scholarly journals New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

2016 ◽  
Vol 8 (1) ◽  
pp. 122-130 ◽  
Author(s):  
Neil Johns ◽  
Cynthia Stretch ◽  
Benjamin H.L. Tan ◽  
Tora S. Solheim ◽  
Sveinung Sørhaug ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Cancer Cachexia ◽  
Skeletal Muscle Index ◽  
Genetic Signatures

Cancer cachexia syndrome in the prediction of outcome in patients with metastatic non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs): Results from a single-institution, prospective, observational study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21644-e21644
Author(s):  
Dimitrios Mavroudis ◽  
Konstantinos Rounis ◽  
Dimitrios Makrakis ◽  
Alexandra Georgiou ◽  
Nikolaos Galanakis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Observational Study ◽  
Prospective Observational Study ◽  
Cancer Cachexia ◽  
Lumbar Vertebra ◽  
Response Rates ◽  
Skeletal Muscle Index ◽  
Potential Biomarker ◽  
Cachexia Syndrome

e21644 Background: Cancer cachexia syndrome (CCS) is a multifactorial inflammatory syndrome affecting a large subset of patients (pts) with NSCLC which in preclinical models negatively impairs antitumor immunity. We conducted a prospective, observational study to investigate the effect of CCS and sarcopenia on the efficacy of ICIs in NSCLC. Methods: CCS was defined as weight loss of > 5% in the last 6 months or any degree of weight loss > 2% in combination with BMI < 20% or baseline skeletal muscle index at the level of the 3rd lumbar vertebra consistent with sarcopenia. Skeletal muscle index was calculated using slice-o-matic tomovision software in the abdominal CT scan before starting ICIs. Results: 83 pts were included in the analysis. Median follow up was 9.5 months. Median age was 66 years, 61.4% had non-squamous histology, 20.5% received ICIs as first and the remaining as second-line therapy. 20.5% of pts experienced partial response (PR), 31% had stable disease (SD) and 48.2% had disease progression (PD). Median progression-free survival (PFS) was 4.4 months and median overall survival (OS) was 10.33 months. 43.4% of the whole group were categorized as having CCS, whereas 63.3% of 30 pts evaluated using tomovision had sarcopenia. CCS negatively affected response rates (p = 0.003) but not response duration (p = 0.266). CCS was associated with reduced PFS (2.46 vs 5.77 months, p = 0.006) and OS (4.8 vs 14.53 months, p = 0.001). In the multivariate analysis, CCS independently predicted for shorter OS (HR = 2.01; CI: 1,14-3,54; p = 0.014). Sarcopenia was also associated with reduced OS (5.4 vs 17.9 months, p = 0.012). Analysis on the whole pt population will be presented at the conference. Conclusions: CCS is associated with lower response rates and independently predicts for shorter OS in pts with NSCLC treated with ICIs. Further research on CCS could better define its role as a potential biomarker and a research platform for maximizing immunotherapy efficacy.

scholarly journals Continued Weight Loss and Sarcopenia Predict Poor Outcomes in Locally Advanced Pancreatic Cancer Treated with Chemoradiation

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 709 ◽  
Author(s):  
Patrick Naumann ◽  
Jonathan Eberlein ◽  
Benjamin Farnia ◽  
Thilo Hackert ◽  
Jürgen Debus ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Weight Loss ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Statistical Tests ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Skeletal Muscle Index ◽  
Poor Outcomes

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery.

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

2013 ◽  
Vol 31 (12) ◽  
pp. 1539-1547 ◽  
Author(s):  
Lisa Martin ◽  
Laura Birdsell ◽  
Neil MacDonald ◽  
Tony Reiman ◽  
M. Thomas Clandinin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Mass Index ◽  
Weight Loss ◽  
Body Mass ◽  
Normal Weight ◽  
Cancer Center ◽  
Skeletal Muscle Index ◽  
Patients With Cancer ◽  
C Statistic ◽  
Muscle Attenuation

Purpose Emerging evidence suggests muscle depletion predicts survival of patients with cancer. Patients and Methods At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models. Results Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001). Conclusion CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

scholarly journals The Extract of Arctium lappa L. Fruit (Arctii Fructus) Improves Cancer-Induced Cachexia by Inhibiting Weight Loss of Skeletal Muscle and Adipose Tissue

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3195
Author(s):  
Yo-Han Han ◽  
Jeong-Geon Mun ◽  
Hee Dong Jeon ◽  
Dae Hwan Yoon ◽  
Byung-Min Choi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Adipose Tissue ◽  
Cancer Cachexia ◽  
Uncoupling Protein ◽  
Body Weight Loss ◽  
In Vivo Experiments ◽  
Wasting Syndrome

Background: Cachexia induced by cancer is a systemic wasting syndrome and it accompanies continuous body weight loss with the exhaustion of skeletal muscle and adipose tissue. Cancer cachexia is not only a problem in itself, but it also reduces the effectiveness of treatments and deteriorates quality of life. However, effective treatments have not been found yet. Although Arctii Fructus (AF) has been studied about several pharmacological effects, there were no reports on its use in cancer cachexia. Methods: To induce cancer cachexia in mice, we inoculated CT-26 cells to BALB/c mice through subcutaneous injection and intraperitoneal injection. To mimic cancer cachexia in vitro, we used conditioned media (CM), which was CT-26 colon cancer cells cultured medium. Results: In in vivo experiments, AF suppressed expression of interleukin (IL)-6 and atrophy of skeletal muscle and adipose tissue. As a result, the administration of AF decreased mortality by preventing weight loss. In adipose tissue, AF decreased expression of uncoupling protein 1 (UCP1) by restoring AMP-activated protein kinase (AMPK) activation. In in vitro model, CM increased muscle degradation factors and decreased adipocytes differentiation factors. However, these tendencies were ameliorated by AF treatment in C2C12 myoblasts and 3T3-L1 cells. Conclusion: Taken together, our study demonstrated that AF could be a therapeutic supplement for patients suffering from cancer cachexia.

scholarly journals Identification of circulating protein biomarkers for pancreatic cancer cachexia

2018 ◽  
Author(s):  
Safi Shahda ◽  
Ashok Narasimhan ◽  
Joshua Kays ◽  
Susan M. Perkins ◽  
Lijun Cheng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Cell Signaling ◽  
B Cell ◽  
Expression Analysis ◽  
Killer Cell ◽  
Model Systems ◽  
Protein Biomarkers ◽  
Skeletal Muscle Index ◽  
Secreted Factors

AbstractBackgroundOver 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis.MethodsSerum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r≥ 0.5 and p<0.05) was performed using DAVID Bioinformatics. Protein co-expression analysis was determined using pairwise Spearman’s correlation.ResultsOverall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction.ConclusionTaken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

scholarly journals Stage-specific muscle wasting mechanisms in a novel cancer cachexia mouse model for ovarian granulosa cell tumor

2020 ◽  
Author(s):  
Yaqi Zhang ◽  
Jie Zhu ◽  
So-Youn Kim ◽  
Megan M Romero ◽  
Kelly A Even ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Granulosa Cell ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Activin A ◽  
Mice Model ◽  
E3 Ligases ◽  
Ovarian Granulosa Cell ◽  
Specific Muscle

AbstractCachexia is a progressive muscle wasting syndrome that increases mortality risk in cancer patients, while there are still no effective treatment due to the complexity of syndrome and the lack of preclinical models. We identified a transgenic mice model with ovarian granulosa cell tumors mimic the progression of cachexia seen in humans, including drastic weight loss, skeletal muscle wasting and increased serum cachexia biomarker activin A and GDF15. Hypercatabolism was detected in skeletal muscle, having upregulation of E3 ligases Atrogin-1 and Murf-1. Our cachexia model exhibited stage-specific muscle wasting mechanisms. At precachexia stage, elevation of activin A activates p38 MAPK. Inhibition of activin A with Follistatin reversed weight loss at precachexia stage. At cachexia stage, energy stress in skeletal muscle activates AMPKα and leads to upregulation of FoxO3. Our results indicate this novel preclinical cancer cachexia model is exploitable for studying pathophysiological mechanisms and testing therapeutic agents of cachexia.

scholarly journals The autophagic-lysosomal and ubiquitin proteasome systems are simultaneously activated in the skeletal muscle of gastric cancer patients with cachexia

2020 ◽  
Vol 111 (3) ◽  
pp. 570-579 ◽  
Author(s):  
Ying Zhang ◽  
Jiwei Wang ◽  
Xulin Wang ◽  
Tingting Gao ◽  
Hao Tian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Muscle Fiber ◽  
Cancer Cachexia ◽  
Ubiquitin Proteasome System ◽  
Muscle Loss ◽  
Fiber Morphology ◽  
Cross Sectional ◽  
Ubiquitin Proteasome

ABSTRACT Background Cancer cachexia is characterized by weight loss, especially ongoing skeletal muscle loss, and is associated with poor patient outcomes. However, the molecular mechanism of skeletal muscle wasting is not fully understood. Objectives We aimed to investigate muscle fiber morphology and proteolysis system activity changes that may account for cancer cachexia and to relate these changes to patients’ clinical phenotypes. Methods We divided 39 patients with resectable gastric cancer into 4 groups based on the presence of cachexia (weight loss) and/or sarcopenia (low muscularity), including a noncachexia/nonsarcopenia group (N, n = 10), a cachexia/sarcopenia group (CS, n = 13), a cachexia/nonsarcopenia group (C, n = 9), and a noncachexia/sarcopenia group (S, n = 7). Rectus abdominis muscle biopsy specimens were obtained intraoperatively. Muscle fiber size, ultrastructural architecture, and the expression of autophagic-lysosomal system (ALS) and ubiquitin proteasome system (UPS) markers were assayed. Results Mean ± SD muscle fiber cross-sectional areas were significantly decreased in the CS (460 ± 120 μm2) and S groups (480 ± 135 μm2) compared with the N (1615 ± 388 μm2, both P &lt; 0.05) and C groups (1219 ± 302 μm2, both P &lt; 0.05). In the C, S, and CS groups, the muscle exhibited tissue disorganization and autophagosome formation to different degrees. The levels of ALS and UPS markers were significantly increased in the CS, C, and S groups compared with the N group. Alterations in muscle fiber morphology and increased ALS and UPS activity were related to severe muscle loss, but not weight loss. Conclusions The ALS and UPS are simultaneously activated in cancer cachexia and may play coordinated roles in cachexia-induced muscle loss.

scholarly journals Skeletal Muscle Fibrosis in Pancreatic Cancer Patients with Respect to Survival

2018 ◽  
Vol 2 (3) ◽  
Author(s):  
Sarah M Judge ◽  
Rachel L Nosacka ◽  
Daniel Delitto ◽  
Michael H Gerber ◽  
Miles E Cameron ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Body Weight ◽  
Cellular Response ◽  
Cancer Cachexia ◽  
Cancer Control ◽  
Body Weight Loss ◽  
Collagen Content ◽  
Calcium Deposition ◽  
Control Subjects

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-β 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.

scholarly journals Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3787
Author(s):  
Ashok Narasimhan ◽  
Safi Shahda ◽  
Joshua K. Kays ◽  
Susan M. Perkins ◽  
Lijun Cheng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Weight Loss ◽  
Plasma Proteins ◽  
Cancer Cachexia ◽  
Ductal Adenocarcinoma ◽  
Cancer Stage ◽  
Protein Biomarkers ◽  
Skeletal Muscle Index ◽  
Novel Proteins ◽  
Upstream Regulator

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

Inclusion criteria for cancer cachexia clinical trials: CT-defined skeletal muscle loss versus body weight loss.

2015 ◽  
Vol 33 (29_suppl) ◽  
pp. 67-67
Author(s):  
Eric Roeland ◽  
Sandahl H Nelson ◽  
Ashleigh Campillo ◽  
Sean Heavey ◽  
Joseph D. Ma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Loss ◽  
Cancer Cachexia ◽  
Ct Scans ◽  
Muscle Loss ◽  
Inclusion Criteria ◽  
Cross Sectional ◽  
Skeletal Muscle Loss ◽  
Visceral Adipose ◽  
Over Time

67 Background: Cancer cachexia is defined by skeletal muscle loss, with or without fat loss (Fearon et al 2011); however, inclusion criteria for cachexia clinical trials requires a defined weight loss over time rather than muscle loss. We hypothesized that cross sectional imaging may reveal the presence of cachexia otherwise obscured by fat mass changes. Methods: A retrospective analysis of longitudinal CT scans was performed in metastatic colorectal cancer (mCRC) patients screened for a cancer cachexia trial, which required ≥5% weight loss in the prior 6 mos. De-identified CT images were analyzed for total muscle, subcutaneous, and visceral fat cross-sectional areas (cm2) at the 3rd lumbar vertebra at baseline and up to 12 mos prior (Lieffers et al 2009). Logistic regression was used to test differences between patients with <5% vs ≥5% weight loss. Random intercept regression was used to evaluate significant trends in CT measures over time. Results: 42 mCRC patients were screened and 3(7%) enrolled. Patients were excluded for comorbidity/contraindication 14 (33%), excessive [>20%] weight loss 4 (9.5%), and insufficient [<5%] weight loss 19 (45%). For the <5% weight loss subset, there was a mean of 6.7 CT scans (SD=2.67) and of 9% (SD=5.4, min=0%, 25th percentile=4.9%) mean max muscle loss. Notably this group was simultaneously losing muscle (p=0.002) and gaining visceral adipose (p=0.007). For the ≥5% weight loss subset, there was a mean of 7.5 CT scans (SD=4.5) and 20% (SD=10.0, min=5.2%, 25th percentile =10.6) mean max muscle loss. Greater max muscle loss increased the odds of being in the ≥5% weight loss subset (OR=1.19, 95% CI: 1.06,1.33). This group also had a significant decrease in visceral adipose over time (p<0.001). Redefined inclusion criteria of ≥5% muscle loss would have included 14 of the 19 patients excluded because of <5% weight loss. Conclusions: Defining cancer cachexia as weight loss over time may be limited as it does not capture body composition changes and hinders trial accrual. Cross-sectional CT body composition analysis may improve early detection of muscle loss and improve trial accrual.

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