Loss of oxidative defense and potential blockade of satellite cell maturation in the skeletal muscle of patients with cancer but not in the healthy elderly

Purpose: Muscle wasting in old age or cancer may result from failure of myofibre regeneration and /or accelerated apoptosis both of which may be up-regulated by oxidative stress or inflammation. The aim of this study was to determine from the transcriptome in human skeletal muscle whether there is evidence for oxidative stress and its relationship with satellite cell differentiation or apoptosis in the muscle of patients with cancer (weight-stable: CWS or weight-losing: CWL) or healthy elderly (HE) when compared with healthy middle aged controls (HMAC) . Design: 28 patients with resectable upper GI/pancreatic cancer (CWS: 14 and CWL14), 17 HE and 22 HMAC underwent biopsy of the quadriceps muscle. Markers of muscle regeneration, inflammation, oxidative stress and apoptosis were measured by qPCR. Results: The expression of transcription factors responsible for muscle regeneration (Pax3, Pax7 and MyoD) were increased in the skeletal muscle of CWS and HE when compared with HMAC (P<0.001). In contrast, the expression of myogenic differentiation markers (MyoG and Myh2) was reduced in CWS and CWL but increased in HE when compared with HMAC (P<0.0001). The expression of the pro-apoptotic gene Bax was significantly increased in CWS, CWL and HE compared with HMAC (P<0.0001). Pro-inflammatory cytokine expression was variable with increased expression of TNF in CWS and HE, increased Il-6 in CWS and increased Il-1 in CWL when compared with HMAC. Expression of the oxidative defense genes SOD2, GCLM, and NRF2 was decreased in CWS and CWL but increased in HE when compared with HMA (P<0.0001). Conclusion: There is evidence for blockade of satellite cell maturation, upregulation of apoptosis and reduced oxidative defense in the skeletal muscle of cancer patients. In contrast, in muscle from healthy elderly the potential for myotube differentiation and oxidative defense is maintained

Skeletal Muscle Changes After Elective Colorectal Cancer Resection:A Longitudinal Study

BACKGROUND: Muscle depletion is a poor prognostic indicator in colorectal cancer (CRC) patients, but there were no data assessing comparative temporal body composition changes following elective CRC surgery. We examined patient skeletal muscle index trajectories over time after surgery and determined factors that may contribute to those alterations. METHODS: Patients diagnosed with CRC undergoing elective surgical resection between 2006 and 2013 were included in this study. Image analysis of serial computed tomography (CT) scans was used to calculate lumbar skeletal muscle index (LSMI). A multilevel mixed-effect linear regression model was applied using STATA (version 12.0) using the xtmixed command to fit growth curve models (GCM) for LSMI and time. RESULTS: In 856 patients, a total of 2136 CT images were analyzed; 856 (38.2 %) were preoperative. A quadratic GCM with random intercept and random slope for patients’ LSMI was identified that demonstrated laparoscopy produces a positive change on the LSMI curve [estimate = 0.17 cm(2)/m(2), standard error (SE) 0.06 cm(2)/m(2); p = 0.03], whereas Union for International Cancer Control (UICC) stage III + IV disease contributed to a negative curve change (estimate = −0.19 cm(2)/m(2), SE 0.09 cm(2)/m(2); p = 0.03). Older age (p < 0.01), female gender (p < 0.01), higher American Society of Anesthesiologists (ASA) score (p < 0.01), and altered systemic inflammatory response [SIR] (p = 0.03) were factors significantly associated with lower values of LSMI over time. CONCLUSION: In patients undergoing CRC surgery, laparoscopy and the absence of a significantly elevated SIR favored preservation and restoration of skeletal muscle, postoperatively. These emerging data may permit the development of new treatment protocols whereby monitoring and modification of body composition has therapeutic potential

Cancer cachexia is associated with the IL10-1082 gene promoter polymorphism in patients with gastroesophageal malignancy

Background: The genetic predisposition of the host to local or systemic inflammation may contribute to the effect of cancer cachexia. Objective: We investigated the relation between cytokine polymorphisms (IL1B -511, IL6 -174, IL10 -1082, TNFA -308, and LTA +252) and markers of nutritional status among patients with gastroesophageal cancer to determine whether any such association was reflected by cytokine concentrations in the tumor or plasma compartments. Design: Patients (n = 203) with a diagnosis of gastroesophageal cancer underwent nutritional assessment (body mass index, anthropometric measures, dysphagia scoring, and estimation of dietary intake). Single nucleotide polymorphism genotyping was performed by TaqMan allelic discrimination genotyping. Serum cytokine and C-reactive protein concentrations were determined by enzyme-linked immunosorbent assay. Tumor tissue cytokine protein concentrations (n = 56) were determined by using the Cytometric Bead Array System. Results: IL10 GG and IL6 CC polymorphisms were associated with elevated serum C-reactive protein concentrations, and the IL6 CC genotype was also associated with elevated tumor tissue cytokine concentrations. At diagnosis, the IL10 GG, but not the IL6, genotype was linked with increased total weight loss: 4.9% for AA, 7.1% for AG, and 12.0% for GG (P = 0.007). Serum C-reactive protein concentrations correlated with increased weight loss (r = 0.24, P &lt; 0.001). Compared with other genotypes, the IL10 GG genotype retained an independent association in determining the extent of weight loss on multivariate analysis (95% CI: 0.52, 3.43; P = 0.008). Possession of the GG allele was associated with a 2.3 times increased risk of developing cachexia (95% CI: 1.2, 4.3; P = 0.014). Conclusions: These data suggest that the IL10 genotype of the host can influence the development of cachexia among patients with gastroesophageal malignancy.<br/

Health-status outcomes with invasive or conservative care in coronary disease

BACKGROUND In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline

Initial invasive or conservative strategy for stable coronary disease

BACKGROUND Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, 121.8 percentage points; 95% CI, 124.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used