Differentiated resistance training of the paravertebral muscles in patients with unstable spinal bone metastasis under concomitant radiotherapy: study protocol for a randomized pilot trial

Background: Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. Methods/Design: This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. Discussion: Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. Trial registration: ClinicalTrials.gov, identifier: NCT02847754. Registered on 27 July 2016

Exercise recommendations for people with bone metastases: Expert consensus for healthcare providers and clinical exercise professionals

Purpose: Exercise has been underutilized in people with advanced or incurable cancer despite the potential to improve physical function and reduce psychosocial morbidity, especially for people with bone metastases because of concerns over skeletal complications. The International Bone Metastases Exercise Working Group (IBMEWG) was formed to develop best practice recommendations for exercise programming for people with bone metastases on the basis of published research, clinical experience, and expert opinion. Methods: The IBMEWG undertook sequential steps to inform the recommendations: (1) modified Delphi survey, (2) systematic review, (3) cross-sectional survey to physicians and nurse practitioners, (4) in-person meeting of IBMEWG to review evidence from steps 1-3 to develop draft recommendations, and (5) stakeholder engagement. Results: Recommendations emerged from the contributing evidence and IBMEWG discussion for pre-exercise screening, exercise testing, exercise prescription, and monitoring of exercise response. Identification of individuals who are potentially at higher risk of exercise-related skeletal complication is a complex interplay of these factors: (1) lesion-related, (2) cancer and cancer treatment–related, and (3) the person-related. Exercise assessment and prescription requires consideration of the location and presentation of bone lesion(s) and should be delivered by qualified exercise professionals with oncology education and exercise prescription experience. Emphasis on postural alignment, controlled movement, and proper technique is essential. Conclusion: Ultimately, the perceived risk of skeletal complications should be weighed against potential health benefits on the basis of consultation between the person, health care team, and exercise professionals. These recommendations provide an initial framework to improve the integration of exercise programming into clinical care for people with bone metastases

Vascular surveillance by haptotactic blood platelets in inflammation and infection

Breakdown of vascular barriers is a major complication of inflammatory diseases. Anucleate platelets form blood-clots during thrombosis, but also play a crucial role in inflammation. While spatio-temporal dynamics of clot formation are well characterized, the cell-biological mechanisms of platelet recruitment to inflammatory micro-environments remain incompletely understood. Here we identify Arp2/3-dependent lamellipodia formation as a prominent morphological feature of immune-responsive platelets. Platelets use lamellipodia to scan for fibrin(ogen) deposited on the inflamed vasculature and to directionally spread, to polarize and to govern haptotactic migration along gradients of the adhesive ligand. Platelet-specific abrogation of Arp2/3 interferes with haptotactic repositioning of platelets to microlesions, thus impairing vascular sealing and provoking inflammatory microbleeding. During infection, haptotaxis promotes capture of bacteria and prevents hematogenic dissemination, rendering platelets gate-keepers of the inflamed microvasculature. Consequently, these findings identify haptotaxis as a key effector function of immune-responsive platelets

Exercise for individuals with bone metastases: A systematic review

Background Exercise has the potential to improve physical function and quality of life in individuals with bone metastases but is often avoided due to safety concerns. This systematic review summarizes the safety, feasibility and efficacy of exercise in controlled trials that include individuals with bone metastases. Methods MEDLINE, Embase, Pubmed, CINAHL, PEDro and CENTRAL databases were searched up to July 16, 2020. Results A total of 17 trials were included incorporating aerobic exercise, resistance exercise or soccer interventions. Few (n=4, 0.5%) serious adverse events were attributed to exercise participation, with none related to bone metastases. Mixed efficacy results were found, with exercise eliciting positive changes or no change. The majority of trials included an element of supervised exercise instruction (n=16, 94%) and were delivered by qualified exercise professionals (n=13, 76%). Conclusions Exercise appears safe and feasible for individuals with bone metastases when it includes an element of supervised exercise instruction

Associations between genetic variants in mRNA splicing-related genes and risk of lung cancer: a pathway-based analysis from published GWASs

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer

Exercise Recommendation for People With Bone Metastases: Expert Consensus for Health Care Providers and Exercise Professionals

PURPOSE:Exercise has been underutilized in people with advanced or incurable cancer despite the potential to improve physical function and reduce psychosocial morbidity, especially for people with bone metastases because of concerns over skeletal complications. The International Bone Metastases Exercise Working Group (IBMEWG) was formed to develop best practice recommendations for exercise programming for people with bone metastases on the basis of published research, clinical experience, and expert opinion.METHODS:The IBMEWG undertook sequential steps to inform the recommendations: (1) modified Delphi survey, (2) systematic review, (3) cross-sectional survey to physicians and nurse practitioners, (4) in-person meeting of IBMEWG to review evidence from steps 1-3 to develop draft recommendations, and (5) stakeholder engagement.RESULTS:Recommendations emerged from the contributing evidence and IBMEWG discussion for pre-exercise screening, exercise testing, exercise prescription, and monitoring of exercise response. Identification of individuals who are potentially at higher risk of exercise-related skeletal complication is a complex interplay of these factors: (1) lesion-related, (2) cancer and cancer treatment–related, and (3) the person-related. Exercise assessment and prescription requires consideration of the location and presentation of bone lesion(s) and should be delivered by qualified exercise professionals with oncology education and exercise prescription experience. Emphasis on postural alignment, controlled movement, and proper technique is essential.CONCLUSION:Ultimately, the perceived risk of skeletal complications should be weighed against potential health benefits on the basis of consultation between the person, health care team, and exercise professionals. These recommendations provide an initial framework to improve the integration of exercise programming into clinical care for people with bone metastases

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-control-covariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled false-positive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1×10−9). The improvement varied across diseases with a 16% median increase in χ2 test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci

EMG and Heart Rate Responses Decline within 5 Days of Daily Whole-Body Vibration Training with Squatting

In this study, we examined the acute effects of a 5-day daily whole-body vibration (WBV) training on electromyography (EMG) responses of the m. rectus femoris and m. gastrocnemius lateralis, heart rate (HR, continuously recorded), and blood lactate levels. The purpose of the study was to investigate the adaptation of muscle activity, heart rate and blood lactate levels during 5 days of daily training. Two groups of healthy male subjects performed either squat exercises with vibration at 20 Hz on a side alternating platform (SE+V, n = 20, age = 31.9 (+/-) 7.5 yrs., height = 178.8 (+/-) 6.2 cm, body mass = 79.2 (+/-) 11.4 kg) or squat exercises alone (SE, n = 21, age = 28.4 (+/-) 7.3 years, height = 178.9 (+/-) 7.4 cm, body mass = 77.2 (+/-) 9.7 kg). On training day 1, EMG amplitudes of the m. rectus femoris were significantly higher (P,0.05) during SE+V than during SE. However, this difference was no longer statistically significant on training days 3 and 5. The heart rate (HR) response was significantly higher (P<0.05) during SE+V than during SE on all training days, but showed a constant decline throughout the training days. On training day 1, blood lactate increased significantly more after SE+V than after SE (P<0.05). On the following training days, this difference became much smaller but remained significantly different. The specific physiological responses to WBV were largest on the initial training day and most of them eclined during subsequent training days, showing a rapid neuromuscular and cardiovascular adaptation to the vibration stimulus

Do we underestimate maximal oxygen uptake in cancer survivors? Findings from a supramaximal verification test

Cancer survivors demonstrate a reduced maximal oxygen uptake (VO2max) which is clinically relevant in terms of overall survival. However, it remains uncertain whether they attain their true VO2max in a cardiopulmonary exercise test (CPET). In the present study, a supramaximal verification bout (Verif) was applied in cancer survivors to confirm attainment of VO2max. Seventy-five participants (6112 years, n=43 females with breast cancer and n=32 males with prostate cancer, 6-52 weeks after primary therapy) performed a CPET on a cycle ergometer and a Verif at 110% peak power output. As verification criterion, VO2max in Verif should not exceed VO2max in CPET by >3%. On average, VO2max was significantly lower in Verif compared to CPET (1.600.38 l/min vs. 1.650.36 l/min, p=.023). On the individual level, n=51 (68%) satisfied the verification criterion, whereas n=24 (32%) demonstrated a higher VO2max in Verif. N=69 (92%) fulfilled ≥ 2 secondary criteria for maximal exhaustion in the CPET. While VO2max was not underestimated in the CPET on average, still one third of cancer survivors did not attain their true VO2max. Verif appears feasible and beneficial to confirm true VO2max in this population. Furthermore, it might be more reliable than secondary criteria for maximal exhaustion. Novelty bullets: • In about one third of cancer survivors, VO2max is underestimated by a CPET. • This underestimation of VO2max is not necessarily indicated by secondary criteria for maximal exhaustion. • A supramaximal verification bout appears feasible and helpful for the determination of VO2max in cancer survivors.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author