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Personalized care is a topical issue: the demand for an optimal, individualized treatment instead of uniformity and strict guidelines in increasing. Implementing these ideals in clinical practice often appears to be challenging, as a result of heterogeneity in treatment effects and the influence of patient-specific factors. N-of-1 trials are double-blind, randomized, placebo-controlled trials in an individual patient and can be used to objectively examine the (side)effects of a specific drug, and to compare two or more drugs or variants of the same drug. The results can be used when aiming of deprescribing, but also for evaluating patient-reported intolerances or (in)effectiveness. This article discusses the use and advantages of N-of-1-trials in clinical practice, and addresses its specific concerns and possibilities. The N-of-1-trial is an effective, cost-reducing method to evaluate the effects of a certain drug, which is accessible to nearly every physician and can contribute to safe and effective personalized medicine.

Polypharmacy may result in interactions and side effects that lead to morbidity and mortality. Therefore, it is important to evaluate on a regular basis the possibility to stop medication. Sometimes it is necessary to temporarily discontinue certain medication, for example when a patient is unable to swallow or suffers from a delirium. Not all drugs can be stopped abruptly, since this can result in a rebound-effect or withdrawal symptoms Especially drugs that act on the central nervous system (e.g. psychotropic drugs, dopaminergic drugs, opioids) are known to cause (severe) withdrawal symptoms when stopped abruptly In addition, beta-blockers, corticosteroids and proton-pump inhibitors cause symptoms when stopped without tapering. Gradually tapering off these medicines is needed, sometimes under guidance from a specialist. Moreover, it is important to realize that stopping medication can also introduce interactions.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Background: Active acromegaly is characterized by Growth Hormone and Insulin-like Growth Factor (IGF)-1 excess. Voice complaints are common in active acromegaly and are suggested to be caused by effects of Growth Hormone or IGF-1 on vocal folds and the surrounding soft tissues. Prospective studies on the course of voice characteristics in acromegaly patients are scarce and results are conflicting. This study investigates objective changes in voice parameters, self-reported perception of voice and laryngostroboscopic features during the first 2.5 years of acromegaly treatment. Material and Method: In this prospective study, acoustic voice analysis (and videolaryngostroboscopic examination were performed in 27 consecutive treatment-naive acromegaly patients at diagnosis (T0), after 1 year (T1) and after 2.5 years (T2) of treatment. The voice handicap index (VHI-30) questionnaire was taken. Results: During acromegaly treatment, VHI scores decreased, and mucosal edema & hypertrophy diminished. No significant changes in objective voice parameters were detected. The within-subject change in serum IGF-1 levels (97.3 (40.6–208) to 22.4 (10.2–34.1) nmol/L (P < 0.001)) during follow-up correlated positively with the changes in VHI questionnaire scores (R 0.32–0.45; P = 0.002–0.03). Conclusions: At diagnosis and during acromegaly treatment, mean VHI scores were in the normal range, although they decreased during follow-up. Mucosal edema and hypertrophy largely resolved during treatment. No significant changes in objective voice parameters were observed. Voice characteristics are in the normal range in patients with acromegaly, but may change during treatment. However, voice complaints are important to discuss, since they may influence quality of life.

Context Transsphenoidal surgery (TSS) is the primary treatment of choice in acromegaly. It is important to identify patients in whom surgical cure is not attainable at an early stage, both to inform patients on expected treatment outcome and to select those who are more likely to need additional therapy. Objective To identify predictors for remission after TSS in acromegaly. Methods Large multicenter study with retrospective data collection from 3 tertiary neurosurgical referral centers in The Netherlands. We analyzed clinical data since 2000 from 3 cohorts (Groningen, Nijmegen, and Rotterdam, total n = 282). Multivariate regression models were used to identify predictors of early biochemical remission (12 weeks to 1 year postoperatively) according to the 2010 consensus criteria, long-term remission (age- and sex-normalized insulin-like growth factor 1 [IGF-1] and the absence of postoperative treatment until last follow-up), and relative IGF-1 and growth hormone [GH] reduction. Results A larger maximum tumor diameter (odds ratio [OR] 0.91, 95% CI 0.87-0.96, P ≤ .0001) was associated with a lower chance of early biochemical remission. A larger maximum tumor diameter (OR 0.93, 95% CI 0.89-0.97, P = .0022) and a higher random GH concentration at diagnosis (OR 0.98, 95% CI 0.96-0.99, P = .0053) were associated with a lower chance of long-term remission. Conclusion Maximum tumor diameter and random GH concentration at diagnosis are the best predictors for remission after TSS in acromegaly.

Contains fulltext : 229551.pdf (Publisher’s version ) (Open Access) Acromegaly is characterized by Growth Hormone (GH) and Insulin-like Growth Factor 1 (IGF-1) excess. Uncontrolled acromegaly is associated with a strongly increased risk of cardiovascular disease (CVD), and numerous cardiovascular risk factors remain present after remission. GH and IGF-1 have numerous effects on the immune and cardiovascular system. Since endothelial damage and systemic inflammation are strongly linked to the development of CVD, and have been suggested to be present in both controlled as uncontrolled acromegaly, they may explain the presence of both micro- and macrovascular dysfunction in these patients. In addition, these changes seem to be only partially reversible after remission, as illustrated by the often reported presence of endothelial dysfunction and microvascular damage in controlled acromegaly. Previous studies suggest that insulin resistance, oxidative stress, and endothelial dysfunction are involved in the development of CVD in acromegaly. Not surprisingly, these processes are associated with systemic inflammation and respond to GH/IGF-1 normalizing treatment.

Background Obstructive sleep apnea syndrome (OSAS) is common in active acromegaly and negatively influences quality of life, morbidity, and mortality. This prospective study with 3 predetermined timepoints and a standardized treatment protocol investigates changes in sleep parameters during the first 2.5 years of acromegaly treatment. Methods Before initiation of acromegaly treatment (medical pretreatment followed by surgery), polysomnography (PSG) was performed in 27 consecutive patients with treatment-naive acromegaly. PSG was repeated after 1 year (N = 24) and 2.5 years (N = 23), and anthropometric and biochemical parameters were obtained. Results At baseline, 74.1% of the patients was diagnosed with OSAS. The respiratory disturbance index (RDI; P = 0.001), oxygen desaturation index (ODI; P = 0.001), lowest oxygen saturation (LSaO2; P = 0.007) and the Epworth Sleepiness Scale (ESS; P < 0.001) improved significantly during treatment, with the greatest improvement in the first year. After 2.5 years of treatment, all patients had controlled acromegaly. Of the 16 patients with repeated PSG and OSAS at baseline, 11 (68.8%) were cured of OSAS. Changes in RDI, ODI, LSaO2, and ESS correlated with insulin-like growth factor 1 levels. Conclusion OSAS has a high prevalence in active acromegaly. There is a substantial decrease in prevalence and severity of OSAS following acromegaly treatment, with the largest improvement during the first year. Most patients recover from OSAS following surgical or biochemical control of the acromegaly. Therefore, a PSG is advised after diagnosis of acromegaly. When OSAS is present, it should be treated and PSG should be repeated during acromegaly treatment.

Objective Acromegaly has a negative influence on health-related quality of life (HRQoL). Previous studies provide limited information on the course of HRQoL during treatment. This study aims to assess the effect of treatment on the course of HRQoL at six predefined time points. Design This prospective study examines HRQoL in treatment-naive patients before and during the first 2.5 years of acromegaly treatment. Methods Therapy-naive acromegaly patients completed three validated questionnaires (RAND-36, AcroQoL, and the Appearance Self-Esteem (ASE)) at six predetermined time points before, during, and after treatment. Outcomes were correlated to IGF1 levels and disease control status. Results Twenty-seven acromegaly patients completed the questionnaires at all time points. After treatment, all patients had controlled acromegaly. Scores of RAND-36 domains General health, Vitality and Health change, and all AcroQoL dimensions (except for Relations) improved during treatment (P ≤ 0.003); the largest changes were detected during the first year. Gender influenced HRQoL scores, since AcroQoL scores significantly improved in males but not in females. Over time, IGF1 levels were negatively correlated with HRQoL. After 2.5 years of follow-up, HRQoL of controlled patients was still lower than in the general population. Conclusion HRQoL of acromegaly patients was considerably reduced at diagnosis. Disease control was associated with an improvement of HRQoL scores. Males showed a more pronounced improvement than females. The largest changes were detected in the first year of treatment. However, HRQoL during and after treatment remained impaired in acromegaly patients, emphasizing the need of additional support.

Contains fulltext : 187840.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Black tea is a main source of flavonoids in the Western diet and has been associated with reduced risk for cardiovascular disease, possibly through lowering blood pressure. These effects may be mediated through improving endothelial function of resistance arteries. The aim of this study was therefore to examine the acute impact of black tea on forearm resistance artery endothelial function in healthy, normotensive middle-aged subjects. METHODS: Twenty middle-aged men and women (age-range 45-75 years) were recruited into a double-blind, randomized, placebo-controlled crossover intervention study. Forearm resistance artery blood flow (FBF, measured using venous occlusion plethysmography) in response to incremental doses of acetylcholine, sodium nitroprusside and L-N(G)-monomethyl arginine were determined 2 h after consumption of either black tea containing approximately 400 mg flavonoids (equivalent to 2-3 cups of tea) or a taste- and color-matched placebo. RESULTS: The mean FBF-response to acetylcholine after tea consumption was 23% higher compared to the response after placebo (95% CI: -20%, +88%), but this difference did not reach statistical significance (P = 0.32). No significant differences in the FBF-responses to sodium nitroprusside and L-N(G)-monomethyl arginine were found between the tea and placebo interventions (P = 0.96 and 0.74, respectively). Correcting FBF for changes in blood pressure did not alter the outcomes. CONCLUSIONS: We found no evidence that acute intake of black tea significantly altered endothelium-dependent vasodilation of forearm resistance arteries in healthy middle-aged subjects. Interventions with a longer duration of tea ingestion are required to further explore the (long-term) impact of tea flavonoids on blood pressure regulatory mechanisms. This trial was registered at clinicaltrials.gov as NCT02328339. 01 februari 2018

Objective Acromegaly is characterized by an excess of growth hormone (GH) and insulin-like growth factor 1 (IGF1). Cardiovascular disease (CVD) risk factors are common in acromegaly and often persist after treatment. Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Therefore, we hypothesized that inflammation persists in treated acromegaly and may contribute to CVD risk. Methods In this cross-sectional study, we assessed cardiovascular structure and function, and inflammatory parameters in treated acromegaly patients. Immune cell populations and inflammatory markers were assessed in peripheral blood from 71 treated acromegaly patients (with controlled or uncontrolled disease) and 41 matched controls. Whole blood (WB) was stimulated with Toll-like receptor ligands. In a subgroup of 21 controls and 33 patients with controlled disease, vascular ultrasound measurements were performed. Results Leukocyte counts were lower in patients with controlled acromegaly compared to patients with uncontrolled acromegaly and controls. Circulating IL18 concentrations were lower in patients; concentrations of other inflammatory mediators were comparable with controls. In stimulated WB, cytokine production was skewed toward inflammation in patients, most pronounced in those with uncontrolled disease. Vascular measurements in controlled patients showed endothelial dysfunction as indicated by a lower flow-mediated dilatation/nitroglycerine-mediated dilatation ratio. Surprisingly, pulse wave analysis and pulse wave velocity, both markers of endothelial dysfunction, were lower in patients, whereas intima-media thickness did not differ. Conclusions Despite treatment, acromegaly patients display persistent inflammatory changes and endothelial dysfunction, which may contribute to CVD risk and development of CVD.

Acromegaly is characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF1) excess and is accompanied by an increased cardiovascular diseases (CVD) risk. As innate immune responses are crucial in CVD development, and IGF1 is linked to subclinical inflammation, we hypothesized that GH/IGF1 excess contributes to CVD development by potentiating systemic inflammation. We aimed to assess the effects of GH/IGF1 on inflammatory cytokine production. Whole blood from acromegaly patients and healthy volunteers and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were stimulated with Toll-like receptor (TLR) ligands, with or without adding GH or IGF1 (in PBMC). Cytokine concentrations were measured by ELISA. The underlying signalling pathways were investigated by the inhibition of downstream targets of the IGF1 receptor. The following results were obtained. GH or IGF1 alone did not influence cytokine production in PBMCs. GH did not affect TLR-induced cytokine production, but co-stimulation with IGF1 dose dependently increased the TLR ligand-induced production of IL6 (P P = 0.02) and IFNg (P P = 0.01). IGF1 had no effect on IL1B, IL17 and IL22 production. Inhibition of the MAPK pathway, but not mTOR, completely abrogated the synergistic effect of IGF1 on the LPS-induced IL6 and TNF alpha production. In whole blood of acromegaly patients,ex vivoIL6 production was increased (P