Ductal carcinoma in situ (DCIS) is considered to be a non-obligate precursor of invasive breast cancer (IBC). Optimal clinical management of DCIS remains controversial, as we are unable to... Show moreDuctal carcinoma in situ (DCIS) is considered to be a non-obligate precursor of invasive breast cancer (IBC). Optimal clinical management of DCIS remains controversial, as we are unable to identify those DCIS lesions with invasive potential. As a result, current treatment guidelines for DCIS dictate that all women diagnosed with DCIS should undergo treatment to prevent the development of IBC. This makes that many women, who have a low-risk to develop subsequent IBC, are being harmed by this intensive treatment without any benefit. Furthermore, definite proof of DCIS progression to IBC is still lacking.The objectives of this thesis were to identify prognostic markers predictive of the development of subsequent ipsilateral IBC after DCIS and to explore the clonal relatedness of patient-matched DCIS and subsequent ipsilateral IBC. To achieve this, histopathological analysis and molecular profiling were performed using a patient group which was part of a nation-wide population-based cohort including all women diagnosed with and treated for DCIS with breast conserving surgery alone in the Netherlands between 1989 and 2005. The results presented in this thesis will help to stratify a woman’s individual risk of subsequent invasive breast cancer development and will help to avoid overtreatment. Show less
Cytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of... Show moreCytomegalovirus (CMV) infection is a worldwide common infection that in a considerable proportion of individuals remains unnoticed. The congenital CMV infection (cCMV) can induce a variety of clinical manifestations at birth (symptoms at birth), and of permanent long-term impairments (LTI). Of the total of infected neonates at birth, 13% are symptomatic at birth, and half of them will develop LTI. However, 13% of the asymptomatic neonates will still develop the same LTI. Therefore, a quite high percentage of neonates will develop LTI. This thesis aimed to identify prognostic markers, for short- and long-term clinical outcome, and correlates of protection, for future vaccine development. In order to identify such biomarkers, a retrospective nationwide cohort of children with (n=125) and without (n=263) cCMV was used. The findings of this thesis allowed us to get more insights into cCMV pathogenesis, and into the potential processes leading to immune dysfunction, and therefore to a worse clinical outcome. Several approaches have been used to explore prognostic markers. The neonatal immune markers, through DNA quantification of the most common TCR and BCR rearrangements from DBS, together with the maternal-child HLA background, through typing DNA from buccal swabs, seemed to be quite promising for prognostic markers. Show less
LCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of... Show moreLCH lesions are characterized by accumulating LCH-cells, which are related to Langerhans and/or Dendritic cells, and the presence of other elements of the immune system. A significant proportion of LCH-cells display somatic mutations in proteins that drive the constitutive activation of the MAPK-pathway. Outcome is heterogeneous and unpredictable. The main goal of this thesis was to gain insight to the pathogenesis of Langerhans Cell Histiocytosis (LCH) by studying the genetic and immunologic ‘finger-prints’ of therapy-naive LCH lesions. We found a few biomarkers that could predict the outcome of LCH. These include the expression of a chemokine receptor, CXCR4, on LCH-cells and the degree of lymphoid aggregation within the LCH lesions. We found an ever functionally intact IFN-γ-signalling loop in LCH patients and the presence of activated and regulatory T-cells. However, neither an activated or immunosuppressive environment in LCH lesions was associated with a particular LCH manifestation form or outcome. We found another MAPK-pathway activating mutation in LCH-cells which was sensitive towards the FDA approved BRAF-inhibitor vemurafenib. The research described in this thesis support the concept that LCH lesions should be seen as a ‘cocktail’ of genetically aberrant LCH-cells which accumulate at sites with a mixed immunological background. Show less
Engels, C.C.; Kiderlen, M.; Bastiaannet, E.; Eijk, R. van; Mooyaart, A.; Smit, V.T.H.B.M.; ... ; Liefers, G.J. 2016
Colon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival)... Show moreColon cancer is the third most frequent malignancy in the Western world. Average 5 year-survival is around 70% and depends on the stage of the disease being very poor (under 10% 5-year survival) for stage IV patients and excellent (more than 90% 5 year survival) for stage I patients. The prognosis of patients with stage II varies between 80 and 60% 5-year survival. The causes of this variation remain unclear. Furthermore, the prognosis of patients with stage III has improved significantly, reaching 70% 5-year survival, since the introduction of adjuvant chemotherapy. However, still 30% of the patients with stage III disease that do not respond to chemotherapy. Therefore, reliable predictive and prognostic markers in stage II and III colon carcinoma are necessary to be able to elucidate whether a patient is going to respond to therapy or not and to be able to offer personalized treatment. In this research project, we aimed to identify predictive markers of therapy response in stage III disease and prognostic markers in stage II and III colon carcinoma. The first three chapters focus on the value of known single nucleotide polymorphisms (SNP) in genes involved in the activation, metabolism of chemotherapeutic drugs like 5-fluorouracil and oxaliplatin as well as in the repair of DNA damage caused by these drugs as predictive markers for therapy response. In the remaining chapters , the focus is placed on the identification of molecular prognostic markers in stages II and III. Several mutations in known cancer driver genes and genes involved in signal transduction have been studied. Show less
