A randomized pilot trial testing the safety and immunologic effects of a MAGE-A3 protein plus AS15 immunostimulant administered into muscle or into dermal/subcutaneous sites.

INTRODUCTION: Methods to induce T cell responses to protein vaccines have not been optimized. The immunostimulant AS15 has been administered with the recombinant MAGE-A3 protein (recMAGE-A3) i.m. but not i.d. or s.c. This study tests hypotheses that the i.d./s.c. route is safe and will increase CD4(+) and CD8(+) T cell responses to MAGE-A3. PATIENTS AND METHODS: Twenty-five patients with resected stage IIB-IV MAGE-A3(+) melanoma were randomized to immunization with recMAGE-A3 combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) either i.m. (group A, n = 13) or i.d./s.c. (group B, n = 12). Adverse events were recorded. Ab responses to MAGE-A3 were measured by ELISA. T cell responses to overlapping MAGE-A3 peptides were assessed in PBMC and a sentinel immunized node (SIN) after 1 in vitro stimulation with recMAGE-A3, by IFN-γ ELISPOT assay and by flow cytometry for multifunctional (TNF-α/IFN-γ) responses. RESULTS: Both routes of immunization were well tolerated without treatment-related grade 3 adverse events. All patients had durable Ab responses. For all 25 patients, the T cell response rate by ELISPOT assay was 30 % in SIN (7/23) but only 4 % (1/25) in PBMC. By flow cytometry, multifunctional CD8(+) T cell responses were identified in one patient in each group; multifunctional CD4(+) T cell response rates for groups A and B, respectively, were 31 and 64 % in SIN and 31 and 50 % in PBMC. CONCLUSION: The MAGE-A3 immunotherapeutic was well tolerated after i.d./s.c. administration, with trends to higher CD4(+) T cell response rates than with i.m. administration. This study supports further study of AS15 by i.d./s.c. administration.

Gender differences in the prevalence and management of metabolic syndrome and its components in patients with peripheral artery disease.

We compared the prevalence and management of metabolic syndrome (MetS) and its components in men and women with peripheral artery disease (PAD). A total of 70 men and 70 women with PAD were evaluated for presence of MetS. There was no significant gender difference in presence of MetS (P = .399) and the number of MetS components (P = .411). Among PAD patients with each MetS component, there was no significant gender difference in the use (P = .617) and number (P = .716) of blood pressure medications, the use (P = .593) and number (P = .591) of lipid-lowering medications, and the number (P = .155) of diabetic medications. Significantly more women were treated with diabetic medications compared with men (85 vs 57%, P = .026). The prevalence and management of MetS and its components was similar between men and women with PAD, except that more women were treated for diabetes. Patients with PAD having MetS did not receive optimal medical management.

Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial.

BACKGROUND: This prospective, randomized, controlled clinical trial compared changes in exercise performance and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after a home-based exercise program, a supervised exercise program, and usual-care control. METHODS AND RESULTS: Of the 119 patients randomized, 29 completed home-based exercise, 33 completed supervised exercise, and 30 completed usual-care control. Both exercise programs consisted of intermittent walking to nearly maximal claudication pain for 12 weeks. Patients wore a step activity monitor during each exercise session. Primary outcome measures included claudication onset time and peak walking time obtained from a treadmill exercise test; secondary outcome measures included daily ambulatory cadences measured during a 7-day monitoring period. Adherence to home-based and supervised exercise was similar (P=0.712) and exceeded 80%. Both exercise programs increased claudication onset time (P<0.001) and peak walking time (P<0.01), whereas only home-based exercise increased daily average cadence (P<0.01). No changes were seen in the control group (P>0.05). The changes in claudication onset time and peak walking time were similar between the 2 exercise groups (P>0.05), whereas the change in daily average cadence was greater with home-based exercise (P<0.05). CONCLUSIONS: A home-based exercise program, quantified with a step activity monitor, has high adherence and is efficacious in improving claudication measures similar to a standard supervised exercise program. Furthermore, home-based exercise appears more efficacious in increasing daily ambulatory activity in the community setting than supervised exercise.

Walking economy before and after the onset of claudication pain in patients with peripheral arterial disease.

PURPOSE: To determine the walking economy before and after the onset of claudication pain in patients with peripheral arterial disease (PAD), and to identify predictors of the change in walking economy following the onset of claudication pain. METHODS: A total of 39 patients with PAD were studied, in which 29 experienced claudication (Pain group) during a constant load, walking economy treadmill test (speed = 2.0 mph, grade = 0%) and 10 were pain-free during this test (Pain-Free group). Patients were characterized on walking economy (ie, oxygen uptake during ambulation), as well as on demographic characteristics, cardiovascular risk factors, baseline exercise performance measures, and the ischemic window calculated from the decrease in ankle systolic blood pressure following exercise. RESULTS: During the constant load treadmill test, the Pain group experienced onset of claudication pain at 323 +/- 195 seconds (mean +/- standard deviation) and continued to walk until maximal pain was attained at 759 +/- 332 seconds. Walking economy during pain-free ambulation (9.54 +/- 1.42 ml x kg(-1) x min(-1)) changed (P < .001) after the onset of pain (10.18 +/- 1.56 ml x kg(-1) x min(-1)). The change in walking economy after the onset of pain was associated with ischemic window (P < .001), hypertension (P < .001), diabetes (P = .002), and height (P = .003). In contrast, the Pain-Free group walked pain-free for the entire 20-minute test duration without a change in walking economy (P = .36) from the second minute of exercise (9.20 +/- 1.62 ml x kg(-1) x min(-1)) to the nineteenth minute of exercise (9.07 +/- 1.54 ml x kg(-1) x min(-1)). CONCLUSION: Painful ambulation at a constant speed is associated with impaired walking economy, as measured by an increase in oxygen uptake in patients limited by intermittent claudication, and the change in walking economy is explained, in part, by severity of PAD, diabetes, and hypertension.

Association between daily ambulatory activity patterns and exercise performance in patients with intermittent claudication.

PURPOSE: To determine the association between daily ambulatory activity patterns and exercise performance in patients with intermittent claudication. METHODS: One hundred thirty-three patients limited by intermittent claudication participated in this study. Patients were assessed on their ambulatory activity patterns for 1 week with a small, lightweight step activity monitor attached to the ankle using elastic velcro straps above the lateral malleolus of the right leg. The step activity monitor recorded the number of strides taken on a minute-to-minute basis and the time spent ambulating. Patients also were characterized on ankle-brachial index (ABI), ischemic window (IW) after a treadmill test, as well as initial claudication distance (ICD), and absolute claudication distance (ACD) during treadmill exercise. RESULTS: The patient characteristics (mean +/- SD) were as follows: ABI = 0.71 +/- 0.23, IW = 0.54 +/- 0.72 mm Hg.min.meter(-1), ICD = 236 +/- 198 meters, and ACD = 424 +/- 285 meters. The patients took 3366 +/- 1694 strides/day, and were active for 272 +/- 103 min/day. The cadence for the 30 highest, consecutive minutes of each day (15.1 +/- 7.2 strides/min) was correlated with ICD (r = 0.316, P < .001) and ACD (r = 0.471, P < 0.001), and the cadence for the 60 highest, consecutive minutes of each day (11.1 +/- 5.4 strides/min) was correlated with ICD (r = 0.290, P < .01) and ACD (r = 0.453, P < .001). Similarly, the cadences for the highest 1, 5, and 20 consecutive minutes, and the cadence for the 30 highest, nonconsecutive minutes all were correlated with ICD and ACD (P < .05). None of the ambulatory cadences were correlated with ABI (P > .05) or with ischemic window (P > .05). CONCLUSION: Daily ambulatory cadences are associated with severity of intermittent claudication, as measured by ACD and ICD, but not with peripheral hemodynamic measures.

Calf muscle hemoglobin oxygen saturation characteristics and exercise performance in patients with intermittent claudication.

PURPOSE: This study was conducted to determine the association between the characteristics of calf muscle hemoglobin oxygen saturation (StO(2)) and exercise performance in patients with intermittent claudication. METHODS: The study comprised 39 patients with peripheral arterial disease limited by intermittent claudication. Patients were characterized on calf muscle StO(2) before, during, and after a graded treadmill test, as well as on demographic and cardiovascular risk factors, ankle-brachial index (ABI), ischemic window, initial claudication distance (ICD), and absolute claudication distance (ACD). RESULTS: Calf muscle StO(2) decreased 72%, from 55% +/- 18% (mean +/- SD) saturation at rest to the minimum value of 17% +/- 19% saturation attained 459 +/- 380 seconds after the initiation of exercise. After exercise, recovery half-time of calf muscle StO(2) was attained at 129 +/- 98 seconds, whereas full recovery to the resting value was reached at 225 +/- 140 seconds. After adjusting for sex, race, and grouping according to the initial decline constant in calf muscle StO(2) during exercise, the exercise time to minimum calf muscle StO(2) was correlated with the ischemic window (r = -0.493, P = .002), ICD (r = 0.339, P = .043), and ACD (r = 0.680, P < .001). After treadmill exercise, the recovery half-time of calf muscle StO(2) was correlated with the ischemic window (r = 0.531, P < .001), ICD (r = -0.598, P < .001), and ACD (r = -0.491, P = .003). CONCLUSION: In patients limited by intermittent claudication, shorter ICD and ACD values are associated with reaching a minimum value in calf muscle StO(2) sooner during treadmill exercise and with having a delayed recovery in calf muscle StO(2) after exercise.

The effect of hypercholestrolemia on calf muscle hemoglobin oxygen saturation in patients with intermittent claudication.

The purpose was to compare calf muscle hemoglobin oxygen saturation and exercise performance in hypercholesterolemic and normocholesterolemic patients with peripheral arterial disease. Hypercholesterolemic and normocholesterolemic patients had similar ankle/ brachial index (0.72 +/- 0.24 vs 0.79 +/- 0.28, [mean +/- SD]; P = .334). Hypercholesterolemic patients had shorter initial claudication distance (214 +/- 168 m vs 331 +/- 185 m, P = .026), absolute claudication distance (391 +/- 219 m vs 549 +/- 211 m, P = .035), and lower calf muscle hemoglobin oxygen saturation at the occurrence of initial claudication distance (27 +/- 21% vs 39 +/- 20%; P = .013), and absolute claudication distance (26 +/- 21% vs 36 +/- 21%; P = .021). Hypercholesterolemia is associated with shorter walking distances and calf muscle hemoglobin oxygen saturation during exercise in patients limited by intermittent claudication.

Patterns of ambulatory activity in subjects with and without intermittent claudication.

PURPOSE: This study compared the patterns of ambulatory activity in subjects with and without intermittent claudication. METHODS: The study participants were 98 subjects limited by intermittent claudication and 129 controls who were matched for age, gender, and race. Subjects were assessed on their ambulatory activity patterns for 1 week with a small, lightweight step activity monitor attached to the ankle using elastic Velcro (Velcro Industries BV, Manchester, NH) straps above the lateral malleolus of the right leg. The step activity monitor recorded the number of strides taken on a minute-to-minute basis, the time spent ambulating, and the time and number of strides measured at low (<15 strides/min), medium (15 to 30 strides/min), and high (>30 strides/min) cadences. RESULTS: Subjects with intermittent claudication took fewer total strides each day than the controls (3149 +/- 1557 strides/d vs 4230 +/- 1708 strides/d; P < .001) and fewer strides at medium (1228 +/- 660 strides/day vs 1638 +/- 724 strides/day; P = .001) and high (766 +/- 753 strides/day vs 1285 +/- 1029 strides/day; P < .001) cadences. Subjects with intermittent claudication also had a lower daily average cadence than the controls (11.8 +/- 2.9 strides/min vs 13.5 +/- 3.1 strides/min; P < .001) and spent less total time ambulating each day (264 +/- 109 min/day vs 312 +/- 96 min/day; P = .034), primarily at medium (58 +/- 30 min/day vs 75 +/- 32 min/day; P < .001) and at high (19 +/- 17 min/day vs 30 +/- 22 min/day; P = .001) cadences. CONCLUSION: Intermittent claudication is associated with lower total daily ambulatory activity owing both to less time ambulating and to fewer strides taken while ambulating, particularly at moderate and high cadences.

The effect of current cigarette smoking on calf muscle hemoglobin oxygen saturation in patients with intermittent claudication.

The purpose of this study was to compare calf muscle hemoglobin oxygen saturation response during exercise between smokers and non-smokers with peripheral arterial disease. Patients limited by intermittent claudication who were smokers (n = 12) were compared with those who had not smoked (n = 28) for at least 1 year prior to investigation. Ankle/brachial index (ABI) measurements were obtained with Doppler ultrasound, and maximal calf blood flow was measured by venous occlusion plethysmography. Hemoglobin oxygen saturation (StO2) of the calf muscle, initial claudication distance (ICD), and absolute claudication distance (ACD) were obtained during a graded treadmill test. Smokers refrained from smoking on the morning of the test. Smokers had similar ABI values compared with non-smokers (0.70 +/- 0.26 vs 0.73 +/- 0.23 [mean +/- SD]; p = 0.808), whereas the smokers had lower values for maximal calf blood flow (8.71 +/- 5.76 %/min vs 11.48 +/- 4.46 %/min; p = 0.038), ICD (122 +/- 123 m vs 243 +/- 177 m; p = 0.023), and ACD (284 +/- 170 m vs 452 +/- 263 m; p = 0.023). Additionally, smokers had lower calf muscle StO2 values at the end of 1 minute (16 +/- 15% vs 37 +/- 19%; p = 0.002) and 2 minutes of exercise (16 +/- 16% vs 35 +/- 25%; p = 0.008), and at the occurrence of ICD (17 +/- 17% vs 32 +/- 23%; p = 0.033) and ACD (16 +/- 16% vs 32 +/- 24%; p = 0.024). After adjusting for blood flow, calf muscle StO2 values remained lower in the smokers (p < 0.05). Finally, calf muscle StO2 at the end of the first minute of exercise was related to ICD (r = 0.611, p < 0.001) and ACD (r = 0.443, p < 0.01). In conclusion, smokers limited by intermittent claudication have lower calf muscle StO2 during exercise than nonsmokers, and lower StO2 during exercise is associated with shorter ICD and ACD.