No increase in long-term risk for nicotine use disorders after treatment with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD): evidence from a non-randomised retrospective study

Summary Objective. To evaluate long-term effects of methylphenidate (MPH) treatment in ADHD children on the development of nicotine use disorders (SUD-N). Methods. Multisite retrospective non-randomised longitudinal study with 215 ADHD children (diagnosis at 9.2 years of age; reassessment for SUD-N at 21.9 years of age) strictly parallel allocated to MPH treated (n = 106) and drug naive (n = 109) children. Results. There was no difference between the groups with respect to frequency (84% MPH; 89% non-MPH; χ² = 1.6; p = 0.21) and age of onset for first cigarette smoking (log rank 1.68; p = 0.19). Continuous smoking was reached by 51% (MPH) and 61% (non-MPH) of the patients. Survival analyses revealed a small and nominally significant delay in age of onset for continuous smoking in the MPH-group (log rank = 3.85; p = 0.049). Nicotine dependency was reached by 20% (MPH) and 27% (non-MPH). Age of onset does not differ between groups (log rank = 2.24; p = 0.13). Discussion. Limited evidence due to the non-randomised nature of the study is given that MPH does not induce SUD-N. The data suggests there may be a beneficial effect of MPH on delay of onset for continuous nicotine consumption in ADHD patients. Correspondence: Michael Huss, Head of Department for Child and Adolescent Psychiatry, Johannes Gutenberg-University, Langenbeckstr. 1, 55131 Mainz, Germany     

Molekulare Hochdurchsatzforschung beim Prostatakarzinom

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Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression

Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX (gamma-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and gamma-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not gamma-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas gamma-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.     

IgG4-Associated Adrenalitis—a Case Report

A 67-year-old man was adrenalectomized due to a tumor measuring 100 mm. Specimens revealed an inflammation with slight fibrosis and moderate infiltrates of lymphocytes and plasmacytes with immunoreactivity for IgG and IgG4 resulting in the diagnosis of an active IgG4-associated adrenalitis. To our knowledge, this is the first reported active adrenalitis of this type. It should be the precursor lesion of the adrenal calcifying fibrous tumor that was reported once before.     

Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild-type p53 allele in only 50% of tumours.

We describe two Li-Fraumeni syndrome families. Family A was remarkable for two early childhood cases of adrenocortical tumours, family B for a high incidence of many characteristic cancers, including a childhood case of choroid plexus tumour. Using direct sequencing, we analysed exons 5-9 of the p53 gene in constitutional DNA of individuals from both families and found two novel germline mutations in exon 5. In family A, we detected a point substitution in codon 138 (GCC to CCC), which resulted in the replacement of the alanine by a proline residue. Family B harboured a single-base pair deletion in codon 178 (CAC to -AC), resulting in a frameshift and premature chain termination. Three out of six tumours examined from both families, a renal cell carcinoma, a rhabdomyosarcoma and a breast cancer, showed loss of heterozygosity and contained only the mutant p53 allele. The remaining three neoplasms, both adrenocortical tumours and the choroid plexus tumour retained heterozygosity. Immunohistochemistry with anti-p53 antibody confirmed accumulation of p53 protein in tumours with loss of heterozygosity, while the remaining tumours were p53 negative. These results support the view that complete loss of activity of the wild-type p53 need not be the initial event in the formation of all tumours in Li-Fraumeni individuals.     

Die Staphylokokkenesterase und ihre Beziehung zum Hämolysin

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