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Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival.

ABSTRACT: Background:Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia. Methods:Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N?=?20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N?=?16). PDAC patients with a body weight loss of greater than 5% during the previous 6?months were considered cachectic (N?=?15). Statistical tests were two sided. Results:Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P?=?.0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P?=?.0016, r?=?0.672), was increased in patients with lymph node metastasis (P?=?.007, Mann-Whitney U test), and was associated with survival on univariate (HR?=?1.08, 95% confidence interval [CI] = 1.02 to 1.04, P?=?.008) and multivariable analyses (HR?=?1.08, 95% CI = 1.00 to 1.17, P?=?.038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P?=?.042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P?=?.0238), calcium deposition (0.21% vs 2.51%, P?=?.030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-? upregulated in cachectic PDAC patients compared with non-cancer control subjects. Conclusions:To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

SUBMITTER: Judge SM

PROVIDER: S-EPMC6322478 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival.

Judge Sarah M SM Nosacka Rachel L RL Delitto Daniel D Gerber Michael H MH Cameron Miles E ME Trevino Jose G JG Judge Andrew R AR

JNCI cancer spectrum 20180701 3

<h4>Background</h4>Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal mu ...[more]

PMID: 30637373

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Project description:BackgroundIn order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.MethodsOne hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3%). Cachexia was defined as weight-loss ≥5%. Rectus abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time-polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n = 52), forkhead box O transcription factors (n = 59), ubiquitin E3 ligases (n = 59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n = 59, as markers of autophagy), myosin heavy-chain (MyHC, n = 54), dystrophin (n = 39), β-dystroglycan (n = 52), and β-sarcoglycan (n = 52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255 days (range 581-1955 days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving ≤1 vs. >1 year post operatively.ResultsCancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P = 0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P = 0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P = 0.024]. β-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P = 0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326 days, P = 0.023) and dystrophin levels (median 341 vs. 660 days, P = 0.008).ConclusionsThe present study has identified intramuscular protein level of β-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers.

Project description:BACKGROUND:Malnutrition, weight loss, and muscle wasting are common in patients with foregut cancers (oesophagus, stomach, pancreas, liver, and bile ducts) and are associated with adverse clinical outcomes. However, little is known about the changes in body composition that occur in these patients during chemotherapy and its impacts clinical outcomes. PATIENTS AND METHODS:A prospective study of adult foregut cancer patients undergoing chemotherapy between 2012 and 2016 was conducted. Computed tomography images were evaluated for cross-sectional skeletal muscle area (SMA) and adipose tissue area (ATA) at two time points [interval 118 days (IQR 92-58 days)]. Longitudinal changes in SMA and ATA were examined using paired t-tests. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. Cox proportional hazards models were used to estimate mortality hazard ratios for key predictors. RESULTS:A total of 225 foregut cancer patients were included (67% male, median age 66 years). At baseline, 40% were sarcopenic, 49% had low MA, and 62% had cancer cachexia. Longitudinal analysis (n = 163) revealed significant reductions in SMA [-6.1 cm2 (3.9%)/100 days, P < 0.001]. Patients treated with neoadjuvant chemotherapy experienced greater losses in SMA and skeletal muscle mass compared with patients receiving palliative chemotherapy [-6.6 cm2 (95%, confidence interval, CI: -10.2 to -3.1), P < 0.001 and -1.2 kg (95% CI: -1.8 to -0.5), P < 0.001, respectively]. Neither sarcopenia nor low MA at baseline was associated with reduced survival. A loss of SMA >6.0%/100 days (highest fourth) independently predicted overall survival in patients receiving palliative chemotherapy [hazard ratio: 2.66, (95% CI: 1.42 to 4.97), P = 0.002]. CONCLUSIONS:Patients with foregut cancers, particularly those treated with neoadjuvant chemotherapy, experience significant losses of muscle during chemotherapy. A high level of SMA loss is prognostic of reduced survival in patients treated with palliative chemotherapy. Multimodal interventions to stabilize or increase muscle mass and influence outcome warrant further investigation.

Dataset Information

Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival.

Publications

Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival.

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