Remaining questions and current goals in the treatment of rectal cancer include optimizing staging accuracy, establishing the optimal neoadjuvant strategy to be implemented in the different stages... Show moreRemaining questions and current goals in the treatment of rectal cancer include optimizing staging accuracy, establishing the optimal neoadjuvant strategy to be implemented in the different stages of rectal cancer and possibly leading to the evidence-based introduction of organ sparing and non-operative strategies in selected patients. Furthermore, adverse effects of new multi-modality treatments need to be investigated to properly inform patients. Correlating histopathological response to outcome will provide information on efficacy of new neoadjuvant therapies, factors governing distant metastases and potential consequences of scaling down treatment approaches to avoid surgery. The aim of this thesis, addressing the different modalities, was to evaluate these aspects concerning the multidisciplinary treatment of rectal cancer in general, with the focus on patients with locally advanced rectal cancer in particular Show less
High-grade osteosarcoma is a primary bone tumor with complex genetic alterations, for which targeted therapy is lacking. The aim of this thesis was to use high-throughput molecular data analysis of... Show moreHigh-grade osteosarcoma is a primary bone tumor with complex genetic alterations, for which targeted therapy is lacking. The aim of this thesis was to use high-throughput molecular data analysis of high-grade osteosarcoma specimens and model systems, in order to learn more on osteosarcomagenesis and to find possible ways to inhibit this process. By analyzing different microarray data types using a systems biology approach, genomic instability was identified as an important driver of osteosarcomagenesis. A protective role of macrophages against metastasis of osteosarcoma was detected. In addition, the IR/IGF1R and PI3K/Akt signaling pathways were discovered as potential targets for treatment. This thesis provides the first steps in unraveling the genomic and transcriptomic landscape of high-grade osteosarcoma, and provides a biological rationale for certain new options for adjuvant treatment of this highly genomica lly unstable tumor. Show less
The care for acute complications occurring in cancer patients has changed dramatically in recent decades, not only for direct post-operative care following major cancer surgery, but also for cancer... Show moreThe care for acute complications occurring in cancer patients has changed dramatically in recent decades, not only for direct post-operative care following major cancer surgery, but also for cancer patients in need of organ function replacement due to the manifestation of their malignancy or toxicity of the therapies provided. This thesis studies the epidemiology and outcome of critical illness associated with cancer and/or its treatment in the Netherlands. Chapters 2-5 describe the proportion of cancer patients that requires admission to an Intensive Care Unit (ICU) during the course of their disease and their characteristics and outcome once in the ICU. Chapters 6 and 7 focus on infectious complications in cancer patients. Chapter 8 & 9 contains the summary, general discussion and future perspectives. Show less
Cellular responses to DNA damage are highly variable and strongly depend on the cellular and organismic context. Studying the DNA damage response is crucial for a better understanding of cancer... Show moreCellular responses to DNA damage are highly variable and strongly depend on the cellular and organismic context. Studying the DNA damage response is crucial for a better understanding of cancer formation and ageing as well as genotoxic stress-induced cancer therapy. To do justice to the multifaceted cellular changes, elicited by DNA damage, use of high-throughput techniques and integration with bioinformatics tools is of great value. This thesis summarizes recent advances in the field of systems biology studies of the DNA damage response and furthermore shows integrated approaches of the study of DNA damage response signaling networks in embryonic stem and cancer cells. By integration of transcriptional changes and the phosphorylation and metabolic response of cisplatin-treated embryonic stem cells, with RNAi-based knockdown screens we identify novel DNA damage response signaling networks, linking process such as Wnt signaling, translation arrest or altered metabolic pathways to the cellular response to DNA damage. Furthermore, genes, whose knockdown sensitizes embryonic stem cells to DNA damage-induced killing, are tested in cancer cells of varying genetic backgrounds identifying a small subset of genes, which represent potential drug targets for sensitization of cancer cells. Altogether, our systems approach for studying the DNA damage response identifies novel DNA damage-induced signaling networks and molecules, which modulate survival in the presence of DNA damage, potentially providing new targets for therapeutic intervention or biomarker discovery. Show less
