Effect of aerobic exercise on cancer-associated cognitive impairment: A proof-of-concept RCT.

BACKGROUND: Change in cognitive ability is a commonly reported adverse effect by breast cancer survivors. The underlying etiology of cognitive complaints is unclear and to date, there is limited evidence for effective intervention strategies. Exercise has been shown to improve cognitive function in older adults and animal models treated with chemotherapy. This proof-of-concept randomized controlled trial tested the effect of aerobic exercise versus usual lifestyle on cognitive function in postmenopausal breast cancer survivors. METHODS: Women, aged 40 to 65 years, postmenopausal, stages I to IIIA breast cancer, and who self-reported cognitive dysfunction following chemotherapy treatment, were recruited and randomized to a 24-week aerobic exercise intervention (EX; n = 10) or usual lifestyle control (CON; n = 9). Participants completed self-report measures of the impact of cognitive issues on quality of life (Functional Assessment of Cancer Therapy-Cognitive version 3), objective neuropsychological testing, and functional magnetic resonance imaging at baseline and 24 weeks. RESULTS: Compared to CON, EX had a reduced time to complete a processing speed test (trail making test-A) (-14.2 seconds, P < .01; effect size 0.35). Compared to CON, there was no improvement in self-reported cognitive function and effect sizes were small. Interestingly, lack of between-group differences in Stroop behavioral performance was accompanied by functional changes in several brain regions of interest in EX compared to CON at 24 weeks. CONCLUSION: These findings provide preliminary proof-of-concept results for the potential of aerobic exercise to improve cancer-related cognitive impairment and will serve to inform the development of future trials.

Protective effects of acute exercise prior to doxorubicin on cardiac function of breast cancer patients: A proof-of-concept RCT.

BACKGROUND: Preclinical studies have reported that a single treadmill session performed 24h prior to doxorubicin provides cardio-protection. We aimed to characterize the acute change in cardiac function following an initial doxorubicin treatment in humans and determine whether an exercise session performed 24h prior to treatment changes this response. METHODS: Breast cancer patients were randomized to either 30min of vigorous-intensity exercise 24h prior to the first doxorubicin treatment (n=13), or no vigorous exercise for 72h prior to treatment (control, n=11). Echocardiographically-derived left ventricular volumes, longitudinal strain, twist, E/A ratio, and circulating NT-proBNP, a marker of later cardiotoxicity, were measured before and 24-48h after the treatment. RESULTS: Following treatment in the control group, NT-proBNP, end-diastolic and stroke volumes, cardiac output, E/A ratio, strain, diastolic strain rate, twist, and untwist velocity significantly increased (all p≤0.01). Whereas systemic vascular resistance (p<0.01) decreased, and ejection fraction (p=0.02) and systolic strain rate (p<0.01) increased in the exercise group only. Relative to control, the exercise group had a significantly lower NT-proBNP (p<0.01) and a 46% risk reduction of exceeding the cut-point used to exclude acute heart failure. CONCLUSION: The first doxorubicin treatment is associated with acutely increased NT-proBNP, echocardiographic parameters of myocardial relaxation, left ventricular volume overload, and changes in longitudinal strain and twist opposite in direction to documented longer-term changes. An exercise session performed 24h prior to treatment attenuated NT-proBNP release and increased systolic function. Future investigations should verify these findings in a larger cohort and across multiple courses of doxorubicin.

Subgroup effects in a randomised trial of different types and doses of exercise during breast cancer chemotherapy.

BACKGROUND: The Combined Aerobic and Resistance Exercise Trial tested different types and doses of exercise in breast cancer patients receiving chemotherapy. Here, we explore potential moderators of the exercise training responses. METHODS: Breast cancer patients initiating chemotherapy (N=301) were randomly assigned to three times a week, supervised exercise of a standard dose of 25-30 min of aerobic exercise, a higher dose of 50-60 min of aerobic exercise, or a higher dose of 50-60 min of combined aerobic and resistance exercise. Outcomes were patient-reported symptoms and health-related fitness. Moderators were baseline demographic, exercise/fitness, and cancer variables. RESULTS: Body mass index moderated the effects of the exercise interventions on bodily pain (P for interaction=0.038), endocrine symptoms (P for interaction=0.029), taxane/neuropathy symptoms (P for interaction=0.013), aerobic fitness (P for interaction=0.041), muscular strength (P for interaction=0.007), and fat mass (P for interaction=0.005). In general, healthy weight patients responded better to the higher-dose exercise interventions than overweight/obese patients. Menopausal status, age, and baseline fitness moderated the effects on patient-reported symptoms. Premenopausal, younger, and fitter patients achieved greater benefits from the higher-dose exercise interventions. CONCLUSIONS: Healthy weight, fitter, and premenopausal/younger breast cancer patients receiving chemotherapy are more likely to benefit from higher-dose exercise interventions.

Resting energy expenditure and body mass changes in women during adjuvant chemotherapy for breast cancer.

Weight gain is a commonly reported side effect of adjuvant chemotherapy. A change in resting energy expenditure during treatment has been a suggested mechanism for weight gain. We prospectively measured resting energy expenditure, weight change, and body composition (dual-energy x-ray absorptiometry) in 10 women undergoing adjuvant chemotherapy for breast cancer. There was no change in resting energy expenditure across cycles of chemotherapy (P =.78) or from baseline to the end of treatment (1,189.68 +/- 80.27 vs 1,205.76 +/- 56.71 kcal/d; P =.74). Overall, participants did not gain weight across treatment. However, there was an overall trend toward weight gain (66.3 +/- 5.1 vs 68.2 +/- 5.0 kg; P =.09), and participants did show an increase in total fat mass (24.2 +/- 3.8 vs 26.5 +/- 3.2 kg; P =.04), whereas muscle mass remained the same. Although no change in resting energy expenditure was seen, the observed increase in total fat mass is consistent with a decrease in physical activity level commonly reported with adjuvant chemotherapy treatment of breast cancer, and these body composition changes may have important health implications for survivors.

The effect of a whole body exercise programme and dragon boat training on arm volume and arm circumference in women treated for breast cancer.

The purpose of this study was to examine the effect of a whole body exercise programme and dragon boat training on changes in arm volume in breast cancer survivors. A total of 16 female breast cancer survivors with no clinical history of lymphoedema volunteered. The 20-week exercise programme consisted of resistance and aerobic exercise with the addition of dragon boat training at week 8. Arm circumference at two sites (CIRC10, CIRC15), arm volume (VOL), and upper body strength (1-RM) were measured at baseline (T1), week 8 (T2), and week 20 (T3). All statistical tests were two-sided (alpha < or = 0.05). No significant differences between the ipsilateral and contralateral upper extremities at any of the three time points were found. All variables significantly increased from T1 to T3 (CIRC10: difference, d = 0.49 cm, 95% confidence interval, CI = 0.25-0.73, P = 0.000; CIRC15: d = 1.33 cm, CI = 0.78-1.88, P = 0.000; VOL: d = 100 mL, CI = 69-130, P = 0.000). As well, 1-RM significantly increased from T1 to T3 (d = 10.8 kg, CI = 5.6-16.1; P = 0.000). In summary, participation in a whole body exercise programme and dragon boat training resulted in a significant increase in upper extremity volume over time. However, the changes were consistent for both arms and the significant gain in upper body muscular strength likely accounted for the increase in arm volume.

Measurement of upper extremity volume in women after axillary dissection for breast cancer.

OBJECTIVE: To determine if 2 methods of calculating upper extremity volume (using arm circumferences) can substitute for water displacement volumetry. DESIGN: Interrater and test-retest reliability and limits of agreement for volume measures. SETTING: University. PARTICIPANTS: Twenty-five women at risk for lymphedema who had undergone axillary lymph node dissection surgery for breast cancer. INTERVENTIONS: Circumference and volume measurements of both upper extremities were taken by 2 physical therapists at an initial visit and by 1 of the therapists 1 week later. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) were calculated to analyze measurement reliability. Pearson's product-moment correlation coefficient (r) was used to evaluate the relationship between volumetry and calculated truncated cone volumes. Limits of agreement were calculated to determine the level of agreement between the 2 measurement methods. RESULTS: Interrater and test-retest reliability ICCs for circumferential and volumetric data were .99 and .99, respectively. Pearson's r values were .93 and .97 for the single truncated cone and the summed truncated cone volume calculations, respectively. Limits of agreement (mean +/- 2 standard deviations) were -52 +/- 334mL and -40 +/- 234mL, respectively, between volumetry and the single truncated cone and summed truncated cone calculations. CONCLUSIONS: Calculated and volumetric measurements in this population are both reliable and closely related, but do not agree with each another, and thus should not be used interchangeably.

Markers of inflammation and myofibrillar proteins following eccentric exercise in humans.

The purpose of this study was to examine the time-course and relationships of technetium-99m (99mTc) neutrophils in muscle, interleukin-6 (IL-6), myosin heavy chain fragments (MHC), eccentric torque, and delayed onset muscle soreness (DOMS) following eccentric exercise in humans. Twelve male subjects completed a pre-test DOMS questionnaire, performed a strength test and had 100 ml blood withdrawn for analysis of plasma IL-6 and MHC content. The neutrophils were separated, labelled with 99mTc, and re-infused into the subjects immediately before the exercise. Following 300 eccentric repetitions of the right quadriceps muscles on an isokinetic dynamometer, the subjects had 10 ml of blood withdrawn with repeated the eccentric torque exercise tests and DOMS questionnaire at 0, 2, 4, 6, 20, 24, 48, 72 h, and 6 and 9 days. Bilateral images of the quadriceps muscles were taken at 2, 4, and 6 h. Computer analysis of regions of interest was used to determine the average count per pixel. The 99mTc neutrophils and IL-6 increased up to 6 h post-exercise (P < 0.05). The neutrophils were greater in the exercised muscle than the non-exercised muscle (P < 0.01). The DOMS was increased from 0 to 48 h, eccentric torque decreased from 2 to 24 h, and MHC peaked at 72 h post-exercise (P < 0.001). Significant relationships were found between IL-6 and 2 h and DOMS at 24 h post-exercise (r = 0.68) and assessment of the magnitude of change between IL-6 and MHC (r = 0.66). These findings suggest a relationship between damage to the contractile proteins and inflammation, and that DOMS is associated with inflammation but not with muscle damage.

Influence of inhaled nitric oxide on gas exchange during normoxic and hypoxic exercise in highly trained cyclists.

This study tested the effects of inhaled nitric oxide [NO; 20 parts per million (ppm)] during normoxic and hypoxic (fraction of inspired O(2) = 14%) exercise on gas exchange in athletes with exercise-induced hypoxemia. Trained male cyclists (n = 7) performed two cycle tests to exhaustion to determine maximal O(2) consumption (VO(2 max)) and arterial oxyhemoglobin saturation (Sa(O(2)), Ohmeda Biox ear oximeter) under normoxic (VO(2 max) = 4.88 +/- 0.43 l/min and Sa(O(2)) = 90.2 +/- 0.9, means +/- SD) and hypoxic (VO(2 max) = 4.24 +/- 0.49 l/min and Sa(O(2)) = 75.5 +/- 4.5) conditions. On a third occasion, subjects performed four 5-min cycle tests, each separated by 1 h at their respective VO(2 max), under randomly assigned conditions: normoxia (N), normoxia + NO (N/NO), hypoxia (H), and hypoxia + NO (H/NO). Gas exchange, heart rate, and metabolic parameters were determined during each condition. Arterial blood was drawn at rest and at each minute of the 5-min test. Arterial PO(2) (Pa(O(2))), arterial PCO(2), and Sa(O(2)) were determined, and the alveolar-arterial difference for PO(2) (A-aDO(2)) was calculated. Measurements of Pa(O(2)) and Sa(O(2)) were significantly lower and A-aDO(2) was widened during exercise compared with rest for all conditions (P < 0.05). No significant differences were detected between N and N/NO or between H and H/NO for Pa(O(2)), Sa(O(2)) and A-aDO(2) (P > 0.05). We conclude that inhalation of 20 ppm NO during normoxic and hypoxic exercise has no effect on gas exchange in highly trained cyclists.

Cytology in the follow-up of cervical cancer.

OBJECTIVE: To determine the value of cytology in the follow-up of cervical cancer. STUDY DESIGN: The study group consisted of 230 patients with invasive cervical carcinoma who were followed for one to seven years. Forty-four patients developed recurrences or metastases. During this period, cytologic investigations involved 795 exfoliative smears from the cervix or vaginal vault, 10 fine needle aspirates and 5 fluids. RESULTS: Thirty-three patients had positive or inconclusive cervical or vault smears that were histologically proven to be recurrences, and the other 11 patients had clinically obvious recurrences that were not smeared. Cytology first alerted the clinicians to recurrence in eight patients. Of 25 cervical or vault smears reported as malignant, 24 (96%) were histologically confirmed, and 1 showed radiation change on biopsy. In all 22 cases of smears reported as inconclusive, a biopsy followed, and in 9 (41%) of these, recurrence was demonstrated histologically. Inability to distinguish radiation change from recurrent malignancy was the chief cause of inconclusive smears. Five fluids and seven fine needle aspirates were diagnosed as malignant, saving patients an invasive diagnostic procedure. CONCLUSION: Cytology is a useful, cost-effective, noninvasive and accurate investigation in the follow-up of cervical cancer.

Effects of menstrual cycle phase on athletic performance.

The purpose of this study was to examine the effects of menstrual cycle phase on four selected indices of athletic performance: aerobic capacity, anaerobic capacity, isokinetic strength, and high intensity endurance. Sixteen eumenorrheic women (VO2max > or = 50 ml.kg-1.min-1) were tested during the early follicular (F) and midluteal (L) phases of the menstrual cycle. Cycle phases were confirmed by serum estradiol and progesterone assays. No significant differences were observed between F and L tests in weight, percent body fat, sum of skinfolds, hemoglobin concentration, hematocrit, maximum heart rate, maximum minute ventilation, maximum respiratory exchange ratio, anaerobic performance, endurance time to fatigue (at 90% of VO2max), or isokinetic strength of knee flexion and extension. Both absolute and relative VO2max, however, were slightly lower in L than in F (F = 3.19 +/- 0.09.min-1, L = 3.13 +/- 0.08.min-1, P = 0.04; and F = 53.7 +/- 0.9 ml.kg-1.min-1, L = 52.8 +/- 0.8 ml.kg-1.min-1, P = 0.06). These results suggest that the cyclic increases in endogenous female steroid hormones of an ovulatory menstrual cycle may have a slight, deleterious influence on aerobic capacity, with potential implications for individual athletes. Nevertheless, the cycle phase did not impact significantly on the majority of the other performance tests and cardiorespiratory variables measured in this study.

Pulmonary gas exchange during exercise in athletes. I. Ventilation-perfusion mismatch and diffusion limitation.

To investigate pulmonary gas exchange during exercise in athletes, 10 high aerobic capacity athletes (maximal aerobic capacity = 5.15 +/- 0.52 l/min) underwent testing on a cycle ergometer at rest, 150 W, 300 W, and maximal exercise (372 +/- 22 W) while trace amounts of six inert gases were infused intravenously. Arterial blood samples, mixed expired gas samples, and metabolic data were obtained. Indexes of ventilation-perfusion (VA/Q) mismatch were calculated by the multiple inert gas elimination technique. The alveolar-arterial difference for O2 (AaDO2) was predicted from the inert gas model on the basis of the calculated VA/Q mismatch. VA/Q heterogeneity increased significantly with exercise and was predicted to increase the AaDO2 by > 17 Torr during heavy and maximal exercise. The observed AaDO2 increased significantly more than that predicted by the inert gas technique during maximal exercise (10 +/- 10 Torr). These data suggest that this population develops diffusion limitation during maximal exercise, but VA/Q mismatch is the most important contributor (> 60%) to the wide AaDO2 observed.

Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.

Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

Metabolic and work efficiencies during exercise in Andean natives.

Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.

The effects of prelatent/latent iron deficiency on physical work capacity.

In order to examine the effects of mild iron deficiency on physical work capacity, 40 prelatent iron-deficient female endurance runners were studied before and after 8 wk of supplementation with either oral iron (320 mg ferrous sulfate) or a matching placebo. Subjects underwent the following physical work capacity tests: the Wingate cycle ergometer test, the anaerobic speed test, the ventilatory threshold, VO2max, and maximal treadmill velocity during the VO2max test. Muscle biopsy samples pre- and post-treatment were obtained from 17 of the subjects, and these were assayed for citrate synthase and cytoplasmic alpha-glycerophosphate dehydrogenase activity. Subjects were randomly assigned to one of the treatment groups, and a double-blind method of administration of the supplements was used. The differences in improvement scores between the two groups on the work capacity and enzyme activity variables were statistically nonsignificant (P greater than 0.05). Serum ferritin values rose from a mean of 12.4 +/- 4.5 to 37.7 +/- 19.7 ng.ml-1 for the experimental group and from 12.2 +/- 4.3 to 17.2 +/- 8.9 ng.ml-1 for the controls (P = 0.0025), whereas hemoglobin levels remained fairly constant for both groups (P = 0.6). Eight weeks of iron supplementation to prelatent/latent iron-deficient, physically active females did not significantly enhance work capacity. Within the limitations of this study, the presence of a serum ferritin below 20 ng.ml-1 does not pose a significant handicap to physical work capacity.

Ventilatory threshold and training heart rate in exercising cardiac patients.

The purpose of this study was to determine the relationship between previously prescribed training heart rates (THR) for patients training for six months or more in a cardiac rehabilitation program (CRP), calculated Karvonen percentage heart rate reserve (THRk), and the ventilatory threshold (VT). In twenty male patients (ages 41-63) with documented coronary heart disease (CAD) [non-medicated] mean training heart rate (THR, 75% HRmax) was determined by a telemetry during training sessions. Incremental treadmill testing for determinations of the gas-exchange VT VOE vs. (VO2, Excess CO2) was performed, and the HR at the VT (VTHR) was determined. VO2max was 35.57 +/- 5.57 mL.kg-1.min-1; the VT, expressed as a percentage of VO2max, was 54.45%. The mean THR (133.8 +/- 13.4 bpm) and calculated THRk (141.1 +/- 9.74 bpm) were significantly greater (p less than .05) than the VTHR (124.8 +/- 15.5 bpm), indicating that VT occurs below intensities determined by other methods.

Buffering capacity of deproteinized human vastus lateralis muscle.

The in vitro deproteinized vastus lateralis muscle buffer capacity, carnosine, and histidine levels were examined in 20 men from 4 distinct populations (5 sprinters, 800-m runners; 5 rowers; 5 marathoners; 5 untrained). Needle biopsies were obtained at rest from the vastus lateralis muscle. The buffer capacity was determined in deproteinized homogenates by repeatedly titrating supernatant extracts over the pH range of 7.0-6.0 with 0.01 N HCl. Carnosine and histidine levels were determined on an amino acid AutoAnalyzer. Fast-twitch fiber percentage was determined by staining intensity of myosin adenosinetriphosphatase. High-intensity running performance was assessed on an inclined treadmill run to fatigue (20% incline; 3.5 m X s-1). Significantly (P less than 0.01) elevated buffer capacities, carnosine levels, and high-intensity running performances were demonstrated by the sprinters and rowers, but no significant differences existed between these variables for the marathoners vs. untrained subjects. Low but significant (P less than 0.05) interrelationships were demonstrated between buffer capacity, carnosine levels, and fast-twitch fiber composition. These findings indicate that the sprinters and rowers possess elevated buffering capabilities and carnosine levels compared with marathon runners and untrained subjects.