Dropout from exercise trials among cancer survivors—An individual patient data meta-analysis from the POLARIS study

Introduction: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. Methods: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. Results: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI &gt;28.4 kg/m2, performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI &gt;28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. Conclusions: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.</p

Moderators of Exercise Effects on Cancer-related Fatigue:A Meta-analysis of Individual Patient Data

PURPOSE: Fatigue is a common and potentially disabling symptom in patients with cancer. It can often be effectively reduced by exercise. Yet, effects of exercise interventions might differ across subgroups. We conducted a meta-analysis using individual patient data of randomized controlled trials (RCT) to investigate moderators of exercise intervention effects on cancer-related fatigue. METHODS: We used individual patient data from 31 exercise RCT worldwide, representing 4366 patients, of whom 3846 had complete fatigue data. We performed a one-step individual patient data meta-analysis, using linear mixed-effect models to analyze the effects of exercise interventions on fatigue (z score) and to identify demographic, clinical, intervention- and exercise-related moderators. Models were adjusted for baseline fatigue and included a random intercept on study level to account for clustering of patients within studies. We identified potential moderators by testing their interaction with group allocation, using a likelihood ratio test. RESULTS: Exercise interventions had statistically significant beneficial effects on fatigue (β = -0.17; 95% confidence interval [CI], -0.22 to -0.12). There was no evidence of moderation by demographic or clinical characteristics. Supervised exercise interventions had significantly larger effects on fatigue than unsupervised exercise interventions (βdifference = -0.18; 95% CI -0.28 to -0.08). Supervised interventions with a duration ≤12 wk showed larger effects on fatigue (β = -0.29; 95% CI, -0.39 to -0.20) than supervised interventions with a longer duration. CONCLUSIONS: In this individual patient data meta-analysis, we found statistically significant beneficial effects of exercise interventions on fatigue, irrespective of demographic and clinical characteristics. These findings support a role for exercise, preferably supervised exercise interventions, in clinical practice. Reasons for differential effects in duration require further exploration

Targeting exercise interventions to patients with cancer in need:An individual patient data meta-analysis

Background: Exercise effects in cancer patients often appear modest, possibly because interventions rarely target patients most in need. This study investigated the moderator effects of baseline values on the exercise outcomes of fatigue, aerobic fitness, muscle strength, quality of life (QoL), and self-reported physical function (PF) in cancer patients during and post-treatment. Methods: Individual patient data from 34 randomized exercise trials (n = 4519) were pooled. Linear mixed-effect models were used to study moderator effects of baseline values on exercise intervention outcomes and to determine whether these moderator effects differed by intervention timing (during vs post-treatment). All statistical tests were two-sided. Results: Moderator effects of baseline fatigue and PF were consistent across intervention timing, with greater effects in patients with worse fatigue (Pinteraction = .05) and worse PF (Pinteraction = .003). Moderator effects of baseline aerobic fitness, muscle strength, and QoL differed by intervention timing. During treatment, effects on aerobic fitness were greater for patients with better baseline aerobic fitness (Pinteraction = .002). Post-treatment, effects on upper (Pinteraction &lt; .001) and lower (Pinteraction = .01) body muscle strength and QoL (Pinteraction &lt; .001) were greater in patients with worse baseline values. Conclusion: Although exercise should be encouraged for most cancer patients during and post-treatments, targeting specific subgroups may be especially beneficial and cost effective. For fatigue and PF, interventions during and post-treatment should target patients with high fatigue and low PF. During treatment, patients experience benefit for muscle strength and QoL regardless of baseline values; however, only patients with low baseline values benefit post-treatment. For aerobic fitness, patients with low baseline values do not appear to benefit from exercise during treatment

Effects and moderators of exercise on muscle strength, muscle function and aerobic fitness in patients with cancer:A meta-analysis of individual patient data

To optimally target exercise interventions for patients with cancer, it is important to identify which patients benefit from which interventions. Design We conducted an individual patient data meta-analysis to investigate demographic, clinical, intervention-related and exercise-related moderators of exercise intervention effects on physical fitness in patients with cancer. Data sources We identified relevant studies via systematic searches in electronic databases (PubMed, Embase, PsycINFO and CINAHL). Eligibility criteria We analysed data from 28 randomised controlled trials investigating the effects of exercise on upper body muscle strength (UBMS) and lower body muscle strength (LBMS), lower body muscle function (LBMF) and aerobic fitness in adult patients with cancer. Results Exercise significantly improved UBMS (β=0.20, 95% Confidence Interval (CI) 0.14 to 0.26), LBMS (β=0.29, 95% CI 0.23 to 0.35), LBMF (β=0.16, 95% CI 0.08 to 0.24) and aerobic fitness (β=0.28, 95% CI 0.23 to 0.34), with larger effects for supervised interventions. Exercise effects on UBMS were larger during treatment, when supervised interventions included ≥3 sessions per week, when resistance exercises were included and when session duration was >60 min. Exercise effects on LBMS were larger for patients who were living alone, for supervised interventions including resistance exercise and when session duration was >60 min. Exercise effects on aerobic fitness were larger for younger patients and when supervised interventions included aerobic exercise. Conclusion Exercise interventions during and following cancer treatment had small effects on UBMS, LBMS, LBMF and aerobic fitness. Demographic, intervention-related and exercise-related characteristics including age, marital status, intervention timing, delivery mode and frequency and type and time of exercise sessions moderated the exercise effect on UBMS, LBMS and aerobic fitness.Sin financiación12.022 JCR (2019) Q1, 1/85 Sport Sciences3.712 SJR (2019) Q1, 48/2754 Medicine (miscellaneous), 1/284 Orthopedics and Sports Medicine, 1/207 Physical Therapy, Sports Therapy and Rehabilitation, 2/125 Sports ScienceNo data IDR 2019UE

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Effects and moderators of exercise on quality of life and physical function in patients with cancer:An individual patient data meta-analysis of 34 RCTs

This individual patient data meta-analysis aimed to evaluate the effects of exercise on quality of life (QoL) and physical function (PF) in patients with cancer, and to identify moderator effects of demographic (age, sex, marital status, education), clinical (body mass index, cancer type, presence of metastasis), intervention-related (intervention timing, delivery mode and duration, and type of control group), and exercise-related (exercise frequency, intensity, type, time) characteristics. Relevant published and unpublished studies were identified in September 2012 via PubMed, EMBASE, PsycINFO, and CINAHL, reference checking and personal communications. Principle investigators of all 69 eligible trials were requested to share IPD from their study. IPD from 34 randomised controlled trials (n=4,519 patients) that evaluated the effects of exercise compared to a usual care, wait-list or attention control group on QoL and PF in adult patients with cancer were retrieved and pooled. Linear mixed-effect models were used to evaluate the effects of the exercise on post-intervention outcome values (z-score) adjusting for baseline values. Moderator effects were studies by testing interactions. Exercise significantly improved QoL (β=0.15, 95%CI=0.10;0.20) and PF (β=0.18,95%CI=0.13;0.23). The effects were not moderated by demographic, clinical or exercise characteristics. Effects on QoL (βdifference_in_effect=0.13, 95%CI=0.03;0.22) and PF (βdifference_in_effect=0.10, 95%CI=0.01;0.20) were significantly larger for supervised than unsupervised interventions. In conclusion, exercise, and particularly supervised exercise, effectively improves QoL and PF in patients with cancer with different demographic and clinical characteristics during and following treatment. Although effect sizes are small, there is consistent empirical evidence to support implementation of exercise as part of cancer care

The Development of On-line Single / Staggered Multi-Step Elution SPE-CE-MS and Heart-cut 2D–CE-MS

本研究進行固相萃取-毛細電泳質譜前濃縮介面之開發，利用PDMS的絕緣材質銜接SPE與CE管柱製作出SPE-CE-MS的線上銜接介面。 在這個介面的設計中，上下層的設計及正交的排列方向能避免有機相導入電泳通道而影響分離。以雙交錯進樣模式在SPE與電泳通道間提供有效的進樣電場，控制SPE的沖堤流速能決定樣品進樣的寬度(時間)。 胜肽標準品 (angiotensin II，Leu-enkephalin, 及 Met-enkephalin)在介面的測試中，可達到基線分離同時並保有毛細電泳的分離效率(~70-90k plates/m)。 使用固相萃取進行分析樣品的前濃縮，可偵測到低濃度(~86 nM)的色素蛋白C (Cytochrome C)蛋白質水解片段，並具有72%的序列涵蓋率。 分析複雜蛋白質水解胜肽時，為了增加毛細電泳分離複雜樣品的能力，我們提出了多次階段沖堤固相萃取毛細電泳的二維分離策略。 此策略是以多次沖堤固相萃取作為第一個維度的分離，而毛細電泳作為第二個維度分離。使用多次階段沖堤SPE-CE-MS/MS進行蛋白質水解胜肽混合物的分析，可比對到更多的胜肽片段(數量上超過一次沖堤的60%)，提升了蛋白質分析的序列涵蓋率及鑑定比對分數，增加蛋白質鑑定的可信度。 為了能縮短二維分離的時間，我們進一步提出交錯近樣電泳(staggered CE)的方法，能有效消除分析的空載時間(dead time)，節省超過一半的分析時間。 為了能避免耗時的廣泛性二維分析，我們提出心切式的二維電泳分離技術。利用心切介面使第一個分離維度中難以分離的混合物在第二個維度進行分離，並由雙通道電泳質譜達到兩種分離通道的同步分析。 本介面使用區帶電泳 (CZE)及微胞電動毛細層析電泳(MEKC)作為二維毛細電泳的兩種分離系統並以磺胺類的混合物進行心切式二維毛細電泳效能的評估。初步實驗的結果中四個被心切送入MEKC通道進行分離的磺胺類樣品(SDZ、SMR、STZ、SMM)具有相似單一MEKC的順序，初步證實了此系統在心切式二維分離系統上分析的可行性。A PDMS based two-leveled two cross design interface was proposed for on-line coupling SPE-CE-MS. In this interface, the SPE column and the CE separation column were positioned orthogonally and two crosses were fabricated on the interface. With the two cross design, the operation of SPE could be performed independently without unexpected flow through leakage into the separation column. The performance of the interface was optimized using a peptide mixture. The position of the SPE column related to the CE separation channel was found to be critical to the performance of the system. Under the optimal position, the separation efficiency was similar to a CE-MS experiment without SPE. The peptide signals were enhanced 50 to 100-fold and the repeatability was within 4% RSD for migration time and 10% RSD for peak area. A tryptic digest of cytochrome C was used to demonstrate the feasibility of the interface in protein identification at a level of 1 ng/mL. In a protein mixture analysis, the identification of proteins usually suffers in low sequence coverage in the single run CZE-ESI-MS/MS. An original concept of on-line coupling multistep elution solid phase extraction (SPE) to CZE-MS/MS was proposed to increase sequence coverage of protein mixture analysis. The multistep elution SPE (the first dimension) provides an additional dimension of separation prior to CZE (the second dimension) and extends the separation capacity for protein mixture analysis. Furthermore, a staggered CZE method was described to increase the throughput of each CZE runs in the second dimension separation and thus to reduce entire analysis time. In this study for protein mixture standards, more than 60% of additional peptides were discovered , and more than 50% was improved in sequence coverage by using multistep elution SPE-CE-MS/MS. By using staggered CZE method, half of the entire analysis time could be saved (54%) in comparison with the sequential CZE method used in multistep elution SPE-CE-MS/MS and thus avoiding the time-consuming analytical procedure in comprehensive 2D separation. An interface for heart-cut 2D CE-MS was proposed to increase separation selectivity in mixture analysis. Several concepts were adapted to overcome the limitations of heart-cut 2D-CE designed in the present studies. First, the manipulation of chip-based interface provides an isolated buffer system to connect two sets of capillary electrophoresis. Second, the parallel separation of the two dimensional capillary electrophoresis was detected simultaneously by a pulsed electrospray-based duel-channel CE-MS system. In this study, the system was demonstrated by using capillary zone electrophoresis- micellar electrokinetic chromatography (CZE-MEKC) system to analyze sulfonamide mixtures. Under the consideration of correspondence in EOF for fused silica capillary the PDMS based chip channel, 8 sulfonamide standards can be transferred successfully without loss and peak broadening during the heart-cutting operation. The preliminary feasibility of heart-cut CZE-MEKC with dual-channel CE-MS was studied in sulfonamides analysis. Four sulfonamides(SDZ、SMR、STZ、SMM) were transferred into the MEKC channel by the heart-cut interface after separation in the first dimension of CZE. The migration order of four heart-cut sulfonamides was found similar order in the single-run MEKC

Moderators of exercise effects on self-reported cognitive functioning in cancer survivors: an individual participant data meta-analysis

Purpose: This individual participant data meta-analysis (IPD-MA) assesses exercise effects on self-reported cognitive functioning (CF) and investigates whether effects differ by patient-, intervention-, and exercise-related characteristics. Methods: IPD from 16 exercise RCTs, including 1987 patients across multiple types of non-metastatic cancer, was pooled. A one-stage IPD-MA using linear mixed-effect models was performed to assess exercise effects on self-reported CF (z-score) and to identify whether the effect was moderated by sociodemographic, clinical, intervention- and exercise-related characteristics, or fatigue, depression, anxiety, and self-reported CF levels at start of the intervention (i.e., baseline). Models were adjusted for baseline CF and included a random intercept at study level to account for clustering of patients within studies. A sensitivity analysis was performed in patients who reported cognitive problems at baseline. Results: Minimal significant beneficial exercise effects on self-reported CF (β=−0.09 [−0.16; −0.02]) were observed, with slightly larger effects when the intervention was delivered post-treatment (n=745, β=−0.13 [−0.24; −0.02]), and no significant effect during cancer treatment (n=1,162, β=−0.08 [−0.18; 0.02]). Larger effects were observed in interventions of 12 weeks or shorter (β=−0.14 [−0.25; −0.04]) or 24 weeks or longer (β=−0.18 [−0.32; −0.02]), whereas no effects were observed in interventions of 12–24 weeks (β=0.01 [−0.13; 0.15]). Exercise interventions were most beneficial when provided to patients without anxiety symptoms (β=−0.10 [−0.19; −0.02]) or after completion of treatment in patients with cognitive problems (β=−0.19 [−0.31; −0.06]). No other significant moderators were identified. Conclusions: This cross-cancer IPD meta-analysis observed small beneficial exercise effects on self-reported CF when the intervention was delivered post-treatment, especially in patients who reported cognitive problems at baseline. Implications for Cancer Survivors: This study provides some evidence to support the prescription of exercise to improve cognitive functioning. Sufficiently powered trials are warranted to make more definitive recommendations and include these in the exercise guidelines for cancer survivors