Background The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of... Show moreBackground The gut-derived metabolite Trimethylamine N-oxide (TMAO) and its precursors - betaine, carnitine, choline, and deoxycarnitine – have been associated with an increased risk of cardiovascular disease, but their relation to cognition, neuroimaging markers, and dementia remains uncertain. Methods In the population-based Rotterdam Study, we used multivariable regression models to study the associations between plasma TMAO, its precursors, and cognition in 3,143 participants. Subsequently, we examined their link to structural brain MRI markers in 2,047 participants, with a partial validation in the Leiden Longevity Study (n=318). Among 2,517 participants, we assessed the risk of incident dementia using multivariable Cox proportional hazard models. Following this, we stratified the longitudinal associations by medication use and sex, after which we conducted a sensitivity analysis for individuals with impaired renal function. Results Overall, plasma TMAO was not associated with cognition, neuroimaging markers or incident dementia. Instead, higher plasma choline was significantly associated with poor cognition (adjusted mean difference: -0.170 [95% confidence interval (CI) -0.297;-0.043]), brain atrophy and more markers of cerebral small vessel disease, such as white matter hyperintensity volume (0.237 [95% CI: 0.076;0.397]). By contrast, higher carnitine concurred with lower white matter hyperintensity volume (-0.177 [95% CI: -0.343;-0.010]). Only among individuals with impaired renal function, TMAO appeared to increase risk of dementia (hazard ratio (HR): 1.73 [95% CI: 1.16;2.60]). No notable differences were observed in stratified analyses. Conclusions Plasma choline, as opposed to TMAO, was found to be associated with cognitive decline, brain atrophy, and markers of cerebral small vessel disease. These findings illustrate the complexity of relationships between TMAO and its precursors, and emphasize the need for concurrent study to elucidate gut-brain mechanisms. Show less
In this dissertation, new immune and targeted therapies for advanced melanoma were investigated in daily practice in the Netherlands.From 2013 to 2017, new treatments were implemented fast and save... Show moreIn this dissertation, new immune and targeted therapies for advanced melanoma were investigated in daily practice in the Netherlands.From 2013 to 2017, new treatments were implemented fast and save with an increase of median survival. Increased LDH, distance metastases in ≥3 organsites, brain and liver metastases and ECOG performance score were associated with death. Survival of advanced mucosal melanoma lagged behind. Forty percent of patients receiving systemic treatment did not meet ≥1 selection criteria of clinical trials. In these patients, LDH was the most important prognostic factor, followed by the ECOG performance score and brain metastases. For anti-PD-1 antibody monotherapy, a median survival of 24 months was observed. A complete response or a shorter time to the first response were associated with disease controle when anti-PD-1 montherapy was discontinued in the absence of progression. Half of the patients treated with anti-CTLA-4 plus anti-PD-1 antibodies had a grade 3-4 adverse event, requiering hospital admission in 50%. On the other hand, 37% of patients reached disease control after 2 years, with a median survival of 28.7 months. This dissertation emphasizes that with new treatments there is an "knowledge-gap" between the clinical trials and real-world that should be bridged with real-world data. Show less
Due to a shorter remaining life expectancy, the risk of recurrence in older patients with low risk breast cancer is often reduced and the benefit of treatments may be very limited, especially with... Show moreDue to a shorter remaining life expectancy, the risk of recurrence in older patients with low risk breast cancer is often reduced and the benefit of treatments may be very limited, especially with adjuvant treatments. In the first part of this thesis, we studied the interplay between breast cancer mortality and other-cause mortality. In the second part of this thesis, we investigated the effect of surgery and radiotherapy in subsets of the older population of patients with breast cancer in which the actual treatment effect is questionable. Show less
Winkelman, J.A.; Woude, L. van der; Heineman, D.J.; Bahce, I.; Damhuis, R.A.; Mahtab, E.A.F.; ... ; Dickhoff, C. 2021
Objectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with... Show moreObjectives: Data on national patterns of care for patients with superior sulcus tumors (SST) is currently lacking. We investigated the distribution of surgical care and outcome for patients with SST in the Netherlands. Material and methods: Data was retrieved from the Dutch Lung Cancer Audit for Surgery (DLCA-S) for all patients undergoing resection for clinical stage IIB-IV SST from 2012 to 2019. Because DLCA-S is not linked to survival data, survival for a separate cohort (2015-2017) was obtained from the Netherlands Cancer Registry (NCR). Results: In the study period, 181 patients had SST surgery, representing 1.03% (181/17488) of all lung cancer pulmonary resections. For 2015-2017, the SST resection rate was 14.4% (79/549), and patients with stage IIB/III SST treated with trimodality had a 3-year overall survival of 67.4%. 63.5% of patients were male, and median age was 60 years. Almost 3/4 of tumors were right sided. Surgery was performed in 20 hospitals, with average number of annual resections ranging from < 1 (n = 17) to 9 (n = 1). 39.8% of resections were performed in 1 center and 63.5% in the 3 most active centers. 12.7% of resections were extended (e.g. vertebral resection). 85.1% of resections were complete (R0). Morbidity and 30-day mortality were 51.4% and 3.3% respectively. Despite treating patients with a higher ECOG performance score and more extended resections, the highest volume center had rates of morbidity/mortality, and length of hospital stay that were comparable to those of the medium volume (n = 2) and low-volume centers (n = 1). Conclusion: In the Netherlands, surgery for SST accounts for about 1% of all lung cancer pulmonary resections, the number of SST resections/hospital/year varies widely, with most centers performing an average of < 1/year. Morbidity and mortality are acceptable and survival compares favourably with the literature. Although further centralisation is possible, it is unknown whether this will improve outcomes. Show less
Akpinar, E.O.; Liem, R.S.L.; Nienhuijs, S.W.; Greve, J.W.M.; Marang-van de Mheen, P.J.; Dutch Audit Treatment Obesity Res 2021
Background: Bariatric surgery among patients with obesity and type 2 diabetes (T2D) can induce complete remission. However, it remains unclear whether sleeve gastrectomy (SG) or Roux-en-Y gastric... Show moreBackground: Bariatric surgery among patients with obesity and type 2 diabetes (T2D) can induce complete remission. However, it remains unclear whether sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) has better T2D remission within a population-based daily practice.Objectives: To compare patients undergoing RYGB and SG on the extent of T2D remission at the 1-year follow-up.Setting: Nationwide, population-based study including all 18 hospitals in the Netherlands providing metabolic and bariatric surgery.Methods: Patients undergoing RYGB and SG between October 2015 and October 2018 with 1 year of complete follow-up data were selected from the mandatory nationwide Dutch Audit for Treatment of Obesity (DATO). The primary outcome is T2D remission within 1 year. Secondary outcomes include >= 20% total weight loss (TWL), obesity-related co-morbidity reduction, and postoperative complications with a Clavien-Dindo (CD) grade >= III within 30 days. We compared T2D remission between RYGB and SG groups using propensity score matching to adjust for confounding by indication.Results: A total of 5015 patients were identified from the DATO, and 4132 (82.4%) had completed a 1-year follow-up visit. There were 3350 (66.8%) patients with a valid T2D status who were included in the analysis (RYGB = 2623; SG = 727). RYGB patients had a lower body mass index than SG patients, but were more often female, with higher gastroesophageal reflux disease and dyslipidemia rates. After adjusting for these confounders, RYGB patients had increased odds of achieving T2D remission (odds ratio [OR], 1.54; 95% confidence interval [CI], 1.14-2.1; P<.01). Groups were balanced after matching 695 patients in each group. After matching, RYGB patients still had better odds of T2D remission (OR, 1.91; 95% CI, 1.27-2.88; P<.01). Also, significantly more RYGB patients had >= 20%TWL (OR, 2.71; 95% CI, 1.96-3.75; P<.01) and RYGB patients had higher dyslipidemia remission rates (OR, 1.96; 95% CI, 1.39-2.76; P<.01). There were no significant differences in CD >= III complications.Conclusion: Using population-based data from the Netherlands, this study shows that RYGB leads to better T2D remission rates at the 1-year follow-up and better metabolic outcomes for patients with obesity and T2D undergoing bariatric surgery in daily practice. (C) 2021 American Society for Bariatric Surgery. Published by Elsevier Inc. Show less
Background The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific... Show moreBackground The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer. Methods Women included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2-17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression. Results Incidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p < 0.05). DCIS was less likely to be treated within 3 months (odds ratio [OR](wks2-8): 2.04, ORwks9-11: 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (ORwks12-13: 0.52) or by breast conserving surgery (ORwks14-17: 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (ORwks9-11: 0.59, ORwks12-13: 0.66), but more likely for those diagnosed at the end (ORwks14-17: 1.31). Primary hormonal treatment was more common (ORwks2-8: 1.23, ORwks9-11: 1.92, ORwks12-13: 3.01). Only women diagnosed in weeks 2-8 of 2020 experienced treatment delays. Conclusion The incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes. Show less
Akpinar, E.O.; Marang- Van de Mheen, P.J.; Nienhuijs, S.W.; Greve, J.W.M.; Liem, R.S.L. 2021
Introduction Pooling population-based data from all national bariatric registries may provide international real-world evidence for outcomes that will help establish a universal standard of care,... Show moreIntroduction Pooling population-based data from all national bariatric registries may provide international real-world evidence for outcomes that will help establish a universal standard of care, provided that the same variables and definitions are used. Therefore, this study aims to assess the concordance of variables across national registries to identify which outcomes can be used for international collaborations. Methods All 18 countries with a national bariatric registry who contributed to The International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Global Registry report 2019 were requested to share their data dictionary by email. The primary outcome was the percentage of perfect agreement for variables by domain: patient, prior bariatric history, screening, operation, complication, and follow-up. Perfect agreement was defined as 100% concordance, meaning that the variable was registered with the same definition across all registries. Secondary outcomes were defined as variables having "substantial agreement" (75-99.9%) and "moderate agreement" (50-74.9%) across registries. Results Eleven registries responded and had a total of 2585 recorded variables that were grouped into 250 variables measuring the same concept. A total of 25 (10%) variables have a perfect agreement across all domains: 3 (18.75%) for the patient domain, 0 (0.0%) for prior bariatric history, 5 (8.2%) for screening, 6 (11.8%) for operation, 5 (8.8%) for complications, and 6 (11.8%) for follow-up. Furthermore, 28 (11.2%) variables have substantial agreement and 59 (23.6%) variables have moderate agreement across registries. Conclusion There is limited uniform agreement in variables across national bariatric registries. Further alignment and uniformity in collected variables are required to enable future international collaborations and comparison. Show less
Previous studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations... Show morePrevious studies have shown that schizophrenia polygenic risk predicts a multitude of mental health problems in the general population. Yet it is unclear by which mechanisms these associations arise. Here, we explored a possible gene-environment correlation in the association of schizophrenia polygenic risk with mental health problems via childhood adversity. This study was embedded in the population-based Generation R Study, including N = 1901 participants with genotyping for schizophrenia polygenic risk, maternal reporting of childhood adversity, and Child Behaviour Checklist measurement of mental health problems. Independent replication was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3641). Associations were analysed with Poisson regression and statistical mediation analysis. Higher burden of schizophrenia polygenic risk was associated with greater exposure to childhood adversity (P-value threshold < 0.5: Generation R Study, OR = 1.08, 95%CI 1.02-1.15, P = 0.01; ALSPAC, OR = 1.02, 95%CI 1.01-1.03, P < 0.01). Childhood adversities partly explained the relationship of schizophrenia polygenic risk with emotional, attention, and thought problems (proportion explained, range 5-23%). Direct effects of schizophrenia polygenic risk and adversity on mental health outcomes were also observed. In summary, genetic liability to schizophrenia increased the risk for mental health problems in the general paediatric population through childhood adversity. Although this finding could result from a mediated causal relationship between genotype and mental health, we argue that these observations most likely reflect a gene-environment correlation, i.e. adversities are a marker for the genetic risk that parents transmit to children. These and similar recent findings raise important conceptual questions about preventative interventions aimed at reducing childhood adversities. Show less
Background: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice... Show moreBackground: The treatment landscape has completely changed for advanced melanoma. We report survival outcomes and the differential impact of prognostic factors over time in daily clinical practice.Methods: From a Dutch nationwide population-based registry, patients with advanced melanoma diagnosed from 2013 to 2017 were analysed (n = 3616). Because the proportional hazards assumption was violated, a multivariable Cox model restricted to the first 6 months and a multivariable landmark Cox model from 6 to 48 months were used to assess overall survival (OS) of cases without missing values. The 2017 cohort was excluded from this analysis because of the short follow-up time.Results: Median OS of the 2013 and 2016 cohort was 11.7 months (95% confidence interval [CI]: 10.4-13.5) and 17.7 months (95% CI: 14.9-19.8), respectively. Compared with the 2013 cohort, the 2016 cohort had superior survival in the Cox model from 0 to 6 months (hazard ratio [HR] = 0.55 [95% CI: 0.43-0.72]) and in the Cox model from 6 to 48 months (HR = 0.68 [95% CI: 0.57-0.83]). Elevated lactate dehydrogenase levels, distant metastases in >= 3 organ sites, brain and liver metastasis and Eastern Cooperative Oncology Group performance score of >= 1 had stronger association with inferior survival from 0 to 6 months than from 6 to 48 months. BRAF-mutated melanoma had superior survival in the first 6 months (HR = 0.50 [95% CI: 0.42-0.59]).Conclusion(s): Prognosis for advanced melanoma in the Netherlands has improved from 2013 to 2016. Prognostic importance of most evaluated factors was higher in the first 6 months after diagnosis. BRAF-mutated melanoma was only associated with superior survival in the first 6 months. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Purpose Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy... Show morePurpose Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries. Methods A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries. Results BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p < 0.001) was observed in the Netherlands. In both countries, variation in BCP rates between hospitals decreased over time. NAC followed by BCT and postmastectomy IBR was substantially more often used in the Netherlands compared to Denmark, specifically in patients younger than 50 years. Conclusions In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities. Show less
Abdollahpour, I.; Mooijaart, S.; Aguilar-Palacio, I.; Salimi, Y.; Nedjat, S.; Mansournia, M.A.; Courten, M. de 2019
Background: There is little evidence comparing the role of subjective versus objective indicators of socioeconomic status (SES) on individuals' self-rated health (SRH) in Iran.Objectives: We aimed... Show moreBackground: There is little evidence comparing the role of subjective versus objective indicators of socioeconomic status (SES) on individuals' self-rated health (SRH) in Iran.Objectives: We aimed to investigate underlying predictors of SRH including subjective and objective SES in Tehran, a multi-ethnic city.Method: This is an analysis of cross-sectional survey data on subjective and objective SES from a population-based case-control study conducted in Tehran, Iran (2015). We used random digit dialing for study sample recruitment. Linear regression models were used for estimating crude and adjusted coefficients (95% confidence intervals). Age, gender, SES as well as cigarette smoking were included as confounders.Results: 15-50 years old residents of Tehran were recruited in the study (n = 1057). High reported objective and subjective SES was consistently associated with a better SRH. Subjective current SES (p < .001), subjective adolescence SES (p = .018), change in subjective SES (current vs. adolescent) (p = .034) and participants' education years (p < .001). Improvements over time in current SES in comparison to SES rated during adolescence increased the participants' SRH after adjustment for potential confounders (coefficient = 0.170, 95% CI: (0.015, 0.325)). Female participants (coefficient = -0.305, 95% CI: (-0.418, -0.192)) and smokers (high category vs. never smokers) (coefficient = -0.456, 95% CI: (-0.714, -0.197)) reported significantly worse SRH. Increasing age - 0.008 (95% CI: -0.014, -0.002) was associated with decreased SRH.Conclusion: High subjective and objective SES consistently was the most important predictor of high SRH. Show less
Structural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are... Show moreStructural brain markers are studied extensively in the field of neurodegeneration, but are thought to occur rather late in the process. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain structure and function are also affected by ‘normal’ brain ageing. More information is needed on how functional connectivity relates to aging, particularly in the absence of overt neurodegenerative disease. We investigated the association of age with resting-state functional connectivity in 2878 non-demented persons between 50 and 95 years of age (54.1% women) from the population-based Rotterdam Study. We obtained nine well-known resting state networks using data-driven methodology. Within the anterior default mode network, ventral attention network, and sensorimotor network, functional connectivity was significantly lower with older age. In contrast, functional connectivity was higher with older age within the visual network. Between resting state networks, we found patterns of both increases and decreases in connectivity in approximate equal proportions. Our results reinforce the notion that the aging brain undergoes a reorganization process, and serves as a solid basis for exploring functional connectivity as a preclinical marker of neurodegenerative disease. Show less
