Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism

Experimentele farmacotherapi

Effect of CYP2C19 genotypes on tamoxifen metabolism and early-breast cancer relapse

CYP2C19*2 and CYP2C19*17 might influence tamoxifen metabolism and clinical outcome. Our aim was to investigate the effect of CYP2C19 genotypes on tamoxifen concentrations and metabolic ratios (MRs) and breast cancer recurrence in a large cohort of Caucasian women. Genetic variants (CYP2D6 and CYP2C19 genotypes), tamoxifen and metabolites concentrations, baseline characteristics, and breast cancer recurrence from the CYPTAM study (NTR1509) were used. CYP2C19*2 and CYP2C19*17 genotypes were evaluated as alleles and as groups based on CYP2D6 genotypes (high, intermediate and low activity). Log-rank test and Kaplan-Meier analysis were used to evaluate differences in recurrence defined as relapse-free survival (RFS). Classification tree analyses (CTAs) were conducted to assess the levels of interactions per polymorphism (CYP2D6 and CYP2C19 genotypes) on endoxifen concentrations. No differences in mean concentrations and MRs were observed when comparing CYP2C19 genotypes (CYP2C19*1/*1; CYP2C19*1/*2; CYP2C19*2/*2; CYP2C19*1/*17; CYP2C19*17/*17; CYP2C19*2/*17). Only significant differences (p value<0.05) in mean concentrations and MRs were observed when comparing tamoxifen activity groups (high, intermediate and low activity). A log-rank test did not find an association across CYP2C19 genotypes (p value 0.898). CTAs showed a significant relationship between CYP2D6 and endoxifen (p value<0.0001), but no association with CYP2C19 genotypes was found. CYP2C19 polymorphisms do not have a significant impact on tamoxifen metabolism or breast cancer relapse.Personalised Therapeutic

Phase 1 study to evaluate the safety of reducing the prophylactic dose of dexamethasone around docetaxel infusion in patients with prostate and breast cancer

Simple Summary: Docetaxel has been approved as an anti-cancer agent in 1995. High rates of hypersensitivity reactions (HSR) and fluid retention were observed when this agent was first introduced. The use of high dose systemic corticosteroids around docetaxel infusion appeared to decrease the incidence of HSR and fluid retention and has been applied in daily practice ever since. However, there is little evidence that supports this high dose of dexamethasone. Furthermore, the application of high-dosed corticosteroids can lead to undesirable adverse effects. In this phase 1 study, we aim to evaluate the impact of reducing the dose of dexamethasone as an adjunct to docetaxel on the incidence of HSR and fluid retention in patients with prostate or breast cancer. Background: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Patients and methods: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Results: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg-8 mg-4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. Conclusions: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome.Metabolic health: pathophysiological trajectories and therap

Update on the use of aromatase inhibitors in early-stage breast cancer

Aromatase inhibitors are currently included in the 'optimal' management of early-stage breast cancer. Uncertainty remains, however, as to the most appropriate treatment strategy, particularly for newly diagnosed women as they seek to trade off the cost, toxicities and efficacy of the treatment options. Recent publications provide conflicting advice on the role of aromatase inhibitors in the treatment of postmenopausal patients with early-stage hormone receptor-positive breast cancer. This review provides updates on the clinical trials of aromatase inhibitors in early breast cancer and tries to provide practical clinical guidance on their optimal use

Designing an engaging game for assessing motion disorders

The Technology in Motion project (TIM) has the goal to create an objective and non-invasive assessment method for motion disorders using novel technologies. Currently the TIM project has been looking at Augmented Reality (AR) as a potential technology for this purpose. A part of the project is to design a game that incites the patient to make the necessary movements, pushing him to the limit of his capabilities and so enabling the doctor to make the right decision. But a game is more than a set of steps to follow. A game that interests the player, engages him to participate, is a much stronger tool (Garris, Ahlers, and Driskell 2002; Dickey 2005) and will transform tedious repetition in a pleasant activity. But the target audience of this game will be patients with motion disorders who usually are older than 50, a group not often associated with gaming. This leads to the question “How can an AR game that facilitates engaging motion disorder assessment be designed?”. To answer this question, a motion disorder assessment game prototype is developed and tested to find the factors that are vital to the design. To create a game that facilitates engagement, it was decided to combine game design approaches from both serious game theories and entertainment game theories. This resulted in the game theories Rollings and Adams (2003) being integrated into the design cycle of Sebastiaan Meijer (2009). Meijer’s approach was chosen because it brings a clear, iterative structure to the process and also has space to add different design theories. For these theories, Rollings and Adams provide a clear overview of important design decisions that needs to be tuned to the target audience to create the best engagement possible. The approach of Meijer is based on determining requirements to be combined with the game design theory to create a game. These requirements are the vital factors to the game design. The game is then tested and using the results of this experiment, the requirements are improved. This cycle can continue until the game is ready to be used. To compile the initial list of requirements, two sides of the procedure were studied. First, two sessions for patients’ assessment were observed and an expert on movement sciences was consulted to determine the requirements of clinicians. Second, several patients were interviewed to determine the requirements of the target audience. These two steps resulted in the requirements that led to the concept game “Post office trouble”. In this game, the player has to sort packages in a sorting cabinet but instead of an address, the package only has an image on it that corresponds to a country. Using a Head Mounted Display (HMD) equipped with motion sensors will allow the game to track the hand movements of the player and use this as input. The player can thus use physical movements to play the game. The data from the sensors can be used as quantitative data for the motion disorder assessment. The game was tested by letting eight healthy people play a prototype of the game. Two validated questionnaires measuring usability and engagement were used in the experiment. Using the data from these questionnaires it was determined if the factors found truly lead to an engaging game. The results show that the game’s usability still needs improvement and that the engagement value is below average. These results can be explained in three different ways. The first option is that the engagement value could be true and the game is a little bit engaging. Secondly, the game is not engaging and the test participants were only interested because of the novelty of the AR technology. Third, the game was engaging but the low usability made it difficult for the participants to get into the game, resulting in the lower scores. All three options are possible so it is recommended that future research focusses on improving the usability so that an experiment with a larger sample-group can verify the results of this study.Systems EngineeringMulti Actor SystemsTechnology, Policy and Managemen

Sunitinib treatment in a patient with metastatic renal cell carcinoma and bariatric surgery

Contains fulltext : 154030.pdf (publisher's version ) (Closed access