SNP array profiling of childhood adrenocortical tumors reveals distinct pathways of tumorigenesis and highlights candidate driver genes

Childhood adrenocortical tumors (ACT) are rare malignancies, except in southern Brazil, where a higher incidence rate is associated to a high frequency of the founder R337H TP53 mutation. To date, copy number alterations in these tumors have only been analyzed by low-resolution comparative genomic hybridization.

Adolescent survivors of childhood cancer: are they vulnerable for psychological distress?

OBJECTIVES: We aimed to (i) evaluate psychological distress in adolescent survivors of childhood cancer and compare them to siblings and a norm population; (ii) compare the severity of distress of distressed survivors and siblings with that of psychotherapy patients; and (iii) determine risk factors for psychological distress in survivors. METHODS: We sent a questionnaire to all childhood cancer survivors aged <16 years when diagnosed, who had survived ≥5 years and were aged 16-19 years at the time of study. Our control groups were same-aged siblings, a norm population, and psychotherapy patients. Psychological distress was measured with the Brief Symptom Inventory-18 (BSI-18) assessing somatization, depression, anxiety, and a global severity index (GSI). Participants with a T-score ≥57 were defined as distressed. We used logistic regression to determine risk factors. RESULTS: We evaluated the BSI-18 in 407 survivors and 102 siblings. Fifty-two survivors (13%) and 11 siblings (11%) had scores above the distress threshold (T ≥ 57). Distressed survivors scored significantly higher in somatization (p = 0.027) and GSI (p = 0.016) than distressed siblings, and also scored higher in somatization (p ≤ 0.001) and anxiety (p = 0.002) than psychotherapy patients. In the multivariable regression, psychological distress was associated with female sex, self-reported late effects, and low perceived parental support. CONCLUSIONS: The majority of survivors did not report psychological distress. However, the severity of distress of distressed survivors exceeded that of distressed siblings and psychotherapy patients. Systematic psychological follow-up can help to identify survivors at risk and support them during the challenging period of adolescence. Copyright © 2013 John Wiley & Sons, Ltd.

Biological safety concepts of genetically modified live bacterial vaccines

Live vaccines possess the advantage of having access to induce cell-mediated and antibody-mediated immunity; thus in certain cases they are able to prevent infection, and not only disease. Furthermore, live vaccines, particularly bacterial live vaccines, are relatively cheap to produce and easy to apply. Hence they are suitable to immunize large communities or herds. The induction of both cell-mediated immunity as well as antibody-mediated immunity, which is particularly beneficial in inducing mucosal immune responses, is obtained by the vaccine-strain's ability to colonize and multiply in the host without causing disease. For this reason, live vaccines require attenuation of virulence of the bacterium to which immunity must be induced. Traditionally attenuation was achieved simply by multiple passages of the microorganism on growth medium, in animals, eggs or cell cultures or by chemical or physical mutagenesis, which resulted in random mutations that lead to attenuation. In contrast, novel molecular methods enable the development of genetically modified organisms (GMOs) targeted to specific genes that are particularly suited to induce attenuation or to reduce undesirable effects in the tissue in which the vaccine strains can multiply and survive. Since live vaccine strains (attenuated by natural selection or genetic engineering) are potentially released into the environment by the vaccinees, safety issues concerning the medical as well as environmental aspects must be considered. These involve (i) changes in cell, tissue and host tropism, (ii) virulence of the carrier through the incorporation of foreign genes, (iii) reversion to virulence by acquisition of complementation genes, (iv) exchange of genetic information with other vaccine or wild-type strains of the carrier organism and (v) spread of undesired genes such as antibiotic resistance genes. Before live vaccines are applied, the safety issues must be thoroughly evaluated case-by-case. Safety assessment includes knowledge of the precise function and genetic location of the genes to be mutated, their genetic stability, potential reversion mechanisms, possible recombination events with dormant genes, gene transfer to other organisms as well as gene acquisition from other organisms by phage transduction, transposition or plasmid transfer and cis- or trans-complementation. For this, GMOs that are constructed with modern techniques of genetic engineering display a significant advantage over random mutagenesis derived live organisms. The selection of suitable GMO candidate strains can be made under in vitro conditions using basic knowledge on molecular mechanisms of pathogenicity of the corresponding bacterial species rather than by in vivo testing of large numbers of random mutants. This leads to a more targeted safety testing on volunteers and to a reduction in the use of animal experimentation.

Isolated extraordinary daytime urinary frequency of childhood: a case series of 26 children in Switzerland

BACKGROUND: The term 'isolated extraordinary daytime urinary frequency' designates an abnormally increased diurnal frequency of painless urination in a completely toilet-trained child with normal urinalysis. METHODS: We report the history of 26 children (16 boys and 10 girls; aged between 4.1 and 10 years) who were referred to us between 2002 and 2006 and subsequently diagnosed with this condition. RESULTS: Possible psychosocial problems, or recent emotional stressors, were disclosed in the majority of the children: recent (36 months or less) asylum seekers (n = 9), school-related problems (n = 4), parental divorce (n = 2) or death of the mother (n = 1). Possible dietary causes were observed in 9 patients: oxalate-rich beverages (n = 5) and liberal ingestion of 'acidic' juices (n = 4). A diet low in oxalates was recommended when children were consuming large quantities of oxalate-rich beverages; and a diet low in acidic juice was recommended in those liberally ingesting acidic juices. Reassurance and observation were the approach in the remaining cases. The median duration of the symptoms was 5 months. A longer (p < 0.05) duration was noted in children of asylum seekers. CONCLUSIONS: This functional condition is easily identifiable, but often under- or misdiagnosed. Confounding the condition might result in redundant investigation.

Incidence of childhood cancer in Switzerland: the Swiss Childhood Cancer Registry

BACKGROUND: This report describes the incidence of childhood cancer in Switzerland, based on the data from the Swiss Childhood Cancer Registry (SCCR), a national hospital-based cancer registry with very high coverage, founded in 1976 by the Swiss Paediatric Oncology Group (SPOG). PROCEDURE: Malignancies were coded according to the International Classification of Childhood Cancer (ICCC-3). Incidence rates per 100,000 person-years were calculated for all malignancies and groups of malignancies in Swiss residents less than 15 years of age for the decade 1995-2004. RESULTS: The SCCR annually registered on average 174 new cases of cancer in Swiss residents aged <15 years, with a median age at diagnosis of 5.6 years. The crude incidence of childhood cancer in children aged <15 years was 13.5, higher for boys (15.0 per 100,000) than for girls (12.1 per 100,000), and was nearly twice as high in the first 5 years of life (19.3 per 100,000) than in the age group 5 to 14 years (10.8 per 100,000). CONCLUSION: Incidence of childhood cancers in the SCCR was similar to neighbouring countries and to data published by regional cancer registries in Switzerland for the same period, suggesting good completeness of registration. This makes the SCCR a valuable resource for national and international research on childhood cancer.

Experimental models of CNS infections. Contributions to concepts of disease and treatment

Lessons learned from studies of experimental meningitis and brain abscess in animal models of infection represent major, highly significant contributions to our understanding of the pathogenesis and antimicrobial chemotherapy of these infections. For example, studies of experimental meningitis in rabbits demonstrated that the subarachnoid space is deficient in local host defenses, a finding that explains why only bactericidal antibiotic regimens are effective in treating this disease; studies of the efficacy of corticosteroids as adjunctive therapy for meningitis yielded data indicating that both beneficial and detrimental effects on the host are imparted by these compounds. These and a number of other key investigations of experimental meningitis and brain abscess, the results of these investigations, and the clinical significance of these results are presented in this article.

Obesity in long-term survivors of childhood acute lymphoblastic leukemia

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) with current cure rates reaching 80% emphasizes the necessity to determine treatment related long-term effects. The present study examines the prevalence of and the risk factors for overweight and obesity in a cohort of ALL survivors treated and living in the French speaking part of Switzerland. METHODS: In this retrospective two-center study, height and weight of 54 patients diagnosed with ALL in first complete remission and treated with chemotherapy only were recorded at specified time points during treatment and off-therapy. Body mass index (BMI) and its age- and gender-adjusted standard deviation score (BMI-SDS) were calculated for the patients and their parents separately. Overweight and obesity were defined by a threshold of BMI-SDS >1.645 and BMI-SDS >1.96, respectively. RESULTS: At last follow-up, 16 (30%) of the 54 survivors were overweight and 10 (18%) were obese. The off-treatment period was most at risk with 11 of the 16 becoming overweight and 9 of the 10 becoming obese during that period. Overweight/obesity at diagnosis and abnormal maternal BMI were significantly associated with abnormal weight at follow-up, while age at diagnosis, gender, cumulative dose of steroids and paternal BMI showed no association. CONCLUSIONS: Consistent with published evidence from other regions of the developed and developing world, there is a significant prevalence of obesity in young ALL survivors in the French speaking part of Switzerland. Factors significantly associated with this late effect were mostly related to the familial background rather than to the treatment components.

Distinguishing phenotypes of childhood wheeze and cough using latent class analysis

Airway disease in childhood comprises a heterogeneous group of disorders. Attempts to distinguish different phenotypes have generally considered few disease dimensions. The present study examines phenotypes of childhood wheeze and chronic cough, by fitting a statistical model to data representing multiple disease dimensions. From a population-based, longitudinal cohort study of 1,650 preschool children, 319 with parent-reported wheeze or chronic cough were included. Phenotypes were identified by latent class analysis using data on symptoms, skin-prick tests, lung function and airway responsiveness from two preschool surveys. These phenotypes were then compared with respect to outcome at school age. The model distinguished three phenotypes of wheeze and two phenotypes of chronic cough. Subsequent wheeze, chronic cough and inhaler use at school age differed clearly between the five phenotypes. The wheeze phenotypes shared features with previously described entities and partly reconciled discrepancies between existing sets of phenotype labels. This novel, multidimensional approach has the potential to identify clinically relevant phenotypes, not only in paediatric disorders but also in adult obstructive airway diseases, where phenotype definition is an equally important issue.