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ResultsMuscle dysfunction is evident across all stages of the cancer trajectory. The causes of cancer-related muscle dysfunction are complex, but may involve a wide range of tumor-, therapy- and/or lifestyle-related factors, depending on the clinical setting of the individual patient. The main importance of muscle dysfunction in cancer patients lies in the correlation to vital clinical end points such as cancer-specific and all-cause mortality, therapy complications and quality of life (QoL).

Such associations strongly emphasize the need for effective therapeutic countermeasures to be developed and implemented in oncology practice. Significant progress has been made over the last decade in the field of exercise oncology, indicating that exercise training constitutes a potent modulator of skeletal muscle function in patients with cancer.

ConclusionThere are clear associations between muscle dysfunction and critical clinical end points. Yet there is a discrepancy between timing of exercise intervention trials, which can improve muscle function, and study populations in whom muscle function are proven prognostic important for clinical end points. Thus, future exercise trials should in early-stage patients, be powered to evaluate clinical outcomes associated with improvements in muscle function, or be promoted in advanced stage settings, aiming to reverse cancer-related muscle dysfunction, and thus potentially improve time-to-progression, treatment toxicity and survival. , introductionSkeletal muscle is the largest organ in the human body, constituting 40%–50% of total body mass in healthy nonobese humans.

Skeletal muscle function is classically defined as the ability to perform muscular contractions, generating external mechanical force, which enables physical activities of daily living and exercise. In addition, skeletal muscle plays a vital role in primary and secondary disease prevention as an essential regulator of metabolic and inflammatory homeostasis. Indeed, substantial evidence shows that muscle function, defined as strength or muscle composition (muscle mass or size), in healthy individuals is a strong independent predictor of all-cause-, cancer- and cardiovascular disease (CVD) mortality risk.Within oncology, interest in muscle function has traditionally been confined to the clinical entity of cancer cachexia, which is characterized by severe muscle wasting, systemic inflammation and malnutrition in patients with advanced stage disease.

But emerging evidence shows that decreased muscle mass (sarcopenia ) is a prevalent condition in cancer patients regardless of disease stage and nutritional status , and is associated with higher mortality rates in both advanced stage and early-stage patients. The reports of skeletal muscle as a prognostic factor emphasize the need for a better understanding of the complex etiology of muscle dysfunction in the oncology setting, and the need for effective therapeutic countermeasures in clinical practice.

Exercise training constitutes a potent modulator of skeletal muscle function, and growing evidence suggests that exercise is a safe, feasible and effective therapeutic strategy with the capacity to mitigate and/or reverse muscle dysfunction in patients with cancer.Here, we review the current evidence describing the degree, causes and clinical implications of muscle dysfunction in cancer patients. Moreover, we will discuss the potential of exercise training to mitigate or reverse muscle dysfunction. Search strategyA comprehensive search of the literature was conducted in the PubMed (NIH), Medline and EMBASE databases (January 1966 to March 2013) using keyword combinations of the medical subject headings (MeSH) ‘body composition’, ‘muscle, skeletal’, ‘muscular atrophy’, ‘muscle function’, ‘muscle strength’, ‘exercise’, ‘cancer’, ‘neoplasms’. Relevant reference lists were also manually searched. The search was confined to include independent studies in adults diagnosed with solid malignancies, thus studies on childhood cancers and hematological diseases were excluded (Table ).

Definition and measurement of muscle functionMuscle contraction is a central feature of muscle function, enabling locomotor activity and metabolic control through the production of external force and induction of glucose uptake and other metabolic processes in the contracting muscles. The exertion of muscle contraction is measured as muscle strength.

Muscles are composed of individual muscle fibers, which are characterized by their size, twitch velocity and metabolic phenotype. Together the composition plays a central role for regulation of voluntary function (muscle contraction) and nonvoluntary functions (e.g. Muscle metabolism). Against this background, we adopt the following organizing framework to evaluate the available evidence of muscle function defined by (i) muscle strength and (ii) muscle composition. The latter may be evaluated on three levels: (I) whole-body level (whole-body muscle mass), (II) single muscle (group) level (muscle/muscle group size or volume) and (III) muscle fiber level (phenotypic characteristics; i.e. Morphology, cellular signaling and gene expression profile).

Accordingly, we define ‘cancer-related muscle dysfunction’, as any measurable impairment in muscle strength or muscle composition independent of the underlying cause in patients diagnosed with cancer.Table provides a summary of commonly applied methods, which directly assess muscle strength or composition in humans. In brief, contractile muscle function can be measured by isometric or isokinetic force/torque or more pragmatic methods including repetition maximum (RM) tests or handgrip strength. Whole-body muscle mass can be measured by body composition assessments including dual-energy X-ray absorptiometry (DXA) scans or bioelectrical impendence. Single muscle (or muscle group) size or volume is measured via cross-sectional area (CSA) assessments by imaging modalities, i.e. Computerized topography (CT), magnetic resonance imaging (MRI) or ultrasonography. For assessment of cellular muscle structure, muscle tissue biopsying is a valuable method allowing for detailed assessment of muscle fiber morphology, biochemical indices and gene expression profiles.

MeasurementMethodsData outcomeDefined cutoff pointsAdvantagesLimitationsMuscle contractionMuscle strength.Isokinetic/isometric.Maximum voluntary contraction test.Force (Newton).Torque (Newton meter).Not defined.Gold standard strength testing procedure.Possible use of interpolation twitch technique (for assessment of central fatigue).Expensive test equipment.Repetition maximum (RM) tests.Mass (kg).Not defined.Can be carried out for most muscle/muscle groups.Strong risk of praxis adaptation.Handgrip strength test.Mass (kg).Force (Newton)Sarcopenia defined by handgrip strength b:Male. MeasurementMethodsData outcomeDefined cutoff pointsAdvantagesLimitationsMuscle contractionMuscle strength.Isokinetic/isometric.Maximum voluntary contraction test.Force (Newton).Torque (Newton meter).Not defined.Gold standard strength testing procedure.Possible use of interpolation twitch technique (for assessment of central fatigue).Expensive test equipment.Repetition maximum (RM) tests.Mass (kg).Not defined.Can be carried out for most muscle/muscle groups.Strong risk of praxis adaptation.Handgrip strength test.Mass (kg).Force (Newton)Sarcopenia defined by handgrip strength b:Male. MeasurementMethodsData outcomeDefined cutoff pointsAdvantagesLimitationsMuscle contractionMuscle strength.Isokinetic/isometric.Maximum voluntary contraction test.Force (Newton).Torque (Newton meter).Not defined.Gold standard strength testing procedure.Possible use of interpolation twitch technique (for assessment of central fatigue).Expensive test equipment.Repetition maximum (RM) tests.Mass (kg).Not defined.Can be carried out for most muscle/muscle groups.Strong risk of praxis adaptation.Handgrip strength test.Mass (kg).Force (Newton)Sarcopenia defined by handgrip strength b:Male.

MeasurementMethodsData outcomeDefined cutoff pointsAdvantagesLimitationsMuscle contractionMuscle strength.Isokinetic/isometric.Maximum voluntary contraction test.Force (Newton).Torque (Newton meter).Not defined.Gold standard strength testing procedure.Possible use of interpolation twitch technique (for assessment of central fatigue).Expensive test equipment.Repetition maximum (RM) tests.Mass (kg).Not defined.Can be carried out for most muscle/muscle groups.Strong risk of praxis adaptation.Handgrip strength test.Mass (kg).Force (Newton)Sarcopenia defined by handgrip strength b:Male. Muscle dysfunction in cancer patientsIn total, we identified 194 independent clinical studies (, Table ), which reported measures of muscle function in adult cancer patients across more than 15 diagnoses, and different disease phases (before-, during- or after primary cancer therapy) and tumor stages (early- or advanced stage disease). Below we summarize these studies, focusing on the degree, causes and clinical implications of muscle dysfunction in cancer patients. Degree of muscle dysfunction muscle strengthThe majority of studies reporting muscle strength have used one RM measurement (predominantly in exercise intervention trials) or assessment of handgrip strength. Collectively, the studies indicate that cancer patients have significant impairments in muscle strength regardless of disease stage, when compared with healthy controls matched by age, sex, BMI and/or physical activity level. For example Burden et al.

found that 54% of newly diagnosed early-stage colorectal patients had a handgrip strength, which was below 85% of the age-matched reference range. In accordance, patients with locally advanced prostate cancer undergoing androgen deprivation therapy (ADT), which lowers bioavailable testosterone, had 29% lower handgrip strength compared with healthy controls. Furthermore, breast cancer survivors evaluated after completion of primary therapy displayed consistently lower muscle strength (20%–30%) in seven different upper body exercises compared with healthy individuals.

Finally, evidence of late effects on muscle strength has been shown in adult survivors of childhood cancers. For example Ness et al. found that 18% survivors of extracranial solid tumors, assessed a median of 25 years after diagnosis, displayed muscle weakness, defined as the dorsiflexion torque within the lowest 10th percentile compared with healthy age-matched reference subjects. Muscle compositionConsistent with the reports of decreased muscle strength, putative evidence demonstrates changes in muscle composition across diagnoses and disease phases. Whole-body levelThe vast majority of studies identified by our search, reported data on whole-body muscle mass assessed by DXA scan or bioelectrical impendence.

For example a cross-sectional study of 714 newly diagnosed patients with mixed diagnoses (i.e. Lung, gastric, esophagus, colorectal or pancreas cancer) found that cancer patients had 0.9 kg lower muscle mass compared with healthy controls , before initiation of antineoplastic therapy. Moreover, during the course of adjuvant chemotherapy early-stage breast cancer patients lost 1.3 kg lean body mass, and continued to lose lean body mass after therapy completion. In comparison, early-stage prostate cancer patients on long-term (6 months) ADT had ∼2.5 kg lower muscle mass (reported as 4.5% lower lean body mass) compared with healthy BMI-matched controls , while metastatic prostate cancer patients, who were weight stabile during 12 months of ADT, lost 11.8 kg lean body mass. Single muscle levelMost studies reporting muscle composition at the single muscle/muscle group level have used diagnostic CT scans to measure ‘muscle index’ (muscle area in the third lumbar L3 vertebrae region normalized by height).

By such method, Prado et al. evaluated prevalence of sarcopenia among 441 newly diagnosed obese patients with cancer of gastrointestinal (GI) or respiratory tracts, and found that 15.2% of all patients were sarcopenic.

Interestingly, these patients did not report a prediagnostic weight loss, and presence of sarcopenia was not associated with disease stage. In a prospective study of patients with esophagus or gastric cancer, 100 days of neoadjuvant chemotherapy resulted in a 10-cm 2 reduction in L3 muscle area , increasing the prevalence of sarcopenia from 57% to 78% in this population. Muscle fiber levelEvaluation of dysfunctional features at the cellular level can be carried out through histological or molecular analyses of muscle biopsies. In newly diagnosed cancer patients undergoing intrathoracic surgery, primarily for GI cancer, muscle biopsies show significant upregulation of muscle degradation pathways such as ubiquitin ligases , calpain activity and myostatin compared with patients, who were operated for nonmalignant diseases. In advanced stage patients, Weber et al. found severe reductions (40%–50%) in myofiber size primarily in Type IIx fibers. Causes of muscle dysfunctionWhether muscle dysfunction should be considered an intrinsic part of a cancer disease or a generalized response to multiple atrophic stimuli can be debated.

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Commonly, all cancer patients are subjected to a wide range of cancer-specific and noncancer-specific degenerative factors, which are all potent causes of muscle dysfunction including aging, malnutrition, physical inactivity and factors directly related to disease pathophysiology and therapy toxicity. Age and co-morbiditiesThe incidence of cancer increases with age, and more than 50% of all newly diagnosed cancer patients are older than 65 years. An age-related decline in muscle mass is observed from the end of the fifth decade and has been estimated to 1.9 kg per decade for men and 1.1 kg per decade for women. Biopsy studies have shown that the age-related loss in muscle mass is primarily driven by selective loss of Type II muscle fibers , possibly caused by progressive denervation and motorneuron failure.

Depending on diagnosis between 30% and 80% of all patients present with other age-related co-morbidities (e.g. Type II diabetes or CVD), which may contribute to the aging effects through low-grade inflammation, impaired metabolism and deconditioning. MalnutritionMalnutrition is a major problem, particularly in patients diagnosed with head and neck, GI tract, pancreas and lung cancer. A recent study in 1453 oncology outpatients with mixed diagnoses, reported that 32% were at ‘high nutritional risk’ (a score ≥ 3 on The Nutritional Risk Screening NRS 2002).

The underlying causes may include decreased central drive to eat, chemosensory disturbances (taste and smell), decreased upper GI motility, nausea and constipation. In an energy-depleted state, muscle protein serves as the primary reservoir of circulating amino acids, resulting in net release from the muscles.

In accordance, progressive muscle dysfunction has been reported in malnourished colorectal cancer patients, who had 29% lower handgrip strength and 12.2 kg lower whole-body muscle mass, but the same level of fat mass compared with well-nourished patients. Physical inactivityPatients diagnosed with cancer often reduce their daily physical activity.

Most profoundly following major surgery, where prolonged bed rest can cause muscle dysfunction as seen in elderly men, whom following 10 days bed rest had a 16% decline in isokinetic muscle strength and a loss of 1.5 kg whole-body muscle mass, including 1 kg from the lower extremities. Adverse effects like pain, physical weakness or therapy toxicity can furthermore reduce daily physical activity. A recent study found that patients receiving neoadjuvant chemotherapy or radiotherapy walked ∼4000 steps per day, compared with 9000 steps in healthy controls. In accordance, breast cancer patients undergoing adjuvant chemotherapy reduced their daily energy expenditure from 514 to 461 kcal during therapy, which was associated with a loss of 0.4 kg muscle mass. Tumor-derived factorsThe direct tumor-derived impact on muscle tissue has been extensively studied in preclinical models demonstrating roles for tumor-induced inflammation and altered metabolism (reviewed in ). Studies in mice with large tumor burden show that proinflammatory cytokines like TNF-α, IL1-β and IFN-γ are derived from the tumor, resulting in increased systemic inflammation.

This systemic inflammation can activate NF-κβ signaling in muscles, inducing transcription of the ubiquitin ligases, Atrogin-1 and Murf1 and muscle protein degradation ,. Induction of these pathways has also been reported in muscle biopsies from newly diagnosed cancer patients.

The mRNA levels correlated with tumor stage but not preillness weight loss , indicating that tumor burden directly initiates early phases of muscle degradation, which is present before muscle wasting is detectable.In addition to tumor-derived inflammation, most tumors are highly metabolically active with glycolysis as the main energy-generating pathway. To meet the substrate need for the high glycolytic rate, tumors take up large amounts of glucose, competing directly for the energy availability with other glucose-dependent tissues. Moreover, recent studies have shown that tumors are also largely dependent on supply of glutamine. This requirement for amino acids might through unidentified mechanisms accelerate protein degradation in the muscles. Cancer therapyCancer management typically involves combinations of locoregional and/or systemic therapies, which potentially impact nontargeted tissues. Very few studies have investigated the direct effects of cancer therapy on muscle function, least of all compared the effects of different treatment regimens.

Nonetheless, surgery and/or radiotherapy can affect the structural integrity of skeletal musculature in the anatomical treated regions. For example women treated for early-stage breast cancer experience markedly impaired muscle strength in the affected side compared with the nonaffected side. Moreover, systemic cancer therapies greatly influence muscle composition. For example Hamilton et al. found that prostate cancer patients receiving ADT lost 1.8 kg muscle mass during the first 6 months of therapy despite an overall weight gain. Advanced stage colorectal cancer patients treated with the VEGF receptor inhibitor Bevacizumab for 3 months reduced L3 muscle area by 3 cm 2/m 2 equivalent to ∼1 kg muscle mass , which was independent of tumor progression. Likewise, biopsies taken before and after a 50-day period of chemotherapy with doxorubicin (DOX) or melphalan in patients with melanoma or sarcoma showed severe reductions in myofiber size, neurogenic alterations and mitochondria-related damages.

In line with this, preclinical studies show that DOX decrease maximal twitch force and impair relaxation, associated with intracellular Ca 2+ accumulation in the muscles. Supportive care medicationSupportive care medications like glucocorticoids are frequently administrated concomitant to systemic antineoplastic therapy.

These drugs counteract therapy-induced adverse events like nausea and pain through anti-inflammatory effects, but they also have considerable impact on muscle composition and metabolism. Eight days of prednisone use in healthy young men caused significant insulin resistance, evident by a 65% lower insulin-stimulated glucose uptake compared with placebo users. Moreover, long-term use of glucocorticoids is associated with muscle wasting and weakness.

Clinical implications of muscle dysfunctionMuscle function is a strong independent predictor of all-cause, CVD- and cancer mortality , morbidity and QoL in noncancer populations. Although not as thoroughly investigated, similar associations exist for cancer patients, as summarized in the following and in Table.

Clinical end pointReferencesMuscle assessment (method)Population, NMain findingMortalityChen et al. Handgrip strength (MVC)Esophageal cancer, stages I–IV, N = 61Handgrip strength below 25 kg associated with.Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 no CI reported, P 2 days), 15% versus 4% no CI reported; P. Clinical end pointReferencesMuscle assessment (method)Population, NMain findingMortalityChen et al. Handgrip strength (MVC)Esophageal cancer, stages I–IV, N = 61Handgrip strength below 25 kg associated with.Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 no CI reported, P 2 days), 15% versus 4% no CI reported; P. Clinical end pointReferencesMuscle assessment (method)Population, NMain findingMortalityChen et al. Handgrip strength (MVC)Esophageal cancer, stages I–IV, N = 61Handgrip strength below 25 kg associated with.Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 no CI reported, P 2 days), 15% versus 4% no CI reported; P. Clinical end pointReferencesMuscle assessment (method)Population, NMain findingMortalityChen et al.

Handgrip strength (MVC)Esophageal cancer, stages I–IV, N = 61Handgrip strength below 25 kg associated with.Surgical mortality rate (within 6 months), 35% versus 4.8%: OR ≈8 no CI reported, P 2 days), 15% versus 4% no CI reported; P. Mortality and disease progressionThe importance of muscle dysfunction as a predictor of prognosis was recently reported in patients with early-stage breast cancer. Amd phenom tm ii n640 dual core processor driver download.

Survivors diagnosed with sarcopenia, assessed on average 12 months after diagnosis, had almost three-fold higher all-cause mortality rate (HR = 2.86) compared with nonsarcopenic survivors. Of importance, this study was the first in early-stage patients to report what several prior studies have found in patients with advanced disease. For example sarcopenia is associated with poorer prognosis in patients with advanced cancer of colon , respiratory and GI tracts and melanoma. In line with this, Prado et al. found that sarcopenic patients with metastatic breast cancer had shorter time-to-tumor progression (101 days) relative to nonsarcopenic patients (173 days). Therapy complicationsSignificant associations between muscle function and treatment complications are emerging from recent studies.

In advanced stage breast cancer patients treated with capecitabine, 50% of the patients presenting with sarcopenia experienced dose-limiting toxicity, compared with 19.5% of the non-sarcopenic patients. In accordance, presence of sarcopenia was associated with dose-limiting toxicity in advanced stage renal cell and colon cancer patients.

Following hepatic resection of colorectal metastasis, sarcopenia was associated with increased risk of major postsurgical complications (OR = 3.12) , and low handgrip strength predicted longer hospital stay in patients undergoing esophagectomy with reconstruction for esophageal cancer. Patient-reported outcomesConsistent reports have found associations between muscle function and patient-reported outcomes, in particular fatigue, in early- and advanced stage cancer patients. For example a study in patients with low-grade primary glioma showed that thigh muscle CSA predicted fatigue ( r = −0.74, P.

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. 305 Downloads.AbstractThe treatment of late-onset Pompe disease (LOPD) relies on enzyme replacement therapy (ERT) and physiotherapy but the most appropriate exercise program is not yet established. Whole-body vibration training (WBVT) has showed promising results, improving motor performances in various populations. Our aim is to assess the effects of WBVT performed by two LOPD patients in addition to ERT and physiotherapy.

A side-alternating WBVT lasting 2 years; clinical assessments included: manual muscle testing (MRC sumscore), knee extension and arm flection isometric strength (multi-muscle tester M3diagnos), timed function tests (10 m walking, standing-up from chair, ascending 4-steps), 6 min walking (6 MWT), motor disability (Walton Gardner-Medwin scale), pulmonary function. Follow-up evaluations performed for 9 years since ERT start (pre-WBVT and post-WBVT) are reported for comparison. MRC sumscore improved in both patients (Pt.1:41 → 48, Pt.2:42 → 47) as isometric strength of knee extension (Pt.1: + 62%, Pt.2: + 26%) and arm flection (Pt.1: + 88%, Pt.2: + 66%), 6 MWT improved in Pt.1 (+75 m). Timed function tests did not greatly change. Patients reported no significant CK elevation or WBVT-related complaints.

WBVT may be safely used in LOPD and seems to moderately boost muscle strength in patients receiving ERT and physiotherapy for more than 3 years. Larger cohorts should be studied to better assess WBVT potential as adjunctive exercise tool in LOPD.