The Swiss Childhood Cancer Registry: rationale, organisation and results for the years 2001-2005

QUESTIONS UNDER STUDY: Childhood cancer is a rare but severe disease. Therefore central registration of all cases is essential for surveillance and management. This paper describes the methodology and basic results of the Swiss Childhood Cancer Registry (SCCR). METHODS: The SCCR was established in 1976, originally as a national hospital-based registry of childhood malignancies. All 9 paediatric oncology-haematology clinics in Switzerland provide baseline and follow-up information on all children diagnosed with cancer. These data are registered centrally and diagnoses are coded according to the International Classification of Childhood Cancer. RESULTS: From 2001-2005, 887 cases of childhood cancer in Swiss residents under the age of 15 years were registered in the SCCR. Of these, 281 (31.7%) were leukaemias, 223 (24.0%) were CNS tumours, and 116 (13.1%) were lymphomas. The age-standardised annual incidence per 1 Million person-years (age below 15 years; world standardisation) was 154.0 (95% CI 143.7-164.3; N = 887). The incidence was higher for boys (170.2, 155.0-185.4; N = 501) than for girls (136.9, 123.0-150.8; N = 386). CONCLUSION: The close collaboration between all paediatric oncologists-haematologists in Switzerland and a university department allowed the creation of a national population-based cancer registry with detailed clinical information. The SCCR produces cancer type specific incidence and survival estimates and allows the development of nested research projects on childhood cancer aetiology, management and outcome, both on a national and on an international level.     

Efficacy of central nervous system stimulant treatment for cocaine dependence: a systematic review and meta-analysis of randomized controlled clinical trials

AIMS: To evaluate the efficacy of central nervous system (CNS) stimulants compared with placebo for the treatment of cocaine dependence. METHODS: A systematic review and meta-analysis was carried out. Bibliographic databases were searched, reference lists of retrieved studies were hand-searched and the first authors of each study were contacted. All randomized controlled clinical trials (RCCT) comparing the efficacy of any CNS stimulant with placebo in cocaine-dependent patients were included. Quantitative data synthesis was performed for each single CNS stimulant and for all CNS stimulants. RESULTS: Nine RCCT met the inclusion criteria. These RCCT included 640 patients and compared five CNS stimulants: mazindol, dextroamphetamine, methylphenidate, modafinil and bupropion with placebo. No CNS stimulant improved study retention [RR = 0.94 (0.81-1.09)] or cocaine use [RR = 0.90 (0.79-1.02)]. An exploratory analysis using indirect estimations of cocaine use showed that the proportion of cocaine-positive urine screens was lower with dexamphetamine than with placebo [RR = 0.73 (0.60-0.90)] and that all CNS stimulants pooled together also suggested a significant decrease of cocaine use [RR = 0.87 (0.77-0.99)]. Data on craving could not be meta-analysed due to heterogeneity, but no RCCT found differences in cocaine craving between active drug and placebo except one, whose outcome favoured dexamphetamine. No serious adverse event (AE) was reported. Average of AE-induced dropouts was low and was greater for CNS stimulants than placebo: 4.4% versus 1.3% (P = 0.03). CONCLUSION: The main outcomes of this study do not support the use of CNS stimulants for cocaine dependence. Nevertheless, secondary analyses provide some hopeful results that encourage further research with these drugs, mainly with dexamphetamine and modafinil.     

Fatigue in irritable bowel syndrome: characterization and putative role of leptin

OBJECTIVES: Fatigue has received little attention in the irritable bowel syndrome. Emerging evidence exists that leptin may be involved in the pathogenesis of fatigue in several conditions. We aimed to evaluate the occurrence of fatigue and its characteristics in irritable bowel syndrome and to analyze the relationship between fatigue and leptin. METHODS: We enrolled 51 consecutive irritable bowel syndrome patients and 22 healthy controls without fatigue. None of them were depressed. The Fatigue Impact Scale was used to evaluate fatigue. RESULTS: In all, 62.7% of irritable bowel syndrome patients verbally expressed fatigue and rated more than 4 on the visual analog scale. The total score of fatigue was significantly higher in irritable bowel syndrome than in controls. In irritable bowel syndrome patients, but not in controls, a significant association was found between the total score of fatigue and leptin and this association was more pronounced in 32 irritable bowel syndrome patients who verbally expressed fatigue (r=0.60; P=0.0003). In irritable bowel syndrome, leptin correlated with fatigue independently from age, sex, fat mass and body mass index. CONCLUSIONS: Our study shows that fatigue occurs in 62.7% of irritable bowel syndrome patients when systematically asked for. Fatigue influences all three domains of the Fatigue Impact Scale in irritable bowel syndrome, the most being the physical and the psychosocial domains. Fatigue is associated with circulating leptin levels independently from age, sex, fat mass and body mass index in irritable bowel syndrome. The metabolic sequence involved in the occurrence of fatigue remains to be determined.     

WAERS: an application for Web-assisted estimation of relative survival

Net cancer survival estimation is usually performed by computing relative survival (RS), which is defined as the ratio between observed and expected survival rates. The mortality of a reference population is required in order to compute the expected survival rate, which can be performed using a variety of statistical packages. A new Web interface to compute RS, called WAERS, has been developed by the Catalan Institute of Oncology. The reference population is first selected, and then the RS of a cohort is computed. A remote server is used for this purpose. A mock example serves to illustrate the use of the tool with a hypothetical cohort, for which RS is estimated based on three different reference populations (a province of Spain, an autonomous community (Region), and the entire Spanish population). At present, only mortality tables for different areas of Spain are available. Future improvements of this application will include mortality tables of Latin American and European Union countries, and stratified (control variable) analysis. This application can be also useful for cohort mortality studies and for registries of several diseases.     

Prognostic value of hyperintense vessel signals on fluid-attenuated inversion recovery sequences in acute cerebral ischemia

BACKGROUND: Fluid-attenuated inversion recovery (FLAIR) sequences may reveal hyperintense vessel signals (HVS) at the acute stage of cerebral ischemia. The aim of this study was to test the hypothesis that HVS are associated with a worse outcome. METHODS: We included 30 consecutive patients admitted within 12 h after onset of hemispheric cerebral ischemia. The outcome was assessed with the modified Rankin Scale at month 1. RESULTS: Proximal HVS were present in 9 patients and distal HVS in 16. All patients with proximal occlusions on time-of-flight sequences had distal HVS on FLAIR. Patients with poor outcome at month 1 (modified Rankin Scale 3-6) more frequently had had HVS on MRI (12/13 vs. 4/17; p< 0.001). CONCLUSION: Distal HVS found on FLAIR sequences within 12 h of acute cerebral ischemia are associated with a worse 1-month outcome.     

BH3-only proteins Bid and Bim(EL) are differentially involved in neuronal dysfunction in mouse models of Huntington's disease

Apoptosis, a cell death mechanism regulated by Bcl-2 family members, has been proposed as one of the mechanisms leading to neuronal loss in Huntington's disease (HD). Here we examined the regulation of Bcl-2 family proteins in three different mouse models of HD with exon 1 mutant huntingtin: the R6/1, the R6/1:BDNF+/-, and the Tet/HD94 in which the huntingtin transgene is controlled by the tetracycline-inducible system. Our results disclosed an increase in the levels of the BH3-only proteins Bid and Bim(EL) in the striatum of HD mouse models that was different depending on the stage of the disease. At 16 weeks of age, Bid was similarly enhanced in the striatum of R6/1 and R6/1:BDNF+/- mice, whereas Bim(EL) protein levels were enhanced only in R6/1:BDNF+/- mice. In contrast, at later stages of the disease, both genotypes displayed increased levels of Bid and Bim(EL) proteins. Furthermore, Bax, Bak, Bad, Bcl-2, and Bcl-x(L) proteins were not modified in any of the points analyzed. We next explored the potential reversibility of this phenomenon by analyzing conditional Tet/HD94 mice. Constitutive expression of the transgene resulted in increased levels of Bid and Bim(EL) proteins, and only the Bid protein returned to wild-type levels 5 months after mutant huntingtin shutdown. In conclusion, our results show that enhanced Bid protein levels represent an early mechanism linked to the continuous expression of mutant huntingtin that, together with enhanced Bim(EL), may be a reporter of the progress and severity of neuronal dysfunction.     

Contribution of hand motor circuits to counting

The finding that number processing activates a cortical network partly overlapping that recruited for hand movements has renewed interest in the relationship between number and finger representations. Further evidence about a possible link between fingers and numbers comes from developmental studies showing that finger movements play a crucial role in learning counting. However, increased activity in hand motor circuits during counting may unveil unspecific processes, such as shifting attention, reciting number names, or matching items with a number name. To address this issue, we used transcranial magnetic stimulation to measure changes in corticospinal (CS) excitability during a counting task performed silently and using either numbers or letters of the alphabet to enumerate items. We found an increased CS excitability of hand muscles during the counting task, irrespective of the use of numbers or letters, whereas it was unchanged in arm and foot muscles. Control tasks allowed us to rule out a possible influence of attention allocation or covert speech on CS excitability increase of hand muscles during counting. The present results support a specific involvement of hand motor circuits in counting because no CS changes were found in arm and foot muscles during the same task. However, the contribution of hand motor areas is not exclusively related to number processing because an increase in CS excitability was also found when letters were used to enumerate items. This finding suggests that hand motor circuits are involved whenever items have to be put in correspondence with the elements of any ordered series.     

Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10

AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10–NADP⁺–tolrestat was determined at 1.25-Å resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.