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
Significant advances in supportive care for patients with transfusion-dependent thalassemia major (TDT) have improved patients' life expectancy. However, transfusion-associated iron overload... Show moreSignificant advances in supportive care for patients with transfusion-dependent thalassemia major (TDT) have improved patients' life expectancy. However, transfusion-associated iron overload remains a significant barrier to long-term survival with good quality of life. Today, allogeneic hematopoietic stem cell transplantation (HSCT) is the current curative standard of care. Alongside selection of the best available donor, an optimized conditioning regimen is crucial to maximize outcomes for patients with TDT undergoing HSCT. The aim of this retrospective analysis was to investigate the role of busulfan-fludarabine-based and treosulfan-fludarabine-based conditioning in TDT patients undergoing HSCT. We included 772 patients registered in the European Society for Blood and Marrow Transplantation (EBMT) database who underwent first HSCT between 2010 and 2018. Four hundred ten patients received busulfan-fludarabine-based conditioning (median age 8.6 years) and 362 patients received treosulfan-fludarabine-based conditioning (median age 5.7 years). Patient outcomes were retrospectively compared by conditioning regimen. Two-year overall survival was 92.7% (95% confidence interval: 89.3-95.1%) after busulfan-fludarabine-based conditioning and 94.7% (95% confidence interval: 91.7-96.6%) after treosulfan-fludarabine-based conditioning. There was a very low incidence of second HSCT overall. The main causes of death were infections, graft-versus-host disease, and rejection. In conclusion, use of busulfan or treosulfan as the backbone of myeloablative conditioning for patients with TDT undergoing HSCT resulted in comparably high cure rates. Long-term follow-up studies are warranted to address the important issues of organ toxicities and gonadal function. Show less
The immune system is a complex mechanism of defence to prevent/limit infections and to guarantee homeostasis and repair. It consists of an interactive network of lymphoid organs, humoral factors... Show moreThe immune system is a complex mechanism of defence to prevent/limit infections and to guarantee homeostasis and repair. It consists of an interactive network of lymphoid organs, humoral factors and several types of specialized cells that develop from hematopoietic stem cells. In this thesis we gained additional knowledge on normal immune development, with detailed focus on the transcriptional network (Notch, Tcf1, Gata3, Bcl11b) orchestrating T-cell development.The disruption of normal lymphoid development can lead to severe illnesses known as immunodeficiencies. Severe Combined Immunodeficiency (SCID) is a devastating and fatal immune disorder affecting infants lacking a functional immune system. We focused on developing an efficient and safe gene therapy approach to correct both RAG1 and RAG2 immune defects causing SCID. The successful pre-clinical development together with a favorable safety substantiates the first phase I/II clinical trial worldwide for RAG1-SCID gene therapy.Additionally, we optimized related protocols by developing novel tools allowing better characterizing the product prior infusion. Lastly, we aimed to reduce the toxicity of the used conditioning regimens for a safer and more efficient allogeneic and autologous gene therapy transplantation outcome.Altogether, the work described in this thesis moves towards a regular enforcement of gene therapy treatment for immunodeficiencies. Show less
Background: Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol... Show moreBackground: Learned placebo effects induced by pharmacological conditioning affect immune and endocrine outcomes and may offer new possibilities for clinical applications. Whether or not cortisol is subject to this type of associative learning processes, and whether conditioning may affect responses to stress, is currently unclear.Method: A randomized placebo-controlled trial was conducted in 48 healthy young women. During acquisition, participants received a pill containing either 100 mg hydrocortisone (unconditioned stimulus) or placebo, paired with a gustatory conditioned stimulus on three consecutive days. During evocation, all participants received placebo paired with the conditioned stimulus, again on three consecutive days. During the third evocation trial, participants underwent a psychosocial stress task. The main outcome parameter salivary cortisol and secondary outcome parameters salivary alpha-amylase, self-reported positive affect and tension, heart rate, and skin conductance level were measured at several time points.Results: Significant baseline group differences on cortisol were found at several time points, which complicate the interpretation of group differences. During the first evocation session, the conditioned group showed a moderately smaller cumulative decrease in salivary cortisol from baseline than the placebo control group. No significant differences were found between the groups on cortisol during the second and third evocation or in response to stress, nor on other outcome measures.Conclusion: Although the results provide potential further indications for effects of conditioning on cortisol, baseline differences make it impossible to draw clear conclusions. No indications for possible effects of conditioning on the cortisol stress response or autonomous or affective responses to stress were found. Show less
Placebo and nocebo effects are positive or negative treatment effects respectively, unrelated to the treatment mechanism, which are induced by patients’ expectations. Placebo and nocebo effects are... Show morePlacebo and nocebo effects are positive or negative treatment effects respectively, unrelated to the treatment mechanism, which are induced by patients’ expectations. Placebo and nocebo effects are known to play a role in treatment effects for various symptoms and conditions, especially in the field of pain. The aim of the current disseration was to increase understanding of placebo and nocebo effects on itch.The results of the studies presented in this thesis further underline that placebo and nocebo effects play a role in itch perception. We found that itch is highly susceptible to suggestions and placebo and nocebo effects can be induced on itch by verbal suggestion and conditioning. Most notably, our findings show for the first time that particularly the combination of conditioning with verbal suggestion is most promising for inducing both placebo and nocebo effects on itch, which is in accordance with placebo research on pain. Moreover, a new and promising finding is that counterconditioning has shown to reverse nocebo effects on itch. Future research may build upon the findings of this thesis to further enlarge our knowledge on placebo and nocebo effects on itch and how to maximize or minimize them, respectively, also in a clinical setting, to eventually optimize available interventions for patients suffering from chronic itch. Show less
Nocebo hyperalgesia is a clinically relevant phenomenon and may be formed as a result of associative learning, implemented by classical conditioning. This study explored for the first time distinct... Show moreNocebo hyperalgesia is a clinically relevant phenomenon and may be formed as a result of associative learning, implemented by classical conditioning. This study explored for the first time distinct nocebo conditioning methods and their consequences for nocebo attenuation methods. Healthy participants (N = 140) were recruited and randomized to the following nocebo hyperalgesia induction groups: conditioning with continuous reinforcement (CRF), conditioning with partial reinforcement (PRF), and a sham-conditioning control group. In the attenuation phase, counterconditioning was compared with extinction. During induction, participants experienced increased thermal pain in 100% of nocebo trials in the CRF groups, while in only 70% of nocebo trials in the PRF groups. During evocation, pain stimulation was equivalent across all trials. During attenuation, pain stimulation was decreased on nocebo trials relative to control trials for the counterconditioning groups, while pain remained equivalent across all trials for the extinction groups. Results showed that both PRF and CRF significantly induced nocebo hyperalgesia, but CRF was a more potent nocebo induction method, as compared to PRF. Counterconditioning was more effective than extinction in attenuating nocebo hyperalgesia. Neither CRF nor PRF resulted in resistance to extinction. However, compared with CRF, conditioning with PRF resulted in more resistance to counterconditioning. These findings demonstrate that the more ambiguous learning method of PRF can induce nocebo hyperalgesia and may potentially explain the treatment resistance and chronification seen in clinical practice. Further research is required to establish whether attenuation with counterconditioning is generalizable to clinical settings. Show less
This dissertation investigated placebo and nocebo effects in itch. Placebo and nocebo effects are positive and negative treatment outcomes respectively, that cannot be attributed to active... Show moreThis dissertation investigated placebo and nocebo effects in itch. Placebo and nocebo effects are positive and negative treatment outcomes respectively, that cannot be attributed to active treatment ingredients. Consistent with previous research, the dissertation shows that these effects play an important role in itch. The studies moreover illustrate that placebo effects can still occur when people are informed about them.The results described in this dissertation show that expectations about itch can be formed in various ways. People's expectations of treatment outcomes have been found underlie placebo and nocebo effects. For instance, the information that is given about how much itch an experimental test elicits (i.e., verbal suggestions) can influence expectations and lead to placebo or nocebo effects. The results also show that placebo effects can be automatically induced for itch by associative learning (through pharmacological conditioning). In addition, these effects may also occur when people know they are placebo effects. These results illustrate the importance of expectations and the psychosocial context in the treatment of somatic symptoms complaints such as itch. The results of this thesis may help improve existing treatments for itch. For example, medicine use can potentially be reduced by applying pharmacological conditioning, existing treatment can be improved by providing optimal treatment information, and the importance of expectations for treatment outcomes can be discussed with patients. Show less
Manai, M.; Middendorp, H. van; Veldhuijzen, D.S.; Pol, J.A. van der; Huizinga, T.W.J.; Evers, A.W.M. 2020
Background In pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo... Show moreBackground In pharmacological conditioning associations are formed between the effects of medication and contextual factors related to the medication. Pharmacological conditioning with placebo medication can result in comparable treatment effects and reduced side effects compared to regular treatment in various clinical populations, and may be applied to achieve enhanced drug effects. In the current study protocol, pharmacological conditioning is applied to achieve enhanced treatment effects in patients with recent-onset rheumatoid arthritis (RA). The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness for patients with inflammatory conditions, such as recent-onset RA. Methods A multicenter, randomized controlled clinical trial is conducted in patients with recent-onset RA. Participants start on standardized pharmacological treatment for 16 weeks, which consists of methotrexate (MTX) 15 mg/week and a tapered schedule of prednisone 60 mg or 30 mg. After 4 months, participants in clinical remission (based on the rheumatologist's opinion and a targeted score below 1.6 on a 44-joint disease activity score (DAS44)) are randomized to 1 of 2 groups: (1) the control group (C), which continues with a standardized treatment schedule of MTX 15 mg/week or (2) the pharmacological conditioning group (PC), which receives an MTX treatment schedule in alternating high and low dosages. In the case of persistent clinical remission after 8 months, treatment is tapered and discontinued linearly in the C group and variably in the PC group. Both groups receive the same cumulative amount of MTX during each period. Logistic regression analysis is used to compare the proportion of participants with drug-free clinical remission after 12 months between the C group and the PC group. Secondary outcome measures include clinical functioning, laboratory assessments, and self-reported measures after each 4-month period up to 18 months after study start. Discussion The results from this study broaden the knowledge on the potential of pharmacological conditioning and provide a potential innovative treatment option to optimize long-term pharmacological treatment effectiveness in patients with inflammatory conditions, such as recent-onset RA. Show less
Itch is a commonly experienced symptom of acute and chronic dermatological and systemic conditions. Placebo and nocebo effects, positive and negative effects experienced after both real and sham... Show moreItch is a commonly experienced symptom of acute and chronic dermatological and systemic conditions. Placebo and nocebo effects, positive and negative effects experienced after both real and sham interventions, putatively due to positive or negative outcome expectancies, can have a significant impact on the experience of itch and its treatment. Experimental methods to induce and study placebo and nocebo effects on itch have been developed, utilizing various combinations of expectancy-induction methods (eg, conditioning, verbal suggestions) and short-acting itch-evoking stimuli (eg, histamine, electrical, or mechanical stimulation). The aim of this review is to describe the current research methods used to induce placebo and nocebo effects on itch, and the results of these studies. The benefits and drawbacks of different expectancy-induction methods and itch-evoking stimuli are described, and future directions for research and clinical application are discussed. Show less
Placebo effects are health improvements, for example pain reduction, due to an inert treatment. These effects are typically ascribed to a person’s expectations about the beneficial outcomes of... Show morePlacebo effects are health improvements, for example pain reduction, due to an inert treatment. These effects are typically ascribed to a person’s expectations about the beneficial outcomes of the placebo. The literature and experimental research in the current dissertation shows that expectancies, and thereby placebo effects, can be induced via verbal suggestion, conditioning, and mental imagery. Especially verbal suggestions may enhance analgesic treatments for patients. We found, for the first time, that mental imagery of reduced pain can induce analgesia via its effects on pain expectancies. We also observed that people’s expectations about the effectiveness of medications depend on the route of administration and targeted symptom. These findings suggest that harnessing placebo effects by targeting expectancies is promising for enhancing standard clinical care of physical symptoms. Show less
Both, S.; Brauer, M.; Weijenborg, P.; Laan, E. 2017
