BackgroundAfter an acute infection, older persons may benefit from geriatric rehabilitation (GR).ObjectivesThis study describes the recovery trajectories of post-COVID-19 patients undergoing GR and... Show moreBackgroundAfter an acute infection, older persons may benefit from geriatric rehabilitation (GR).ObjectivesThis study describes the recovery trajectories of post-COVID-19 patients undergoing GR and explores whether frailty is associated with recovery.DesignMulticentre prospective cohort study.Setting59 GR facilities in 10 European countries.ParticipantsPost-COVID-19 patients admitted to GR between October 2020 and October 2021.MethodsPatients’ characteristics, daily functioning (Barthel index; BI), quality of life (QoL; EQ-5D-5L) and frailty (Clinical Frailty Scale; CFS) were collected at admission, discharge, 6 weeks and 6 months after discharge. We used linear mixed models to examine the trajectories of daily functioning and QoL.Results723 participants were included with a mean age of 75 (SD: 9.91) years. Most participants were pre-frail to frail (median [interquartile range] CFS 6.0 [5.0–7.0]) at admission. After admission, the BI first steeply increased from 11.31 with 2.51 (SE 0.15, P < 0.001) points per month and stabilised around 17.0 (quadratic slope: −0.26, SE 0.02, P < 0.001). Similarly, EQ-5D-5L first steeply increased from 0.569 with 0.126 points per month (SE 0.008, P < 0.001) and stabilised around 0.8 (quadratic slope: −0.014, SE 0.001, P < 0.001). Functional recovery rates were independent of frailty level at admission. QoL was lower at admission for frailer participants, but increased faster, stabilising at almost equal QoL values for frail, pre-frail and fit patients.ConclusionsPost-COVID-19 patients admitted to GR showed substantial recovery in daily functioning and QoL. Frailty at GR admission was not associated with recovery and should not be a reason to exclude patients from GR. Show less
Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology—a strategy that is based on perturbing primary... Show morePrecision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology—a strategy that is based on perturbing primary tumor cells from cancer patients—could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC. Show less
Gelderblom, H.; Jones, R.L.; Blay, J.Y.; George, S.; Mehren, M. von; Zalcberg, J.R.; ... ; Bauer, S. 2023
PurposeIn the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously... Show morePurposeIn the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL).Patients and methodsPatients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up.ResultsQuestionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days).ConclusionPatients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib. Show less
With an ageing global population and an increasing focus on aging in place, the number of people in need of geriatric rehabilitation (GR) is rapidly increasing. As current GR practice is very... Show moreWith an ageing global population and an increasing focus on aging in place, the number of people in need of geriatric rehabilitation (GR) is rapidly increasing. As current GR practice is very heterogenous, cross-country comparisons could allow us to learn from each other and optimise the effectiveness of GR. However, international GR research comes with many challenges. This article summarises the facilitators and barriers relating to the recruitment of rehabilitation centres, the inclusion of patients, and data collection, as experienced by experts in the field of international GR research. The three most important methodological recommendations for conducting cross-national collaborative research in the field of GR are (1) make use of existing (inter)national networks and social media to aid recruitment of GR centres; (2) clearly define the GR treatment, setting, and patient characteristics in the inclusion criteria; and (3) use a hierarchical study structure to communicate transparently and regularly with both national and local coordinators. International GR research would greatly benefit from the implementation of a core dataset in regular GR care. Therefore, future studies should focus on developing an international consensus regarding the outcomes and corresponding cross-culturally validated measurement instruments to be used during GR. Show less
Schoeffski, P.; George, S.; Heinrich, M.C.; Zalcberg, J.R.; Bauer, S.; Gelderblom, H.; ... ; Mehren, M. von 2022
Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and... Show moreBackground: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in >= fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. Conclusion: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. Show less
Schoeffski, P.; George, S.; Heinrich, M.C.; Zalcberg, J.R.; Bauer, S.; Gelderblom, H.; ... ; Mehren, M. von 2022
Background: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVIC‑ TUS phase 3 trial, ripretinib increased median progression-free survival and... Show moreBackground: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVIC‑ TUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥fourth-line advanced GIST. Here, we report prespecifed analysis of quality of life (QoL) as assessed by patientreported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. Methods: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covari‑ ance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. Results: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO meas‑ ures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically signifcant diferences between treatments (nominal P<0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. Conclusion: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. Show less
Coronavirus disease 2019 (COVID-19) poses a threat to the health and independence of older people in particular. In this article we elaborate on the content and importance of post-acute COVID-19... Show moreCoronavirus disease 2019 (COVID-19) poses a threat to the health and independence of older people in particular. In this article we elaborate on the content and importance of post-acute COVID-19 geriatric rehabilitation from a European perspective. We explain the geriatric rehabilitation paradox and how this can and should be solved. We also present what post-acute COVID-19 geriatric rehabilitation should entail. This might not only help us to develop better geriatric rehabilitation services, but it should also inform pandemic preparedness in the future. Show less
The sustainability of healthcare of older people in Europe is at stake. Many experts currently focus on the COVID-19 pandemic and its consequences. But there are other elements coming up that might... Show moreThe sustainability of healthcare of older people in Europe is at stake. Many experts currently focus on the COVID-19 pandemic and its consequences. But there are other elements coming up that might even have a greater impact. Healthcare systems, geriatric care and geriatric rehabilitation in particular, will face disruptive changes due to both demographic demand and a shortage of human and financial resources. This decade will be transformed by a high proportion of the older health workforce transitioning to retirement. This expertise must be retained. The brain drain of health care workers migrating from Eastern parts to Western Europe is diminishing. Discussing and deciding upon the priorities of value-based health care for older people such as equity and access is required. The acute healthcare sector in most countries focuses on fee-for-service models instead of building systemic approaches to maximise independence and autonomy of older citizens. In this commentary, we build on recent book chapters and articles on geriatric rehabililtation. Our main questions for the anniversary edition of Age and Ageing is what it is that geriatric rehabilitation could, should and must contribute in the roaring 2020s? Show less
Shahneh, F.; Johann, K.; Bohn, T.; Klein, M.; Bopp, T.; Barz, M.; Becker, C. 2022
The acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non... Show moreThe acidic tumor microenvironment in melanoma drives immune evasion by up-regulating cyclic adenosine monophosphate (cAMP) in tumor-infiltrating monocytes. Here we show that the release of non-toxic concentrations of an adenylate cyclase (AC) inhibitor from poly(sarcosine)-block-poly(L-glutamic acid γ-benzyl ester) (polypept(o)id) copolymer micelles restores antitumor immunity. In combination with selective, non-therapeutic regulatory T cell depletion, AC inhibitor micelles achieve a complete remission of established B16-F10-OVA tumors. Single-cell sequencing of melanoma-infiltrating immune cells shows that AC inhibitor micelles reduce the number of anti-inflammatory myeloid cells and checkpoint receptor expression on T cells. AC inhibitor micelles thus represent an immunotherapeutic measure to counteract melanoma immune escape. Show less
Grund, S.; Caljouw, M.A.A.; Haaksma, M.L.; Gordon, A.L.; Balen, R. van; Bauer, J.M.; ... ; COGER STUDY SUBGRP EUGMSS IG GR 2021
Objectives There is insufficient knowledge about the functional and medical recovery of older people infected with SARS-CoV-2. This study aims to gain insight into the course of functional and... Show moreObjectives There is insufficient knowledge about the functional and medical recovery of older people infected with SARS-CoV-2. This study aims to gain insight into the course of functional and medical recovery of persons who receive geriatric rehabilitation (GR) following SARS-CoV-2 infection across Europe. Special attention will be paid to the recovery of activities of daily living (ADL) and to the GR services offered to these patients. Design A multi-center observational cohort study. Setting and participants This study will include several European countries (EuGMS member states) each providing at least 52 comparable routine datasets (core dataset) of persons recovering from a SARS-CoV-2 infection and receiving geriatric rehabilitation. The routine data will be anonymously collected in an online CASTOR database. The ethical regulations of each participating country will be followed. Primary outcome ADL functioning. Secondary outcomes Length of stay, discharge destination, hospital readmission and mortality. Other variables that will be collected are quality of life, treatment modalities, complications, cognition, frailty, mood/anxiety, BMI, nutrition and pain. All variables will be reported at admission and compared with follow-up scores (discharge, 6 weeks and 6 months follow-up). Conclusion This study will explore the effect of geriatric rehabilitation on post-COVID-19 patients, especially on ADL recovery, and the variety of geriatric rehabilitation services across Europe. Information from this study may help improve recovery of older persons infected with SARS-CoV-2 and improve geriatric rehabilitation services in the ongoing COVID-19 pandemic. Show less
Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on... Show moreThrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism. Show less
Key summary pointsAim The consensus statement about core principles and future priorities of geriatric rehabilitation has the aim to help healthcare providers which need strategies to support older... Show moreKey summary pointsAim The consensus statement about core principles and future priorities of geriatric rehabilitation has the aim to help healthcare providers which need strategies to support older people who have experienced functional decline. Findings Geriatric rehabilitation is now defined in a way that is compatible with existing service models across Europe. Message This consensus statement can provide a starting point for further development of geriatric rehabilitation.Purpose In response to the growing recognition of geriatric rehabilitation and to support healthcare providers which need strategies to support older people with frailty who have experienced functional decline, we developed a consensus statement about core principles and future priorities for geriatric rehabilitation. Methods We used a three-stage approach to establish consensus-preparation, consensus and review. Results The consensus statement is grouped under 11 headings from (1) "Definition of GR" to (11) "Effective strategies to develop GR in Europe", which define geriatric rehabilitation in a way that is compatible with existing service models across Europe. Additionally future goals around research and education are highlighted. Conclusion The definitions of the consensus statement can provide a starting point for those wishing to further develop geriatric rehabilitation in their jurisdiction and help to develop strategic alliances with other specialties, serving as a basis for a pan-European approach to geriatric rehabilitation. Show less
