Clinical impact of sarcopenia on prognosis in pancreatic cancer

J cachexia sarcopenia muscle

Bachman

et al. 2021

Background Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model. Methods Female C57BL/6J mice 6–8 weeks of age underwent orthotopic injection with KCKO‐luc tumour cells. Solid tumour was verified on Day 5, post‐tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual‐energy X‐ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of ‘failure to thrive’. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction. Results We found a strong correlation between primary tumour size and survival (r2 = 0.83, P < 0.0001). A significant decrease in lower limb lean mass was first detected at Day 38 post‐implantation vs. no tumour controls (NTCs) (P < 0.0001). SMW was confirmed by histology, which demonstrated a 38%, 32.7%, and 39.9% decrease in fibre size of extensor digitorum longus, soleus, and tibialis anterior muscles, respectively, in PDAC mice vs. NTC (P < 0.002). Histology also revealed a 67.6% increase in haematopoietic cells within the muscle of PDAC mice when compared with NTC. Bulk RNAseq on muscles from PDAC mice vs. NTC revealed significant increases in c/ebpβ/Δ, il‐1, il‐6, and tnf gene expression. Pathway analyses to identify potential upstream factors revealed increased adipogenic gene expression, including a four‐fold increase in igfbp‐3. Histomorphometry of Oil Red‐O staining for fat content in tibialis anterior muscles demonstrated a 95.5% increase in positively stained fibres from PDAC mice vs. NTC. Conclusions Together, these findings support a novel model of PDAC‐associated SMW and mortality in which systemic inflammation leads to inflammatory cell infiltration into skeletal muscle with up‐regulated myocellular lipids.

Section: Introductionmentioning

confidence: 99%

Increased myocellular lipid and IGFBP‐3 expression in a pre‐clinical model of pancreatic cancer‐related skeletal muscle wasting

J cachexia sarcopenia muscle

Bachman

et al. 2021

“…Importantly, a large percentage of patients with PDAC experience cancer-related SMW and these patients have reduced physical function, increased postoperative morbidity, reduced response to treatment, and shorter life expectancy [9]. Furthermore, SMW has been identified as a prognostic factor in pancreatic cancer [10] and is an independent predictor of infectious disease and postoperative mortality in resected patients [11,12] , . Thus, reductions in the incidence of SMW in patients with pancreatic cancer may reduce disease and treatment-related complications, which adversely affect dose and length of treatment.…”

Section: Introductionmentioning

confidence: 99%

Dual Energy X-ray Absorptiometry (DEXA) as a longitudinal outcome measure of cancer-related muscle wasting in mice

Beck²,

Robinson

et al. 2020

PLoS ONE

“…Importantly, a large percentage of patients with PDAC experience cancer-related SMW (10), and these patients have reduced physical function, increased postoperative morbidity, reduced response to chemotherapy, and shorter life expectancy (11). Furthermore, SMW has been identified as a prognostic factor in pancreatic cancer (12) and is an independent predictor of infectious disease and postoperative mortality in resected patients (13),(14). Thus, reductions in the incidence of SMW in patients with pancreatic cancer may reduce disease and treatment-related complications, which adversely affect the dose and length of treatment.…”

Section: Introductionmentioning

confidence: 99%

Dual Energy X-ray Absorptiometry (DEXA) as a Longitudinal Outcome Measure of Cancer-Related Muscle Wasting in Mice

Robinson

et al. 2020

Preprint

300 out of 300 Words) 25 Introduction 26 Pancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting 27 (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly 28 understood. Thus, there is a great need for a faithful small animal model with a quantitative 29 longitudinal outcome measure that recapitulates clinical PDAC, to define SMW onset and assess 30 progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a 31 longitudinal outcome of lean body mass, and demonstrate its utility to quantify SMW in the KCKO 32 murine model of PDAC. 33 Methods 34In vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n=4), and 2) a 35 cohort of mice with (n=20) and without PDAC (n=10), was determined via DEXA, and lean mass of the 36 lower hind limbs was predicted via a region of interest analysis by two independent observers. Total 37 body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for 38 histomorphometry immediately post-mortem. Statistical differences between groups were assessed 39 using t-tests and ANOVA. Linear regression models and correlation analysis were used to measure the 40 association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass 41 correlation coefficient (ICC). 42 Results 43Lean mass in growing untreated mice determined by DEXA correlated with TA mass (r 2 = 0.94; p 44 <0.0001) and body weight (r 2 = 0.89; p <0.0001). DEXA measurements were highly reproducible 45 between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC 3 46 cohort (r 2 = 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of 47 implantation by DEXA, TA mass, and histomorphometry. 48 Conclusions 49 DEXA is a longitudinal outcome measure of lower limb lean mass in mice. The KCKO syngeneic 50 model is a bona fide model of PDAC-associated SMW that can be quantified with longitudinal DEXA. 51 4 52