000 µg/day for adults, including pregnant and lactating women, 200 µg/day for children aged 1-3 years, 300 µg/day for 4-6 years, 400 µg/day for 7-10 years, 600 µg/day for 11-14 years and 800 µg/day for 15-17 years. A UL of 200 µg/day is established for infants aged 4-11 months. The ULs apply to the combined intake of folic acid, (6S)-5-methyltetrahydrofolic acid glucosamine and l-5-methyltetrahydrofolic acid calcium salts, under their authorised conditions of use. It is unlikely that the ULs for supplemental folate are exceeded in European populations, except for regular users of food supplements containing high doses of folic acid/5-methyl-tetrahydrofolic acid salts.

Scientific opinion on the tolerable upper intake level for selenium.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for selenium. Systematic reviews of the literature were conducted to identify evidence regarding excess selenium intake and clinical effects and potential biomarkers of effect, risk of chronic diseases and impaired neuropsychological development in humans. Alopecia, as an early observable feature and a well-established adverse effect of excess selenium exposure, is selected as the critical endpoint on which to base a UL for selenium. A lowest-observed-adverse-effect-level (LOAEL) of 330 µg/day is identified from a large randomised controlled trial in humans (the Selenium and Vitamin E Cancer Prevention Trial (SELECT)), to which an uncertainty factor of 1.3 is applied. A UL of 255 µg/day is established for adult men and women (including pregnant and lactating women). ULs for children are derived from the UL for adults using allometric scaling (body weight0.75). Based on available intake data, adult consumers are unlikely to exceed the UL, except for regular users of food supplements containing high daily doses of selenium or regular consumers of Brazil nuts. No risk has been reported with the current levels of selenium intake in European countries from food (excluding food supplements) in toddlers and children, and selenium intake arising from the natural content of foods does not raise reasons for concern. Selenium-containing supplements in toddlers and children should be used with caution, based on individual needs.

Tolerable upper intake level for dietary sugars.

Following a request from five European Nordic countries, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was tasked to provide scientific advice on a tolerable upper intake level (UL) or a safe level of intake for dietary (total/added/free) sugars based on available data on chronic metabolic diseases, pregnancy-related endpoints and dental caries. Specific sugar types (fructose) and sources of sugars were also addressed. The intake of dietary sugars is a well-established hazard in relation to dental caries in humans. Based on a systematic review of the literature, prospective cohort studies do not support a positive relationship between the intake of dietary sugars, in isocaloric exchange with other macronutrients, and any of the chronic metabolic diseases or pregnancy-related endpoints assessed. Based on randomised control trials on surrogate disease endpoints, there is evidence for a positive and causal relationship between the intake of added/free sugars and risk of some chronic metabolic diseases: The level of certainty is moderate for obesity and dyslipidaemia (> 50-75% probability), low for non-alcoholic fatty liver disease and type 2 diabetes (> 15-50% probability) and very low for hypertension (0-15% probability). Health effects of added vs. free sugars could not be compared. A level of sugars intake at which the risk of dental caries/chronic metabolic diseases is not increased could not be identified over the range of observed intakes, and thus, a UL or a safe level of intake could not be set. Based on available data and related uncertainties, the intake of added and free sugars should be as low as possible in the context of a nutritionally adequate diet. Decreasing the intake of added and free sugars would decrease the intake of total sugars to a similar extent. This opinion can assist EU Member States in setting national goals/recommendations.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

Draft for internal testing Scientific Committee guidance on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments.

EFSA requested its Scientific Committee to prepare a guidance document on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments. The guidance document provides an introduction to epidemiological studies and illustrates the typical biases of the different epidemiological study designs. It describes key epidemiological concepts relevant for evidence appraisal. Regarding study reliability, measures of association, exposure assessment, statistical inferences, systematic error and effect modification are explained. Regarding study relevance, the guidance describes the concept of external validity. The principles of appraising epidemiological studies are illustrated, and an overview of Risk of Bias (RoB) tools is given. A decision tree is developed to assist in the selection of the appropriate Risk of Bias tool, depending on study question, population and design. The customisation of the study appraisal process is explained, detailing the use of RoB tools and assessing the risk of bias in the body of evidence. Several examples of appraising experimental and observational studies using a Risk of Bias tool are annexed to the document to illustrate the application of the approach. This document constitutes a draft that will be applied in EFSA's assessments during a 1-year pilot phase and be revised and complemented as necessary. Before finalisation of the document, a public consultation will be launched.

Dietary reference values for sodium.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) derived dietary reference values (DRVs) for sodium. Evidence from balance studies on sodium and on the relationship between sodium intake and health outcomes, in particular cardiovascular disease (CVD)-related endpoints and bone health, was reviewed. The data were not sufficient to enable an average requirement (AR) or population reference intake (PRI) to be derived. However, by integrating the available evidence and associated uncertainties, the Panel considers that a sodium intake of 2.0 g/day represents a level of sodium for which there is sufficient confidence in a reduced risk of CVD in the general adult population. In addition, a sodium intake of 2.0 g/day is likely to allow most of the general adult population to maintain sodium balance. Therefore, the Panel considers that 2.0 g sodium/day is a safe and adequate intake for the general EU population of adults. The same value applies to pregnant and lactating women. Sodium intakes that are considered safe and adequate for children are extrapolated from the value for adults, adjusting for their respective energy requirement and including a growth factor, and are as follows: 1.1 g/day for children aged 1-3 years, 1.3 g/day for children aged 4-6 years, 1.7 g/day for children aged 7-10 years and 2.0 g/day for children aged 11-17 years, respectively. For infants aged 7-11 months, an Adequate Intake (AI) of 0.2 g/day is proposed based on upwards extrapolation of the estimated sodium intake in exclusively breast-fed infants aged 0-6 months.

Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food.

The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL-PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre- and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005-TEQ/g fat in blood sampled at age 9 years based on PCDD/F-TEQs. No association was observed when including DL-PCB-TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F-TEQ only was on average 2.4- and 2.7-fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL-PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

Statement on the validity of the conclusions of a mouse carcinogenicity study on sucralose (E 955) performed by the Ramazzini Institute.

The Panel on Food Additives and Nutrient Sources added to Food (ANS) was requested from the European Commission to provide a statement on the validity of the conclusions of a mouse study on the carcinogenic potential of sucralose (E 955) performed by the Ramazzini Institute (Soffritti et al., 2016). Sucralose (E 955) is authorised as a food additive in the EU in accordance with Annex II to Regulation (EC) No 1333/2008 on food additives. According to Commission Regulation (EU) No 257/2010, the full re-evaluation of sucralose shall be completed by December 2020. Taking into consideration the publication from Soffritti et al. (2016), the technical report and additional information provided by the Ramazzini Institute and other information available for sucralose (E 955), the Panel noted: (i) the design of the bioassay that considers exposure from gestation up to natural death of animals implies an increase in background pathology that results in the possibility of misclassifications and a difficult interpretation of data, especially in the absence of both an appropriate concurrent control group and a recent historical database; (ii) the lack of a dose-response relationship between the exposure to sucralose and incidence of lymphomas and leukaemias (combined); (iii) the lack of a mode of action and failure to meet all the Bradford-Hill considerations for a cause-effect relationship between intake of sucralose and the development of tumours in male mice only; (iv) a comprehensive database was available for sucralose and no carcinogenic effect was reported in adequate studies in rats and mice. Moreover, there was no reliable evidence of in vivo genotoxicity. Therefore, the Panel concluded that the available data did not support the conclusions of the authors (Soffritti et al., 2016) that sucralose induced haematopoietic neoplasias in male Swiss mice.

Flaws in animal studies exploring statins and impact on meta-analysis.

BACKGROUND: Animal experiments should be appropriately designed, correctly analysed and transparently reported to increase their scientific validity and maximise the knowledge gained from each experiment. This systematic review of animal experiments investigating statins evaluates their quality of reporting and methodological aspects as well as their implications for the conduction of meta-analyses. METHODS: We searched medline and embase for studies reporting research on statins in mice, rats and rabbits. We collected detailed information about the characteristics of studies, animals and experimental methods. RESULTS: We retrieved 161 studies. A little over half did not report randomisation (55%) and most did not describe blinding (88%). All studies reported details on the experimental procedure, although many omitted information about animal gender, age or weight. Four percent did not report the number of animals used. None reported the sample size. Fixed- and random-effects models gave different results (ratio of effect size increased by five folds). Heterogeneity was consistently substantial within animal models, for which accounting for covariates had minimal impact. Publication bias is highly suspected across studies. CONCLUSIONS: Although statins showed efficacy in animal models, preclinical studies highlighted fundamental problems in the way in which such research is conducted and reported. Results were often difficult to interpret and reproduce. Different meta-analytic approaches were highly inconsistent: a reliable approach to estimate the true parameter was imperceptible. Policies that address these issues are required from investigators, editors and institutions that care about the quality standards and ethics of animal research.

Multifactorial central nervous system recurrence susceptibility in patients with HER2-positive breast cancer: epidemiological and clinical data from a population-based cancer registry study.

BACKGROUND: A series of retrospective studies have reported that patients with human epidermal growth factor receptor 2(HER2)-positive breast cancer are at a greater risk of central nervous system (CNS) metastases. Trastuzumab, which does not cross the blood-brain barrier, has been associated with this increased risk. METHODS: The authors evaluated incidence, survival, and risk factors for CNS metastases in the incident breast cancer population systematically collected by the Parma Province Cancer Registry over the 4-year period between 2004 and 2007. RESULTS: A total of 1458 patients with a diagnosis of stage I to III invasive breast cancer were analyzed for study purposes. At a median follow-up of 4.1 years, CNS events were observed in 1.3% and 5% of HER2-negative patients and HER2-positive patients, respectively (P < .0001). The administration of trastuzumab either as adjuvant therapy or for metastatic disease was associated with a significantly increased risk of CNS involvement at first disease recurrence and after first extracranial recurrence, respectively. According to multivariate analysis, HER2-positive status and trastuzumab treatment, high Ki-67 index, and hormone receptor negativity remained independent risk factors for the development of CNS metastasis. CONCLUSIONS: To the authors' knowledge, this is the first population-based cancer registry study analyzing factors associated with CNS recurrence in a general population of newly diagnosed breast cancer patients with known HER2 status. The data from the current study provide evidence that patients with HER2-positive breast cancer have a significantly higher incidence of CNS metastasis after treatment with trastuzumab. Improvements in systemic control and overall survival associated with trastuzumab-based therapy may lead to an "unmasking" of CNS disease recurrence that would otherwise remain clinically silent before a patient's death.

Survival for ethmoid sinus adenocarcinoma in European populations.

BACKGROUND: Adenocarcinoma of the ethmoid sinus is rare. EUROCARE data provide a good opportunity to study the survival of this rare disease in a population of continental size. PATIENTS AND METHODS: A total of 204 cases, age 15 to 99 years, diagnosed with primary ethmoid sinus adenocarcinoma between 1983 and 1994, were analyzed. The data were contributed by 22 population-based cancer registries from the nine countries participating in EUROCARE. Relative survival by sex, age, period of diagnosis, region and stage, and adjusted relative excess risk (RER) of death, were estimated. RESULTS: Survival was 83%, 58% and 46%, 1, 3 and 5 years, respectively after diagnosis. Five-year survival was best (60%) in patients of 55-64 years and worst (33%) in the oldest age group (> or =65 years). Five-year survival differ between European population: in Norway (55%, 95% confidence interval 26.4-80.9) and western Europe that includes populations from Eindhoven, Saarland, Geneva, Italy and France (56%, 95%CI 41.3-68.9) was higher than in the UK (41%, 95% CI 30.8-51.8) and eastern Europe which includes Slovakia and Slovenia, (22%, 95% CI 3.5-54.4). Five-year survival did not improve over time. Due to the rarity of the disease, all the survival differences did not reach the statistical significance. CONCLUSIONS: Since no survival improvement with time was evident from this study, efforts should be made to improve early diagnosis. GPs and ENT specialists should be alerted to the disease and encouraged to take occupational histories in people with persistent nasal symptoms, which may lead to a reasonable suspicion of malignancy. Monitoring of exposed workers may also improve early diagnosis. Patients with suspected ethmoid cancer should be referred immediately a specialized diagnosis and treatment centre.

Multiple tumours in survival estimates.

In international comparisons of cancer registry based survival it is common practice to restrict the analysis to first primary tumours and exclude multiple cancers. The probability of correctly detecting subsequent cancers depends on the registry's running time, which results in different proportions of excluded patients and may lead to biased comparisons. We evaluated the impact on the age-standardised relative survival estimates of also including multiple primary tumours. Data from 2,919,023 malignant cancers from 69 European cancer registries participating in the EUROCARE-4 collaborative study were used. A total of 183,683 multiple primary tumours were found, with an overall proportion of 6.3% over all the considered cancers, ranging from 0.4% (Naples, Italy) to 12.9% (Iceland). The proportion of multiple tumours varied greatly by type of tumour, being higher for those with high incidence and long survival (breast, prostate and colon-rectum). Five-year relative survival was lower when including patients with multiple cancers. For all cancers combined the average difference was -0.4 percentage points in women and -0.7 percentage points in men, and was greater for older registries. Inclusion of multiple tumours led to lower survival in 44 out of 45 cancer sites analysed, with the greatest differences found for larynx (-1.9%), oropharynx (-1.5%), and penis (-1.3%). Including multiple primary tumours in survival estimates for international comparison is advisable because it reduces the bias due to different observation periods, age, registration quality and completeness of registration. The general effect of inclusion is to reduce survival estimates by a variable amount depending on the proportion of multiple primaries and cancer site.

Survival from salivary glands adenoid cystic carcinoma in European populations.

Adenoid cystic carcinoma (ACC) of salivary gland origin is rare. The EUROCARE data provide a good opportunity to study the survival of this uncommon cancer in a large population. A total of 2611 cases, aged 15 to 99 years, diagnosed between 1983 and 1994 with primary salivary gland ACC were analyzed. Thirty-two population based cancer registries from seventeen countries participating in EUROCARE contributed the data. Relative survival by sex, age, period of diagnosis, region, site and stage, and the adjusted relative excess risk (RER) of death were estimated. Survival since diagnosis was 94%, 78% and 65% at 1, 5 and ten years, respectively. Ten-year survival was best (69%) in patients of the youngest age group (15-54 years) and from Northern Europe (69%). In the UK was higher (65%) than in Western (62%) and Eastern (56%) Europe. ACCs in nasal cavity (RER 2.6), pharynx (RER 3.5) and larynx and bronchus (RER 3.9) had a worse prognosis compared to those of oral cavity. A strong effect of stage at diagnosis on RERs and some worsening of survival at five years over time (80% in 1983-1985, 76% in 1992-1994) were also evident. The findings of the present study, as those from clinical studies, confirm the important impact of primary site and stage at diagnosis on survival. Furthermore, we could demonstrate that survival for ACC did not improve over time and that cases from Eastern countries had a significant worse prognosis. Improvements in the disease detection in its early stage and international collaborative research should be encouraged.

Long-term survival expectations of cancer patients in Europe in 2000-2002.

Period analysis has been shown to provide more up-to-date estimates of long-term cancer survival rates than traditional cohort-based analysis. Here, we provide detailed period estimates of 5- and 10-year relative survival by cancer site, country, sex and age for calendar years 2000-2002. In addition, pan-European estimates of 1-, 5- and 10-year relative survival are provided. Overall, survival estimates were mostly higher than previously available cohort estimates. For most cancer sites, survival in countries from Northern Europe, Central Europe and Southern Europe was substantially higher than in the United Kingdom and Ireland and in countries from Eastern Europe. Furthermore, relative survival was also better in female than in male patients and decreased with age for most cancer sites.

Survival in patients with uveal melanoma in Europe.

OBJECTIVE: To estimate survival in patients in whom uveal melanoma was diagnosed between January 1, 1983, and December 31, 1994, in Europe. METHODS: Survival analysis of data from 32 cancer registries in 16 European countries adhering to the European Cancer Registry for 5788 patients with uveal melanoma diagnosed between January 1, 1983, and December 31, 1994, with follow-up to 1999. RESULTS: Five-year relative survival was 68.9% overall and remained stable with the period of diagnosis. Relative excess risk of death was 2.45 (95% confidence interval [CI], 2.10-2.86) in patients aged 75 years or older compared with patients aged 54 years or younger and was slightly higher in male patients (relative excess risk, 1.10; 95% CI, 1.02-1.19) than in female patients. Survival was similar in Nordic countries (relative excess risk, 1.03; 95% CI, 0.87-1.21) compared with the United Kingdom (reference country) and was lower in eastern and western European countries (1.26; 1.05-1.52, and 1.25; 0.90-1.60, respectively) compared with the reference country. CONCLUSIONS: In this large series of patients with uveal melanoma, 5-year relative survival remained stable with the introduction of conservative treatment in individuals in whom uveal melanoma was diagnosed between 1983 and 1994. We found differences in survival between sexes and in European areas that should be investigated in studies that consider tumor characteristics at the individual level.

Incidence of uveal melanoma in Europe.

PURPOSE: To estimate incidence rates of uveal melanoma in Europe from 1983 to 1994. DESIGN: Incidence analysis of data from cancer registries adhering to the European Cancer Registry-based study on survival and care of cancer patients (EUROCARE) (cases diagnosed from 1983 to 1994). PARTICIPANTS: Data of 6673 patients with ocular melanoma (as defined by International Classification of Diseases for Oncology morphology codes 8720 to 8780 [melanoma] and International Classification of Diseases 9 (ICD9) codes 190.0 [iris and ciliary body], 190.5 [retina], 190.6 [choroid], and 190.9 [unspecified ocular location]) from 33 cancer registries of 16 European countries. METHODS: Incidence rate ratios (IRRs) were obtained from a multilevel Poisson regression model. MAIN OUTCOME MEASURES: Incidence rates and IRRs associated with demographic and geographic variables. RESULTS: Standardized incidence rates increased from south to north across registries, from a minimum of <2 per million in registries of Spain and southern Italy up to >8 per million in Norway and Denmark. The inclusion of tumors with unspecified ocular location (code 190.9) increased incidence rates in most United Kingdom registries, but not in the other geographic areas, where this code was seldom used for uveal melanomas. Incidence increased noticeably up to age 55 (IRR, 1.46 per 5 years; 95% confidence interval [CI], 1.36-1.57) but leveled off after age 75 (IRR, 0.99 per 5 years; 95% CI, 0.93-1.05), with intermediate levels midway (IRR, 1.18 per 5 years; 95% CI, 1.12-1.23). It was also higher in males (IRR, 1.22; 95% CI, 1.16-1.28). Rates were stable during the study period, but a cohort effect was evidenced, accounting for higher incidence rates in people born during the period 1910 to 1935 (P = 0.005). Incidence increased with latitude (P = 0.008), which explained most differences in rates among areas. CONCLUSIONS: In this large series of uveal melanomas, we found stable incidence during the years 1983 to 1994. The north-to-south decreasing gradient supports the protective role of ocular pigmentation. European ophthalmologists should develop guidelines to standardize the coding of tumors treated conservatively using the ICD classification to improve the registration and surveillance of uveal melanoma by cancer registries.

Late outcomes of colorectal cancer treatment: a FECS-EUROCARE study.

BACKGROUND: Colorectal cancer survival has increased in recent years, however, the impact of these cancers and their treatment on long-term survivors has not been extensively investigated at the population level. This pilot study assessed the prevalence of late outcomes in long-term colorectal cancer survivors registered by two European population-based cancer registries (CRs) to determine the feasibility of using the approach on a wider basis in Europe. METHODS: Long-term survivors diagnosed in 1990 and in 1997 in Côte d'Or (France) and Varese (Italy) CRs were surveyed. Questionnaires to general practitioners (GPs) and survivors investigated a wide range of outcomes. Information on stage at diagnosis, primary treatment, stoma inserted during main surgery, and vital status was available from a previous study. Logistic regression was used to identify associations of late outcomes with sex, age at survey, country, year of diagnosis, and site. RESULTS: Participation was 51.8% (45.2% of French and 56.6% of Italian cases identified). Of the 256 survivors available for analysis, 10% had bowel incontinence, about 70% had other bowel, gastrointestinal, or urination problems, 10% had second primary cancer, 4% had colorectal recurrence, and 10% had stoma. The proportion with stoma reduced by 65% in survivors diagnosed between 1990 and 1997, but no other outcomes reduced in prevalence with time. Most (67%) had optimal GP-assessed ECOG performance status. Around 80% were followed-up with liver imaging or colonoscopy. CONCLUSIONS: We identified non-trivial rates of bowel and bladder problems after colorectal treatment, but overall good levels of functioning. High-resolution studies of this kind must be population-based to provide data useful for public health provision. This pilot study encountered difficulties in contacting GPs and suffered from low compliance. However, it is the first to investigate late outcome trends after treatment for colorectal cancer.

Incidence of and survival from Wilms' tumour in adults in Europe: data from the EUROCARE study.

Wilms' tumour, or nephroblastoma, is an embryonal cancer of the kidney that occurs mainly in young children. This is a very rare tumour among adults, with an incidence rate of less than 0.2 per million per year. The aims of this study were to report the survival of adults diagnosed with nephroblastoma in Europe and to analyse time trends and geographic variations in survival. All the adults (age range 15-99 years) diagnosed with a Wilms' tumour during 1983-1994 and registered by one of the 22 cancer registries in 16 countries contributing to the EUROCARE (European cancer registries study on cancer patients' survival and care) database were analysed. Relative survival at 1 and 5 years after diagnosis was estimated by age, sex, geographic area, period of diagnosis and tumour stage. A total of 143 patients, with a median age of 34 years, were included in the analysis. Crude annual incidence rates varied geographically between 0.17 and 0.27 per million. Overall relative survival was 69.9% (95% confidence interval (CI) 61.8-78.0%) at 1 year and 47.3% (38.2-56.4%) at 5 years. Survival was 2.1-fold higher for women than for men (95% CI 1.3-3.5). There was a non-significant trend for better survival for younger patients and localised tumours, but no improvement in survival by period of diagnosis. Survival was not different between geographic areas. Our results suggest a poorer outcome of nephroblastoma in adults compared with published results in children. This may, at least partly, be explained by the rarity of this diagnosis. Prognosis may be improved by the use of specific treatment guidelines for nephroblastoma in adults.

Survival from rare cancer in adults: a population-based study.

BACKGROUND: Rare cancers are a challenge to clinical practice, and treatment experience, even in major cancer centres to which rare cancers are usually referred, is often limited. We aimed to study the epidemiology of rare cancers in a large population of several countries. METHODS: We analysed survival by age, sex, subsite, and morphology in 57,144 adults with 14 selected rare cancers diagnosed 1983-94. Variations in survival over time and between European regions were also assessed for variations in quality of care. We also estimated the adjusted relative excess risk of death for every rare cancer. FINDINGS: Overall 5-year relative survival was good (ie, >65%) for placental choriocarcinoma (85.4% [95% CI 81.4-89.5]), thyroid medullary carcinoma (72.4% [69.2-75.5]), ovarian germ-cell cancer (73.0% [70.0-76.0]), lung carcinoid (70.1% [67.3-72.9]), and cervical adenocarcinoma (65.5% [64.3-66.6]); intermediate (ie, 35-65%) for testicular cancer at age 65 years or older (64.0% [59.3-68.7]), sarcoma of extremities (60.0% [58.9-61.2]), digestive-system endocrine cancers (55.6% [54.9-56.3]), anal squamous-cell carcinoma (53.1% [51.5-54.8]), and uterine sarcoma (43.5% [42.0-44.9]); low for carcinoma of adrenal-gland cortex (32.7% [28.3-37.2]) and bladder squamous-cell carcinoma (20.4% [18.8-22.0]); and poor for angiosarcoma of liver (6.4% [1.8-11.0]) and mesothelioma (4.7% [4.3-5.2]). Survival was usually better for women than men and poor in those aged 75 years or older. Survival significantly improved over time for ovarian germ-cell cancer, sarcomas of extremities, digestive-system endocrine tumours, anal squamous-cell carcinoma, and angiosarcoma of liver. Survival in northern Europe was higher than in the other geographic groupings for most cancers. INTERPRETATION: Because effective treatments are available for several of the rare cancers we assessed, further research is needed to ascertain why survival is lower in some European countries than in others, particularly in older patients. Audit of best practice for rare cancers with treatment protocols would be useful.

[Mortality risk in intravenous drug users in Emilia Romagna region and its socio-demographic determinants. Results of a longitudinal study]. / La mortalità dei tossicodipendenti nella Regione Emilia Romagna e i suoi determinanti. Risultati di uno studio longitudinale.

Results on general and cause-specific mortality in a retrospective cohort of intravenous drug users in the Emilia Romagna Region (Italy) are presented. Four thousand two hundred and sixty subjects (3324 males, 936 females) in public treatment centres in Piacenza, Modena and Ferrara provinces have been observed for up to 20 years in the period 1975-95. AIDS age-adjusted death rates dramatically increased all during the period, while overdose and other causes (mostly accidental) increase up to the early nineties and then tend to decrease. This last pattern has not been described in other Italian cohorts, and could be related with changes in therapeutic strategies. General mortality is very high in this cohort, as in other studies (males: SMR 16.7, LC 15.3-18.2; females: SMR 33.4, LC 27.9-39.9). Survival probability after 15 years of observation is 65% in males and females combined. Apart from overdose and AIDS, other relevant excesses are observed for accidental deaths (especially car accidents), cirrhosis, infective causes and cancer in males; in females, accidental deaths (among which homicides) and digestive tract diseases. A higher death risk is observed for males who began drug use before age 20, who contacted treatment centres in the nineties and at an older age, and who came in contact with the law.