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White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1-positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature.

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n  = 179) or a 9-month supervised exercise program (exercise group, n  = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (−5.3 (95% confidence interval (CI), −10.0 to −0.6), Bonferroni–Holm-adjusted P  = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2–7.4), Bonferroni–Holm-adjusted P  = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care. ClinicalTrials.gov Identifier: NCT04120298 . In this large interventional, randomized controlled trial, structured and individualized exercise in patients with metastatic breast cancer led to lower levels of fatigue and improved health-related quality of life.

Background Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. Methods The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. Discussion This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. Trial registration ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

Background Exercise is an effective strategy to reduce cancer- and treatment-related side effects and improve quality of life (QoL). Larger exercise effects are observed in cancer survivors with a higher symptom burden and when exercise interventions are supervised. Most studies conducted to date have not screened for symptoms at baseline and tailored the exercise intervention accordingly. Additionally, time and travel distance are common barriers to participation in supervised in-person exercise programs. Live-remote exercise, where exercise sessions are supervised by an exercise professional via a videoconferencing platform, might help overcome these barriers. Here, we describe the design of the LION randomized controlled trial (RCT). This RCT aims to assess the (cost-)effectiveness of side effect-targeted, live-remote exercise on QoL and the participants’ most burdensome side effect—fatigue, emotional distress, low physical functioning, or chemotherapy-induced peripheral neuropathy (CIPN)—in individuals who have completed primary curative cancer treatment. Methods The LION study is a multinational RCT that will enroll 352 individuals who have completed primary curative cancer treatment including chemotherapy, within the previous 12–52 weeks and screen positive for ≥ 1 of the targeted side effects. Participants are randomly allocated (1:1) to the intervention or wait list control group. Participants in the intervention group receive a 12-week supervised exercise program consisting of three live-remote exercise sessions per week. Each participant receives the same base module (2×/week) and one specific module (1×/week) targeting their most burdensome side effect. Wait list control participants receive the same exercise program 12 weeks post-baseline. The primary outcomes are HRQoL (EORTC QLQ-C30 summary score) and a standardized symptom score based on each participant’s most burdensome side effect (physical fatigue: EORTC QLQ-FA12, emotional distress: PHQ-ADS, physical functioning: EORTC QLQ-C30 modified physical functioning scale, CIPN: EORTC QLQ-CIPN20), assessed at baseline, 6, 12 (primary time point), 18 (wait list control group only), 24 and 36 weeks post-baseline. Discussion This RCT will provide evidence regarding the (cost-)effectiveness of side effect-targeted, live-remote exercise in individuals experiencing side effects following primary curative cancer treatment. If proven (cost-)effective, live-remote exercise could be offered to individuals as part of standard follow-up cancer care to extend the reach of exercise support. Trial registration NCT06270628. Registered on February 13, 2024.

Purpose As survival of patients with metastatic breast cancer (MBC) improves, their work situation is gaining importance. The aim of the current study was to identify factors associated with work status and quality of working life (QWL) in patients with MBC. Additionally, we investigated the effects of an exercise intervention on work status. Methods Within the multinational PREFERABLE‐EFFECT exercise trial, 287 patients with MBC of working age (18–65 years) reported on their working situation over 9 months as a secondary endpoint. Among a subgroup of participants, QWL was assessed by the Quality of Working Life Questionnaire for Cancer Survivors (QWLQ‐CS) (N = 59). Results At baseline, 157 (54.7%) participants were employed, of whom one‐third reported having recently reduced their amount of work because of fatigue (41.7%), cognitive problems (33.3%), or inability to meet work demands (33.3%). Participants wished for more flexible working hours (29.2%) and less productivity pressure (37.5%). Participants were less likely to work if they experienced higher levels of pain (p = 0.014). Among working participants, an academic education and higher levels of psychological distress were associated with a higher number of working hours (all p < 0.05). Fatigue, an academic education, and performing mentally strenuous tasks at work were negatively associated with QWL (all p < 0.05). The exercise intervention did not affect the number of hours worked during the study. Conclusions Symptom management might be important for patients' ability to work. To help patients stay employed and improve QWL, employers should consider offering more flexible work arrangements and adapting to their employees' changing needs and abilities. Trial Registration: The PREFERABLE‐EFFECT trial was registered with ClinicalTrials.gov on October 9, 2019 (NCT04120298).