Long-Term Outcomes After Chemoradiotherapy and Surgery for Superior Sulcus Tumors.

Introduction: Superior sulcus tumors (SSTs) are uncommon, and their anatomical location can make treatment challenging. We analyzed late outcomes of patients with SST treated with concurrent chemoradiotherapy followed by surgical resection (trimodality) in a single tertiary institution. Methods: Patients with non-small cell SSTs, who underwent trimodality therapy between 2002 and 2017, were selected from a prospective institutional surgical database. Patients were uniformly staged with 18F-fluorodeoxyglucose-positron emission tomography, computed tomography scan of the chest and upper abdomen, and brain imaging. Patients undergoing resection of the lung plus chest wall were grouped as limited SST and those needing extensive resections (e.g., including the vertebral body) as extended SST. Kaplan-Meier survival analysis was performed to determine difference in survival. Multivariate Cox regression was used to identify prognostic factors. Results: A total of 123 patients were identified with a median follow-up of 4.9 years (interquartile range: 1.6-8.9 y). The 90-day postoperative mortality and morbidity (Clavien-Dindo grades III-V) were 6.5% and 21.1%, respectively. Patients with a radical resection (R0: 92.7%) had better survival (p = 0.002), as did those who had major pathologic response (73%) (p = 0.001). Ten-year overall survival (OS) and disease-free survival were 48.1% and 42.6%, respectively. There were no differences in 90-day mortality (p = 0.31) and OS (p = 0.79) between extended SST and limited SST patients. Conclusions: In patients with SST, trimodality resulted in a 10-year estimated OS and disease-free survival of 48.1% and 42.6%, respectively, which were improved after radical resection (R0) and major pathologic response. Survival for limited and extended resections was comparable, and distant relapse was the main pattern of failure. Better systemic treatments are therefore needed.

Postural control in women with multiple sclerosis: effects of task, vision and symptomatic fatigue.

People with multiple sclerosis (MS) often report problems with balance, which may be most apparent during challenging postural tasks such as leaning or reaching, and when relying on non-visual sensory systems. An additional obstacle facing people with MS is a high incidence of symptomatic fatigue (>70%). The purpose of this study was to investigate the changes in balance during upright stance in individuals with mild-to-moderate disability due to MS under normal and restricted vision and different levels of self-reported fatigue. Limb loading asymmetry, sway and magnitude of postural shift in center of pressure, and time-to-contact the stability boundary of the center of mass and center of pressure were assessed during quiet standing and maximal lean and reach tasks. Compared to controls, people with MS displayed greater postural sway, greater loading asymmetry, and shorter time-to-contact during quiet standing. In the postural perturbation tasks the MS group had smaller postural shifts and reduced stability compared to controls in the direction perpendicular to the lean and reach. Limiting vision increased loading asymmetry during quiet standing and postural instability during backward lean in the MS group. Inducing additional fatigue in the MS group did affect postural control in the more challenging balance conditions but had no impact during quiet upright standing. The results of this study indicate subtle changes in postural control during standing in people with mild-to-moderate impairments due to MS.

Blood flow does not limit skeletal muscle force production during incremental isometric contractions.

It has been suggested that a transient limitation in blood flow during intermittent muscular contractions can contribute to muscle fatigue, and that this limitation is greater as contraction intensity increases. We investigated skeletal muscle blood flow and fatigue in 13 healthy, untrained men (21-27 years) during 16 min of intermittent (4 s contract, 6 s relax) isometric dorsiflexor contractions. Contractions began at 10% of pre-exercise maximal voluntary contraction (MVC) force and increased by 10% every 2 min. Hyperemia (i.e., post-contraction blood flow, measured by venous occlusion plethysmography) and MVC were measured at the end of each stage. Muscle volume measures were obtained using magnetic resonance imaging. After 10 min of exercise, submaximal force and post-contraction hyperemia plateaued. MVC fell from 8 min of exercise onwards (p=0.004), and this onset of fatigue preceded the plateau in submaximal force and hyperemia. Despite a large range in dorsiflexor muscle size (66.3-176.4 cm(3)) and strength (112.5-421.8 N), neither muscle size nor strength were related to fatigue. The temporal dissociation between changes in blood flow and the onset of fatigue (fall of MVC) suggest that limited blood flow was not a factor in the impaired force production observed during intermittent isometric dorsiflexor contractions in healthy young men. Additionally, post-contraction hyperemia increased linearly with increasing contraction intensity, reflecting a match between blood flow and force production throughout the protocol that was independent of fatigue.

MRI measures of perfusion-related changes in human skeletal muscle during progressive contractions.

Although skeletal muscle perfusion is fundamental to proper muscle function, in vivo measurements are typically limited to those of limb or arterial blood flow, rather than flow within the muscle bed itself. We present a noninvasive functional MRI (fMRI) technique for measuring perfusion-related signal intensity (SI) changes in human skeletal muscle during and after contractions and demonstrate its application to the question of occlusion during a range of contraction intensities. Eight healthy men (aged 20-31 yr) performed a series of isometric ankle dorsiflexor contractions from 10 to 100% maximal voluntary contraction. Axial gradient-echo echo-planar images (repetition time = 500 ms, echo time = 18.6 ms) were acquired continuously before, during, and following each 10-s contraction, with 4.5-min rest between contractions. Average SI in the dorsiflexor muscles was calculated for all 240 images in each contraction series. Postcontraction hyperemia for each force level was determined as peak change in SI after contraction, which was then scaled to that obtained following a 5-min cuff occlusion of the thigh (i.e., maximal hyperemia). A subset of subjects (n = 4) performed parallel studies using venous occlusion plethysmography to measure limb blood flow. Hyperemia measured by fMRI and plethysmography demonstrated good agreement. Postcontraction hyperemia measured by fMRI scaled with contraction intensity up to approximately 60% maximal voluntary contraction. fMRI provides a noninvasive means of quantifying perfusion-related changes during and following skeletal muscle contractions in humans. Temporal changes in perfusion can be observed, as can the heterogeneity of perfusion across the muscle bed.

Functional relationships of central and peripheral muscle alterations in multiple sclerosis.

The functional implications of central motor impairment and peripheral muscle alterations in multiple sclerosis are unclear. Muscle strength, central and peripheral activation, and symptomatic fatigue were investigated in 16 patients with multiple sclerosis (MS) and 18 control subjects. Voluntary and electrically stimulated isometric contractions were obtained from the ankle dorsiflexor muscles. Maximal voluntary contraction (MVC) was 27% lower in MS patients than controls, although electrically stimulated force was similar. Muscle fat-free cross-sectional area (CSA) was similar in both groups. These data indicate central activation impairment in MS. Such impairment in MS was further demonstrated by decreased foot-tap speed, rate of voluntary force development, and central activation ratio. Peripheral activation changes in MS patients were modest. Although stimulated tetanic force was similar, force relaxation was slower in MS patients compared to controls, resulting in a left-shifted force-frequency relationship in MS. Motor function changes were not associated with fatigue but were associated with impaired ambulation. Thus, weakness and walking impairment, but not fatigue, were related to impaired central activation in MS. These findings may help optimize rehabilitation strategies designed to improve function in persons with MS.

Effects of age on human muscle torque, velocity, and power in two muscle groups.

The purpose of this study was to test the hypotheses that, under isovelocity conditions, older compared with young humans would 1). be slower to reach target velocity and 2). exhibit a downward shift in the torque-velocity and power-velocity relationships in the ankle dorsiflexor and knee extensor muscles. We studied 12 young (26 +/- 5 yr, 6 men/6 women) and 12 older (72 +/- 6 yr, 6 men/6 women) healthy adults during maximal voluntary concentric contractions at preset target velocities (dorsiflexion: 0-240 degrees /s; knee extension: 0-400 degrees /s) using an isokinetic dynamometer. The time to target velocity was longer in older subjects in the dorsiflexors and knee extensors (both P

Human skeletal muscle responses vary with age and gender during fatigue due to incremental isometric exercise.

The purpose of this study was to compare the magnitude and mechanisms of ankle dorsiflexor muscle fatigue in 20 young (33 +/- 6 yr, mean +/- SD) and 21 older (75 +/- 6 yr) healthy men and women of similar physical activity status. Noninvasive measures of central and peripheral (neuromuscular junction, sarcolemma) muscle activation, muscle contractile function, and intramuscular energy metabolism were made before, during, and after incremental isometric exercise. Older subjects fatigued less than young (P < 0.01); there was no effect of gender on fatigue (P = 0.24). For all subjects combined, fatigue was modestly related to preexercise strength (r = 0.49, P < 0.01). Neither central (central activation ratio) nor peripheral (compound muscle action potential) activation played a significant role in fatigue in any group. During exercise, intracellular concentrations of P(i) and H(2)PO increased more and pH fell more in young compared with older subjects (P < 0.01) and in men compared with women (P < 0.01). These varied metabolic responses to exercise suggest a greater reliance on nonoxidative sources of ATP in young compared with older subjects and in men compared with women. These results suggest that the mechanisms of fatigue vary with age and gender, regardless of whether differences in the magnitude of fatigue are observed.

Validation of questionnaires to estimate physical activity and functioning in end-stage renal disease.

BACKGROUND: Patients on dialysis are less physically active than sedentary persons with normal kidney function. To assess the consequences of inactivity and the results of efforts to increase activity in the end-stage renal disease (ESRD) population, valid instruments to measure physical activity and physical functioning in this group are needed. METHODS: We performed a cross-sectional study to establish the validity in ESRD of several questionnaires designed to measure physical activity or physical functioning in the general population. Questionnaires studied included the Stanford 7-day Physical Activity Recall questionnaire (PAR), the Physical Activity Scale for the Elderly (PASE), the Human Activity Profile (HAP), and the Medical Outcomes Study Short Form 36-item questionnaire (SF-36). Physical activity was measured using three-dimensional activity monitors (accelerometers) over a seven-day period (the "gold standard"). Patients also underwent physical performance tests, including measurement of gait speed, stair climbing time, and chair rising time. Study questionnaires were administered, and questionnaire results were compared with each other and with activity monitor and physical performance test results. RESULTS: Thirty-nine maintenance hemodialysis patients participated in the study. Dialysis patients scored worse than previously published healthy norms on all tests. All questionnaires correlated with seven-day accelerometry and with at least one measure of physical performance. The HAP correlated best with accelerometry (r = 0.78, P < 0.0001). Seventy-five percent of the variability in physical activity measured by accelerometry could be explained by a model that combined information from the HAP and the PASE. The HAP and the physical functioning scale of the SF-36 were about equally well correlated with physical performance measures. CONCLUSIONS: These questionnaires are valid in patients on hemodialysis and should be used to study the physical activity and rehabilitation efforts in this population further.

Recent developments in medicine and law.

This article addresses important developments in the field of medicine and law during the period of September 1999 through August 2000. Although it does not discuss every reported case or piece of legislation, it broadly surveys some of the more significant developments in the medicine and law arena.

Skeletal muscle oxidative capacity in young and older women and men.

It has been suggested that a decline in skeletal muscle oxidative capacity is a general consequence of aging in humans. However, previous studies have not always controlled for the effects of varying levels of physical activity on muscle oxidative capacity. To test the hypothesis that, when matched for comparable habitual physical activity levels, there would be no age-related decline in the oxidative capacity of a locomotor muscle, the postexercise recovery time of phosphocreatine was compared in the tibialis anterior muscle of young [n = 19; 33.8 +/- 4.8 (SD) yr] and older [n = 18; 75.5 +/- 4.5 yr] healthy women and men of similar, relatively low, activity levels. The intramuscular metabolic measurements were accomplished by using phosphorus magnetic resonance spectroscopy. The results indicate that there was no age effect on the postexercise recovery time of phosphocreatine recovery, thus supporting the stated hypothesis. These data suggest that there is no requisite decline in skeletal muscle oxidative capacity with aging in humans, at least through the seventh decade.

Physical activity levels in patients on hemodialysis and healthy sedentary controls.

BACKGROUND: Patients on dialysis have reduced exercise tolerance compared with age-matched sedentary controls. The reasons for this debility have not been fully elucidated, but physical inactivity could be a contributing factor. The purpose of the current study was to determine whether patients on hemodialysis are less active than healthy sedentary controls and to explore clinical correlates of physical activity level in a group of hemodialysis patients. METHODS: Thirty-four hemodialysis patients and 80 healthy sedentary individuals participated in the study. Physical activity was measured for seven days with a three-dimensional accelerometer and with an activity questionnaire. RESULTS: Vector magnitude values from the accelerometer for the dialysis and control subjects were 104,718 +/- 9631 and 161,255 +/- 6792 arbitrary units per day, respectively (P < 0.0001, mean +/- SEM). The estimated energy expenditure values derived from the questionnaire were 33.6 +/- 0.5 kcal/kg/day and 36.2 +/- 0.5 kcal/kg/day (P = 0.002). The difference between patients on dialysis and controls increased with advancing age. Among the dialysis subjects, some measures of nutritional status correlated with physical activity level, including serum albumin concentration (r = 0.58, P = 0.003), serum creatinine concentration (r = 0.37, P = 0. 03), and phase angle derived from bioelectrical impedance analysis (r = 0.40, P = 0.02). CONCLUSIONS: Patients on hemodialysis are less active than healthy sedentary controls, and this difference is more pronounced among older individuals. There is an association between the level of physical activity and nutritional status among patients on dialysis. These findings are of great concern, given the trend toward increasing age in incident dialysis patients and the well-known association between inactivity and increased mortality in the general population.

Central fatigue during isometric exercise in amyotrophic lateral sclerosis.

While both upper and lower motor neuron dysfunction may contribute to impaired muscle function in amyotrophic lateral sclerosis (ALS), the precise mechanisms of muscle fatigue have not been clarified in this disease. Therefore, the central and peripheral factors in muscle fatigue were investigated during intermittent submaximal isometric ankle dorsiflexion in 7 patients with ALS and 6 healthy control subjects. Voluntary and electrically stimulated force, central and peripheral indices of muscle activation, and intramuscular energy metabolism were measured before and during exercise. At the end of exercise, only the ALS group had an increase in the "added force" in response to a stimulus train imposed during maximal voluntary contraction, indicating significant central fatigue in ALS. In support of this conclusion, patients with ALS had less intramuscular phosphocreatine depletion and less fatigue of stimulated tetanic force during exercise compared to control. Thus, due to the central failure, there was decreased muscle activation resulting in a smaller metabolic demand and less fatigue within the muscle itself. These data demonstrate a major contribution of central factors to muscle fatigue in ALS.

Blunted pressor and intramuscular metabolic responses to voluntary isometric exercise in multiple sclerosis.

To test the hypothesis that a lower mean arterial pressure (MAP) response during voluntary isometric exercise in multiple sclerosis (MS) is related to a dampened muscle metabolic signal, 9 MS and 11 control subjects performed an isometric dorsiflexor contraction at 30% maximal voluntary contraction until target failure (endurance time). We made continuous and noninvasive measurements of heart rate and MAP (Finapres) and of intramuscular pH and P(i) (phosphorus magnetic resonance spectroscopy) in a subset of 6 MS and 10 control subjects. Endurance times and change in heart rate were similar in MS and control subjects. The decrease in pH and increase in P(i) were less throughout exercise in MS compared with control subjects, as was the change in MAP response. Differences in muscle strength accounted for some of the difference in MAP response between groups. Cardiovascular responses during Valsalva and cold pressor tests were similar in MS and control subjects, suggesting that the blunted MAP response during exercise in MS was not due to a generalized dysautonomia. The dampened metabolic response in MS subjects was not explained by inadequate central muscle activation. These data suggest that the blunted pressor response to exercise in MS subjects may be largely appropriate to a blunted muscle metabolic response and differences in contracting muscle mass.

Skeletal muscle contractile and noncontractile components in young and older women and men.

To examine the influences of age, gender, and habitual physical activity level on human skeletal muscle composition, we developed a relatively simple magnetic resonance imaging method for the quantitation of leg anterior compartment contractile and noncontractile content. We studied 23 young (11 women and 12 men, 26-44 yr old) and 21 older (10 women and 11 men, 65-83 yr old) healthy adults. Analysis was by two-factor (age, gender) ANOVA. Physical activity, quantitated by three-dimensional accelerometer worn about the waist for 1 wk, was not different between groups. Men had larger contractile and noncontractile cross-sectional areas (cm(2)) than women, with no gender effect on percent noncontractile area. Young subjects had larger contractile areas and smaller absolute (cm(2)) and relative (percent total) noncontractile areas than older subjects. There was a significant linear relationship between physical activity and percent noncontractile area in older (r = -0.68, P = 0.002) but not young subjects. These data demonstrate a more than twofold increase in the noncontractile content of locomotor muscles in older adults and provide novel support for physical activity as a modulator of this age-related change in muscle composition.

Slowed muscle contractile properties are not associated with a decreased EMG/force relationship in older humans.

We tested the hypothesis that, as a result of slower muscle contractile properties, the electromyogram (EMG)/force relationship is decreased during voluntary contractions in older compared to young humans. We studied 22 young (32 +/- 1 yr, mean +/- SE) and 20 older (72 +/- 1) men and women. To quantitate ankle dorsiflexor muscle properties, we measured isometric twitch time to peak force and maximal relaxation rate, the rates of tetanic (50 Hz, 1 s) force development and relaxation, and the stimulated force-frequency relationship. The voluntary EMG/force relationship was determined during isometric dorsflexion from 10% to 100% MVC (maximal voluntary isometric contraction force) in 10% MVC increments. Twitch time to peak force and the rates of tetanic force development and relaxation were slower in the older subjects. Greater relative force was produced in older compared to young adults at 10 Hz. During voluntary contractions, EMG was greater in older compared to young subjects at lower intensities (10% and 20% MVC). Thus, although the older adults exhibited a slowing of contractile properties and summation of force when stimulated at 10 Hz, the voluntary EMG/force relationship was increased rather than decreased at low contraction intensities, compared to young adults. We conclude that the slowing of contractile properties does not result in increased neural "efficiency" of voluntary force production in older adults. This novel observation may have important functional relevance to the performance of activities of daily living, particularly in a more frail older population.

Specific strength and voluntary muscle activation in young and elderly women and men.

The extents to which decreased muscle size or activation are responsible for the decrease in strength commonly observed with aging remain unclear. Our purpose was to compare muscle isometric strength [maximum voluntary contraction (MVC)], cross-sectional area (CSA), specific strength (MVC/CSA), and voluntary activation in the ankle dorsiflexor muscles of 24 young (32 +/- 1 yr) and 24 elderly (72 +/- 1 yr) healthy men and women of similar physical activity level. Three measures of voluntary muscle activation were used: the central activation ratio [MVC/(MVC + superimposed force)], the maximal rate of voluntary isometric force development, and foot tap speed. Men had higher MVC and CSA than did women. Young men had higher MVC compared with elderly men [262 +/- 19 (SE) vs. 197 +/- 22 N, respectively], whereas MVC was similar in young and elderly women (136 +/- 15 vs. 149 +/- 16 N, respectively). CSA was greater in young compared with elderly subjects. There was no age-related impairment of specific strength, central activation ratio, or the rate of voluntary force development. Foot tap speed was reduced in elderly (34 +/- 1 taps/10 s) compared with young subjects (47 +/- 1 taps/10 s). These results suggest that isometric specific strength and the ability to fully and rapidly activate the dorsiflexor muscles during a single isometric contraction were unimpaired by aging. However, there was an age-related deficit in the ability to perform rapid repetitive dynamic contractions.

Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort.

The purpose of this study was to estimate the relative contributions of central and peripheral factors to the development of human muscle fatigue. Nine healthy subjects [five male, four female; age = 30 (2) years, mean (SE)] sustained a maximum voluntary isometric contraction (MVC) of the ankle dorsiflexor muscles for 4 min. Fatigue was quantitated as the fall in MVC. Three measures of central activation and one measure of peripheral activation (compound muscle action potential, CMAP) were made using electromyography (EMG) and electrical stimulation. Measures of intramuscular metabolism were made using magnetic resonance spectroscopy. After exercise, MVC and electrically stimulated tetanic contraction (50 Hz, 500 ms) forces were 22.2 (3.7)% and 37.3 (7.1)% of pre-exercise values, respectively. The measures of central activation suggested some central fatigue during exercise: (1) the central activation ratio [MVC/(MVC + superimposed tetanic force)] fell from 0.94 (0.03) to 0.78 (0.09), (2) the MVC/tetanic force ratio fell from 2.3 (0.7) to 1.3 (0.7), and (3) the integral of the EMG (iEMG) signal decreased to 72.6 (9.1)% of the initial value, while the CMAP amplitude was unchanged. Intramuscular pH was associated by regression with the decline in MVC force (and therefore fatigue) and iEMG. The results indicate that central factors, which were not associated with altered peripheral excitability, contributed approximately 20% to the muscle fatigue developed, with the remainder being attributable to intramuscular (i.e., metabolic) factors. The association between pH and iEMG is consistent with proton concentration as a feedback mechanism for central motor drive during maximal effort.

Functional significance of upper and lower motor neuron impairment in amyotrophic lateral sclerosis.

The objective of this study was to examine the contribution of lower motor neuron (LMN) and upper motor neuron (UMN) dysfunction to weakness and impaired motor control in 27 patients with amyotrophic lateral sclerosis (ALS). Isometric strength was measured by dorsiflexor maximum voluntary contraction force (MVC). LMN function was measured by tetanic force, twitch force, and the amplitude of the compound muscle action potential. UMN function was measured by the speed of rapid foot taps, the maximum rate of rise of voluntary force, and the central activation ratio [CAR = MVC/(MVC + superimposed tetanic force)]. The results suggest that (1) LMN loss appears to be the primary cause of progressive weakness in ALS; while (2) UMN impairment in ALS leads to slowing of contraction speed and rapid movements, and modest decreases in central activation; and (3) during 6 months of progression, LMN changes were greater than UMN changes.