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Abstract Background Cancer cachexia is a multifactorial metabolic syndrome characterized by systemic inflammation and ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Whereas lipid accumulation in skeletal muscle is associated with cancer cachexia as well as the prognosis of cancer patients, surprisingly little is known about the nature of the lipids that accumulate in the muscle during cachexia, and whether this is related to inflammation. We aimed to identify the types and distributions of intramyocellular lipids in patients with and without cancer cachexia. Methods Rectus abdominis muscle biopsies were collected during surgery of patients with pancreatic ductal adenocarcinoma (n = 10 without cachexia, n = 20 cachectic without inflammation (CRP

Abstract Background Most patients with pancreatic cancer develop cachexia, which is characterized by progressive muscle loss. The mechanisms underlying muscle loss in cancer cachexia remain elusive. Pancreatic tumour organoids are 3D cell culture models that retain key characteristics of the parent tumour. We aimed to investigate the effect of pancreatic tumour organoid‐derived factors on processes that determine skeletal muscle mass, including the regulation of muscle protein turnover and myogenesis. Methods Conditioned medium (CM) was collected from human pancreatic cancer cell lines (PK‐45H, PANC‐1, PK‐1, and KLM‐1), pancreatic tumour organoid cultures from a severely cachectic (PANCO‐9a) and a non‐cachectic patient (PANCO‐12a), and a normal pancreas organoid culture. Differentiating C2C12 myoblasts and mature C2C12 myotubes were exposed to CM for 24 h or maintained in control medium. In myotubes, NF‐kB activation was monitored using a NF‐κB luciferase reporter construct, and mRNA expression of E3‐ubiquitin ligases and REDD1 was analysed by RT‐qPCR. C2C12 myoblast proliferation and differentiation were monitored by live cell imaging and myogenic markers and myosin heavy chain (MyHC) isoforms were assessed by RT‐qPCR. Results Whereas CM from PK‐1 and KLM‐1 cells significantly induced NF‐κB activation in C2C12 myotubes (PK‐1: 3.1‐fold, P

Abstract Background Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short‐chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. Methods Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme‐linked immunosorbent assay. Serum C‐reactive protein and leucocyte counts were retrieved from medical records. Results Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial α‐diversity was not significantly different between cachectic cancer patients (N = 33), non‐cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (β‐diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P

Abstract Background Myosteatosis has been associated with shorter overall survival in cancer patients. The increase in ectopic fat might not be limited to skeletal muscle only and might also extend to other sites such as the liver, resulting in non‐alcoholic fatty liver disease (NAFLD). In this study, we assessed the relationship between myosteatosis and NAFLD and their association with overall survival in patients with colorectal liver metastases undergoing partial hepatectomy. Methods Patients were selected from a prospective cohort of 289 consecutive patients with colorectal liver metastases. All patients with a preoperative computed tomography (CT)‐scan and liver biopsy obtained during surgery were included. If available a second pre‐operative CT scan was used to calculate changes in body composition over time. Muscle radiation attenuation was defined as the average Hounsfield units on CT of all muscle tissue at the L3 level. Liver biopsies were graded by a liver pathologist using the steatosis, activity, and fibrosis scoring system for NAFLD. Results Two‐hundred and eighteen patients had an available liver biopsy of which 131 patients had two available pre‐operative CT scans with an average time interval of 3.2 months. One‐hundred and thirty‐five (62%) biopsies were classified as NAFLD. In multivariable Cox‐regression analysis, NAFLD [hazard ratio (HR): 1.8, 95%‐confidence interval (CI) 1.0–3.0, P = 0.037], increase in myosteatosis (HR 1.8, 95%‐CI 1.1–2.9, P = 0.018), and skeletal muscle loss (HR 1.7, 95%‐CI 1.0–2.9, P = 0.035) were independently associated with shorter overall survival while high visceral adipose tissue fat content was associated with longer overall survival (HR: 0.7, 95%‐CI 0.5–0.9, P = 0.014). Conclusions Ectopic fat content of liver as well as skeletal muscle tissue is independently associated with shorter overall survival in patients with colorectal liver metastases, while increased visceral adipose tissue fat content is associated with longer overall survival.

Abstract Background Cancer cachexia is characterized by impaired function of skeletal and cardiac muscle. Smooth muscle is abundantly present in the body and critical for the function of the gastrointestinal tract. Given the frequently reported gastrointestinal symptoms in cancer patients, we hypothesized that the smooth musculature could be compromised in cancer patients with sarcopenia. Methods Full‐thickness jejunal tissue sections from 57 pancreatic cancer patients were analysed by picrosirius red stains and immunohistochemistry for α‐smooth muscle actin (α‐SMA), smoothelin, and CD117 (c‐kit). Muscle wall thickness, contractile marker expression, and collagen deposition were quantified. Patients were assigned to a sarcopenia or non‐sarcopenia group based on their skeletal muscle index. Results Intestinal smooth muscle wall thickness did not differ between the sarcopenia and non‐sarcopenia group (1,661 ± 125.0 vs. 1,439 ± 93.5 μm, P = 0.41). Whereas α‐SMA staining intensity was similar in both groups, staining intensity of smoothelin, a key marker of the contractile smooth muscle cell phenotype, was reduced (143.0 ± 22.6 vs. 125.4 ± 29.3 arbitrary units, P = 0.02) in sarcopenic patients. The distribution of CD117+ interstitial cells of Cajal was similar in both groups, but pronounced collagen deposition around the myenteric plexus was more often observed in patients with sarcopenia (P = 0.04). Conclusions These data suggest that cancer cachexia is not only associated with skeletal and cardiac muscle wasting, but also affects the intestinal smooth musculature. Reduced contractile smooth muscle marker expression and fibrosis around the myenteric plexus suggest that both contractile function of smooth muscle cells and regulation of their contractile functionality could be compromised.

Abstract Background In vivo muscle protein synthesis rates are typically assessed by measuring the incorporation rate of stable isotope labelled amino acids in skeletal muscle tissue collected from vastus lateralis muscle. It remains to be established whether muscle protein synthesis rates in the vastus lateralis are representative of muscle protein synthesis rates of other muscle groups. We hypothesized that post‐absorptive muscle protein synthesis rates differ between vastus lateralis and rectus abdominis, pectoralis major, or temporalis muscle in vivo in humans. Methods Twenty‐four patients (62 ± 3 years, 42% female), scheduled to undergo surgery, participated in this study and underwent primed continuous intravenous infusions with l‐[ring‐13C6]‐phenylalanine. During the surgical procedures, serum samples were collected, and muscle tissue was obtained from the vastus lateralis as well as from the rectus abdominis, pectoralis major, or temporalis muscle. Fractional mixed muscle protein synthesis rates (%/h) were assessed by measuring the incorporation of l‐[ring‐13C6]‐phenylalanine into muscle tissue protein. Results Serum l‐[ring‐13C6]‐phenylalanine enrichments did not change throughout the infusion period. Post‐absorptive muscle protein synthesis rates calculated based upon serum l‐[ring‐13C6]‐phenylalanine enrichments did not differ between vastus lateralis and rectus abdominis (0.032 ± 0.004 vs. 0.038 ± 0.003%/h), vastus lateralis and pectoralis major, (0.025 ± 0.003 vs. 0.022 ± 0.005%/h) or vastus lateralis and temporalis (0.047 ± 0.005 vs. 0.043 ± 0.005%/h) muscle, respectively (P > 0.05). When fractional muscle protein synthesis rates were calculated based upon tissue‐free l‐[ring‐13C6]‐phenylalanine enrichments as the preferred precursor pool, muscle protein synthesis rates were significantly higher in rectus abdominis (0.089 ± 0.008%/h) compared with vastus lateralis (0.054 ± 0.005%/h) muscle (P

Abstract Background Body composition assessment, measured using single‐slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis [i.e. low skeletal muscle radiation attenuation (SM‐RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post‐operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery. Methods A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single‐slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold ( V̇O2 at AT), oxygen uptake at peak exercise ( V̇O2 peak), skeletal muscle mass, and SM‐RA. Results Of 123 patients recruited [77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2], 113 patients had good‐quality abdominal CT scans available and were included. Of the CT body composition variables, SM‐RA had the strongest correlation with V̇O2 peak (r = 0.57, P

Abstract Background Living tissues maintain a fine balance between protein synthesis and protein breakdown rates. Animal studies indicate that protein synthesis rates are higher in organs when compared with skeletal muscle tissue. As such, organ and tumour protein synthesis could have major effects on whole‐body protein metabolism in wasting disorders such as cancer cachexia. We aimed to assess protein synthesis rates in pancreatic tumour tissue and healthy pancreas, liver, and skeletal muscle tissue in vivo in humans. Methods In eight patients with pancreatic cancer undergoing pancreaticoduodenectomy, primed continuous infusions with L‐[ring‐13C6]phenylalanine and L‐[3,5‐2H2]tyrosine were started prior to surgery and continued throughout the surgical procedures. During surgery, plasma samples and biopsies from the pancreas, pancreatic tumour, liver, and vastus lateralis muscle were taken. Post‐absorptive fractional protein synthesis rates were determined by measuring incorporation of labelled L‐[ring‐13C6]phenylalanine in tissue protein using the weighed plasma L‐[ring‐13C6]phenylalanine enrichments as the precursor pool. Results Five male patients and three female patients with a mean age of 67 ± 2 years were included into this study. Plasma L‐[ring‐13C6]phenylalanine enrichments (6–9 mole per cent excess) did not change during surgery (P = 0.60). Pancreatic tumour protein synthesis rates were 2.6‐fold lower than surrounding pancreatic tissue protein synthesis rates (0.268 ± 0.053 vs. 0.694 ± 0.228%/h, respectively; P = 0.028) and 1.7‐fold lower than liver protein synthesis rates (0.268 ± 0.053 vs. 0.448 ± 0.043%/h, respectively; P = 0.046). Among healthy organ samples, protein synthesis rates were 20‐fold and 13‐fold higher in pancreas and liver, respectively, compared with skeletal muscle tissue (0.694 ± 0.228 and 0.448 ± 0.043 vs. 0.035 ± 0.005%/h, respectively; P

Abstract Background Most prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer. Methods Clinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis. Results Skeletal muscle was significantly correlated with VAT (r = 0.46, P