Doctoral Dissertations Series – serie

“Treat with respect the power you have to form an opinion. By it alone can the helmsman within you avoid forming opinions that are at variance with nature and with the constitution of a reasonable being. From it you may look to attain circumspection, good relations with your fellow-men, and conformity with the will of heaven.”Marcus Aurelius, AD 121-180. Meditations

Accumulating evidence indicates that CRC is a heterogeneous disease, which affects outcome beyond what can be predicted by disease stage and other conventional prognostic factors. Thus, there is a great need to identify new biomarkers to enable a more accurate prognostication, and to help select patients for adjuvant treatment. In this thesis, the associations of a series of putative biomarkers with survival, treatment response and clinicopathological factors were investigated in a large cohort of incident CRC, with special attention to sex differences. Tumours from 557 incident cases of CRC, assembled in tissue microarrays, were evaluated for expression of cyclin D1, mismatch repair proteins, beta-catenin and epidermal growth factor receptor (EGFR) by immunohistochemistry, and further, EGFR gene copy number (GCN) alterations by brightfield double-in situ hybridization. In addition, KRAS and BRAF mutational status was assessed by pyrosequencing. The results demonstrate several relevant associations of the investigative biomarkers with prognosis and treatment response in CRC. Moreover, substantial sex differences in the clinicopathological correlates and prognostic significance of some of the biomarkers were observed.

The principle of non-discrimination and its exceptions play an essential role in relation to safeguard measures. According to WTO law safeguard measures are to be applied in a non-discriminative manner, which means that they shall target all imports of the product at issue irrespective of their origin. This principle is however not always upheld. Of particular interest for this study is the question of how the rules on safeguards de jure and de facto are applied in a selective way to achieve developmental goals and regional free trade.