Background: Endoscopic transsphenoidal surgery (ETSS) for prolactinoma is reserved for dopamine agonist (DA) resistance, intolerance, or apoplexy. High remission (overall 67%, microprolactinoma up... Show moreBackground: Endoscopic transsphenoidal surgery (ETSS) for prolactinoma is reserved for dopamine agonist (DA) resistance, intolerance, or apoplexy. High remission (overall 67%, microprolactinoma up to 90%), low recurrence (5-20%) rates highlighted that surgery might be first-line treatment.Aims: To report on outcomes of ETSS in a cohort of prolactinomas.Methods: Multicenter retrospective cohort of 137 prolactinoma patients (age 38.2 +/- 13.7 years; 61.3% female, median follow-up 28.0 [15.0-55.5] months) operated between 2010-2019 with histopathological confirmation.Results: Median preoperative prolactin levels were 166 (98-837 mu g/L; males 996 [159-2145 mu g/L] vs. females 129 [84-223 mu g/L], p <0.001). 56 (40.9%) microprolactinomas, 69 (50.4%) macroprolactinomas, and 7 (5.1%) giant prolactinomas were included, whereas no adenoma was detected in 5 (3.6%) patients. Males had larger tumors (macroprolactinomas: 38, 71.7%) vs. 31 (36.9%), p <0.001; giant prolactinomas: 7 (13.2%) vs. 0 (0.0%), (p <0.001). Prolactinomas were graded as KNOSP-3 in 15 (11.5%), and KNOSP-4 in 20 (15.3%) patients. Primary indication was DA intolerance (59, 43.1%); males 14 (26.4%) vs. females 45 (53.6%), p = 0.006. Long-term remission (i.e., DA-free prolactin level <1xULN) was achieved in 87 (63.5%) patients, being higher in intended complete resection (69/92 [75.0%]), and lower in males (25 [47.2%] vs. 62 females [73.8%], p = 0.002). Transient DI (n = 29, 21.2%) was the most frequent complication.Conclusions: Despite high proportions of macroprolactinoma and KNOSP 3-4, long-term remission rates were 63.5% overall, and 83.3% in microprolactinoma patients. Males had less favorable remission rate compared to females. These findings highlight that ETSS may be a safe and efficacious treatment to manage prolactinoma.(c) 2023 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved. Show less
De eetbuistoornis is de meest voorkomende eetstoornis en komt in vergelijking met anorexia en boulima veel meer onder alle lagen van de bevolking voor. Wereldwijd is er een gebrek aan kennis over... Show moreDe eetbuistoornis is de meest voorkomende eetstoornis en komt in vergelijking met anorexia en boulima veel meer onder alle lagen van de bevolking voor. Wereldwijd is er een gebrek aan kennis over de eetbuistoornis. Door gebrekkige (h)erkenning krijgen individuen met een eetbuistoornis vaak verkeerde zorg, waardoor de eetbuien juist toenemen. Daarnaast zijn er lange wachttijden voor specialistische behandeling en heeft niet iedereen toegang tot behandeling. Deze these is tweeledig: er wordt onderzoek gedaan naar risicofactoren van de eetbuistoornis in Arabische landen en twee diagnostische vragenlijsten worden gevalideerd. In Nederland wordt de werkzaamheid van een traditionele en een digitale begeleide zelfhulp behandeling onderzocht. In Arabische landen bleken een hoog BMI en lichaamsontevredenheid geassocieerd te zijn met eetstoornispathologie. De eating disorder examination questionnaire meet accuraat eetstoornisklachten en de body shape questionnaire lichaamsontevredenheid. In Nederland blijkt cognitive behavioral therapy een werkzame behandeling voor de eetbuistoornis, zowel op de traditionale manier, als digitaal aangeboden. De digitale variant vergroot de toegang tot specialistische zorg en kan mogelijk de lange wachttijden voor behandeling verkorten. Show less
BackgroundAdequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical... Show moreBackgroundAdequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical benefit of leadless pacing.ObjectiveThe purpose of this study was to evaluate the long-term safety and efficacy of LP therapy in a real-world cohort.MethodsIn this retrospective cohort study, all consecutive patients with a first LP implantation from December 21, 2012, to December 13, 2016, in 6 Dutch high-volume centers were included. The primary safety endpoint was the rate of major procedure- or device-related complications (ie, requiring surgery) at 5-year follow-up. Analyses were performed with and without Nanostim battery advisory-related complications. The primary efficacy endpoint was the percentage of patients with a pacing capture threshold ≤2.0 V at implantation and without ≥1.5-V increase at the last follow-up visit.ResultsA total of 179 patients were included (mean age 79 ± 9 years), 93 (52%) with a Nanostim and 86 (48%) with a Micra VR LP. Mean follow-up duration was 44 ± 26 months. Forty-one major complications occurred, of which 7 were not advisory related. The 5-year major complication rate was 4% without advisory-related complications and 27% including advisory-related complications. No advisory-related major complications occurred a median 10 days (range 0–88 days) postimplantation. The pacing capture threshold was low in 163 of 167 patients (98%) and stable in 157 of 160 (98%).ConclusionThe long-term major complication rate without advisory-related complications was low with LPs. No complications occurred after the acute phase and no infections occurred, which may be a specific benefit of LPs. The performance was adequate with a stable pacing capture threshold. Show less
Hany, M.; Aboudeeb, M.F.; Shapiro-Koss, C.; Agayby, A.S.S.; Torensma, B. 2023
Introduction Patients living with psychiatric illnesses (PIs) have a high prevalence of obesity. In a 2006 survey, 91.2% of professionals in the bariatric field identified "psychiatric issues" as... Show moreIntroduction Patients living with psychiatric illnesses (PIs) have a high prevalence of obesity. In a 2006 survey, 91.2% of professionals in the bariatric field identified "psychiatric issues" as clear contraindications to weight-loss surgery. Methods This retrospective matched case-control study investigated the impact, safety, and possible relapse after bariatric metabolic surgery (BMS) in patients with PIs. Also, we tested the incidence of patients who developed PI after BMS and compared the post-procedural weight loss with that in a matched control group without PIs. The cases were matched in a ratio of 1:4 to the control patients standardized for age, sex, preoperative BMI, and type of BMS. Results Of 5987 patients, 2.82% had a preoperative PI; postoperative de novo PI was present in 0.45%. Postoperative BMI was significantly different between the groups when compared to preoperative BMI (p < 0.001). Percentage of total weight loss (%TWL) after six months was not significantly different between the case (24.6% +/- 8.9) and control groups (24.0% +/- 8.4, p = 1.000). Early and late complications were not significantly different between the groups. The psychiatric drug use and dosage changes did not differ significantly pre- and postoperatively. Of the psychiatric patients, 5.1% were postoperatively admitted to a psychiatric hospital (p = 0.06) unrelated to BMS, and 3.4% had a prolonged absence from work after surgery. Conclusion BMS is an effective weight loss treatment and a safe procedure for patients with psychiatric disorders. We found no change in the patients' psychiatric status outside the usual disease course. Postoperative de novo PI was rare in the present study. Furthermore, patients with severe psychiatric illness were excluded from undergoing surgery and, therefore, from the study. Careful follow-up is necessary to guide and protect patients with PI. Show less
eHealth is most effective when integrated into conventional health care in a “hybrid” health care model. In order to achieve high-quality hybrid health care, eHealth must benefit patients and must... Show moreeHealth is most effective when integrated into conventional health care in a “hybrid” health care model. In order to achieve high-quality hybrid health care, eHealth must benefit patients and must be effectively integrated and organized within regular health care. This thesis describes the evaluation of eHealth from both a patient perspective and an organizational perspective. Chapters 2 and 3 present patients’ views of an online patient portal. Chapters 4 and 5 describe the factors that affect the organization of high-quality hybrid health care and use these as inputs to develop a tailored quality management model and accompanying self-assessment questionnaire: the Hybrid Health Care Quality Assessment (HHQA) (Chapter 5). Health care organizations can use the model and questionnaire to gain insight into ways of improving the quality of their hybrid care. Show less
Kantidakis, G.; Litiere, S.; Neven, A.; Vinches, M.; Judson, I.; Blay, J.Y.; ... ; Gelderblom, H. 2022
BackgroundRecently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, >= 10 adult patients) to update long-standing reference values for... Show moreBackgroundRecently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, >= 10 adult patients) to update long-standing reference values for leiomyosarcomas. This work is extended for liposarcomas (LPS) and synovial sarcomas (SS).Materials and methodsStudy endpoints were progression-free survival rates (PFSRs) at 3 and 6 months. Trial-specific estimates were pooled per treatment line (first-line or pre-treated) with random effects meta-analyses. The choice of the therapeutic benefit to target in future trials was guided by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS).ResultsInformation was acquired for 1030 LPS patients (25 trials; 7 first-line, 17 pre-treated, 1 both) and 348 SS patients (13 trials; 3 first-line, 10 pre-treated). For LPS, the overall pooled first-line PFSRs were 69% (95%-CI 60-77%) and 56% (95%-CI 45-67%) at 3 and 6 months, respectively. These rates were 49% (95%-CI 40-57%)/28% (95%-CI 22-34%) for >1 lines. For SS, first-line PFSRs were 74% (95%-CI 58-86%)/56% (95%-CI 31-78%) at 3 and 6 months, and pre-treated rates were 45% (95%-CI 34-57%)/25% (95%-CI 16-36%). Following ESMO-MCBS guidelines, the minimum values to target are 79% and 69% for first-line LPS (82% and 69% for SS) at 3 and 6 months. For pre-treated LPS, recommended PFSRs at 3 and 6 months suggesting drug activity are 63% and 44% (60% and 41% for SS).ConclusionsNew benchmarks are proposed for advanced/metastatic LPS or SS to design future histology-specific phase II trials. More data are needed to provide definitive thresholds for the different LPS subtypes. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement... Show moreBackground: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Current knowledge about this subject. COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation.. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups.. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study. Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a twoyear follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5.. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group.. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy. Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19.. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy. Show less
Kantidakis, G.; Litiere, S.; Neven, A.; Vinches, M.; Judson, I.; Schoffski, P.; ... ; Gelderblom, H. 2021
Background: In 2002, the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group reported well-established values for conducting phase II trials for soft... Show moreBackground: In 2002, the European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group reported well-established values for conducting phase II trials for soft-tissue sarcomas. An update is provided for leiomyosarcoma (LMS). Materials and methods: Clinical trials with advanced or metastatic LMS were identified via literature review in PubMed (published 2003-2018, >10 adult LMS patients). End-points were 3-and 6-month progression-free survival rates (PFSR-3m and PFSR-6m). When estimates could not be derived from publications, data requests were sent out. Treatments were classified as recommended (R-T) or non-recommended (NR-T) according to the ESMO 2018 guidelines. A random effects meta-analysis was used to pool trial-specific estimates for first-line (1L) or pre-treated (2L+) patients separately. The ESMO Magnitude of Clinical Benefit Scale was used to guide the treatment effect to target in future trials. Results: From 47 studies identified, we obtained information on 7 1L and 16 2L+ trials for 1500 LMS patients. Overall, in 1L, PFSR-3m and PFSR-6m were 74% (95% confidence interval [CI] 64-82%) and 58% (95% CI 50-66%), respectively. For 2L+, PFSR-3m was 48% (95% CI 41-54%), and PFSR-6m was 28% (95% CI 22-34%). No difference was observed between R-T and NR-T for first or later lines. Under the alternative that the true benefit amounts to a hazard ratio of 0.65, a PFSR-6m >70% can be considered to suggest drug activity in 1L. For 2L+, a PFSR-3m >62% or PFSR-6m >44% would suggest drug activity. Specific results are also provided for uterine LMS. Conclusions: This work provides a new benchmark for designing phase II studies for advanced or metastatic LMS. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
This thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for... Show moreThis thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for chemotherapy outcome.Preclinical research is evaluated, which shows that short-term fasting during chemotherapy is effective. The effects of short-term fasting in humans is not evident yet. Although the first small clinical studies of short-term fasting as adjunct to chemotherapy are promising in terms of decreased toxicity and enhanced efficacy, the exact mechanism and effects are not established yet. More studies and a longer follow-up are needed to prove this.Insulin-like growth factor 1 (IGF-1) and insulin are members of the IGF-1 pathway, which is involved in cell growth and proliferation. The effects of the IGF-1 pathway on chemotherapy outcome and the pathway itself as target for cancer therapy are described. The disappointing results of clinical studies of IGF-1R inhibitors may be caused by the complexity of the IGF-1R pathway. Lowering both insulin and IGF-1, perhaps with a short-term fasting intervention, serves as a possible target in cancer therapy. Show less
Slingerland-Boot, R.; Bouw-Ruiter, M.; Manen, C. van; Arbous, S.; Zanten, A. van 2021
Introduction: In critically ill patients, nasogastric (NG) and nasojejunal (NJ) feeding tube placements are standard procedures. However, about 1.9% of blind tube insertions are malpositioned in... Show moreIntroduction: In critically ill patients, nasogastric (NG) and nasojejunal (NJ) feeding tube placements are standard procedures. However, about 1.9% of blind tube insertions are malpositioned in the tracheopulmonary system, whereas guided procedures may result in a significant delay in nutritional delivery. Guided methods, such as Cortrak and fluoroscopy, have success rates of 82.6-85% and 93% respectively. The current study aims to investigate the performance of video-assisted feeding tube placement in the post-pyloric position using Integrated Real Time Imaging System (IRIS-) technology. Methods: A prospective cohort study in patients requiring enteral feeding was conducted in a mixed medical-surgical intensive care unit (ICU). The primary outcome was the post-pyloric placement of IRIS feeding tubes, as confirmed by X-ray. Secondary study objectives included gastric placement, ease of use and adverse events. Results: Thirty-one feeding tubes were placed using IRIS-technology; one patient was excluded for analysis due to protocol violation. One procedure was terminated due to significant bleeding (epistaxis) and desaturation. Only eighteen (58%) feeding tubes were placed in post-pyloric position (including two past the ligament of Treitz). In subjects who needed post-pyloric placement due gastroparesis, IRIS was mostly unsuccessful (success rate of 25%). However, when gastric placement was the primary objective, 96.8% of tubes were correctly placed. During insertion, tracheal visualization occurred in 27% of cases, and the IRIS feeding tube was repositioned early in the procedure without causing patient harm. Conclusions: Real-time video-assisted post-pyloric feeding tube placement in critically ill ICU patients was only successful in 58% of cases and therefore currently cannot be recommended for this indication. However, a high success rate (96.8%) for gastric placement was achieved. IRIS tube placement detected tracheal misplacement immediately and had few adverse events. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Background: Accurate determination of the efficacy of antimicrobial agents requires neutralization of residual antimicrobial activity in the samples before microbiological assessment of the number... Show moreBackground: Accurate determination of the efficacy of antimicrobial agents requires neutralization of residual antimicrobial activity in the samples before microbiological assessment of the number of surviving bacteria. Sodium polyanethol sulfonate (SPS) is a known neutralizer for the antimicrobial activity of aminoglycosides and polymyxins. In this study, we evaluated the ability of SPS to neutralize residual antimicrobial activity of antimicrobial peptides [SAAP-148 and pexiganan; 1% (wt/v) in PBS], antibiotics [mupirocin (Bactroban) and fusidic acid (Fucidin) in ointments; 2% (wt/wt))] and disinfectants [2% (wt/wt) silver sulfadiazine cream (SSD) and 0.5% (v/v) chlorhexidine in 70% alcohol].Methods: Homogenates of human skin models that had been exposed to various antimicrobial agents for 1 h were pipetted on top of Methicillin-resistant Staphylococcus aureus (MRSA) on agar plates to determine whether the antimicrobial agents display residual activity.To determine the optimal concentration of SPS for neutralization, antimicrobial agents were mixed with PBS or increasing doses of SPS in PBS (0.05-1% wt/v) and then 105 colony forming units (CFU)/mL MRSA were added. After 30min incubation, the number of viable bacteria was assessed. Next, the in vitro efficacy of SAAP-148 against various gram-positive and gram-negative bacteria was determined using PBS or 0.05% (wt/v) SPS immediately after 30 min incubation of the mixture. Additionally, ex vivo excision wound models were inoculated with 105 CFU MRSA for 1 h and exposed to SAAP-148, pexiganan, chlorhexidine or PBS for 1 h. Subsequently, samples were homogenized in PBS or 0.05% (wt/v) SPS and the number of viable bacteria was assessed.Results: All tested antimicrobials displayed residual activity in tissue samples, resulting in a lower recovery of surviving bacteria on agar. SPS concentrations at >= 0.05% (wt/v) were able to neutralize the antimicrobial activity of SAAP-148, pexiganan and chlorhexidine, but not of SSD, Bactroban and Fucidin. Finally, SPS-neutralization in in vitro and ex vivo efficacy tests of SAAP-148, pexiganan and chlorhexidine against gram-positive and gram-negative bacteria resulted in significantly higher numbers of CFU compared to control samples without SPS-neutralization.Conclusions: SPS was successfully used to neutralize residual activity of SAAP-148, pexiganan and chlorhexidine and this prevented an overestimation of their efficacy. Show less
Background: We investigated the efficacy of a synthetic antimicrobial peptide SAAP-148, which was shown to be effective against Methicillin-resistant Staphylococcus aureus (MRSA) on tape-stripped... Show moreBackground: We investigated the efficacy of a synthetic antimicrobial peptide SAAP-148, which was shown to be effective against Methicillin-resistant Staphylococcus aureus (MRSA) on tape-stripped mice skin. Unexpectedly, SAAP-148 was not effective against MRSA in our pilot study using rats with excision wounds. Therefore, we investigated factors that might have contributed to the poor efficacy of SAAP-148. Subsequently, we optimised the protocol and assessed the efficacy of SAAP-148 in an adapted rat study.Methods: We incubated 100 mu L of SAAP-148 with 1 cm(2) of a wound dressing for 1 h and determined the unabsorbed volume of peptide solution. Furthermore, 10(5) colony forming units (CFU)/mL MRSA were exposed to increasing dosages of SAAP-148 in 50% (v/v) human plasma, eschar- or skin extract or PBS. After 30 min incubation, the number of viable bacteria was determined. Next, ex vivo skin models were inoculated with MRSA for 1 h and exposed to SAAP-148. Finally, excision wounds on the back of rats were inoculated with 10(7) CFU MRSA overnight and treated with SAAP-148 for 4 h or 24 h. Subsequently, the number of viable bacteria was determined.Results: Contrary to Cuticell, Parafilm and Tegaderm film, < 20% of peptide solution was recovered after incubation with gauze, Mepilex border and Opsite Post-op. Furthermore, in plasma, eschar- or skin extract > 20-fold higher dosages of SAAP-148 were required to achieve a 2-log reduction (LR) of MRSA versus SAAP-148 in PBS. Exposure of ex vivo models to SAAP-148 for 24 h resulted in a 4-fold lower LR than a 1 h or 4 h exposure period. Additionally, SAAP-148 caused a 1.3-fold lower mean LR at a load of 10(7) CFU compared to 10(5) CFU MRSA. Moreover, exposure of ex vivo excision wound models to SAAP-148 resulted in a 1.5-fold lower LR than for tape-stripped skin. Finally, SAAP-148 failed to reduce the bacterial counts in an adapted rat study.Conclusions: Several factors, such as absorption of SAAP-148 by wound dressings, components within wound exudates, re-colonisation during the exposure of SAAP-148, and a high bacterial load may contribute to the poor antimicrobial effect of SAAP-148 against MRSA in the rat model. Show less
Davido, B.; Batista, R.; Dinh, A.; Truchis, P. de; Terveer, E.M.; Roberts, B.; ... ; Caballero, S. 2019
During the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of... Show moreDuring the course of drug discovery translational steps are made. The translation from in vitro to in vivo experiments is not as predictive as one would desire, resulting in selection of inefficacious compounds but also in overlooking of promising drug candidates. This is not different for the mGlu2 receptor for which no drugs are available on the market so far despite enormous drug discovery efforts. Therefore, there is a need to improve the molecular understanding of key in vitro parameters that drive in vivo efficacy. Hence, this thesis focuses on the concepts of target binding kinetics and functional efficacy of both allosteric and orthosteric ligands of the mGlu2 receptor. Show less
Lam, S.W.; Noort, V. van der; Straaten, T. van der; Honkoop, A.H.; Peters, G.J.; Guchelaar, H.J.; E. boven 2018
Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly... Show moreElectroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to produce generalized seizure for the treatment of selected psychiatric disorders, mostly treatment resistant depression, acute mania, and schizophrenic syndromes. Safety of ECT increases the efficacy of therapy and provides fulfillment of a series of required treatments resulting in longer treatment effect of ECT. During the last few decades, researchers have been attempting to improve the effectiveness of ECT, to learn how and why it works, and to understand its risks and adverse side effects. As a result, the safety and efficacy of ECT has been improved and its indications have been relatively defined to increase the efficiency of outcome of therapy. While there has been considerable improvement in safety features, further investigation have been done to promote both the safety and efficacy of the treatment. Such efforts could increase our knowledge on the biological mechanisms involved in effectiveness of ECT that might result in discovery of new treatments. In this dissertation, we investigate how preprocedural medications could improve the safety and efficacy of ECT and further investigated the potential role of pharmacogenetics in the efficacy of ECT and procedural side effects such as cognitive disorders. Show less
Berg, H. van den; Paulussen, M.; Teuff, G. le; Judson, I.; Gelderblom, H.; Dirksen, U.; ... ; Euro-EWING99 Grp 2015
Treatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects.... Show moreTreatment for advanced colorectal cancer (ACC) consists primarily of systemic treatment, mostly without curative intent. Systemic therapies are associated with potentially severe side effects. Furthermore, treatment is not effective in all patients. Currently, pre-treatment predictors for efficacy and toxicity in systemic treatment of ACC are scarce. Germline genetic variation in genes encoding for enzymes involved in pharmacokinetics or pharmacodynamics of cytotoxic drugs could explain intra-patient differences in treatment effects. Pharmacogenetic studies aim at finding such germline genetic predictors. This thesis focusses on pharmacogenetics of capecitabine and oxaliplatin in treatment of ACC. First, it is established that results derived from DNA in archived tumor samples can be reliably compared to those using DNA from peripheral blood leukocytes. Then, germline genetic markers in MTHFR and MTRR, as well as markers derived from an in vitro genome-wide association study (GWAS) are tested for their association with capecitabine toxicity. Next, effects of ERCC1 genotype on oxaliplatin cytotoxicity in vitro and in clinical association analysis are addressed. The influence of genetic variation in organic cation transporters on oxaliplatin-induced neurotoxicity is examined. Lastly, the results of a GWAS searching for germline predictors of treatment efficacy of capecitabine, oxaliplatin and bevacizumab, with or without cetuximab, are presented. Show less
