Preventive Effect of Neuromuscular Training on Chemotherapy-Induced Neuropathy: A Randomized Clinical Trial.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and clinically relevant adverse effect of chemotherapy, negatively impacting patient quality of life. The lack of effective preventive or therapeutic options regarding CIPN often requires changes in cancer therapy, potentially resulting in reduced survival. Objective: To determine whether sensorimotor training (SMT) and whole-body vibration (WBV) training reduce symptoms and decrease the onset of CIPN. Design, Setting, and Participants: This prospective multicenter randomized clinical trial (STOP) followed up patients over 5 years at 4 centers in or near Cologne, Germany. Patients undergoing treatment with oxaliplatin or vinca alkaloids were recruited. Participants were recruited from May 2014 to November 2020. Data were last analyzed in June 2021. Interventions: Participants in the intervention groups performed supervised SMT or WBV training sessions twice a week, each lasting approximately 15 to 30 minutes, concomitant to medical therapy. Main Outcomes and Measures: The primary end point was the incidence of CIPN. Secondary end points included subjective neuropathy symptoms, balance control, physical activity levels, quality of life, and clinical outcome. For cross-stratum evaluations, the Mantel-Haenszel test (MH) was used, and within individual strata, Fisher exact test was used for analysis. Results: A total of 1605 patients were screened, and 1196 patients did not meet all inclusion criteria, with 251 further excluded or declining participation. A total of 158 patients (mean [SD] age, 49.1 [18.0-82.0] years; 93 [58.9%] male) were randomized into 1 of 3 groups: 55 (34.8%) in SMT, 53 (33.5%) in WBV, and 50 (31.6%) in treatment as usual (TAU). The incidence of CIPN in participants was significantly lower in both intervention groups compared to the control group (TAU): (SMT, 12 of 40 [30.0%; 95% CI, 17.9%-42.1%] and WBV, 14 of 34 [41.2%; 95% CI, 27.9%-54.5%] vs TAU, 24 of 34 [70.6%; 95% CI, 58.0%-83.2%]; P = .002 for intention to treat-MH). Patients receiving vinca alkaloids and performing SMT benefited the most. Results were more pronounced in a per-protocol analysis (>75% participation in the intervention) (SMT, 8 of 28 [28.6%; 95% CI, 16.6%-40.5%] and WBV, 9 of 24 [37.5%; 95% CI, 24.4%-50.5%] vs TAU, 22 of 30 [73.3%; 95% CI, 61.6%-85.6%]). Improvements in favor of SMT compared to TAU were found for balance control bipedal with eyes open; bipedal with eyes closed; monopedal, vibration sensitivity, sense of touch, lower leg strength, pain reduction, burning sensation, chemotherapy dose reductions, and mortality. Conclusion and Relevance: This randomized clinical trial provides initial evidence that neuromuscular training decreases the onset of CIPN. Trial Registration: German Clinical Trials Register: DRKS00006088.

Preoperative exercise induces endothelial progenitor cell mobilisation in patients undergoing major surgery - A prospective randomised controlled clinical proof-of-concept trial.

Introduction: Prehabilitation is increasingly recognised as a therapeutic option to reduce postoperative complications. Investigating the beneficial effects of exercise on cellular mechanisms, we have previously shown that a single episode of exhaustive exercise effectively stimulates endothelial progenitor cells (a cell population associated with vascular maintenance, repair, angiogenesis, and neovascularization) in correlation with fewer postoperative complications, despite the ongoing debate about the appropriate cell surface marker profiles of these cells (common phenotypical definitions include CD45dim, CD133+, CD34+ and/or CD31+). In order to translate these findings into clinical application, a feasible prehabilitation programme achieving both functional and cellular benefits in a suitable timeframe to expedite surgery is necessary. Objective: The objective of this study was to test the hypothesis that a four-week prehabilitation programme of vigorous-intensity interval exercise training is feasible, increases physical capacity (primary outcome) and the circulatory number of endothelial progenitor cells within peripheral blood. Methods: In this unblinded, parallel-group, randomised controlled proof-of-concept clinical trial (German Clinical Trial Register number: DRKS00000527) conducted between 01st December 2014 and 30th November 2016, fifteen female adult patients scheduled for incontinence surgery with abdominal laparotomy at the University Hospital Cologne were allocated to either an exercise (n = 8, exclusion of 1 patient, analysed n = 7) or non-exercise group (n = 7, exclusion of 1 patient, analysed n = 6). The exercise group's intervention consisted of a vigorous-intensity interval training for four weeks preoperatively. Cardiopulmonary Exercise Testing accompanied by peripheral blood collection was performed before and after the (non-)training phase. Cellular investigations were conducted by flow cytometry and cluster-based analyses. Results: Vigorous-intensity interval training over four weeks was feasible in the exercise group (successful completion by 8 out of 8 patients without any harms), with significant improvements in patients' functional capacity (increased oxygen uptake at anaerobic threshold [intervention group mean + 1.71 ± 3.20 mL/min/kg vs. control group mean -1.83 ± 2.14 mL/min/kg; p = 0.042] and peak exercise [intervention group mean + 1.71 ± 1.60 mL/min/kg vs. control group mean -1.67 ± 1.37 mL/min/kg; p = 0.002]) and a significant increase in the circulatory number of endothelial progenitor cells (proportionate CD45dim/CD14dim/CD133+/CD309+/CD34+/CD31 + subpopulation within the circulating CD45-pool [p = 0.016]). Conclusions: We introduce a novel prehabilitation concept that shows effective stimulation of an endothelial progenitor cell subpopulation within four weeks of preoperative exercise, serving as a clinical cell-mediated intervention with the aim to reduce surgical complications. Funding: Institutional funding. DFG (German Research Foundation, 491454339) support for the Article Processing Charge.

Acute exercise impacts AhR and PD-1 levels of CD8+ T-cells-Exploratory results from a randomized cross-over trial comparing endurance versus resistance exercise.

PURPOSE: The programmed cell death protein 1 (PD-1) has become a promising target in cancer immunotherapy. PD-1 expression of CD8+ T-cells may be increased via the exploitation of aryl hydrocarbon receptor (AhR) signaling with kynurenine (KYN) as a ligand. Since exercise affects KYN metabolism, we exploratory investigated the influence of acute exercise bouts on AhR and PD-1 levels of CD8+ T-cells. METHOD: In this study, 24 healthy males (age: 24.6 ± 3.9 years; weight 83.9 ± 10.5 kg; height: 182.4 ± 6.2 cm) completed a single bout of endurance (EE) and resistance exercise (RE) in a randomly assigned order on separate days. Blood samples were drawn before (t0), after (t1), and 1 h after (t2) both conditions. T-cell populations, the level of cytoplasmic AhR, and surface PD-1 were assessed by flow cytometry. RESULTS: T-cell populations changed over time, indicated by an increase in the absolute numbers of CD3+ lymphocytes after EE (p < .001) and RE (p = .036) and in PD-1+ CD8+ T-cells after EE (p = .021). Proportions of T-cell populations changed only after EE (t0-t2: p = .029; t1-t2: p = .006). The level of cytoplasmic AhR decreased immediately after exercise in both exercise conditions (EE: p = .009; RE: p = .036). The level of surface PD-1 decreased 1 h after EE (p = .005). CONCLUSION: We analyzed the level of surface PD-1 and cytoplasmic AhR following acute physical exercise for the first time. Especially EE was observed to impact both AhR and PD-1 levels, undermining its role as the AhR-PD-1 axis modulator. These results provide new insights into the impact of exercise on AhR-signaling, which could potentially be relevant for various chronic diseases.

Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training.

INTRODUCTION: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise. METHODS: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes. RESULTS: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session. CONCLUSIONS: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations.

Cellular immune response to acute exercise: Comparison of endurance and resistance exercise.

OBJECTIVES: Exercise-induced cellular mobilization might play a role in treatment and prevention of several diseases. However, little is known about the impact of different exercise modalities on immune cell mobilization and clinical cellular inflammation markers. Therefore, the present study aimed to investigate differences between acute endurance exercise (EE) and resistance exercise (RE) on cellular immune alterations. METHODS: Twenty-four healthy men conducted an acute EE (cycling at 60% of peak power output) and RE (five exercise machines at 70% of the one-repetition maximum) session lasting 50 minutes in randomized order. Blood samples were collected before, after and one hour after exercise cessation. Outcomes included counts and proportions of leukocytes, neutrophils (NEUT), lymphocytes (LYM), LYM subsets, CD4/CD8 ratio, and the clinical cellular inflammation markers NEUT/LYM ratio (NLR), platelets/LYM ratio (PLR), and systemic immune inflammation index (SII). RESULTS: Alterations in all outcomes were revealed except for CD8+ T cells, CD4/CD8 ratio, NLR, and PLR. EE induced a stronger cellular immune response and provoked alterations in more immune cell populations than RE. SII was altered only after EE. CONCLUSION: An acute EE session causes a stronger mobilization of immune cells than RE. Additionally, SII represents an integrative marker to depict immunological alterations.

Do Acute Exercise-Induced Activations of the Kynurenine Pathway Induce Regulatory T-Cells on the Long-Term? - A Theoretical Frame Work Supported by Pilot Data.

Regular physical activity and exercise interventions are suspected to have anti-inflammatory effects depending on exercise modality, thereby potentially reducing the risk and progress of several chronic diseases. Alterations in the kynurenine pathway may represent a link between inflammatory responses following acute exercise and chronic anti-inflammatory properties, such as increased levels of regulatory T-cells (Treg). Here, we hypothesize that acute exercise activates the kynurenine pathway and physical fitness is associated with proportions of circulating anti-inflammatory Treg in older healthy women. Nineteen older healthy female participants (55 years (SD: ± 5.6)) completed a cardiopulmonary incremental exercise test (CPET) with spirometry on a bicycle ergometer until exhaustion with maximum oxygen uptake (VO2max) as outcome. Blood samples were taken before (T0) and one minute after (T1) the CPET. Levels of tryptophan, serotonin and kynurenine were determined by enzyme-linked immunosorbent assays. Flow cytometry was used to identify proportions of T-cell subsets. Both, kynurenine (p = 0.003, d = 0.40) and the kynurenine/tryptophan ratio (p = 0.034, d = 0.48) increased significantly after acute exercise. Moreover, participants` VO2max was strongly correlated with Treg levels (p < 0.001, r = 0.689). This is the first study indicating a kynurenine pathway activation following acute exercise in older healthy women. The observed correlation between Treg levels and VO2max emphasizes a potential link between short-term upregulated kynurenine levels and longer-term anti-inflammatory properties of exercise. Future research is needed to clarify to what extend acute exercise-induced activations of the kynurenine pathway contribute to Treg differentiation.

Individually tailored whole-body vibration training to reduce symptoms of chemotherapy-induced peripheral neuropathy: study protocol of a randomised controlled trial-VANISH.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and clinically meaningful side effect of cancer treatment. CIPN is induced by neurotoxic agents, causing severe sensory and/or motor deficits, resulting in disability and poor recovery, reducing patients' quality of life and limiting medical therapy. To date, effective treatment options are lacking. Whole-body vibration (WBV) training can attenuate motor and sensory deficits. We are conducting a two-armed, multicentre, assessor-blinded, randomised controlled trial, to investigate the effects of WBV on relevant symptoms of CIPN and determine the training characteristics. METHODS AND ANALYSIS: In this ongoing study, 44 patients who have completed therapy in the past 3 months, with a neurologically confirmed CIPN are assessed before and after a 12-week intervention and follow-up. The intervention group receives WBV twice a week. Exercises are individually tailored according to the initially determined optimal neuromuscular response. The control group receives care as usual.Primary endpoint is the patient reported reduction of CIPN-related symptoms (Functional Assessment of Cancer Therapy/Gynaecology Oncology Group-Neurotoxicity). Secondary endpoints are compound muscle action potentials, distal motor latency, conduction velocity, F-waves from the tibial and peroneal nerve, antidromic sensory nerve conduction studies of the sural nerve, normalised electromyographic activity, peripheral deep sensitivity, proprioception, balance, pain, the feasibility of training settings, quality of life and the level of physical activity. AIM, ETHICS AND DISSEMINATION: The study was approved by both responsible ethics committees. (1) Our results may contribute to a better understanding of the effects of WBV on motor and sensory functions and (2) may provide information whether WBV at the most effective setting, is feasible for neuropathic patients. (3) Our results may also contribute to improve supportive care in oncology, thereby enhancing quality of life and enabling the optimal medical therapy. All results will be published in international peer-reviewed journals as well as a manual for clinical practice. TRIAL REGISTRATION NUMBER: NCT03032718.

Acute and chronic effects of exercise on the kynurenine pathway in humans - A brief review and future perspectives.

Tryptophan (TRP) is an essential amino acid. Metabolites of TRP have been identified as important mediators in immune regulation and function of the central nervous system. Inflammation strongly stimulates to the breakdown of TRP into Kynurenine (KYN), representing the initial step of the KYN pathway. Recently, exercise interventions have been able to demonstrate a modification of the KYN pathway plausibly by altering inflammation. However, modifications differ between acute and chronic exercise interventions. As such, this review examines the current studies that have investigated the effect of an acute (single bout) or chronic (training) exercise intervention on levels of TRP and KYN in both healthy and diseased populations.

The preventive effect of sensorimotor- and vibration exercises on the onset of Oxaliplatin- or vinca-alkaloid induced peripheral neuropathies - STOP.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and clinically relevant side effect of chemotherapy. Approximately 50% of all leukemia, lymphoma, colorectal- and breast cancer patients are affected. CIPN is induced by neurotoxic chemotherapeutic agents and can manifest with sensory and/or motor deficits. It is associated with significant disability and poor recovery. Common symptoms include pain, altered sensation, reduced or absent reflexes, muscle weakness, reduced balance control and insecure gait. These symptoms not only affect activities of daily living, subsequently reducing patients' quality of life, they have far more become a decisive limiting factor for medical therapy, causing treatment delays, dose reductions, or even discontinuation of therapy, which can affect the outcome and compromise survival. To date, CIPN cannot be prevented and its occurrence presents a diagnostic dilemma since approved and effective treatment options are lacking. Promising results have recently been achieved with exercise. We have revealed that sensorimotor training (SMT) or whole body vibration (WBV) can reduce the symptoms of CIPN and attenuate motor and sensory deficits. We furthermore detected a tendency that it may also have a preventive effect on the onset of CIPN. METHODS: We are therefore conducting a prospective, multicentre, controlled clinical trial involving 236 oncological patients receiving either oxaliplatin (N = 118) or vinca-alkaloid (N = 118) who are randomized to one of two interventions (SMT or WBV) or a treatment as usual (TAU) group. Primary endpoint is the time to incidence of neurologically confirmed CIPN. Secondary endpoints are pain, maintenance of the functionality of sensory as well as motor nerve fibres as well as the level of physical activity. The baseline assessment is performed prior to the first cycle of chemotherapy. Subsequent follow-up assessments are conducted at 12 weeks, after completion of chemotherapy, and at a 3-month follow-up. Patients who develop CIPN receive an additional assessment at this time point, as it represents the primary endpoint. DISCUSSION: We hypothesize that SMT and WBV prevent the onset or delay the progression of CIPN, decrease the likelihood of dose reductions or discontinuation of cancer treatment and improve patients' quality of life. TRIAL REGISTRATION: Deutsche Register Klinischer Studien ( DRKS00006088 , registered 07.05.2014).

Persons with secondary progressive and relapsing remitting multiple sclerosis reveal different responses of tryptophan metabolism to acute endurance exercise and training.

Disturbances in Tryptophan metabolism play a crucial role in multiple sclerosis (MS). Exercise is suspected to counteract the progress of MS and its side effects. Current research suggests alterations of Tryptophan metabolism in healthy individuals in response to exercise. We investigated the influence of acute aerobic exercise and training on Tryptophan metabolism in 57 inpatients with relapsing remitting ((RRMS) n=33) and secondary progressive ((SPMS) n=24) MS. Serotonin increased after training, whereas the kynurenine pathway was only activated in persons with RRMS. Further research is warranted to investigate whether these changes are associated with clinical measures (e.g. depressions and immune function).

Impact of training volume and intensity on RBC-NOS/NO pathway and endurance capacity.

BACKGROUND: Acute exercise increases red blood cell-nitric oxide synthase (RBC-NOS) activation and RBC deformability but the effect of regular training remains unclear. OBJECTIVE: To detect the chronic effect of enduring moderate and high intensity training on the RBC-NOS/NO pathway and to detect a relation between RBC deformability and endurance capacity. METHODS: 38 healthy male subjects were randomly assigned to one of three training groups: High Volume Training (HVT; 120-140 beats per minute (bpm)), High Intensity Training (HIT; 160-180 bpm) and Moderate Intensity Training (MIT; 140-160 bpm). Blood parameters, maximum oxygen capacity (VO2 max), RBC deformability, RBC nitrite level and RBC-NOS activation were measured after venous blood sampling at rest pre (T0) and after six weeks of training (T1). RESULTS: RBC-NOS activation, RBC nitrite concentration and RBC deformability were significantly increased at T1 in the HIT group. Parameters were unaltered in MIT and HVT. Maximum oxygen uptake was only significantly increased in the HIT group and regression analysis revealed positive regression between VO2 max and RBC deformability. CONCLUSIONS: High intensity training was the only training programme that sustainably affected RBC-NOS dependent NO production and performance capacity. HIT therefore represents a time efficient training program resulting in improved RBC function potentially improving physical condition.

Decrease in red blood cell deformability is associated with a reduction in RBC-NOS activation during storage.

During storage, red blood cells (RBC) become more susceptible to hemolysis and it has also been shown that RBC deformability, which is influenced by RBC nitric oxide synthase (RBC-NOS) activity, decreases during blood storage while a correlation between these two parameters under storage conditions has not been investigated so far. Therefore, blood from 15 male volunteers was anticoagulated, leuko-reduced and stored as either concentrated RBC or RBC diluted in saline-adenine-glucose-mannitol (SAGM) for eight weeks at 4°C and results were compared to data obtained from freshly drawn blood. During storage, decrease of RBC deformability was related to increased mean cellular volume and increased cell lysis but also to a decrease in RBC-NOS activation. The changes were more pronounced in concentrated RBC than in RBC diluted in SAGM suggesting that the storage method affects the quality of blood. These data shed new light on mechanisms underlying the phenomenon of storage lesion and reveal that RBC-NOS activation and possibly nitric oxide production in RBC are key elements that are influenced by storage and in turn alter deformability. Further studies should therefore also focus on improving these parameters during storage to improve the quality of stored blood with respect to blood transfusion.