Clinical Guidance for Dosing and Monitoring Oral Antihormonal Drugs in Patients with Breast Cancer After Roux-en-Y Gastric Bypass.

ABSTRACT: Obesity is associated with an increased risk of cancers, such as breast cancer. Roux-en-Y gastric bypass (RYGB) is a common surgical intervention used to induce weight loss, reduce comorbidities, and improve overall survival. Due to alterations in the gastrointestinal tract, RYGB is associated with changes in oral drug disposition, which can affect treatment outcomes. Oral antihormonal agents were monitored in 9 patients who previously underwent RYGB. The results of therapeutic drug monitoring and estradiol concentrations were analyzed, and a review of the relevant literature was performed. As only 1 of the 6 patients prescribed tamoxifen achieved a therapeutic endoxifen concentration with the standard dose of 20 mg/d, a higher starting dose of 40 mg/d was recommended to increase the probability of attaining a therapeutic plasma concentration. All patients with decreased CYP2D6 metabolic activity could not achieve therapeutic plasma concentrations; therefore, CYP2D6 genotyping was recommended before the initiation of tamoxifen therapy to identify patients who should be switched to aromatase inhibitors. Anastrozole and letrozole exposure in patients who underwent RYGB patients appeared sufficient, with no dose adjustment required. However, until more data become available, monitoring aromatase inhibitor efficacy is recommended. Monitoring the drug concentrations is a viable option; however, only indicative data on therapeutic drug monitoring are available. Therefore, estradiol concentrations should be measured.

Systemic anticancer treatment in the Netherlands: Few hospitals treat many patients, many hospitals treat few patients.

INTRODUCTION: The correlation between patient volume and clinical outcomes is well known for various oncological treatments, especially in the surgical field. The current level of centralisation of systemic treatment of (hemato-)oncology indications in Dutch hospitals is unknown. OBJECTIVES: The aim of this study was to gain insight in patient volumes per hospital of patients treated with systemic anticancer treatment in the Netherlands. METHODS: National claims data (Vektis) of all 73 Dutch hospitals that provide systemic anticancer medication in the Netherlands for the time period 2019 were used. The distribution of volumes of patients treated with anticancer medication for 38 different haematological or oncological indications was analysed. Hospitals were categorized into academic/specialised, general, and top clinical. Two volume cut off points (10 and 30 patients) were used to identify hospitals treating relatively few patients with anticancer medication. Four indications were investigated in more detail. RESULTS: A wide distribution in patient volumes within hospitals was observed. Top clinical hospitals generally treated the most patients per hospital, followed by general and academic/specialised oncology hospitals. The volume cut off points showed that in 19 indications (50%) the majority (>50%) of all hospitals treated less than 10 patients and in 25 indications (66%) the majority of all hospitals treated less than 30 patients with anticancer medication. Four case studies demonstrated that relatively few hospitals treat many patients while many hospitals treat few patients with anticancer medication. CONCLUSION: In the majority of oncology indications, a large proportion of Dutch hospitals treat small numbers of unique patients with anticancer medication. The high level of fragmentation gives ground for further exploration and discussion on how the organisation of care can support optimization of the efficiency and quality of care. Professional groups, policy makers, patients, and healthcare insurers should consider per indication whether centralisation is warranted.

Arabidopsis thaliana rosette habit is controlled by combined light and energy signaling converging on transcriptional control of the TALE homeobox gene ATH1.

In the absence of light signals, Arabidopsis plants fail to develop the rosette habit typical for this species. Instead, plants display caulescent growth due to elongation of rosette internodes. This aspect of photomorphogenic development has been paid little attention and molecular events involved, downstream of photoreceptor signaling, remain to be identified. Using a combination of genetic and molecular approaches, we show that Arabidopsis rosette habit is a photomorphogenic trait controlled by induction of ARABIDOPSIS THALIANA HOMEOBOX GENE1 (ATH1) as downstream target of multiple photoreceptors. ATH1 induction prevents rosette internode elongation by maintaining the shoot apical meristem (SAM) rib zone area inactive and requires inactivation of photomorphogenesis inhibitors, including PHYTOCHROME INTERACTING FACTOR (PIF) proteins. ATH1 activity results in tissue-specific inhibition of PIF expression, establishing double-negative feedback-regulation at the SAM. Light-requirement for ATH1 expression can be overcome by high sugar availability to the SAM. Both sugar and light signals that induce ATH1 and, subsequently, rosette habit are mediated by TOR kinase. Collectively, our data reveal a SAM-specific, double-negative ATH1-PIF feedback loop at the basis of rosette habit. Upstream, TOR kinase functions as central hub integrating light and energy signals that control this for Arabidopsis quintessential trait.

Associations between uncertainties identified by the European Medicines Agency and national decision making on reimbursement by HTA agencies.

We aimed to determine whether uncertainties identified by the European Medicines Agency (EMA) were associated with negative relative effectiveness assessments (REAs) and negative overall reimbursement recommendations by national health technology assessment (HTA) agencies. Therefore, we identified all HTA reports from Haute Autorité de Santé (HAS; France), National Institute for Health and Care Excellence (NICE; England/Wales), Scottish Medicine Consortium (SMC; Scotland), and Zorginstituut Nederland (ZIN; The Netherlands) for a cohort of innovative medicines that the EMA had approved in 2009 to 2010 (excluding vaccines). Uncertainty regarding pivotal trial methodology, clinical outcomes, and their clinical relevance were combined to reflect a low, medium, or high level of uncertainty. We assessed associations by calculating risk ratios (RRs) and 95% confidence intervals (CIs), and agreement between REA and overall reimbursement recommendation outcomes. We identified 36 medicines for which 121 reimbursement recommendations had been issued by the HTA agencies between September 2009 and July 2018. High versus low uncertainty was associated with an increased risk for negative REAs and negative overall reimbursement recommendations: RRs 1.9 (95% CI 0.9-3.9) and 1.6 (95% CI 0.7-3.5), respectively, which was supported by further sensitivity analyses. We identified a lack of agreement between 33 (27%) REA and overall reimbursement recommendation outcomes, which were mostly restricted recommendations that followed on negative REAs in case of low or medium uncertainty. In conclusion, high uncertainty identified by the EMA was associated with negative REAs and negative overall reimbursement recommendations. To reduce uncertainty and ultimately facilitate efficient patient access, regulators, HTA agencies, and other stakeholders should discuss how uncertainties should be weighed and addressed early in the drug life cycle of innovative treatments.

Role of Rehabilitation in Promoting Engagement in Daily Life in Multiple Sclerosis: Facing the Challenges of the 21st Century.

The purpose of this narrative review is to define the theoretical constructs of engagement, participation, and balance. The implementation of these constructs in multiple sclerosis (MS) rehabilitation are described because MS symptoms such as fatigue and cognitive decline may affect engagement in daily life. The constructs of engagement and participation can be considered to be different when they are studied. The constructs related to balance are of interest when targeting engagement. Multidisciplinary rehabilitation programs may have beneficial effects in optimizing engagement. Therefore, the measurement of these constructs is primordial because they give us a deeper understanding of the meaning of activity performance that reflects engagement in daily life. Future research may focus on describing engagement in both men and women at all stages of MS and may explore variables that influence engagement in daily life to integrate engagement optimization in MS rehabilitation. Engagement may have beneficial effects as part of multidisciplinary rehabilitation in MS.