The research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of... Show moreThe research presented in this thesis explores the chemotherapeutic potential of metal-based compounds as chemotherapy agents, with an initial focus on the synthesis and DNA interaction studies of platinum and palladium compounds utilizing the [Pt(bapbpy)]2+ scaffold. The study identifies intercalation as the primary mechanism of action for these complexes. Furthermore, it provides a detailed structure-activity relationship analysis, highlighting the critical role of the complex's protonation state in influencing its biological activity and efficacy. Subsequently, the study delves into photoactivated chemotherapy (PACT) using ruthenium (II) complexes, where light activation of ruthenium complexes enables targeted drug delivery to tumor cells, thereby reducing adverse effects. This research emphasizes the development of ruthenium-based compounds that can photorelease a DNA repair inhibitor, specifically targeting the RAD51 protein, essential for Homologous Recombination (HR). By disrupting the DNA repair mechanisms in cancer cells, this approach seeks to enhance the cytotoxicity of the therapy and address drug resistance. Show less
Pancreatic surgery today involves a wide variety of surgical and non-surgical medical disciplines. Several aspects to improve the multidisciplinary management of patients undergoing pancreatic... Show morePancreatic surgery today involves a wide variety of surgical and non-surgical medical disciplines. Several aspects to improve the multidisciplinary management of patients undergoing pancreatic surgery were identified, implemented and used to design future studies. More than 15 medical disciplines were involved during the studies involved in this thesis. Highly needed further improvement of outcome of pancreatic patients can be made by multidisciplinary collaborations on a hospital, regional, national and international level. Show less
This thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the... Show moreThis thesis focuses on treatment outcomes of high risk endometrial cancer and corresponding patients’ and clinicians’ preferences regarding adjuvant treatment decisions; molecular studies on the etiology of mismatch repair deficiency (MMRd) in intermediate and high risk endometrial cancer; and the combination of immunotherapy and PARP inhibition for the treatment of recurrent or metastatic endometrial cancer.The overall aims of this thesis were:• To evaluate health-related quality of life up to 5 years after chemoradiotherapy compared with pelvic radiotherapy alone in the adjuvant treatment of high risk endometrial cancer in the PORTEC-3 trial;• To investigate the preferences of patients and clinicians regarding the benefit-risk trade-off of the addition of chemotherapy to adjuvant pelvic radiotherapy;• To investigate the prevalence and prognosis of Lynch syndrome-associated endometrial cancer among MMRd endometrial cancers;• To evaluate the role of combined checkpoint inhibition and PARP inhibition in women with metastatic or recurrent endometrial cancer in terms of progression-free survival and toxicity in the DOMEC trial. Show less
For part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and... Show moreFor part I population-based data from the national cancer registries of Belgium, the Netherlands, Norway, and Sweden was used. In all countries, the use of chemotherapy increased with stage and decreased with age. Also, 30-day and one-year excess mortality decreased over the years for colon and rectal cancer. After surviving the first postoperative year, the survival of surgically treated older patients aligned with their younger counterparts, except for patients with stage III disease. Part II describes the results of the analyses of the RAPIDO trial. DRTF decreased from 30% in the standard-care group to 24% in the experimental group at 3 years after randomisation, mainly due to a decrease in DM, which is probably due to better compliance preoperatively and perhaps due the earlier treatment of micrometastases in the treatment process. Although patients with DM in the experimental group had worse survival compared to patients in the standard-care group, the cumulative probability of overall survival remained comparable for both treatment groups. If the patients with a complete response can be identified during reassessment after neoadjuvant therapy, surgery may be omitted, a W&W after a cCR with an appropriate follow-up has no additional oncological risk in young patients compared to older patients (part III). This opens the door for potential organ preservation. Show less
This dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This... Show moreThis dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This research topic is motivated by specific clinical questions aimed at gaining insights into personalised treatments for cardiological and oncological patients. The main purpose is to enrich the knowledge available for modelling patients’ survival with relevant features related to the time-varying processes of interest.The efforts of this work address the complexities of both (i) developing adequate dynamic characterizations of the processes under study (i.e., representation problem) and (ii) identifying and quantifying the association between time-varying processes and patient survival (i.e., time-to-event modelling problem). In both cases, the main issue is dealing with complex data sources while taking into account the nature of the processes and managing the complex trade-off between clinical interpretability and mathematical formulation.By solving the aforementioned statistical complexities, this work is not only impacting the community of researchers in mathematics and statistics. The development of these novel methodologies may represent a significant step forward in the definition of customized and flexible monitoring tools to support doctors and clinicians in their work.*********This doctoral dissertation was part of a cotutelle agreement between the Politecnico di Milano and Leiden University Show less
Gemcitabine was examined as switch maintenance therapy after standard first line chemotherapy in the NVALT19 trial, which provided the first conformation of gemcitabine activity in malignant... Show moreGemcitabine was examined as switch maintenance therapy after standard first line chemotherapy in the NVALT19 trial, which provided the first conformation of gemcitabine activity in malignant mesothelioma (MM). We describe additional analyses to confirm the prognostic value of CYFRA 21-1 and examine the prognostic value of CYFRA 21-1 in MM patients treated with gemcitabine. We also searched how gemcitabine could improve antitumor immune responses by positively modulating the immune system.In this thesis we describe a cohort of 107 malignant mesothelioma patients treated with nivolumab in the Netherlands. The real- world data of single agent PD-1 blocking were disappointing compared to previous reported single arm phase II trials. To examine clinical and peripheral blood biomarkers univariable and multivariable analyses were performed.As malignant peritoneal mesothelioma is even rarer then pleural mesothelioma, we hypothesized that centralization of care for peritoneal mesothelioma could benefit patients as they would likely receive treatment more often.Prognosis has a significant influence on the treatment preferences of patients, but prognosis of individual MM patients is variable and is hard to predict. We presented the MESOPRO score for patient with MM which are about the start with any systemic treatment. Show less
In this thesis, the effects of a new form of immunotherapy was investigated and studied how it can be used against different types of cancers. The investigated immunotherapy is based on injecting... Show moreIn this thesis, the effects of a new form of immunotherapy was investigated and studied how it can be used against different types of cancers. The investigated immunotherapy is based on injecting nanoparticles loaded with various immunologically active molecules (immunomodulatory nanoparticles) that can modulate the immune system to attack cancer cells more efficiently. The effectiveness of this immunomodulatory nanoparticles have been studied on different mouse cancer models and investigated as a single treatment or in combination with other known therapies, such as chemotherapy, therapeutic cancer vaccination, or photodynamic therapy. Show less
Door de toepassing van hoofdhuidkoeling kan haaruitval worden verminderd of voorkomen. Hoofdhuidkoeling heeft, afhankelijk van de soort chemotherapie, bij ongeveer 50% van de patiënten een positief... Show moreDoor de toepassing van hoofdhuidkoeling kan haaruitval worden verminderd of voorkomen. Hoofdhuidkoeling heeft, afhankelijk van de soort chemotherapie, bij ongeveer 50% van de patiënten een positief effect. Farmacologische interventies om haaruitval te voorkomen zijn niet toereikend. De incidentie van haaruitval kan verminderd worden door de methode van hoofdhuidkoeling te optimaliseren.De afgelopen jaren is door het Leids Universitair Medisch Centrum, Noordwest Ziekenhuisgoep en Integraal Kankercentrum Nederland in samenwerking met verschillende ziekenhuizen in Nederland onderzoek verricht naar factoren die van invloed kunnen zijn op het effect van hoofdhuidkoeling. Show less
Approximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to... Show moreApproximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to reduce the risk of recurrence. In the international PORTEC-3 trial we have investigated the added value of adjuvant chemotherapy during and after radiotherapy in terms of efficacy, toxicity and quality of life. It was found that both overall and recurrence-free survival were significantly improved with the addition of chemotherapy to radiotherapy, especially for women with more advanced disease (stage 3) or with serous histological type. This comes however at the expense of increased and more serious toxicity and an impaired quality of life during and in the first 6 months after treatment. About 25% of women treated with chemotherapy still reported tingling and numbness of hands and/or feet at 2 years after treatment. It is therefore important to discuss the benefits and costs of the addition of chemotherapy in shared decision making, for which the results discussed in this thesis provide valuable information. Currently molecular analysis of the PORTEC-3 tissue samples is done to evaluate which patients benefit most from added chemotherapy. Show less
The field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity... Show moreThe field of transition-metal based chemotherapeutics are dominated by derivatives of cisplatin, but a major downside of these platinum based chemotherapeutics is their lack of selectivity that leads to undesirable side effects. In this work we present alternative strategies such as light-activation with different transition-metals such as ruthenium and palladium that have the potential to be more selective than cisplatin type of drugs. Show less
The decision to treat elderly patients with cancer aged 70 years or older with chemotherapy is generally based on clinical judgment of the clinician, in combination with the evidence obtained from... Show moreThe decision to treat elderly patients with cancer aged 70 years or older with chemotherapy is generally based on clinical judgment of the clinician, in combination with the evidence obtained from clinical studies performed in younger age groups. The instrument GA might be helpful to detect hidden shortcomings and may aid clinical decision making with regard to the feasibility of treatment with chemotherapy and prediction of survival in the elderly patients with cancer. The following questionnaires and tests were considered appropriate to obtain a practical GA: MNA, GFI, IQCODE, MMSE, and laboratory values of albumin, creatinine, lactate dehydrogenase and hemoglobin. The main questions we tried to answer were firstly to assess the predictive value prior to the start of chemotherapy of the chosen GA with respect to the probability to complete the planned chemotherapy and overall survival and secondly to analyze and determine which elements of the chosen GA were independently predictive to complete chemotherapy and which elements predicted early mortality.This thesis is the result of clinical research on certain elements of GA that might be useful for routine daily oncology practice, in order to select the proper patients and improve the outcome of treatment with chemotherapy. Show less
Metastatic castrate-resistant prostate cancer (mCRPC) is the second deadliest cancer in men in the Western world. Therapy options are limited, but expanding. In the current thesis, various aspects... Show moreMetastatic castrate-resistant prostate cancer (mCRPC) is the second deadliest cancer in men in the Western world. Therapy options are limited, but expanding. In the current thesis, various aspects of (pre)clinical research are discussed, all sharing the ultimate aim to improve therapy options for this group of cancer patients. Both basic, translational, biomarker, clinical and epidemiological studies have been performed, focusing primarily on novel agents that have been introduced recently into clinical practice (cabazitaxel, abiraterone, radium-223), and agents that may become antitumor agents against mCRPC in the future, such as antimitotics (polo-like kinase 1 inhibitors, aurora kinase inhibitors, Eg5), histone deacetylase inhibitors, and agents that stimulate expression of the metastasis-suppressor gene NDRG1. Furthermore, minority enrollment in phase III studies with mCRPC patients is being evaluated. Show less
The studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell... Show moreThe studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell tumour (GCT) patients. We report a twofold increased prevalence of Metabolic Syndrome (MetS) in GCT patients who received chemotherapy compared to that in patients with stage 1 disease who did not receive chemotherapy, or to that in healthy controls. Thereafter, we describe disadvantageous metabolic changes and acute alterations in diastolic heart function in GCT patients treated with cisplatin-based chemotherapy. In the same group of patients we show that, during chemotherapy administrations, serum non-protein bound iron concentrations were inversely related to the latent iron-binding capacity and serum iron concentrations. This suggests that chemotherapy-associated iron overload may play a role in short and long-term chemotherapy induced toxicity in GCT patients. The study on bone metabolism shows an increased prevalence of vertebral fractures, independent of BMD and anticancer treatment, in newly diagnosed as well as long term survivors of testicular cancer. The last chapter reports on a significant decline in lumbar and femoral BMD in metastatic GCT patients one year after chemotherapeutic treatment. Show less
Colorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain.... Show moreColorectal cancer is one of the most common cancers worldwide. Although there have been several improvements in screening, staging, and treatment in the past decades, survival differences remain. For example among certain subgroups of patients, such as elderly patients and patients with comorbidities. Besides, inequalities in the quality of care between European countries remain. Quality control on surgery, radiotherapy, and pathology have been introduced in trials, followed by incorporation in the general care. Another option to incorporate improved quality of care is via an audit structure in which hospitals and clinicians can improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Although all these audit structures have achieved excellent results within countries, differences in outcome between European countries remain. A next step will b e to combine these national audits. The combined audit structure will provide a network in which __best practices__ can be compared and identified, including for certain subgroups, which has been initiated as European Registration of Cancer Care (EURECCA). To achieve optimal care for all patients, multidisciplinary care is the only way. By comparing multidisciplinary audit structures across countries, optimal treatment strategies within subgroups can be identified Show less
Various cytotoxics cause severe alopecia, it is estimated to affect more than 15.000 Dutch cancer patients per year. Hair loss has high impact on the majority of these patients, they describe it as... Show moreVarious cytotoxics cause severe alopecia, it is estimated to affect more than 15.000 Dutch cancer patients per year. Hair loss has high impact on the majority of these patients, they describe it as stigmatizing and a constant reminder of cancer disease. Scalp cooling decreases hair loss and is well tolerated. It however induces a risk if it would protect micro-metastases in the scalp skin besides protection of hair matrix cells. In thousands of patients with solid tumors, an unfavourable development of the disease due to scalp cooling has never been reported. Furthermore, data from the Dutch Scalp Cooling Registry showed that overall 50% of the 1,411 scalp-cooled patients from 28 Dutch hospitals did not wear a head cover during their last chemotherapy session. And a randomized trial showed that the post-infusion cooling time (PICT) for 3-weekly docetaxel chemotherapy can be shortened from 90 to 45 minutes with the same effectiveness of scalp cooling. Scalp cooling is cost-effective, as is purchasing a wig or head cover. This justifies the choice between both options. Effectiveness of scalp cooling has to be and will be improved, preferably by examining optimal scalp skin temperatures and cooling times, with special attention for the patient__s tolerance. At the time of starting this PhD project, 4 Dutch hospitals applied scalp cooling, which nowadays has increased to over 75. Though, in many hospitals scalp cooling eligibility criteria are too restricted, inducing undertreatment of several patient groups. All patients facing severe alopecia should receive patient-tailored information about the possibility, effectiveness, possible side-effects and potential risk of scalp cooling in order to make an informed treatment decision Show less
Nausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin... Show moreNausea and vomiting are well known side effects related to chemotherapy. Indeed, nausea and vomiting are the most distressing side effects of chemotherapy in cancer patients. Dopamine, serotonin and neurokinin1 are thought to be the neurotransmitters that play role in the pathophysiology of Chemotherapy Induced Nausea Vomiting (CINV). Thus, the antagonists of those neurotransmitters are considered as prophylactic antiemetics for CINV. In the 1990s, the use of 5-Hydroxytriptamine receptor antagonists (5-HT3RAs) highly improved the patients__ response rate to antiemetic drugs. In addition, the combination of a neurokinin 1 antagonist, a 5HT3RA and a corticosteroid can further increase the response rate up by 15% in acute phase and 20% in delayed phase. Thus, the international guideline of clinical oncology recommend this combination as prophylactic antiemetic drugs in the acute phase and a combination of dexamethasone __ metoclopramide as prophylactic antiemetics in the delayed phase. However, when the standard antiemetic drug regimens are administered to patients, there are still 20-30% patients in the acute phase and 40% patients in the delayed phase experiencing CINV. Thus, there is a high interindividual variability in response to antiemetic drugs in oncology patients. Some patient characteristics such as female gender, younger patients and history of alcohol drinking could increase the risk of CINV from 20% to 70%. Therefore, individualizing of the use of antiemetics could start by considering the patient characteristics. This thesis focuses on determining the impact of CINV on QoL in Indonesian cancer patients and optimizing the prevention and treatment of CINV by exploration of pharmacogenetic biomarkers. Show less
One of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic... Show moreOne of the most effective anticancer therapy still remains chemotherapy, however, both used as single agent as in combinational regimens, chemotherapy still encounters the problem of therapeutic resistance. Limitations of chemotherapy have led to the exploration of alternative anti-cancer approaches in order to improve efficacy, such as chemoprevention. Chemopreventive agents interfere with rate limiting steps in tumor progression, such as for example the establishment of a functional tumor vasculature. Currently, there is a large and unfolding picture of rate-limiting steps during tumor progression which can provide us with numerous potential therapeutic targets, where it is becoming increasingly clear both the tumor itself as its microenvironment contribute in these steps. Current research focuses on exploring chemopreventive approaches as part of combination strategies. One of the most investigated approaches in these combinational strategies is targeting the tumor with chemotherapy together with chemopreventive agents. This thesis explores the use of chemopreventive approaches as monotherapy and in combinational approaches with chemotherapy and explores and discusses their effects on both the tumor as the tumor__s microenvironment. It shows that these combinational approaches hold great promise, if taking both the tumor as the tumor__s microenvironment into account as therapeutic targets. Show less
Survival rates after surgical treatment of gastric, colon and rectal cancer can improve with preoperative and/or postoperative adjuvant treatment with chemo- and/or radiotherapy. The role of... Show moreSurvival rates after surgical treatment of gastric, colon and rectal cancer can improve with preoperative and/or postoperative adjuvant treatment with chemo- and/or radiotherapy. The role of epigenetic aberrancies such as DNA methylation is established to play a pivotal role in gastrointestinal carcinogenesis and malignant progression. This thesis describes novel epigenetic biomarkers that could tailor (neo)adjuvant treatment regimens to the patients who would benefit from them. The same markers could further be used to exclude those patients who would not gain more survival-years and would be unnecessarily exposed to the morbidity/mortality of additional chemo- and/or radiation therapy. Currently, nodal status is the single most important prognostic indicator in gastrointestinal cancers however this can only be reliably assessed by the pathologist after surgery. Currently, neoadjuvant regimens are more and more being studied and shown to be of benefit. This development necessitates biomarkers that are available before the operation. An important derived conclusion from this thesis is that the preoperative availability of primary tumor DNA methylation biomarkers holds great potential for tailoring neoadjuvant therapy. The thesis also describes technical advancements that will enable primary tumor DNA methylation assessment in small amounts of tissue as preoperative diagnostic tumor biopsies harvested during gastroscopy or colonoscopy Show less
The aim of this thesis was to unravel the role of the humoral immune system in rheumatoid arthritis patients by employing new immunosuppressive strategies, i.e. specific B-cell depletion with... Show moreThe aim of this thesis was to unravel the role of the humoral immune system in rheumatoid arthritis patients by employing new immunosuppressive strategies, i.e. specific B-cell depletion with Rituximab and non-specific lymfoablative treatment with high dose chemotherapy and hematopoeietic stem cell transplantation. This thesis evaluates the clinical benefit of these strategies as well as the immunological changes that coincide with clinical improvement. By combining clinical outcome with immunological parameters of the humoral immune system, these studies provide a unique approach to investigatepathologic mechanisms in rheumatoid arthritis. Show less
One of the major problems in the treatment of patients with acute leukemia is failure of therapy due to acquired resistance, which may partially be caused by defects in the apoptotic machinery of... Show moreOne of the major problems in the treatment of patients with acute leukemia is failure of therapy due to acquired resistance, which may partially be caused by defects in the apoptotic machinery of these leukemic cells. Apoptosis is induced and regulated by a complex network of proteins connected via various signal transduction cascades, eventually leading to death of the target cell. The results described in this thesis demonstrate that apoptosis induction in leukemic cells after treatment with chemotherapy or (cellular) immunotherapy is very complex and frequently dependent on the target cell studied, and on the interaction between target and effector cell. G0 cells derived from patients with B-CLL compared to G0 cells from patients with acute leukemia responded differently to Ara-C treatment, which may be partially explained by the different mechanisms of action exerted by Ara-C. The role of the death receptor pathway in both chemotherapy-induced and CTL-induced apoptosis of leukemic cells was also unraveled in more detail. It will be worthwhile to focus future strategies in the treatment of leukemia on modulation or activation of proteins that are common in multiple apoptotic pathways, like caspase-8, since this approach will sensitize the leukemic cells simultaneously to chemotherapy and cellular immunotherapy. Show less
