Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients

BACKGROUND: Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state‐of‐the‐science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies. METHODS: Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross‐sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (μm(2)), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle. RESULTS: Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight‐losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross‐sectional area, mean fibre cross‐sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co‐morbid conditions and medications. CONCLUSIONS: Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer‐associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial β-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.</jats:p

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial &beta;-oxidation (CPT1&alpha;) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism

Sarcopenia Severity Based on Computed Tomography Image Analysis in Patients with Cirrhosis

Standardized sex-specific cut-offs for sarcopenia in cirrhosis are needed to identify the risk of clinical complications and to discriminate the severity of sarcopenia. We aimed to compare clinical characteristics between patients with cirrhosis categorized according to the severity of sarcopenia. Computed tomography images were taken at the 3rd lumbar vertebra from 603 patients with cirrhosis and 129 adult donors for living liver transplantation. Patients with skeletal muscle index (SMI) two standard deviations (SD) below the sex-specific mean value of young donors (18–40 years old) were categorized as having severe sarcopenia whereas patients with SMI between −1 and −2 SD of the sex-specific young adult mean values were categorized as having sarcopenia. In the cirrhosis group, 408 patients (68%) were male with the mean age of 57 ± 0.4 years, and MELD score of 14 ± 0.4. Patients were divided into three groups: severe-sarcopenic (SMI &lt; 30 cm2/m2 in females and &lt;42 cm2/m2 in males), sarcopenic (30 ≤ SMI &lt; 37 cm2/m2 in females and 42 ≤ SMI &lt; 50 cm2/m2 in males) and non-sarcopenic (SMI ≥ 37 cm2/m2 in females and ≥50 cm2/m2 in males). Patients with cirrhosis and severe sarcopenia had lower muscle radiodensity and higher plasma neutrophil as well as neutrophil to lymphocyte ratio levels than both non- and sarcopenic groups. The frequency of alcohol-induced cirrhosis, refractory ascites, hepatic encephalopathy, CRP &gt; 20 mg/mL, and severe malnutrition was also higher in severe-sarcopenic patients. The interval between sarcopenia and severe sarcopenia may reflect a window of opportunity in which to intervene and mitigate muscle wasting to improve patient outcomes.</jats:p

Sarcopenia Severity Based on Computed Tomography Image Analysis in Patients with Cirrhosis

Standardized sex-specific cut-offs for sarcopenia in cirrhosis are needed to identify the risk of clinical complications and to discriminate the severity of sarcopenia. We aimed to compare clinical characteristics between patients with cirrhosis categorized according to the severity of sarcopenia. Computed tomography images were taken at the 3rd lumbar vertebra from 603 patients with cirrhosis and 129 adult donors for living liver transplantation. Patients with skeletal muscle index (SMI) two standard deviations (SD) below the sex-specific mean value of young donors (18&ndash;40 years old) were categorized as having severe sarcopenia whereas patients with SMI between &minus;1 and &minus;2 SD of the sex-specific young adult mean values were categorized as having sarcopenia. In the cirrhosis group, 408 patients (68%) were male with the mean age of 57 &plusmn; 0.4 years, and MELD score of 14 &plusmn; 0.4. Patients were divided into three groups: severe-sarcopenic (SMI &lt; 30 cm2/m2 in females and &lt;42 cm2/m2 in males), sarcopenic (30 &le; SMI &lt; 37 cm2/m2 in females and 42 &le; SMI &lt; 50 cm2/m2 in males) and non-sarcopenic (SMI &ge; 37 cm2/m2 in females and &ge;50 cm2/m2 in males). Patients with cirrhosis and severe sarcopenia had lower muscle radiodensity and higher plasma neutrophil as well as neutrophil to lymphocyte ratio levels than both non- and sarcopenic groups. The frequency of alcohol-induced cirrhosis, refractory ascites, hepatic encephalopathy, CRP &gt; 20 mg/mL, and severe malnutrition was also higher in severe-sarcopenic patients. The interval between sarcopenia and severe sarcopenia may reflect a window of opportunity in which to intervene and mitigate muscle wasting to improve patient outcomes

Skeletal Muscle Pathological Fat Infiltration (Myosteatosis) Is Associated with Higher Mortality in Patients with Cirrhosis

Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17&ndash;1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64&ndash;3.00, p &lt; 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes