Cancer Cachexia in the Age of Obesity: Skeletal Muscle Depletion Is a Powerful Prognostic Factor, Independent of Body Mass Index

Muscle Depletion Is an Important and Clinically Relevant Predictor of Outcomes after Autologous Hematopoietic Cell Transplantation

Muscle attenuation, not skeletal muscle index, is an independent prognostic factor for survival in gastric cancer patients with overweight and obesity

Baseline CT-derived muscle quality influences post-operative morbidity and five-year survival following pancreatic surgery

Body composition parameters including low muscle mass, muscle attenuation (which reflects muscle quality) and adipose tissue measurements have emerged as prognostic factors in cancer patients. However, knowledge regarding the possibility of excessive muscle loss during specific systemic therapies is unknown. We describe the changes in body composition and muscle attenuation (MA) during taxane- and anthracycline-based regimens and its association with overall survival (OS) in metastatic breast cancer patients. The lumbar skeletal muscle index (LSMI) was used as marker of muscle mass. LSMI, MA, subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and intramuscular adipose tissue (IMAT) were measured before and after first-line treatment with paclitaxel (n=73) or 5-fluorouracil-doxorubicin-cyclophosphamide (FAC) (n=25) using CT-images. Determinants of the change of LSMI and MA were analyzed using multiple linear regression. OS was assessed using Cox proportional hazard models. MA significantly decreased during paclitaxel treatment (-0.9 HU, p=0.03). LSMI (p=0.40), SAT (p=0.75), VAT (p=0.84) and IMAT (p=0.10) remained stable. No significant alterations in body composition parameters during FAC-treatment were observed. Previous (neo-)adjuvant chemotherapy contributed to larger loss of MA during the current treatment. Body composition changes during chemotherapy were not associated with OS. MA decreased during treatment with paclitaxel, while muscle mass was stable. Body composition changes are not associated with survival in the absence of progressive disease.

Characterising the impact of body composition change during neoadjuvant chemotherapy for pancreatic cancer

Dendritic cells (DCs) are antigen-presenting cells that can acquire tumour antigens and initiate cytotoxic T cell reactions. Obesity has been proposed as a cause for tumours escaping immune surveillance, but few studies investigate the impact of other body composition parameters. We examined the relationship of DC phenotype with computer tomography (CT)-defined parameters in patients with colorectal cancer (CRC). DCs were identified within peripheral blood mononuclear cells by flow cytometry as HLA-DR positive and negative for markers of other cell lineages in 21 patients. Analysis of CT scans was used to calculate lumbar skeletal muscle index (LSMI) and mean muscle attenuation (MA). Positive correlation between the LSMI and expression of CD40 in all DCs (r = 0.45; p = 0.04) was demonstrated. The MA was positively correlated with scavenger receptor CD36 [all DCs (r = 0.60; p = 0.01) and myeloid DCs (r = 0.63; p < 0.01)]. However, the MA was negatively correlated with CCR7 expression in all DCs (r = -0.46, p = 0.03.) and with CD83 [all DCs (r = -0.63; p = 0.01) and myeloid DCs (r = -0.75; p < 0.01)]. There were no relationships between the fat indexes and the DC phenotype. These results highlight a direct relationship between muscle depletion and changes in stimulatory, migratory and fatty acid-processing potential of DC in patients with CRC.

We examined the relationships between computed tomography (CT)-defined skeletal muscle parameters and the systemic inflammatory response (SIR) in patients with operable primary colorectal cancer (CRC). Muscle depletion is characterized by a reduced muscle mass (myopenia) and increased infiltration by inter- and intramuscular fat (myosteatosis). It is recognized as a poor prognostic indicator in patients with cancer, but the underlying factors remain unclear. A total of 763 patients diagnosed with CRC undergoing elective surgical resection between 2006 and 2013 were included. Image analysis of CT scans was used to calculate Lumbar skeletal muscle index (LSMI), and mean muscle attenuation (MA). The SIR was quantified by the preoperative neutrophil to lymphocyte ratio (NLR) and albumin levels. Correlation and multivariate regression analysis was performed to identify independent relationships between patient SIR and muscle characteristics. Patients with NLR > 3 had significantly lower LSMI and lower MA than those with NLR < 3 [LSMI = 42.07 cmm vs 44.27 cmm (P = 0.002) and MA = 30.04 Hounsfield unit (HU) vs 28.36 HU (P = 0.016)]. Multivariate logistic regression analysis showed that high NLR [odds ratio (OR) = 1.78 (95% confidence interval [CI]: 1.29-2.45), P < 0.001] and low albumin [OR = 1.80 (95% CI: 1.17-2.74), P = 0.007] were independent predictors of reduced muscle mass. High NLR was significantly related with a low mean MA and hence myosteatosis [OR = 1.60 (95% CI: 1.03-2.49), P = 0.038]. These results highlight a direct association between myopenia, myosteatosis, and the host SIR in patients with operable CRC. A better understanding of factors that regulate muscle changes such as myopenia and myosteatosis may lead to the development of novel therapies that influence a more metabolically "healthy" skeletal muscle and potentially alter cancer outcomes.

Cancer cachexia is characterized by skeletal muscle loss. A feature of muscle wasting, reduction in the mean muscle attenuation from computed tomography images is believed to reflect pathological infiltration of fat into muscle. It is a reported prognostic indicator in cancer patients. To develop an explanatory multivariate model of muscle attenuation of cancer patients incorporating age, sex, disease characteristics, body composition. Time to death ≤92 days was included in the model as the demarcation of end-stage disease. Multivariate general linear model regression analysis of total mean muscle attenuation and change in muscle attenuation. Regional cancer center (Alberta, Canada). Patients with gastrointestinal and respiratory tract cancers (mean age 64±11 years, 44% female). Total adipose tissue and skeletal muscle cross sectional area, and mean muscle attenuation at the 3rd lumbar vertebra were assessed from baseline computed tomography (n=1719), and a subset with repeated measures (n=246 patients with a total of 871 images). At baseline, muscle attenuation associated with total skeletal muscle (β 0.09; 95% CI 0.07 to 0.11; p<0.001) and adipose tissue (β -0.032; 95% CI -0.035 to -0.029; p<0.001) cross sectional areas, age (β -0.28; 95% CI -0.32 to -0.24; p<0.001), time to death ≤92 days (β -1.9; 95% CI -3.1 to -0.7; p=0.003) and male sex (β -2.3; 95% CI -3.5 to -1.1; p<0.001). Change in muscle attenuation over time associated with total adipose tissue cross sectional area (β -0.008; 95% CI -0.012 to -0.004; p<0.001) and time to death ≤92 days (β -1.6; 95% CI -3.0 to -0.2; p=0.03). The radiation attenuation of skeletal muscle is lowest in individuals who are older, less muscular, have a higher fat mass and are within 92 days of death. Men had lower muscle attenuation than women when controlled for other variables.

Observational data investigating the relationship between body habitus and outcomes in breast cancer have been variable and inconsistent, largely centered in the curative setting and focused on weight-based metrics. This study evaluated the impact of muscle measures on outcomes in patients with metastatic breast cancer receiving endocrine-based therapy. Baseline CT scans were collected from ECOG-ACRIN E2112, a randomized phase III placebo-controlled study of exemestane with or without entinostat. A CT cross-sectional image at the L3 level was extracted to obtain skeletal muscle mass and attenuation. Low muscle mass (LMM) was defined as skeletal muscle index <41 cm2/m2 and low muscle attenuation (LMA) as muscle density <25 HU or <33 HU if overweight/obese by body mass index (BMI). Multivariable Cox proportional hazard models determined the association between LMM or LMA and progression-free survival (PFS) and overall survival (OS). Correlations between LMM, LMA, and patient-reported outcomes were determined using 2-sample t tests. Analyzable CT scans and follow-up data were available for 540 of 608 patients. LMM was present in 39% (n=212) of patients and LMA in 56% (n=301). Those with LMA were more likely to have obesity and worse performance status. LMM was not associated with survival (PFS hazard ratio [HR]: 1.13, P=.23; OS HR: 1.05, P=.68), nor was LMA (PFS HR: 1.01, P=.93; OS HR: 1.00, P=.99). BMI was not associated with survival. LMA, but not LMM, was associated with increased frequency of patient-reported muscle aches. Both low muscle mass and density are prevalent in patients with hormone receptor-positive metastatic breast cancer. Muscle measures correlated with obesity and performance status; however, neither muscle mass nor attenuation were associated with prognosis. Further work is needed to refine body composition measurements and select optimal cutoffs with meaningful endpoints in specific breast cancer populations, particularly those living with metastatic disease.

Associations between trunk muscle composition and physical function have not been examined previously in older adults. We hypothesized that lower trunk muscle area and attenuation (higher fat infiltration) are associated with decreased functional capacity. The study sample consisted of a biracial cohort of well functioning men (739) and women (788) aged 70-79 from the Pittsburgh site of the Health, Aging and Body Composition (Health ABC) study. Computed tomography was used to measure trunk muscle area (cm2) and muscle attenuation (Hounsfield Unit [HU]) of the following muscle groups: lumbar paraspinals, lateral abdominals, and rectus abdominis. An average score was calculated for both trunk area and attenuation. The Health ABC Physical Performance Battery (PPB) and its individual components (usual and narrow walk, chair stands, and standing balance) were used to measure functional capacity. Linear regression analyses adjusting for demographic factors, height, body fat, thigh muscle composition, disease status, and low back pain (LBP) found that average trunk muscle area was not associated with any element of functional capacity (p >.10), whereas average trunk muscle attenuation was positively associated with the Health ABC Physical Performance Battery (p <.05) and chair stands (p <.001). Participants reporting higher LBP severity during the past year had lower muscle attenuation (p <.001 for trend), but there was no difference in average trunk muscle area according to LBP status. Findings suggest a link between trunk muscle composition and history of LBP as well as reduced functional capacity in older adults. Improving trunk muscle quality may lead to reduced LBP severity and improved functional status.

ObjectiveExamine the relationship between ectopic adiposity and markers of cardiometabolic risk, autonomic control, and subclinical cardiovascular disease (CVD).MethodsCross-sectional analyses of 324 overweight and obese subjects were performed. Single-slice CT images were analyzed to calculate thigh muscle attenuation (MA), a measure of ectopic adiposity. Autonomic control was assessed using low-frequency to respiratory-frequency heart rate variability (LFa/RFa ratio). Carotid intima-media thickness (IMT) was a marker of subclinical CVD.ResultsAmong overweight participants, those with low MA had lower HDL-c, higher LFa/RFa ratio, and less subcutaneous thigh fat compared to high MA individuals despite no difference in visceral fat or insulin resistance. Significant associations were not observed in the class I obese group. In the class II obese group, those with high MA had higher triglycerides and insulin levels, yet there was no difference in visceral fat compared to the low MA group. Mean IMT was significantly higher in the low MA compared to the high MA overweight group (0.63 mm vs. 0.58 mm, p=0.04) but was similar between the low and high MA class II obese groups.ConclusionsExcess ectopic adiposity in muscle tissue is associated with metabolic and autonomic risk factors and subclinical CVD, most notably in overweight individuals, independent of insulin resistance and visceral abdominal fat.

Prediction of 90 Day and Overall Survival after Chemoradiotherapy for Lung Cancer: Role of Performance Status and Body Composition

Muscle depletion is characterized by reduced muscle mass (myopenia), and increased infiltration by intermuscular and intramuscular fat (myosteatosis). This study examined the role of particular body composition profiles as prognostic markers for patients with colorectal cancer undergoing curative resection. Patients with colorectal cancer undergoing elective surgical resection between 2006 and 2011 were included. Lumbar skeletal muscle index (LSMI), visceral adipose tissue (VAT) surface area and mean muscle attenuation (MA) were calculated by analysis of CT images. Reduced LSMI (myopenia), increased VAT (visceral obesity) and low MA (myosteatosis) were identified using predefined sex-specific skeletal muscle index values. Univariable and multivariable Cox regression models were used to determine the role of different body composition profiles on outcomes. Some 805 patients were identified, with a median follow-up of 47 (i.q.r. 24·9-65·6) months. Multivariable analysis identified myopenia as an independent prognostic factor for disease-free survival (hazard ratio (HR) 1·53, 95 per cent c.i. 1·06 to 2·39; P = 0·041) and overall survival (HR 1·70, 1·25 to 2·31; P < 0·001). The presence of myosteatosis was associated with prolonged primary hospital stay (P = 0·034), and myopenic obesity was related to higher 30-day morbidity (P = 0·019) and mortality (P < 0·001) rates. Myopenia may have an independent prognostic effect on cancer survival for patients with colorectal cancer. Muscle depletion may represent a modifiable risk factor in patients with colorectal cancer and needs to be targeted as a relevant endpoint of health recommendations.

Visceral adiposity is negatively associated with bone density and muscle attenuation

Computed tomographic measurements of the psoas muscle as a predictor of mortality in hip fracture patients: Muscle attenuation helps predict mortality in hip fracture patients