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Mara van Osch,1 AJM Rövekamp,2 Stephanie N Bergman-Agteres,1 Liselotte W Wijsman,3,4 Sharon J Ooms,5 Simon P Mooijaart,3,4,6 Joan Vermeulen71Netherlands Institute for Health Services Research, Utrecht, 2Netherlands Organization for Applied Scientific Research, 3Department of Gerontology and Geriatrics, Leiden University Medical Centre, 4Netherlands Consortium for Healthy Ageing, Leiden, 5Department of Geriatric Medicine, Radboud Alzheimer Centre, Radboud University Nijmegen Medical Centre, Nijmegen, 6Institute for Evidence-Based Medicine in Old Age, Leiden, 7Research School, CAPHRI, Maastricht University, Maastricht, the NetherlandsBackground: The iVitality online research platform has been developed to gain insight into the relationship between early risk factors (ie, poorly controlled hypertension, physical or mental inactivity) and onset and possibly prevention of dementia. iVitality consists of a website, a smartphone application, and sensors that can monitor these indicators at home. Before iVitality can be implemented, it should fit the needs and preferences of users, ie, offspring of patients with dementia. This study aimed to explore users’ motivation to participate in home-based health monitoring research, to formulate requirements based on users’ preferences to optimize iVitality, and to test usability of the smartphone application of iVitality.Methods: We recruited 13 participants (aged 42–64 years, 85% female), who were offspring of patients with dementia. A user-centered methodology consisting of four iterative phases was used. Three semistructured interviews provided insight into motivation and acceptance of using iVitality (phase 1). A focus group with six participants elaborated on expectations and preferences regarding iVitality (phase 2). Findings from phase 1 and 2 were triangulated by two semistructured interviews (phase 3). Four participants assessed the usability of the smartphone application (phase 4) using a think aloud procedure and a questionnaire measuring ease and efficiency of use (scale 1–7; higher scores indicated better usability).Results: All participants were highly motivated to contribute to dementia research. However, the frequency of home-based health monitoring should not be too high. Participants preferred to receive feedback about their measurements and information regarding the relationship between these measurements and dementia. Despite minor technical errors, iVitality was considered easy and efficient to use (mean score 5.50, standard deviation 1.71).Conclusion: Offspring of patients with dementia are motivated to contribute to home-based monitoring research by using iVitality and are able to use the smartphone application. The formulated requirements will be embedded to optimize iVitality.Keywords: e-health, m-health, technology, patient preferences, dementia, self-monitoring, usability

Introduction: To balance benefits and risks of cancer treatment in older patients, prognostic information is needed. The Glasgow Prognostic Score (GPS), composed of albumin and C-reactive protein (CRP), might provide such information. This study first aims to investigate the association between GPS and frailty, functional decline, and health-related quality of life (HRQoL) decline as indicators of health problems in older patients with cancer. The second aim is to study the predictive value of GPS for mortality, in addition to clinical predictors., Materials and Methods: This prospective cohort study included patients aged ≥70 years with a solid malignant tumor who underwent a geriatric assessment and blood sampling before treatment initiation. GPS was calculated using serum albumin and CRP measured in batch, categorized into normal (0) and abnormal GPS (1-2). Outcomes were all-cause mortality and a composite outcome of decline in daily functioning and/or HRQoL, or mortality at one year follow-up. Daily functioning was assessed by Activities of Daily Living and Instrumental Activities of Daily Living questionnaires and HRQoL by the EQ-5D-3L and EQ-VAS questionnaires., Results: In total, 192 patients with a median age of 77 years (interquartile range 72.3-81.0) were included. Patients with abnormal GPS were more often frail compared to those with normal GPS (79 % vs. 63 %, p = 0.03). Patients with abnormal GPS had higher mortality rates after one year compared to those with normal GPS (48 % vs. 23 %, p < 0.01) in unadjusted analysis. Abnormal GPS was associated with increased mortality risk (hazard ratio 2.8, 95 % CI 1.7-4.8). The area under the receiver operating characteristics curve of age, distant metastasis, tumor site, comorbidity, and malnutrition combined was 0.73 (0.68-0.83) for mortality prediction, and changed to 0.78 (0.73-0.86) with GPS (p = 0.10). The composite outcome occurred in 88 % of patients with abnormal GPS versus 83 % with normal GPS (p = 0.44)., Discussion: Abnormal GPS was associated with frailty and mortality. The addition of GPS to clinical predictors showed a numerically superior mortality prediction in this cohort of older patients with cancer, although not statistically significant. While GPS may improve the stratification of future older patients with cancer, larger studies including older patients with similar tumor types are necessary to evaluate its clinical usefulness., Trial Registration: The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019., Competing Interests: Declaration of Competing Interest The authors have no conflicts., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Managing older patients with acute pulmonary embolism (PE) is challenging due to their underrepresentation in clinical trials, comorbidities and increased complication risk. This study evaluates risk assessment and management outcomes in older PE patients focussing on home and reperfusion treatment., Methods: A retrospective analysis was conducted on patients aged ≥70 years diagnosed with acute PE at an academic medical centre (2015-2022)., Results: 242 patients with a mean age of 77 years were included. All 59 patients with negative Hestia criteria were discharged ≤24h, and in total 81 patients (35%) received home treatment. Among these 14-day mortality and recurrent venous-thromboembolism were 0% and major bleeding occurred in 1.3% (one patient, 95%CI 0.11-6.1). European Society of Cardiology (ESC) risk-classification showed 9 low-risk PE (3.9%), 199 intermediate-risk (87%), and 20 high-risk PE patients (8.8). In 5 of the 20 high-risk patients, hypotension was mainly caused by another condition, i.e. sepsis. Eight high-risk patients received reperfusion therapy. Fourteen-day mortality was 51% in high-risk patients (95%CI 27-71); 5 out of 8 patients receiving reperfusion treatment died within 5 days. Patients with an Acute Presenting Older Patient (APOP) score of ≥45% had higher 14-day mortality (28%; 95%CI 12-46) compared to <45% (3.2%; 95%CI 0.85-8.3; HR 10.2; 95%CI 2.6-39)., Conclusion: Selecting for home treatment using Hestia was safe for older PE patients in our cohort. Mortality in the high-risk group was high also when receiving reperfusion treatment. The ESC risk-classification and APOP score identified patients at higher mortality risk, suggesting their potential utility in clinical decision-making., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Older people living with frailty are frequent users of emergency care and have multiple and complex problems. Typical evidence-based guidelines and protocols provide guidance for the management of single and simple acute issues. Meanwhile, person-centred care orientates interventions around the perspectives of the individual. Using a case vignette, we illustrate the potential pitfalls of applying exclusively either evidence-based or person-centred care in isolation, as this may trigger inappropriate clinical processes or place undue onus on patients and families. We instead advocate for delivering a combined evidence-based, person-centred approach to healthcare which considers the person's situation and values, apparent problem and available options., Competing Interests: Competing interests: The authors declare holding or having held voluntary leadership roles in geriatric emergency medicine special interest groups in Europe: European Society of Emergency Medicine (JvO, PH, JAL) and European Geriatric Medicine Society (SM, SC); North America: Geriatric Emergency Department Collaborative (DM) and Society for Academic Emergency Medicine (SWL, TR); and internationally: International Federation for Emergency Medicine (CH, RM, DM)., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The 1-HMR metabolomics-based MetaboHealth score, comprised of 14 serum metabolic markers, associates with disease-specific mortality, but it is unclear whether the score also reflects cognitive changes and functional impairment. We aimed to assess the associations between the MetaboHealth score with cognitive function and functional decline in older adults at increased cardiovascular risk. A total of 5292 older adults free of dementia at baseline with mean age 75.3 years (SD = 3.4) from the Prospective Study of Pravastatin in the Elderly (PROSPER). MetaboHealth score were measured at baseline, and cognitive function and functional independence were measured at baseline and every 3 months during up to 2.5 years follow-up. Cognitive function was assessed using the Stroop test (selective attention), the Letter Digit Coding test (LDCT) (processing speed), and the two versions of the Picture Learning test (delayed and immediate; memory). Two tests of functional independence were used: Barthel Index (BI) and instrumental activities at daily living (IADL). A higher MetaboHealth score was associated with worse cognitive function (in all domains) and with worse functional independence. For example, after full adjustments, a 1-SD higher MetaboHealth score was associated with 9.02 s (95%CI 7.29, 10.75) slower performance on the Stroop test and 2.79 (2.21, 3.26) less digits coded on the LDCT. During follow-up, 1-SD higher MetaboHealth score was associated with an additional decline of 0.53 s (0.23, 0.83) on the Stroop test and - 0.08 (- 0.11, - 0.06) points on the IADL. Metabolic disturbance, as reflected by an increased metabolomics-based health score, may mark future cognitive and functional decline., (© 2024. The Author(s).)

Background: Despite uncertain benefit-risk profile near the end of life, antithrombotic therapy (ATT) is prevalent in patients with terminal cancer., Objectives: To examine adherence and persistence with ATT in terminally ill cancer patients and investigate risks of major and clinically relevant bleeding, venous thromboembolism (VTE), and arterial thromboembolism (ATE) by ATT exposure., Methods: Using a Danish nationwide cohort of terminal cancer patients, ATT adherence in the year following terminal illness declaration was measured by the proportion of days covered (PDC) by prescription. Discontinuation was defined as a treatment gap of ≥30 days between prescription renewals. One-year cumulative incidences of bleeding complications, VTE, and ATE were calculated, considering the competing risk of death., Results: During 2013-2022, 86 732 terminally ill cancer patients were identified (median age, 75 years; 47% female; median survival, 57 days). At terminal illness declaration, 37.5% were receiving ATT (66.6% platelet inhibitors, 23.0% direct oral anticoagulants, and 10.4% vitamin K antagonists [VKAs]). The mean PDC with ATT was 88% (SD, 30%), highest among platelet inhibitor users (mean PDC, 89%) and lowest among VKA users (73%). One-year ATT discontinuation incidence was 7.9% (95% CI, 7.7%-8.1%). Most patients continued ATT until death (74.8% platelet inhibitors, 58.8% direct oral anticoagulants, and 61.6% VKAs). Patients receiving ATT had a lower 1-year VTE risk but higher risks of ATE and major bleeding., Conclusion: Despite uncertain benefit-risk profile, most terminally ill cancer patients continue ATT until the end of life. These findings provide insights into current ATT utilization and discontinuation dynamics in the challenging context of terminal illness., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Impaired cognition, poor health-related quality of life (HRQoL) and depressive symptoms are common in older patients with kidney failure. Understanding what influences HRQoL is important, as older patients regard HRQoL as a health priority. This study examines whether cognitive functioning is associated with HRQoL and whether depressive symptoms mediate this effect in older patients with kidney failure., Methods: Outpatients aged ≥ 65 years from 35 Dutch and Belgian hospitals with eGFR 20-10 mL/min/1.73 m 2 were included from the ongoing DIALOGICA study. Cognitive functioning was assessed using the Montreal Cognitive Assessment. Depressive symptoms were screened with 2 Whooley Questions and thereafter assessed with the 15-item Geriatric Depression Scale. HRQoL was assessed using the 12-item Short-Form Health Survey. To assess whether cognitive functioning is associated with HRQoL, cross-sectional multivariable linear regression analyses were performed. Subsequent mediation analyses were performed with PROCESS using the product method., Results: In total, 403 patients were included, with a mean age of 76.5 years (SD 5.8) and estimated glomerular filtration rate (eGFR) of 14.5 mL/min/1.73 m 2 (SD 3.0). Cognitive functioning was associated with mental HRQoL (adjusted β 0.30, 95% CI 0.05;0.55) but not physical HRQoL (adjusted β 0.18, 95% CI -0.09;0.44). This effect is mediated by depressive symptoms (adjusted β 0.14, 95% CI 0.04;0.25)., Conclusion: Lower cognitive functioning was negatively associated with mental HRQoL, which was mediated by depressive symptoms in older patients with kidney failure. Future research should explore whether cognitive interventions and treatment of depression improve HRQoL in this vulnerable patient population., (© 2024. The Author(s).)

Background: No previous study has investigated fatigue in older patients with Inflammatory Bowel Disease (IBD)., Aims: To describe the prevalence of fatigue in older patients and compare it to the prevalence in younger patients with IBD, and to determine factors associated with fatigue., Methods: A prospective, multicenter cohort study, including older- (≥ 65 years) and younger patients with IBD (18-64 years). A geriatric assessment was performed in older patients to measure deficits in geriatric assessment (DiG). Fatigue was defined by one item from the short Inflammatory Bowel Disease Questionnaire. Active disease was defined as the presence of clinical or biochemical disease activity., Results: Fatigue prevalence in the 405 older patients varied between 45.4% (71/155) in active disease to 23.6% (60/250) in remission. Fatigue prevalence in 155 younger patients was 59.5% (47/79) and 57.4% (89/155), respectively. Female sex, clinical disease activity, use of immunomodulators and presence of DiG were associated with fatigue in older patients with IBD., Conclusions: Fatigue prevalence is lower in older patients with IBD compared to younger patients with IBD, but increases when active disease is present. Clinicians should be aware that fatigue is a relevant symptom in older patients with IBD, as it is associated with DiG., Competing Interests: Conflict of Interest The authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The Value-Based Health Care (VBHC) model of care provides insights into patient characteristics, outcomes, and costs of care delivery that help clinicians counsel patients. This study compares the allocation and value of curative oncological treatment in frail and fit older patients with esophageal cancer in a dedicated VBHC pathway., Materials and Methods: Data was collected from patients with primary esophageal cancer without distant metastases, aged 70 years or older, and treated at a Dutch tertiary care hospital between 2015 and 2019. Geriatric assessment (GA) was performed. Outcomes included treatment discontinuation, mortality, quality of life (QoL), and physical functioning over a one-year period. Direct hospital costs were estimated using activity-based costing., Results: In this study, 89 patients were included with mean age 75 years. Of 56 patients completing GA, 19 were classified as frail and 37 as fit. For frail patients, the treatment plan was chemoradiotherapy and surgery (CRT&S) in 68% (13/19) and definitive chemoradiotherapy (dCRT) in 32% (6/19); for fit patients, CRT&S in 84% (31/37) and dCRT in 16% (6/37). Frail patients discontinued chemotherapy more often than fit patients (26% (5/19) vs 11% (4/37), p = 0.03) and reported lower QoL after six months (mean 0.58 [standard deviation (SD) 0.35] vs 0.88 [0.25], p < 0.05). After one year, 11% of frail and 30% of fit patients reported no decline in physical functioning and QoL and survived. Frail and fit patients had comparable mean direct hospital costs (€24 K [SD €13 K] vs €23 K [SD €8 K], p = 0.82)., Discussion: The value of curative oncological treatment was lower for frail than for fit patients because of slightly worse outcomes and comparable costs. The utility of the VBHC model of care depends on the availability of sufficient data. Real-world evidence in VBHC can be used to inform treatment decisions and optimization in future patients by sharing results and monitoring performance over time., Trial Registration: The study was retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107 (date of registration: 22-10-2019)., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59-3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01-1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56-0.75) and 0.60 (0.51-0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68-0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74-0.87) (p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69-0.83) (p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019., (© 2024. The Author(s).)

Introduction: Treating older adults with chemotherapy remains a challenge, given their under-representation in clinical trials and the lack of robust treatment guidelines for this population. Moreover, older patients, especially those with frailty, have an increased risk of developing chemotherapy-related toxicity, resulting in a decreased quality of life (QoL), increased hospitalisations and high healthcare costs. Phase II trials have suggested that upfront dose reduction of chemotherapy can reduce toxicity rates while maintaining efficacy, leading to fewer treatment discontinuations and an improved QoL. The DOSAGE aims to show that upfront dose-reduced chemotherapy in older patients with metastatic colorectal cancer is non-inferior to full-dose treatment in terms of progression-free survival (PFS), with adaption of the treatment plan (monotherapy or doublet chemotherapy) based on expected risk of treatment toxicity., Methods and Analysis: The DOSAGE study is an investigator-initiated phase III, open-label, non-inferiority, randomised controlled trial in patients aged≥70 years with metastatic colorectal cancer eligible for palliative chemotherapy. Based on toxicity risk, assessed using the Geriatric 8 (G8) tool, patients will be stratified to either doublet chemotherapy (fluoropyrimidine with oxaliplatin) or fluoropyrimidine monotherapy. Patients classified as low risk will be randomised between a fluoropyrimidine plus oxaliplatin in either full-dose or with an upfront dose reduction of 25%. Patients classified as high risk will be randomised between fluoropyrimidine monotherapy in either full-dose or with an upfront dose reduction. In the dose-reduced arm, dose escalation after two cycles is allowed. The primary outcome is PFS. Secondary endpoints include grade≥3 toxicity, QoL, physical functioning, number of treatment cycles, dose reductions, hospital admissions, overall survival, cumulative received dosage and cost-effectiveness. Considering a median PFS of 8 months and non-inferiority margin of 8 weeks, we shall include 587 patients. The study will be enrolled in 36 Dutch Hospitals, with enrolment scheduled to start in July 2024. This study will provide new evidence regarding the effect of dose-reduced chemotherapy on survival and treatment outcomes, as well as the use of the G8 to choose between doublet chemotherapy or monotherapy. Results will contribute to a more individualised approach in older patients with metastatic colorectal cancer, potentially leading to improved QoL while maintaining survival benefits., Ethics and Dissemination: This trial has received ethical approval by the ethical committee Leiden Den Haag Delft (P24.018) and will be approved by the Institutional Ethical Committee of the participating institutions. The results will be disseminated in peer-reviewed scientific journals., Trial Registration Number: NCT06275958., Competing Interests: Competing interests: MS reports serving on advisory boards of Bristol-Myers Squibb, Eli Lilly & Company and AstraZeneca outside the submitted work. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Purpose: The aim of the present study was to investigate characteristics and outcomes in vaccinated and unvaccinated older patients hospitalized for COVID-19 infection., Methods: A retrospective multicentre cohort study among patients aged ≥70 years hospitalized for COVID-19 infection., Results: 263 vaccinated and 82 unvaccinated patients were included. Vaccinated patients were older (median age 79 vs. 76 years; p < 0.001), more patients were male (66.2% vs. 53.7%; p = 0.040), had more comorbidities [median Charlson Comorbidity Index (CCI) 2 vs. 1; p 0.016] and were frailer [Clinical Frailty Scale (CFS) ≥ 4 68% vs. 49%; p 0.015]. Vaccinated patients were admitted earlier after symptom onset (median 5 days vs. 7 days) but were equally ill at time of hospital admission. After correction for frailty, comorbidity and disease severity, risk of in-hospital mortality was three times lower for vaccinated patients (HR 0.30 95% CI 0.16-0.56; p < 0.001) compared to unvaccinated patients., Conclusion: Vaccinated patients had lower risk of in-hospital mortality than unvaccinated patients with COVID-19 infection. These findings suggest that vaccinated patients benefit from the protective effect of the vaccine against death during hospital stay, outweighing the increased mortality risk that is associated with older age, greater frailty and more numerous comorbidities. This could be an encouragement for older people to receive age-appropriate vaccines, although no definite conclusions can be drawn for this was no intervention study., (© 2024. The Author(s).)

Purpose: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19., Methods: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex., Results: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74)., Conclusions: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics., (© 2024. The Author(s).)

Background: The prevalence of depressive symptoms and cognitive decline increases with age. We investigated their temporal dynamics in individuals aged 85 and older across a 5-year follow-up period., Methods: Participants were selected from the Leiden 85-plus study and were eligible if at least three follow-up measurements were available (325 of 599 participants). Depressive symptoms were assessed at baseline and at yearly assessments during a follow-up period of up to 5 years, using the 15-item Geriatric Depression Scale (GDS-15). Cognitive decline was measured through various tests, including the Mini Mental State Exam, Stroop test, Letter Digit Coding test and immediate and delayed recall. A novel method, dynamic time warping analysis, was employed to model their temporal dynamics within individuals, in undirected and directed time-lag analyses, to ascertain whether depressive symptoms precede cognitive decline in group-level aggregated results or vice versa., Results: The 325 participants were all 85 years of age at baseline; 68% were female, and 45% received intermediate to higher education. Depressive symptoms and cognitive functioning significantly covaried in time, and directed analyses showed that depressive symptoms preceded most of the constituents of cognitive impairment in the oldest old. Of the GDS-15 symptoms, those with the strongest outstrength, indicating changes in these symptoms preceded subsequent changes in other symptoms, were worthlessness, hopelessness, low happiness, dropping activities/interests, and low satisfaction with life (all P's < 0.01)., Conclusion: Depressive symptoms preceded cognitive impairment in a population based sample of the oldest old., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background: Based on observational studies and randomised controlled trials (RCTs), the benefit-harm balance of antihypertensive treatment in older adults with dementia is unclear., Objective: To assess whether discontinuing antihypertensive treatment reduces neuropsychiatric symptoms (NPSs) and maintains quality of life (QoL) in nursing home residents with dementia., Design: Open-label, blinded-outcome RCT. Randomisation 1:1, stratified by nursing home organisation and baseline NPS. Trial registration: NL7365., Subjects: Dutch long-term care residents with moderate-to-severe dementia and systolic blood pressure (SBP) ≤160 mmHg during antihypertensive treatment. Exclusion criteria included heart failure NYHA-class-III/IV, recent cardiovascular events/procedures or life expectancy <4 months (planned sample size n = 492)., Measurements: Co-primary outcomes NPS (Neuropsychiatric Inventory-Nursing Home [NPI-NH]) and QoL (Qualidem) at 16 weeks., Results: From 9 November 2018 to 4 May 2021, 205 participants (median age 85.8 [IQR 79.6-89.5] years; 79.5% female; median SBP 134 [IQR 123-146] mmHg) were randomised to either antihypertensive treatment discontinuation (n = 101) or usual care (n = 104). Safety concerns, combined with lacking benefits, prompted the data safety and monitoring board to advice a premature cessation of randomisation. At 16-week follow-up, no significant differences were found between groups for NPI-NH (adjusted mean difference 1.6 [95% CI -2.3 to 5.6]; P = 0.42) or Qualidem (adjusted mean difference - 2.5 [95% CI -6.0 to 1.0]; P = 0.15). Serious adverse events (SAEs) occurred in 36% (discontinuation) and 24% (usual care) of the participants (adjusted hazard ratio 1.65 [95% CI 0.98-2.79]). All 32-week outcomes favoured usual care., Conclusion: Halfway through this study, a non-significant increased SAE risk associated with discontinuing antihypertensive treatment was observed, and an associated interim analysis showed that significant worthwhile health gain for discontinuation of antihypertensive treatment was unlikely. This unbeneficial benefit-harm balance shows that discontinuation of antihypertensive treatment in this context does not appear to be either safe or beneficial enough to be recommended in older adults with dementia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Purpose: Palbociclib has become the standard of care for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer, but real-world evidence in older women remains scarce. Therefore, we investigated tolerability of palbociclib in older women with metastatic breast cancer., Methods: Consecutive women aged ≥ 70 with ER+/HER2- metastatic breast cancer, treated with palbociclib in any treatment line in six hospitals, were included. Primary endpoint was grade ≥ 3 palbociclib-related toxicity. Predictors of toxicity were identified using logistic regression models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier., Results: We included 144 women with a median age of 74 years. Grade 3-4 toxicity occurred in 54% of patients, of which neutropenia (37%) was most common. No neutropenic fever or grade 5 toxicity occurred. Dose reduction during treatment occurred in 50% of patients, 8% discontinued treatment due to toxicity and 3% were hospitalized due to toxicity. Polypharmacy (odds ratio (OR) 2.50; 95% confidence interval (CI) 1.12-5.58) and pretreatment low leukocytes (OR 4.81; 95% CI 1.27-18.21) were associated with grade 3-4 toxicity, while comorbidities were not. In first-line systemic therapy, median PFS was 12 months and median OS 32 months. In second-line, median PFS was 12 months and median OS 31 months., Conclusion: Although grade 3-4 toxicity and dose reductions occurred frequently, most were expected and managed by dose reductions, showing that palbociclib is generally well tolerated and thus represents a valuable treatment option in the older population., (© 2024. The Author(s).)

Background: Dialysis might not benefit all older patients with kidney failure, particularly those with multimorbid conditions and frailty. Patients' and healthcare professionals' awareness of the presence of geriatric impairments could improve outcomes by tailoring treatment plans and decisions for individual patients., Objective: We aimed to explore the perspectives of patients and healthcare professionals on nephrology-tailored geriatric assessment to fuel decision-making for treatment choices in older patients with kidney failure., Design: In an exploratory qualitative study using focus groups, participants discussed perspectives on the use and value of nephrology-tailored geriatric assessment for the decision-making process to start or forego dialysis., Participants and Measurements: Patients (n = 18) with kidney failure, caregivers (n = 4), and professionals (n = 25) were purposively sampled from 10 hospitals. Interviews were audio-recorded, transcribed verbatim and inductively analysed using thematic analysis., Results: Three main themes emerged that supported or impeded decision-making in kidney failure: (1) patient psycho-social situation; (2) patient-related factors on modality choice; (3) organisation of health care. Patients reported feeling vulnerable due to multiple chronic conditions, old age, experienced losses in life and their willingness to trade longevity for quality of life. Professionals recognised the added value of nephrology-tailored geriatric assessment in three major themes: (i) facilitating continual holistic assessment, (ii) filling the knowledge gap, and (iii) uncovering important patient characteristics., Conclusions: nephrology-tailored geriatric assessment was perceived as a valuable tool to identify geriatric impairments in older patients with kidney failure. Integration of its outcomes can facilitate a more holistic approach to inform choices and decisions about kidney replacement therapy., (© 2023 The Authors. Journal of Renal Care published by John Wiley & Sons Ltd on behalf of European Dialysis & Transplant Nurses Association/European Renal Care Association.)

Background: Checkpoint inhibition has emerged as an effective treatment strategy for a variety of cancers, including in older adults. However, older patients with cancer represent a heterogenous group as they can vary widely in frailty, cognition, and physical status., Objective: This study aims to investigate the association between clinical frailty and immune-related treatment toxicity, hospitalization, and treatment discontinuation due to immune-related treatment toxicity in older patients treated with checkpoint inhibitors., Methods: Patients aged 70 years and older treated with checkpoint inhibitors were selected from the TENT study, IMAGINE study, and "Tolerability and safety of immunotherapy study". Clinical frailty was assessed by the Geriatric-8 test score and World Health Organization (WHO) status. Outcomes were grades 3-5 toxicity, hospitalization, and treatment discontinuation due to toxicity during treatment., Results: Of 99 patients included, 22% had comorbidities. While 33% of the patients were considered frail based on an abnormal Geriatric-8 test score of < 15, physical impairments were considered absent in 51% (WHO score of 0) and mild in 40% (WHO score of 1). Despite the limited sample size of the cohort, consistent trends were observed with patients with an abnormal Geriatric-8 test score of < 15 or a higher WHO score of 1 for having higher odds of toxicity [odds ratio (OR) 2.32 (95% CI 0.41-13.02); OR 1.33 (95% CI 0.45-4.17)], treatment discontinuation due to immune-related treatment toxicity [OR 2.25 (95% CI 0.61-8.31); OR 2.18 (95% CI 0.7-6.73)], and hospitalization due to immune-related treatment toxicity [OR 3.72 (95% CI 0.39-35.4); OR 1.31 (95% CI 0.35-4.9)]. Moreover, in a sub-analysis, we observed that the treatment discontinuation due to immune-related treatment toxicity occurred often in patients with grade 1-2 toxicity as well., Conclusions: Although not statistically significant, in older patients treated with immunotherapy in a real-life population with cancer, we observed consistent trends towards increased toxicity, hospitalization, and treatment discontinuation with increasing frailty. Larger studies are needed to confirm these exploratory results. Moreover, older patients with a lower toxicity grade 1-2 experienced early treatment discontinuation frequently, suggesting a lower tolerance of toxicity., (© 2024. The Author(s).)

Background: Literature relating older people's goals of care to their varying frailty status is scarce., Objective: To investigate goals of care in case of acute and/or severe disease in relationship to frailty status among the general older population., Method: Older people aged ≥70 in the Netherlands completed a questionnaire. They were divided into three subgroups based on a self-reported Clinical Frailty Scale: fit (CFS 1-3), mildly frail (CFS 4-5) and severely frail (CFS 6-8). Seven goals were graded as unimportant (1-5), somewhat important (6-7) or very important (8-10): extending life, preserving quality of life (QoL), staying independent, relieving symptoms, supporting others, preventing hospital admission and preventing nursing home admission., Results: Of the 1,278 participants (median age 76 years, 63% female), 57% was fit, 32% mildly frail and 12% severely frail. Overall, participants most frequently considered preventing nursing home admission as very important (87%), followed by staying independent (84%) and preserving QoL (83%), and least frequently considered extending life as very important (31%). All frailty subgroups reported similar preferences out of the surveyed goals as the overall study population. However, participants with a higher frailty status attached slightly less importance to each individual goal compared with fit participants (Ptrend-values ≤ 0.037)., Conclusion: Preferred goals of care are not related to frailty status, while the importance ascribed to individual goals is slightly lower with higher frailty status. Future research should prioritise outcomes related to the shared goals of fit, mildly frail and severely frail older people to improve personalised medicine for older patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Background and Aims: Our goals were to study frailty screening in association with hospitalization and decline in quality of life [QoL] and functional status in older patients with inflammatory bowel diseases [IBD]., Methods: This was a prospective multicentre cohort study in IBD patients ≥65 years old using frailty screening [G8 Questionnaire]. Outcomes were all-cause, acute, and IBD-related hospitalization, any infection, any malignancy, QoL [EQ5D-3L], and functional decline (Instrumental Activities of Daily Living [IADL]) during 18 months of follow-up. Confounders were age, IBD type, biochemical disease activity [C-reactive protein ≥10 mg/L and/or faecal calprotectin ≥250 µg/g], and comorbidity [Charlson Comorbidity Index]., Results: Of 405 patients, with a median age of 70 years, 196 [48%] were screened as being at risk for frailty. All-cause hospitalizations occurred 136 times in 96 patients [23.7%], and acute hospitalizations 103 times in 74 patients [18.3%]. Risk of frailty was not associated with all-cause (adjusted hazard ratio [aHR] 1.5, 95% confidence interval [CI] 0.9-2.4), but was associated with acute hospitalizations [aHR 2.2, 95% CI 1.3-3.8]. Infections occurred in 86 patients [21.2%] and these were not associated with frailty. A decline in QoL was experienced by 108 [30.6%] patients, and a decline in functional status by 46 patients [13.3%]. Frailty screening was associated with a decline in QoL (adjusted odds ratio [aOR] 2.1, 95% CI 1.3-3.6) and functional status [aOR 3.7, 95% CI 1.7-8.1]., Conclusions: Frailty screening is associated with worse health outcomes in older patients with IBD. Further studies are needed to assess the feasibility and effectiveness of its implementation in routine care., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Introduction: To tailor treatment for older patients with cancer, an oncogeriatric care pathway has been developed in the Leiden University Medical Center. In this care pathway a geriatric assessment is performed and preferences concerning cancer treatment options are discussed. This study aimed to explore patient experiences with and attitudes towards this pathway., Materials and Methods: A qualitative study was performed using an exploratory descriptive approach. Individual face-to-face semi-structured interviews were conducted with older patients (≥70 years) who had followed the oncogeriatric care pathway in the six months prior to the interview. The interviews were audio-recorded and transcribed verbatim. The transcripts were analyzed inductively using thematic analysis., Results: After interviews with 14 patients with a median age of 80 years, three main themes were identified. (1) Patients' positive experiences with the oncogeriatric pathway: Patients appreciated the attitudes of the healthcare professionals and felt heard and understood. (2) Unmet information needs about the oncogeriatric care pathway: Patients experienced a lack of information about the aim and process. (3) Incomplete information for decision-making: Most patients were satisfied with decision-making process. However, treatment decisions had often been made before oncogeriatric consultation. No explicit naming and explaining of different available treatment options had been provided, nor had risk of physical or cognitive decline during and after treatment been addressed., Discussion: Older patients had predominately positive attitudes towards the oncogeriatric care pathway. Most patients were satisfied with the treatment decision. Providing information on the aim and process of the care pathway, available treatment options, and treatment-related risks of cognitive and physical decline may further improve the oncogeriatric care pathway and the decision-making process., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To systematically evaluate the performance of COVID-19 prognostic models and scores for mortality risk in older populations across three health-care settings: hospitals, primary care, and nursing homes., Study Design and Setting: This retrospective external validation study included 14,092 older individuals of ≥70 years of age with a clinical or polymerase chain reaction-confirmed COVID-19 diagnosis from March 2020 to December 2020. The six validation cohorts include three hospital-based (CliniCo, COVID-OLD, COVID-PREDICT), two primary care-based (Julius General Practitioners Network/Academisch network huisartsgeneeskunde/Network of Academic general Practitioners, PHARMO), and one nursing home cohort (YSIS) in the Netherlands. Based on a living systematic review of COVID-19 prediction models using Prediction model Risk Of Bias ASsessment Tool for quality and risk of bias assessment and considering predictor availability in validation cohorts, we selected six prognostic models predicting mortality risk in adults with COVID-19 infection (GAL-COVID-19 mortality, 4C Mortality Score, National Early Warning Score 2-extended model, Xie model, Wang clinical model, and CURB65 score). All six prognostic models were validated in the hospital cohorts and the GAL-COVID-19 mortality model was validated in all three healthcare settings. The primary outcome was in-hospital mortality for hospitals and 28-day mortality for primary care and nursing home settings. Model performance was evaluated in each validation cohort separately in terms of discrimination, calibration, and decision curves. An intercept update was performed in models indicating miscalibration followed by predictive performance re-evaluation., Main Outcome Measure: In-hospital mortality for hospitals and 28-day mortality for primary care and nursing home setting., Results: All six prognostic models performed poorly and showed miscalibration in the older population cohorts. In the hospital settings, model performance ranged from calibration-in-the-large -1.45 to 7.46, calibration slopes 0.24-0.81, and C-statistic 0.55-0.71 with 4C Mortality Score performing as the most discriminative and well-calibrated model. Performance across health-care settings was similar for the GAL-COVID-19 model, with a calibration-in-the-large in the range of -2.35 to -0.15 indicating overestimation, calibration slopes of 0.24-0.81 indicating signs of overfitting, and C-statistic of 0.55-0.71., Conclusion: Our results show that most prognostic models for predicting mortality risk performed poorly in the older population with COVID-19, in each health-care setting: hospital, primary care, and nursing home settings. Insights into factors influencing predictive model performance in the older population are needed for pandemic preparedness and reliable prognostication of health-related outcomes in this demographic., Competing Interests: Declaration of competing interest All authors have completed the International Committee of Medical Journals Editors uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: funding from the Netherlands Organisation for Scientific Research (ZonMw). KJ and FW have received grants from the program Leren van Data by theDutch Ministry of Health, Welfare and Sport(grantnumber:329517); all declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Older people with progressive chronic kidney disease (CKD) have complex health care needs. Geriatric evaluation preceding decision making for kidney replacement is recommended in guidelines, but implementation is lacking in routine care. We aimed to evaluate implementation of geriatric assessment in CKD care., Study Design: Mixed methods implementation study., Setting & Participants: Dutch nephrology centers were approached for implementation of geriatric assessment in patients aged ≥70 years and with an estimated glomerular filtration rate of ≤20 mL/min/1.73 m 2 ., Quality Improvement Activities/exposure: We implemented a consensus-based nephrology-tailored geriatric assessment: a patient questionnaire and professionally administered test set comprising 16 instruments covering functional, cognitive, psychosocial, and somatic domains and patient-reported outcome measures., Outcomes: We aimed for implementation in 10 centers and 200 patients. Implementation was evaluated by (i) perceived enablers and barriers of implementation, including integration in work routines (Normalization Measure Development Tool) and (ii) relevance of the instruments to routine care for the target population., Analytical Approach: Variations in implementation practices were described based on field notes. The postimplementation survey among health care professionals was analyzed descriptively, using an explanatory qualitative approach for open-ended questions., Results: Geriatric assessment was implemented in 10 centers among 191 patients. Survey respondents (n = 71, 88% response rate) identified determinants that facilitated implementation, ie, multidisciplinary collaboration (with geriatricians) -meetings and reports and execution of assessments by nurses. Barriers to implementation were patient illiteracy or language barrier, time constraints, and patient burden. Professionals considered geriatric assessment sufficiently integrated into work routines (mean, 6.7/10 ± 2.0 [SD]) but also subject to improvement. Likewise, the relevance of geriatric assessment for routine care was scored as 7.8/10 ± 1.2. The Clinical Frailty Score and Montreal Cognitive Assessment were perceived as the most relevant instruments., Limitations: Selection bias of interventions' early adopters may limit generalizability., Conclusions: Geriatric assessment could successfully be integrated in CKD care and was perceived relevant to health care professionals., (© 2024 The Authors.)

Background: The broad concept of health as "the ability to adapt and self-manage in the face of social, physical and emotional challenges" has been operationalized by "Positive Health," a framework increasingly used in the Netherlands. We explored to what degree the impact of the COVID-19 pandemic and preventive measures on Positive Health differed between community-dwelling older adults without, with mild and with complex health problems, as well as differences flowing from their use of preventive measures., Methods: During the second wave in the Netherlands (November 2020-February 2021), a convenience sample of adults aged ≥65 years completed an online questionnaire. Positive Health impact was measured based on self-reported change of current health status, across six dimensions, compared to before the pandemic (decreased/unchanged/increased). The complexity of health problems (past month) was assessed using the validated ISCOPE tool, comparing subgroups without, with mild or with complex health problems. High use of preventive measures was defined as ≥9 of 13 measures and compared to low use (<9 measures)., Results: Of the 2397 participants (median age 71 years, 60% female, and 4% previous COVID-19 infection), 31% experienced no health problems, 55% mild health problems, and 15% complex health problems. Overall, participants reported a median decrease in one Positive Health dimension (IQR 1-3), most commonly in social participation (68%). With an increasing complexity of health problems, subjective Positive Health declined more often across all six dimensions, ranging from 3.3% to 57% in those without, from 22% to 72% in those with mild, and from 47% to 75% in those with complex health problems (p-values for trend <0.001; independent of age and sex). High users of preventive measures more often experienced declined social participation (72% vs. 62%, p < 0.001) and a declined quality of life (36% vs. 30%, p = 0.007) than low users, especially those with complex health problems., Conclusion: As the complexity of health problems increased, the adverse impact of the COVID-19 pandemic and related preventive measures was experienced more frequently across all dimensions of Positive Health. Acknowledging this heterogeneity is pivotal to the effective targeting of prevention and healthcare to those most in need., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: During the COVID-19 pandemic, older patients in primary care were triaged based on their frailty or assumed vulnerability for poor outcomes, while evidence on the prognostic value of vulnerability measures in COVID-19 patients in primary care was lacking. Still, knowledge on the role of vulnerability is pivotal in understanding the resilience of older people during acute illness, and hence important for future pandemic preparedness. Therefore, we assessed the predictive value of different routine care-based vulnerability measures in addition to age and sex for 28-day mortality in an older primary care population of patients with COVID-19., Methods: From primary care medical records using three routinely collected Dutch primary care databases, we included all patients aged 70 years or older with a COVID-19 diagnosis registration in 2020 and 2021. All-cause mortality was predicted using logistic regression based on age and sex only (basic model), and separately adding six vulnerability measures: renal function, cognitive impairment, number of chronic drugs, Charlson Comorbidity Index, Chronic Comorbidity Score, and a Frailty Index. Predictive performance of the basic model and the six vulnerability models was compared in terms of area under the receiver operator characteristic curve (AUC), index of prediction accuracy and the distribution of predicted risks., Results: Of the 4,065 included patients, 9% died within 28 days after COVID-19 diagnosis. Predicted mortality risk ranged between 7-26% for the basic model including age and sex, changing to 4-41% by addition of comorbidity-based vulnerability measures (Charlson Comorbidity Index, Chronic Comorbidity Score), more reflecting impaired organ functioning. Similarly, the AUC of the basic model slightly increased from 0.69 (95%CI 0.66 - 0.72) to 0.74 (95%CI 0.71 - 0.76) by addition of either of these comorbidity scores. Addition of a Frailty Index, renal function, the number of chronic drugs or cognitive impairment yielded no substantial change in predictions., Conclusion: In our dataset of older COVID-19 patients in primary care, the 28-day mortality fraction was substantial at 9%. Six different vulnerability measures had little incremental predictive value in addition to age and sex in predicting short-term mortality., (© 2024. The Author(s).)

Context: With age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown., Objective: To investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism., Design: Pooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial)., Setting: Community-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom., Participants: The pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included., Main Outcome Measures: Incidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization., Results: In the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization., Conclusion: Because TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment., Trial Registration: ClinicalTrials.gov, NCT01660126 and Netherlands Trial Register, NTR3851., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Immunotherapy with checkpoint inhibitors (ICI) has improved cancer treatment in recent years. Older and frail patients are frequently treated with ICIs, but since they have been underrepresented in previous clinical trials, the real impact of ICI in this patient group is not well defined. The aim of this systematic review was to evaluate the evidence for associations between geriatric impairments and treatment outcomes in older patients with advanced and metastatic cancer treated with ICIs., Methods: A systematic search was conducted in PubMed, Cochrane Library, Embase, and Web of Science for relevant articles published before June 2022. Studies investigating the association between impairments in at least two geriatric domains and treatment outcome were considered eligible. Data extraction and risk of bias assessment using the QUIPS tool was performed independently by two investigators., Results: A total of nine studies were included. Median sample size of the studies was 92 patients (interquartile range (IQR) 47-113), with a median of 26 frail patients (IQR 21-35). Five studies investigated disease-related and survival outcomes, and two of them found a statistically significant association between geriatric impairments and either survival or disease progression. Eight studies investigated toxicity outcomes, and two of them showed a statistically significant association between geriatric impairments and immune-related adverse events (irAEs). Few studies suggested a relation between geriatric impairments and worse clinical outcomes., Conclusions: Only a few studies have investigated the association between geriatric impairments and treatment outcomes and these studies were small. Older patients with geriatric impairments seem to be more likely to experience irAEs, but larger studies that include frail patients and use geriatric screening tools are required to confirm this association. These studies will be essential to improve the development of specific strategies to deal with frail patients., Competing Interests: Declaration of Competing Interest M. Slingerland is a paid advisory board member for Bristol-Myers Squibb, AstraZeneca, and Lilly. E. Kapiteijn has consultancy/advisory relationships with Bristol Myers Squibb, Novartis, Merck, Pierre Fabre, Lilly and Bayer, these were paid to the institution. Furthermore, she received research grants not related to this paper from Bristol Myers Squibb, Delcath, Novartis and Pierre Fabre. No potential conflict of interest were disclosed by the other authors. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results., (Copyright © 2024. Published by Elsevier B.V.)