Association Between Changes in Body Composition and Neoadjuvant Treatment for Pancreatic Cancer

Sandini, Marta; Patiño, Manuel; Ferrone, Cristina R.; Alvarez-Pérez, Carlos A; Honselmann, Kim C.; Paiella, Salvatore; Catania, Matteo; Riva, Luca; Tedesco, Giorgia; Casolino, Raffaella; Amato, Alessandra; Salandini, M.C.; Carrara, Giulia; Cristel, Giulia; Damascelli, Anna; Ippolito, Davide; D’Onofrio, Mirko; Lillemoe, Keith D.; Bassi, Claudio; Braga, Marco; Gianotti, Luca; Sahani, Dushyant V.; Castillo, C. Fernandez-del

doi:10.1001/jamasurg.2018.0979

Cited by 114 publications

(100 citation statements)

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“…Treatment-associated toxicity in these patients may be the result of improper drug dosing regimens that are based on antiquated methodology (18). Recent clinical evidence suggests the use of body composition measurement to improve drug dosing, reduce toxicity, and establish early intervention in patients with cancer (7, 9). Therefore, we conclude that the use of DEXA as a tool to characterize SMW to improve dosing is an area that warrants further study.…”

Section: Discussionmentioning

confidence: 99%

“…This study concluded that survival in sarcopenic patients was 1/3 of their non-sarcopenic counterparts, regardless of body weight. In addition, increases in lean mass during neoadjuvant treatment (NAT) has been shown to be independently associated with progression to resection surgery in patients with PDAC (9), even when these patients experienced loss of adipose tissue. Notably, patients who experienced decreases in lean mass during or after NAT underwent surgical exploration, but not resection.…”

Section: Discussionmentioning

confidence: 99%

“…Most notable among the detractors of quality of life for PDAC patients is sarcopenia, also known as skeletal muscle wasting (SMW), which is a growing burden among cancer survivors (4, 5). As such, SMW is prognostic of treatment failure, radiotherapy toxicity, and a shorter time to tumor progression related to survival (6–9). SMW can be defined as any loss of muscle tissue, function, and/or strength due to aging, chronic diseases, low protein-energy intake and physical inactivity (10).…”

Section: Introductionmentioning

confidence: 99%

“…In the context of non-metastatic disease, the only possible cure for PDAC is surgical resection (17). However, less than 20% of PDAC patients meet the criteria for resection due to the locally advanced or metastatic nature of their diagnosis (9). Recent research suggests that neoadjuvant treatment (NAT) may help to improve the resectability rates among patients with PDAC, but may have an adverse effect on body composition that worsen post-surgical outcomes or reduce resection opportunities (9).…”

Section: Introductionmentioning

confidence: 99%

“…However, less than 20% of PDAC patients meet the criteria for resection due to the locally advanced or metastatic nature of their diagnosis (9). Recent research suggests that neoadjuvant treatment (NAT) may help to improve the resectability rates among patients with PDAC, but may have an adverse effect on body composition that worsen post-surgical outcomes or reduce resection opportunities (9). Among many other reasons, the adverse effect of NAT may be the result of an incorrect dosing regimen that is based on body weight or body mass index (BMI).…”

Section: Introductionmentioning

confidence: 99%

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

Cole

Robinson

et al. 2020

Preprint

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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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Cole

Robinson

et al. 2020

Preprint

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Sarcopenia—A New Frontier in the Management Care of Patients With Borderline Resectable Pancreatic Cancer

Griffin

Conlon

2018

JAMA Surg

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

Cole

Bachman

et al. 2021

J cachexia sarcopenia muscle

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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.

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Association Between Changes in Body Composition and Neoadjuvant Treatment for Pancreatic Cancer

Abstract: Patients with PC experience a significant loss of adipose tissue during neoadjuvant chemotherapy, but no muscle wasting. An increase in muscle tissue during NT is associated with resectability.

Cited by 114 publications

References 35 publications

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

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

Sarcopenia—A New Frontier in the Management Care of Patients With Borderline Resectable Pancreatic Cancer

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

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