Musculoskeletal Diseases

Nervous System Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Muscle Weakness

Hematologic Neoplasms

Paresis

Asthenia

Hematologic Diseases

Muscular Diseases

Neuromuscular Manifestations

Neurologic Manifestations

Vasoconstrictor Agents

Respiratory System Agents

All Drugs and Chemicals

Cardiotonic Agents

Oxymetazoline

Phenylephrine

The lower extremity resistance exercise (REx) program was designed by reviewing the exercise principles recommended by the ACSM and the literature on physical activity and hematological cancer patients. The patients were treated for 40-60mins, 6 weeks. The exercise program includes active movements of the upper and lower extremities, stretching exercises, and resistance exercises for the lower extremities. REx to be applied with resistance bands of different resistance or with the patient's body weight. Clinical force generation of therapy bands follows a progression. Our proposed training protocol includes 4-6 different exercises for each extremity. Intensity, sets, and reps were adjusted to a target score of 12 to 14 using the Borg scale. Patients performed 1 set of 10 repetitions of each REx based on their fatigue level. Intensity (\~ RPE 15-16) and resistance were gradually increased. When the patient complained of extreme fatigue, the resistance was reduced to the previous level.

In addition to resistance exercises, NMES will be applied to the quadriceps muscles in both legs of the patients in this group. The application will be made with a portable device using disposable electrodes. One of the electrodes will be placed proximally, that is, at the midpoint of the quadriceps muscle, while the second electrode will be placed on the distal part. In order to ensure that the patients get used to the device, low-intensity current with a frequency range of 5 Hz, 10-30 minutes. Afterward, the treatment program will continue with a high-frequency current with a frequency range of 50 Hz, 15 minutes. Participants were instructed to voluntarily contract the quadriceps muscles during periods of HF-NMES stimulation to increase the strengthening effect and improve NMES tolerance.

Neuromuscular Electrical Stimulation (NMES) is based on the principle of creating a contraction by stimulating the nerve fibers innervating the related muscle in the healthy muscle and the muscle fibers in the denervated muscle with electrical current. The electric currents used in stimulation of muscles and nerves perform this function by changing the electrical potential of cell membranes.

It is contraindicated in pregnancy, presence of pacemaker, severe heart disease, epilepsy, fracture, dementia and impaired consciousness. We prevent contraindicated situations by excluding volunteer participants with these characteristics.

Neuromuscular Electrical Stimulation

Warm-up exercise, main training program and cool down exercise. Main training consists of resistance exercises to be applied with resistance bands of different resistance or with the patient's own body weight. Our prescribed training protocol includes 4-6 different exercises for each limb (bench press with resistance band, upper extremity proprioceptive neuromuscular facilitation exercises, biceps/triceps curl, leg press, knee extension, 4-way hip motion, mini squat). Intensity, sets, and number of repetitions will be adapted to a target score between 12 and 14 using the Borg scale. It will be applied as low intensity, long-term passive stretching exercises to the pectoral, hamstring, and gastrosoleus muscle groups. Patients will perform 1 set of 10 repetitions of each resistance exercise determined by their level of fatigue. Resistance will be increased every three visits. If the patient complains of excessive fatigue, the resistance will be reduced to the previous level.

Structured Exercise

Ant Uzay, MD

Fatma Mutluay, Prof

Elif Es Safran, MSc

Physical activity levels of adult hematologic cancer patients are deficient. The resulting physical inactivity causes fatigue, muscle loss, and deterioration in physical performance values. However, physical exercise programs still play a minor role in treating hematological malignancies. In addition, there are no reliable data in the literature regarding risk factors, feasibility, and exercise results in individuals with hematological malignancies. Although it is known that the use of corticosteroids, which are among the drugs given during chemotherapy, causes muscle weakness, there are no physical exercise programs performed with this patient group in the literature. The current study aims to compare the effects of resistance exercise and resistance exercise combined with neuromuscular electrical stimulation on muscle strength, functional lower extremity strength, and mobility in hematological cancer patients during chemotherapy.

Although people with hematological malignancies have to endure long stages of treatment and inactivity that are known to reduce their physical performance levels, it is still common practice to rest and avoid intense exercise. Although physical activity and exercise are important approaches to many diseases, their effects on cancer have been studied recently. There are still not enough studies in this area and it is not widely used. In recent studies, it is thought that exercise may benefit the symptoms that develop due to treatment in cancer patients. Even in the presence of severe muscle weakness and fatigue, skeletal muscle provides great adaptation when there is an appropriate exercise stimulus. In addition, exercise can increase immune functions, so it is thought that exercise practices in hematological cancer patients can specifically improve cellular functions such as microbial phagocytosis, T-cell proliferation, vaccine response, and killing tumor cells. There are various studies and approaches that try to create a different strategy and include physical exercise in the treatment strategy of hematological malignancies. These exercise programs generally include aerobics, flexibility, and resistance training methods. The necessity of developing alternative methods to exercise is emphasized in the literature due to the development of complications that affect participation in basic exercises such as walking. Resistance exercise training has been effective in improving muscle strength and endurance in cancer survivors, with most of the research on those with breast cancer, prostate cancer, and head and neck cancer. The number of studies providing strengthening training in patients with hematological cancer is limited. Neuromuscular electrical stimulation (NMES) has proven efficacy in improving muscle strength in a variety of populations. NMES training also has applicability for the cancer population to prevent treatment-related complications and improve health-related quality of life. However, there is still no high-level evidence to support the administration of NMES in cancer patients. In the present study, we aimed to evaluate the effect of resistance exercise improve muscle weakness in hematological cancer patients receiving intensive chemotherapy after HSCT. In addition, we aimed to evaluate the effect of resistance exercise and NMES training on fatigue, mobility, and quality of life in hematological cancer patients.

Effects of NMES and Exercise in Hematological Cancer

Effects of Neuromuscular Electrical Stimulation Combined With Resistance Exercises on Muscle Strength in Adult Hematological Cancer Patients: A Randomized Controlled Study

An overall assessment of activity level will be based on the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale based on the degree of muscle weakness found in the Cancer Treatment Evaluation Program Common Toxicity Criteria, and patients with an ECOG performance status of 1-3 will be treated.

Participants' muscle strength measurements will be made using a digital hand dynamometer (J Tech Commander Muscle Tester). The patients will be seated in the appropriate position and the dynamometer will be placed in the dominant leg to give resistance to the muscle to be evaluated. While patients press the dynamometer as hard as possible for three seconds, the evaluator will give resistance to prevent any movement to provide an isometric contraction. Following the familiarization test, patients will perform three trials with standardized verbal encouragement and the highest strength (kilogram, kg) sustained for over half a second will be recorded.

Lower extremity functional strength will be evaluated using the "Sit and Stand for 30 sec" test. The patient will be instructed to stand up and sit back and forth from a standardized chair as quickly as possible in 30 seconds without using his arms. Participants will be able to use their hands to help them stand as needed, and standardized verbal encouragement will be provided to continue sitting and standing throughout the test.

Thigh circumference measurement will be made from the middle of the thigh over the Quadriceps muscle. By marking the inguinal region and the proximal part of the patella, the midpoint between the two points will be found. All measurements will be made on the right side and by the same physiotherapist.

"Timed Up-Go Test" will be applied before and after treatment to evaluate the patient's mobility and functional exercise capacity. The time taken to complete the task is strongly correlated with the level of functional mobility. In other words, the longer the person completes the task, the more dependent he is on daily life activities.

The Brief Fatigue Scale will be used to assess cancer-related fatigue in our study. This scale is one of the standard tests used to evaluate fatigue in cancer patients. Evaluates the level of fatigue in the last 24 hours and the effect of fatigue on daily activities (general activity, mood, walking ability, work life, relationships with other people, joy of life)

The assessment of quality of life will be carried out using the European Cancer Research and Treatment Organization Quality of Life Questionnaire Version 3.0. The scale consists of three subsections: general health status scale, functional scale, and symptom scale, and includes a total of 30 questions.

Medipol University

Acibadem University

Lecturer

Immune System Diseases

Heart and Blood Diseases

Nutritional and Metabolic Diseases

Rare Diseases

Muscular Atrophy

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Wasting Syndrome

Cachexia

Lymphosarcoma

asymmetric biphasic waveforms at 71 pulses per second frequency (Hz), 400 s pulse duration, 5:10s on:off time (50% duty cycle), and 1.5s ramp-up time. Participants will be in control of the muscle stimulator devices at all times and will be instructed to perform all sessions in the supine position. Bilateral NMES will be delivered via asymmetric, biphasic using four cutaneous parallel channels delivered simultaneously using 2"x4" or 3"x5" self-adhesive electrodes. For the active NMES group, participants will be encouraged to increase the amplitude to a level of moderate discomfort, such as that experienced during conventional exercise, but not to induce pain. At minimum, the amplitude should induce visible muscle contraction.

The amplitude of the muscle stimulators for the Sham group will be capped at 15 milliamperes so patients will only feel cutaneous sensation without achieving muscle contraction.

Active or Sham Neuromuscular electrical stimulation. US Food and Drug Administration-approved 2012

RS-4i Plus Sequential Stimulator (RS Medical, Vancouver, WA)

Lindsey J Anderson, PhD

Jose M Garcia, MD PhD

Some blood, bone marrow, and lymphatic (hematologic) cancers such as Hodgkin/Non-Hodgkin lymphomas, chronic lymphocytic leukemia, and multiple myeloma, are over-represented in Veterans due to exposures including Agent Orange and an increased percentage of patients of African American ethnicity. Hematologic transplantation (HCT) is a common treatment for these cancers, but often leads to deconditioning, fatigue, muscle atrophy, and poor quality of life, which are associated with complications such as hospitalization and infection. Despite the significance of these symptoms, there are no approved treatments to prevent/reverse these long-term effects. The cancer itself, side effects of chemotherapy, and sedentary behavior, contribute to these effects. Although exercise before and after HCT has helped reduce these effects, it is inconsistently recommended to patients and most remain sedentary through and after treatment. The investigators are testing an alternative exercise strategy, neuromuscular electrical stimulation, to maintain physical function quality of life after HCT.

Hematopoietic cell transplantation (HCT) reduces physical function and muscle mass and increases fatigue. Neuromuscular electrical stimulation (NMES), when used as a stand-alone intervention, improves muscle strength and muscle mass in non-cancer patients with chronic obstructive pulmonary disease and chronic heart failure. The use of NMES to combat disuse atrophy and functional decline may be particularly useful in the HCT setting as patients undergo intensive preparatory chemotherapy and often experience symptoms including severe fatigue that leave them inactive or isolated for extended time periods surrounding the transplant. However, its use in the setting of cancer has not been well-established. This proposal will contribute to developing strategies toward optimizing the safety and outcomes associated with HCT in Veterans with hematologic malignancies. The overall goals of this study are to assess 1) the efficacy of an NMES vs Sham intervention on HCT-induced reductions in physical function and muscle mass and worsening of patient-reported fatigue and QOL and 2) the association between physical function and prolonged recovery of patient-reported fatigue and QOL. The investigators hypothesize that 1) NMES will attenuate the acute HCT-induced negative impact on physical function, body composition, QOL, and fatigue compared to Sham intervention, and 2) baseline physical function will be a significant predictor of 6-month recovery of patient-reported fatigue and QOL. Aim 1: To determine the efficacy of NMES vs. Sham for attenuation of HCT-induced reductions in physical function, muscle mass, and patient-reported QOL and fatigue in patients undergoing autologous HCT. Patients will be randomized 1:1 (NMES:Sham) stratified by diagnosis. Physical function, body composition, QOL, and fatigue will be assessed at baseline (Pre, after admission to the Bone Marrow Transplant Unit but before initiation of preparatory chemotherapy) and 28 plus or minus 5 days after HCT (Follow-up 1; FU1). The primary outcome will be between-group difference in 6MWT change at FU1 compared to Pre (N=23/group; 46 total). Secondary outcomes include: body composition measured by dual-energy x-ray absorptiometry; previously validated questionnaires (Functional Assessment of Chronic Illness Therapy-Fatigue; Muscle and Joint Measures) to assess patient-reported fatigue, QOL, symptom burden, and functional status; standard of care clinical/laboratory data regarding co-morbidities, adverse events, hospitalizations, treatment history, functional status, and clinical course; and NMES process measures such as feasibility, acceptability, adherence in number of sessions, accurate use, duration/intensity, complications, and satisfaction. Aim 2: To determine predictive ability of baseline 6MWT on delayed recovery of physical function, QOL, and fatigue, patient-reported outcomes, physical function, and chart review will be collected 6-months after HCT (FU2). 6MWT at Pre will be used to determine significant predictors of QOL and fatigue at FU2 (N=46) as assessed by previously validated questionnaires. Clinical measures extracted from medical charts will include changes from FU1 to FU2 in standard of care clinical/laboratory data regarding co-morbidities, adverse events, hospitalizations, functional status, treatment history, disease trajectory, and survival. Aim 3 (exploratory): To investigate the acute impact of NMES vs. Sham during HCT on various aspects of physical function and patient-reported QOL for determining potential endpoints for future clinical trials. Exploratory measures of function (stair climbing power; muscle strength; sit-to-stand; handgrip strength; peak oxygen consumption) assessed at Pre and FU1 will be used to determine significant predictors of exploratory QOL measures (Multidimensional Fatigue Inventory; Short Form-36; European Organization for Research and Treatment of Cancer QOL Questionnaire) assessed at FU2.

Neuromuscular electrical stimulation (active vs sham signal)

During Informed Consent, patients will be instructed to not presume group assignment. An unblinded study coordinator will then randomize each participant to NMES:Sham on a 1:1 basis, stratifying by diagnosis. The unblinded coordinator will ensure each participant performs the appropriate NMES or Sham stimulus on each training day; stimulation will only occur in private exam rooms. NMES and Sham stimulators will be outwardly identical apart from a concealed "A" or "B" label indicating NMES or Sham device; the designation of A or B will only be known to the unblinded study coordinator, and not to the PI. The PI will administer all outcome assessments and conduct all statistical analyses; therefore the PI will remain blinded to NMES vs Sham group assignment until study completion. In the study database, group assignment will be coded as A or B, the PI will not know the coding of A or B. A document containing the coding will be kept in a different electronic location than the study folder.

Muscle Stimulation for Physical Function During Stem Cell Transplant

Neuromuscular Electrical Stimulation for Physical Function Maintenance During Hematopoietic Stem Cell Transplantation

Anderson Symptom Assessment Scale (range 0-10 where 10 is maximum fatigue)

dual energy fan-beam x-ray absorptiometry; bioelectrical impedance

Number of sessions completed out of total sessions

VA Office of Research and Development

Skin and Connective Tissue Diseases

Breast Neoplasms

Fatigue

Neuromuscular electrical stimulation (NMES) group

Neuromuscular electrical stimulation will be performed 5 times/week for one hour each day for 2 months.

Neuromuscular electrical stimulation

Michael J Toth, PhD

Exercise training has beneficial effects in cancer survivors to minimize some of the side effects of cancer and its treatment and improve long-term prognosis, but there are numerous hurdles for individuals diagnosed with, and being treated for, cancer to participate in exercise programs. The goal of this research study is to begin to evaluate whether exercise training via neuromuscular electrical stimulation (NMES) has beneficial effects on skeletal muscle size and function in cancer survivors.

Alternative Exercise Program to Improve Skeletal Muscle Function and Fatigue in Cancer Survivors

Research data (deidentified) which documents, supports and validates research findings will be stored on the University of Vermont College of Medicine computer system and will be made available upon final acceptance for publication of the major findings from the proposed studies. This includes raw data generated from all clinical and laboratory-based assessments under a data-sharing agreement.

Tension (force per unit muscle fiber cross-sectional area) from segments of chemically-skinned single human muscle fibers will be assessed under maximal calcium-activated condition, with muscle fiber type determined post-measurement by gel electrophoresis

Cross-sectional area of skeletal muscle fibers will be evaluated using immunohistochemistry, with specification of all relevant muscle fiber types

Area fraction of intermyofibrillar mitochondria will be assessed by electron microscopy

Single muscle fiber contractile velocity assessed using isotonic load clamps, with muscle fiber type determined post-measurement by gel electrophoresis. The velocity of contraction is expressed relative to the length of the muscle fiber segment evaluated (as measured using a eyepiece micrometer during assessments) per second.

University of Vermont

Associate Professor of Medicine

Neuromuscular electrical stimulation (NMES) group

Neuromuscular electrical stimulation: Neuromuscular electrical stimulation will be performed 5 times/week for one hour each day for 2 months.

NMES

Control

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Weight

Height

Percentage of body fat

Fat mass

Fat-free mass

Appendicular skeletal muscle mass

Our study was powered to detect effects on skeletal muscle at the cellular level over a short time period during treatment.

Michael J. Toth

Baseline testing

Post-intervention testing

The sample sizes reflect the number of volunteers with paired data at both baseline and 2-month testing.

Maximal Calcium-activated Tension Single Muscle Fiber Tension

Cross-sectional Area of Skeletal Muscle Fibers

The sample sizes reflect the number of volunteers with paired data at both baseline and 2-month testing and the fact that electron microscopy measures could not be completed on one volunteer because of insufficient muscle tissue.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effects of NMES and Exercise in Hematological Cancer	NCT04755465	Hematologic Mal... Muscle Weakness	Neuromuscular E... Structured Exer...	18 Years - 65 Years	Acibadem University
Muscle Stimulation for Physical Function During Stem Cell Transplant	NCT04364256	Autologous Hema...	RS-4i Plus Sequ...	18 Years -	VA Office of Research and Development
Alternative Exercise Program to Improve Skeletal Muscle Function and Fatigue in Cancer Survivors	NCT02739620	Breast Cancer	Neuromuscular e...	40 Years - 70 Years	University of Vermont

Spots Global Cancer Trial Database for neuromuscular electrical stimulation