Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile.... Show moreTreosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favourable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationship between systemic treosulfan exposure, early and long term clinical outcome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant diseases is unresolved. In this thesis we aimed to answer these questions. We found a relationship between the level of exposure to treosulfan and acute toxicity, but we found no relationship with the risk of rejection, survival and long-term endocrine complications. A personalized dose of treosulfan can therefore be useful to reduce toxicity in children, but because the toxicity profile of treosulfan is generally relatively mild, it will not be necessary in most cases. This is beneficial, because measuring blood levels is not always available in every hospital. Future research should focus on specific disease categories or patient groups that may benefit from treosulfan monitoring. More research is also needed on the late complications of treosulfan, such as dental, neurocognitive, hair, eye and lung problems, as this aspect becomes increasingly important as more (very young) patients undergo stem cell transplantation. Show less
This PhD research dealt with neurobiological and behavioral aspects of pain. Previous research has demonstrated that pain sensitivity can be worsened as a result of learned negative expectations, a... Show moreThis PhD research dealt with neurobiological and behavioral aspects of pain. Previous research has demonstrated that pain sensitivity can be worsened as a result of learned negative expectations, a phenomenon termed nocebo hyperalgesia –a counterpart to placebo analgesia. This PhD dissertation describes neuroimaging and biobehavioral experimental studies as well as a review and a meta-analysis concerned with such learned effects on pain. The research adds to a growing literature that has been challenging antiquated understandings of pain as a bottom-up process. We conducted a series of biobehavioral studies to further our understanding of how bottom-up pain signaling can be influenced by top-down processing. We examined the types of experiences, such as receiving negative information or experiencing a negative effect first-hand, that may lead to stronger nocebo effects. Behavioral paradigms were used to model real-life pain experiences, through validated methods, novel learning manipulations, as well as a close examination of emotional correlates such as fear. Concurrently, innovative neuroscientific methods –including pharmacological manipulations– were used to examine the biobehavioral underpinnings of learned nocebo responses. Our findings add to the growing knowledgebase from the field of nocebo hyperalgesia, demonstrating that learning by experience can decisively influence the processing and perception of noxious stimuli. Show less
