Correction: Energy expenditure in caving.

[This corrects the article DOI: 10.1371/journal.pone.0170853.].

Energy expenditure in caving.

The aim of this study was to determine the energy expenditure of a group of cavers of both genders and different ages and experience during a 10 hour subterranean exploration, using portable metabolimeters. The impact of caving activity on body composition and hydration were also assessed through bioelectrical impedance, and nutritional habits of cavers surveyed. During cave activity, measured total energy expenditure (TEE) was in the range 225-287 kcal/h for women-men (MET = 4.1), respectively; subjects had an energy intake from food in the range 1000-1200 kcal, thus inadequate to restore lost calories. Bayesian statistical analysis estimated the effect of predictive variables on TEE, revealing that experienced subjects had a 5% lower TEE than the less skilled ones and that women required a comparatively larger energy expenditure than men to perform the same task. BIVA (bioelectrical impedance vector analysis) showed that subjects were within the range of normal hydration before and after cave activity, but bioelectrical changes indicated a reduction of extracellular water in men, which might result in hypo-osmolal dehydration in the case of prolonged underground exercise. All these facts should be considered when planning cave explorations, preparing training programs for subjects practising caving, and optimizing a diet for cavers. Further, information gathered through this study could be of value to reduce accidents in caves related to increase in fatigue.

Physical Capacity and Energy Expenditure of Cavers.

Caves are an extreme environment for humans because of the high humidity, mud, darkness, and slippery conditions. Explorations can last many hours or even days, and require extensive climbing and ropework. Very little is known about the physical capacity of cavers and their energy expenditure (EE) during caving. The physical capacity of 17 (7 females) expert cavers (age 43.9 ± 7.3 years) was assessed during an incremental cycle-ergometer test (IET) with gas exchange analysis. Moreover, a wearable metabolic band (Armband Fit Core) was used to estimate their EE during caving. In terms of physical capacity, the IET showed that cavers had a maximum oxygen uptake (VO2max) of 2,248.7 ± 657.8 ml·min-1 (i.e., 32.4 ± 6.4 ml·kg-1·min-1), while anaerobic threshold (AT) occurred on average at 74.5% of VO2max. Results from caving sessions provided an average time spent in cave of 9.4 ± 1.2 h while the average EE was 268.8 ± 54.8 kcal·h-1, which corresponded to about 40% of VO2max measured during IET. A mean distance of 10.6 ± 2.2 km was covered by subjects. Data from the present investigation provide evidence that cavers have a level of aerobic physical capacity only slightly higher than that of sedentary people, thereby suggesting that a high aerobic fitness is not needed by cavers. Moreover, during caving the EE was on average well below the level of AT. However, in absolute terms, the total EE was elevated (i.e., 2,672.3 ± 576 kcal in total) due to the long time spent in caving.

Long-term, up to 18 months, protective effects of the angiotensin II receptor blocker telmisartan on Epirubin-induced inflammation and oxidative stress assessed by serial strain rate.

PURPOSE: The primary objective of the present study was to show the long lasting cardioprotective activity, at different time-points, up to 18 month-follow-up, of telmisartan in preserving the systolic function (assessed as Strain Rate-SR) in cancer patients treated with EPI both in the adjuvant and metastatic setting; the secondary objective was to confirm the correlation of the cardioprotective activity of telmisartan with a reduction of inflammation and oxidative stress induced by EPI. METHODS: Phase II single blind placebo-controlled randomized trial. Sample size 50 patients per arm: based on a pre-planned interim analysis for early stopping rules, the study was discontinued for ethical reasons at 49 patients. Cardiovascular disease-free patients with cancer at different sites eligible for EPI-based treatment randomized to: telmisartan n = 25 or placebo n = 24. Echocardiography Tissue Doppler imaging (TDI) strain and strain rate was performed, serum levels of proinflammatory cytokines (IL-6, TNF-α) and oxidative stress (reactive oxygen species, ROS) were assessed at baseline, every 100 mg/m(2) EPI dose and at 6-, 12- and 18-month follow-up (FU). RESULTS: Significant SR peak reduction in both arms was observed at t2 (cumulative dose EPI 200 mg/m(2)) vs t0. Conversely, at t3, t4, 6-, 12- and 18-month FU SR increased towards normal range in the telmisartan arm, while in the placebo arm SR remained significantly lower. Differences between SR changes in the placebo and telmisartan arm were significant from t3 up to 18 month-FU. IL-6 and ROS increased significantly in the placebo arm at t2 but did not change in the telmisartan arm. A significant (p < 0.05) correlation between changes of SR vs IL-6 and ROS was observed. CONCLUSIONS: Our results suggest that the protective effect of telmisartan is long lasting, probably by ensuring a permanent (at least up to 18-month FU) defense against chronic or late-onset types of anthracycline-induced cardiotoxicity.

Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome.

BACKGROUND & AIMS: A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine + celecoxib ± megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. METHODS: Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day + Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day + celecoxib 300 mg/day + megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. RESULTS: The results did not show a significant difference between tre atment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. CONCLUSIONS: The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination + megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment.

Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction.

Chronic inflammation, oxidative stress and the renin-angiotensin system (RAS) play a significant role in chemotherapy-induced cardiotoxicity (CTX). Telmisartan (TEL), an antagonist of the angiotensin II type-1 receptor, was found to reduce anthracycline (ANT)-induced CTX. We carried out a phase II placebo (PLA)-controlled randomized trial to assess the possible role of TEL in the prevention of cardiac subclinical damage induced by epirubicin (EPI). Forty-nine patients (mean age ± SD, 53.0±8 years), cardiovascular disease-free with cancer at different sites and eligible for EPI-based treatment, were randomized to one of two arms: TEL n=25; PLA n=24. A conventional echocardiography equipped with Tissue Doppler imaging, strain and strain rate (SR) was performed, and serum levels of proinflammatory cytokines, IL-6 and TNF-α, and oxidative stress parameters, reactive oxygen species (ROS) and glutathione peroxidase were determined. All assessments were carried out at baseline, after every 100 mg/m(2) of EPI dose and at the 12-month follow-up (FU). A significant reduction in the SR peak both in the TEL and PLA arms was observed at t(2) (cumulative dose of 200 mg/m(2) of EPI) in comparison to t(0). Conversely, at t(3) (300 mg/m(2) EPI), t(4) (400 mg/m(2) EPI) and the 12-month FU, the SR increased reaching the normal range only in the TEL arm, while in the PLA arm the SR remained significantly lower as compared to t(0) (baseline). The differences between SR changes in the PLA and TEL arms were significant from 300 mg/m(2) EPI (t(3)) up to the 12-month FU. Serum levels of IL-6 increased significantly in the PLA arm at 200 mg/m(2) EPI (t(2)) in comparison to baseline, but remained unchanged in the TEL arm. The same trend was demonstrated for ROS levels which significantly increased at t(2) vs. baseline in the PLA arm, while remained unchanged in the TEL arm. The mean change in ROS and IL-6 at t(2) was significantly different between the two arms. In the present study, we confirmed at the 3-month FU a trend toward a decrease in ROS and IL-6 from t(2) in the PLA arm. Our results suggest that TEL is able to reverse acute (early) EPI-induced myocardial dysfunction and to maintain later a normal systolic function up to the 12-month FU. These effects are likely to be due to different mechanisms, RAS blockade and prevention of chronic inflammation/oxidative stress.

Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia.

Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase-2 inhibitors, such as celecoxib, may be beneficial in counteracting major symptoms of this devastating syndrome. We carried out a prospective phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites. A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. A significant increase of lean body mass and a significant decrease of TNF-alpha were observed. Moreover, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities. Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment. Our results showed that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Although the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success with a multitargeted approach; in the present study, we were able to show that a treatment, such as celecoxib, addressing a single target, albeit very important as chronic inflammation, could have positive effects. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib.

Persistence, up to 18 months of follow-up, of epirubicin-induced myocardial dysfunction detected early by serial tissue Doppler echocardiography: correlation with inflammatory and oxidative stress markers.

A phase II, open, nonrandomized trial was carried out in a group of epirubicin-treated cancer patients with the aim of detecting early preclinical changes that are predictive of the risk for heart failure. Thirty-one patients (male/female ratio, 8/23; mean age +/- standard deviation, 59 +/- 14 years) with tumors at different sites and scheduled to be treated with an epirubicin-based chemotherapy regimen, were enrolled. We prospectively evaluated the acute (1 week after) and late (3, 6, 12, and 18 months of follow-up) effects of epirubicin administration. A significant impairment in systolic left ventricular (LV) function was observed at a cumulative epirubicin dose of 200 mg/m(2). This was shown by a reduction in the strain rate (SR) peak in comparison with baseline and persisted throughout the treatment and follow-up, up to 18 months; strain (Sigma) remained unchanged. The Sm wave showed a progressive reduction that became significant only at the 18-month follow-up. On TDI the E(m)/A(m) ratio declined at the 200-mg/m(2) cumulative epirubicin dose versus baseline and persisted throughout the treatment and up to the 18-month follow-up. On conventional echocardiography the E/A ratio declined significantly only at the 300-mg/m(2) cumulative epirubicin dose. Interleukin (IL)-6, soluble IL-6 receptor, and reactive oxygen species (ROS) increased significantly at the 200-mg/m(2) dose, and IL-6 was persistently high at the 300- and 400-mg/m(2) doses, returning to within baseline values during follow-up. ROS, after the peak reached at the 200-mg/m(2) dose, returned to within baseline values. A significant inverse correlation between DeltaSR and the increase in both IL-6 and ROS was observed. A multiple regression analysis showed that both the IL-6 and ROS variables were independent and strongly predictive of DeltaSR. The clinical meaningfulness of our findings warrants further investigations on a larger number of patients for a longer period of follow-up.