Breast cancer is the most common malignancy diagnosed in women1. The incidence of breast cancer increases with age; currently, in developed countries more than 40% of breast cancer patients is 65... Show moreBreast cancer is the most common malignancy diagnosed in women1. The incidence of breast cancer increases with age; currently, in developed countries more than 40% of breast cancer patients is 65 years or older at diagnosis1. In the Netherlands in 2011, 5,441 women aged 65 years or older were diagnosed with breast cancer2. The remaining life expectancy of persons aged 65 is still increasing, from almost 19 years in 1980, up to more than 21 years in 2010. Moreover, in last decades the birth rate has decreased, resulting in a higher proportion of older persons in the general population3. Both an increasing life expectancy and the increasing number of elderly in the population will further enhance the number of elderly women confronted with breast cancer Show less
Kiderlen, M.; Glas, N.A. de; Bastiaannet, E.; Water, W. van de; Craen, A.J.M. de; Guicherit, O.R.; ... ; Liefers, G.J. 2014
The aim of the work included in this PhD thesis was to explore the diverse application possibility of using NIR fluorescent probes with specific properties to visualize and characterize cancer and... Show moreThe aim of the work included in this PhD thesis was to explore the diverse application possibility of using NIR fluorescent probes with specific properties to visualize and characterize cancer and cell death. In this thesis, we mainly focus on optical imaging and its application, both at microscopic and macroscopic level. Because we believe optical imaging in particular represents a technology that has unique potential to exploit further our knowledge in preclinical research. First, we imaged breast tumors and their metastases using combinations of four NIR fluorescent probes that possess different optical imaging properties. Then, we studied two different NIR fluorescent probes, PSVue and a heat shock protein-90 alkylator (NIR fluorescent conjugate of GSAO), which can be used to non-invasively imaging cell death with different optical modules in a mouse model of traumatic brain injury. Next, we employed the NIR fluorescently tagged GSAO as a biomarker for monitoring breast cancer cell death after chemotherapy. Moreover, we provides a general discussion about the advantages and the challenging that the state-of-art optical imaging is facing and shares some future prospective. This thesis ends with a summary that outlined the major findings of studies described in different chapters and explored the clinical implications. Show less
Not all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by... Show moreNot all hormone receptor positive breast cancer patients benefit from tamoxifen treatment, but may be nonetheless exposed to its side effects (e.g. hot flashes). Tamoxifen needs bioactivation by formation of the metabolite endoxifen, which is mainly catalyzed by the enzyme CYP2D6. In this thesis, we studied the variation in tamoxifen metabolism in relation to endoxifen serum concentration, tamoxifen efficacy and side effects, focusing on CYP2D6 activity and pharmacogenetics. The importance of good methodology for genotyping and endoxifen measurement was exemplified. In a large trial population, no association between CYP2D6 genotype and disease free survival or the occurence of hot flashes was found, although polymorphisms in the estrogen receptor-1 and UGT2B15 might be related to clinical outcome. Adherence, but not the concomitant use of CYP2D6 inhibiting medication was associated with breast cancer recurrence. CYP2D6 genotype and endoxifen-guided tamoxifen dose escalation led to an increase in endoxifen serum levels and a new 13C-Dextromethorphan breath test was used for phenotyping CYP2D6, which correlated well with CYP2D6 genotype and endoxifen levels. Finally, the CYP2D6 phenotype and endoxifen serum levels are currently prospectively related to breast cancer recurrence. This may lead to therapeutic drug monitoring and selection of patients who benefit most from tamoxifen. Show less
Heijer, M. den; Asperen, C.J. van; Harris, H.; Nippert, I.; Schmidtke, J.; Bouhnik, A.D.; ... ; Tibben, A. 2013