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Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the 'DNA damage response' (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation. In a panel of cervical cancer cell lines, inactivation of ataxia telangiectasia mutated (ATM) or its substrate p53-binding protein-1 (53BP1) clearly gave rise to cell cycle defects in response to irradiation. Concordantly, clonogenic survival analysis revealed that ATM inhibition, but not 53BP1 depletion, strongly radiosensitised cervical cancer cells. In contrast, ATM inhibition did not radiosensitise non-transformed epithelial cells or non-transformed BJ fibroblasts. Interestingly, high levels of active ATM prior to irradiation were related with increased radioresistance. To test whether active ATM in tumours prior to treatment also resulted in resistance to therapy, immunohistochemistry was performed on tumour material of patients with advanced-stage cervical cancer ( n = 375) treated with (chemo)radiation. High levels of phosphorylated (p-)ATM [ p = 0.006, hazard ratio (HR) = 1.817] were related to poor locoregional disease-free survival. Furthermore, high levels of p-ATM predicted shorter disease-specific survival ( p = 0.038, HR = 1.418). The presence of phosphorylated 53BP1 was associated with p-ATM ( p = 0.001, odds ratio = 2.206) but was not related to any clinicopathological features or survival. In conclusion, both our in vitro and patient-related findings indicate a protective role for ATM in response to (chemo)radiation in cervical cancer and point at ATM inhibition as a possible means to improve the efficacy of (chemo)radiation. [ABSTRACT FROM AUTHOR]

This study investigates emotional and behavioural problems in children of parents diagnosed with cancer and examines the relationship with demographic and illness-related variables. Furthermore, agreement and differences between informants regarding child's functioning were examined. Members of 186 families in which a parent had been diagnosed with cancer participated. More emotional problems were reported for latency-aged sons (ill parents) and adolescent daughters (ill parents; self-reports), whereas also better functioning was reported in adolescent children (spouses), compared to the norm group. Age and gender-effects were found: latency-aged sons were perceived as having more emotional problems than adolescent sons (ill parents); adolescent daughters as having more emotional and behavioural problems than adolescent sons (ill parents; self-reports). Results indicated a higher prevalence of problems when the father was ill than when the mother was (spouses and self-reports). The treatment intensity affected adolescent daughter's functioning (spouses), whereas adolescent son's functioning was affected by relapsed disease (self-reports). Adolescents and mothers perceived comparable levels of problems, but fathers perceived problems in children to be less prevalent. Findings suggest that adolescent daughters and latency-aged sons are at risk for emotional problems following the diagnosis of cancer in a parent. The perception of child's functioning and potential influencing variables varied according to informant. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]