Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting.

Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.

Muscle wasting and survival following pre-operative chemoradiotherapy for locally advanced rectal carcinoma.

BACKGROUND & AIMS: Neoadjuvant chemoradiotherapy (NACRT) has increased local control in locally advanced rectal cancer. Reduced skeletal muscle mass (sarcopenia), or ongoing muscle wasting, is associated with decreased survival in cancer. This study aims to assess the change in body composition during NACRT and its impact on outcome using computed tomography (CT) imaging in locally advanced rectal cancer (LARC) patients. METHODS: LARC patients treated with NACRT were selected from a prospectively maintained database and retrospectively analyzed. One-hundred twenty-two patients who received treatment between 2004 and 2012 with available diagnostic CT imaging obtained before and after NACRT were identified. Cross-sectional areas for skeletal muscle was determined, and subsequently normalized for patient height. Differences between skeletal muscle areas before and after NACRT were computed, and their influence on overall and disease-free survival was assessed. RESULTS: A wide distribution in change of body composition was observed. Loss of skeletal muscle mass during chemoradiotherapy was independently associated with disease-free survival (HR0.971; 95% CI: 0.946-0.996; p = 0.025) and distant metastasis-free survival (HR0.942; 95% CI: 0.898-0.988; p = 0.013). No relation was observed with overall survival in the current cohort. CONCLUSIONS: Loss of skeletal muscle mass during NACRT in rectal cancer patients is an independent prognostic factor for disease-free survival and distant metastasis-free survival following curative intent resection.

Systematic Review and Meta-Analysis of the Impact of Computed Tomography-Assessed Skeletal Muscle Mass on Outcome in Patients Awaiting or Undergoing Liver Transplantation.

Liver transplant outcome has improved considerably as a direct result of optimized surgical and anesthesiological techniques and organ allocation programs. Because there remains a shortage of human organs, strict selection of transplant candidates remains of paramount importance. Recently, computed tomography (CT)-assessed low skeletal muscle mass (i.e. sarcopenia) was identified as a novel prognostic parameter to predict outcome in liver transplant candidates. A systematic review and meta-analysis on the impact of CT-assessed skeletal muscle mass on outcome in liver transplant candidates were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nineteen studies, including 3803 patients in partly overlapping cohorts, fulfilled the inclusion criteria. The prevalence of sarcopenia ranged from 22.2% to 70%. An independent association between low muscle mass and posttransplantation and waiting list mortality was described in 4 of the 6 and 6 of the 11 studies, respectively. The pooled hazard ratios of sarcopenia were 1.84 (95% confidence interval 1.11-3.05, p = 0.02) and 1.72 (95% confidence interval 0.99-3.00, p = 0.05) for posttransplantation and waiting list mortality, respectively, independent of Model for End-stage Liver Disease score. Less-consistent evidence suggested a higher complication rate, particularly infections, in sarcopenic patients. In conclusion, sarcopenia is an independent predictor for outcome in liver transplantation patients and could be used for risk assessment.

Systematic review of sarcopenia in patients operated on for gastrointestinal and hepatopancreatobiliary malignancies.

BACKGROUND: Preoperative risk assessment in cancer surgery is of importance to improve treatment and outcome. The aim of this study was to assess the impact of CT-assessed sarcopenia on short- and long-term outcomes in patients undergoing surgical resection of gastrointestinal and hepatopancreatobiliary malignancies. METHODS: A systematic search of Embase, PubMed and Web of Science was performed to identify relevant studies published before 30 September 2014. PRISMA guidelines for systematic reviews were followed. Screening for inclusion, checking the validity of included studies and data extraction were carried out independently by two investigators. RESULTS: After screening 692 records, 13 observational studies with a total of 2884 patients were included in the analysis. There was wide variation in the reported prevalence of sarcopenia (17.0-79 per cent). Sarcopenia was independently associated with reduced overall survival in seven of ten studies, irrespective of tumour site. Hazard ratios (HRs) of up to 3.19 (hepatic cancer), 1.63 (pancreatic cancer), 1.85 (colorectal cancer) and 2.69 (colorectal liver metastases, CLM) were reported. For oesophageal cancer, the HR was 0.31 for increasing muscle mass. In patients with colorectal cancer and CLM, sarcopenia was independently associated with postoperative mortality (colorectal cancer: odds ratio (OR) 43.3), complications (colorectal cancer: OR 0.96 for increasing muscle mass; CLM: OR 2.22) and severe complications (CLM: OR 3.12). CONCLUSION: Sarcopenia identified before surgery by single-slice CT is associated with impaired overall survival in gastrointestinal and hepatopancreatobiliary malignancies, and increased postoperative morbidity in patients with colorectal cancer with or without hepatic metastases.

Body composition and outcome in patients undergoing resection of colorectal liver metastases.

BACKGROUND: Recent evidence suggests that depletion of skeletal muscle mass (sarcopenia) and an increased amount of intra-abdominal fat (central obesity) influence cancer statistics. This study investigated the impact of sarcopenia and central obesity on survival in patients undergoing liver resection for colorectal liver metastases (CLM). METHODS: Diagnostic imaging from patients who had hepatic resection for CLM in one centre between 2001 and 2009, and who had assessable perioperative computed tomograms, was analysed retrospectively. Total cross-sectional areas of skeletal muscle and intra-abdominal fat, and their influence on outcome, were analysed. RESULTS: Of the 196 patients included in the study, 38 (19·4 per cent) were classified as having sarcopenia. Five-year disease-free (15 per cent versus 28·5 per cent in patients without sarcopenia; P = 0·002) and overall (20 per cent versus 49·9 per cent respectively; P < 0·001) survival rates were lower for patients with sarcopenia at a median follow-up of 29 (range 1-97) months. Sarcopenia was an independent predictor of worse recurrence-free (hazard ratio (HR) 1·88, 95 per cent confidence interval 1·25 to 2·82; P = 0·002) and overall (HR 2·53, 1·60 to 4·01; P < 0·001) survival. Central obesity was associated with an increased risk of recurrence in men (P = 0·032), but not in women (P = 0·712). CONCLUSION: Sarcopenia has a negative impact on cancer outcomes following resection of CLM.