Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/ neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients' ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml À1, P ¼ 0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P ¼ 0.197), both uni-and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer -11.7 (95% CI 5.2 -18.3) months -when compared to the progression-free survival of 4.5 (95% CI 3.4 -5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P ¼ 0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/ neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.

We conclude that IGF-1R expression is not a major predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu- overexpressing metastatic breast cancer.

Her-2/neu overexpression in human breast cancer leads to an aggressive biological behavior and poor prognosis. Although the anti-Her-2/neu antibody trastuzumab (Herceptin 1 ) has become a valuable therapeutic option for patients with Her-2/neu-overexpressing breast cancer, many patients do not benefit from this therapy. To evaluate the effect of receptor activation on tumor response, we have investigated the phosphorylation status of Her-2/neu and EGFR in 46 Her-2/neu-overexpressing tumor samples from trastuzumab-treated metastatic breast cancer patients by immunohistochemistry. Activated (p)tyr-1248 Her-2/neu was detected in 9 of 46 breast cancers (20%), and activated (p)tyr-845 and (p)tyr-1173 EGFR were both present in 6 tumors (13%) while EGFR was present in 16 cases (35%). ptyr-1248 Her-2/neu showed a trend to correlate with increased response to trastuzumab (p 5 0.063), while ptyr-845, ptyr-1173 EGFR and EGFR did not. The presence of ptyr-1248 Her-2/neu and ptyr-845 or ptyr-1173 EGFR, however, was a strong predictor of both response to trastuzumab-based treatment (OR 5 8.0, p 5 0.021 and OR 5 8.0, p 5 0.021) and clinical benefit (OR 5 5.47, p 5 0.041 and OR 5 6.22, p 5 0.028 multivariate logistic regression analysis). Furthermore, ptyr-845 EGFR and ptyr-1248 Her-2/neu were both independent predictors of progression-free survival (RR 5 0.21, p 5 0.01 and RR 5 0.45, p 5 0.026, multivariate analysis). Patients with ptyr-845 EGFR positive tumors also tended toward increased overall survival (RR 5 0.17, p 5 0.082). Taken together, we have demonstrated that the determination of activated EGFR improves the utility of ptyr-1248 Her-2/neu staining in predicting the clinical outcome of patients undergoing trastuzumab treatment. We hypothesize that the activation state of both Her-2/neu and EGFR are key determinants for trastuzumab efficacy. ' 2005 Wiley-Liss, Inc.

No abstract

Anticonvulsant drugs have a high risk of adverse drug events. Little is known about the perception of those events by pediatric patients. We performed a survey in the neuropediatric departments of two university hospitals. Using a questionnaire, we interviewed patients aged 6-18 years with current anticonvulsant treatment regarding (i) their fears about potential adverse drug events, (ii) experienced adverse drug events, and (iii) perceived burden of experienced adverse drug events. One hundred patients took part in the interview. (i) 40 (40%) expressed fears that the medication could harm them. Eighteen of 40 (45%) named fears concerning specific adverse drug events. Of those, 12/18 (67%) feared neurologic or psychiatric symptoms. (ii) 37 (37%) of children described altogether 60 experienced adverse drug events. Of those, 38 (63%) concerned neurologic or psychiatric symptoms. (iii) 32/37 (82%) children who experienced adverse drug events felt bothered by the experienced event. Among others, they described an emotional burden (11/37, 30%), and restrictions in school performance (8/37, 22%) and favorite leisure activities (4/37, 11%). Conclusion: School-aged children are well able to describe adverse drug events of their anticonvulsant medication. Almost two thirds of the described events concern neurologic or psychiatric symptoms that cause an emotional burden and restrictions according to the patients. What is Known: • Anticonvulsants have a high potential of adverse drug events. • In an earlier survey, parents expressed fears of severe adverse drug events such as liver failure, which seldom occur, and reported a high number of neurological and psychological adverse drug events. What is New: • Many children fear that their anticonvulsants could harm them, and they fear and experience neurological and psychological adverse drug events. • According to the children, adverse drug events cause an emotional burden and restrictions in school performance and favorite leisure activities.