Special Issue "Cancer Cachexia"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 October 2019).

Special Issue Editors

Dr. Teresa A. Zimmers
Website
Guest Editor
Department of Surgery, Indiana University School of Medicine; Indiana University Purdue University Indianapolis Center for Cachexia Research, Innovation, and Therapy; Indiana University Simon Cancer Center; Richard Roudebush VAMC. IN USA
Interests: pancreatic cancer; muscle atrophy; cancer cachexia; symptom science; cancer metabolism
Dr. Richard Skipworth
Website
Guest Editor
Clinical Surgery, University of Edinburgh, Royal infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
Interests: cancer cachexia; muscle wasting; esophagogastric cancer; surgery; clinical trials

Special Issue Information

Dear Colleagues,

Cachexia is an underappreciated cause of cancer patient morbidity and mortality. It is associated with an impaired response to treatment, increased risk of treatment-related complications, decreased quality of life, and shortened survival. Key clinical components of the cachexia syndrome include wasting of peripheral tissues (namely, skeletal muscle and adipose tissue), primary anorexia, alterations in circulating neuroendocrine hormones, and induction of a systemic inflammatory response. Cachexia is driven by tumor-derived mediators that signal to disrupt host immunity and metabolism. Much progress has been made in the past 20 years in identifying molecular and cellular mediators of cancer cachexia. Major questions remain, however, particularly in understanding tumor–organ crosstalk, in identifying key nodes upstream of known cytokine cascades and inflammation, and in defining targetable end organ responses to cachexia-causing tumors. Additionally, understanding the link between metabolic dysregulation of cachexia and immune suppression could improve the efficacy of immunotherapy.

Despite increased understanding of pathological mechanisms of cachexia and a considerable uptick in anticachexia trials, there is still no effective approved therapy that can prevent or reverse cancer cachexia. Although certain ghrelin analogs and selective androgen receptor modulators have shown to be beneficial in terms of increasing patient lean body mass, these trials have been unable to demonstrate an associated gain in patient functional status. Trial methodology has improved with consensus definitions for clinical cachexia and the use of body composition analysis via diagnostic imaging modalities. However, further improvements in trial methodology, including the identification of early biomarkers, the accommodation of multimodal treatment regimens, and the development of robust coprimary endpoints, are required.

This Special Issue of Cancers will highlight the current state-of-the-art in cachexia biology and develop our understanding of the complexity of this syndrome. Research articles and review articles reporting basic science, translational studies, and clinical studies are all encouraged.

Dr. Teresa A. Zimmers
Dr. Richard Skipworth
Guest Editors

Manuscript Submission Information

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Published Papers (23 papers)

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Open AccessArticle
The Combination of Low Skeletal Muscle Mass and High Tumor Interleukin-6 Associates with Decreased Survival in Clear Cell Renal Cell Carcinoma
Cancers 2020, 12(6), 1605; https://doi.org/10.3390/cancers12061605 - 17 Jun 2020
Abstract
Clear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 [...] Read more.
Clear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Nicotine Induces IL-8 Secretion from Pancreatic Cancer Stroma and Worsens Cancer-Induced Cachexia
Cancers 2020, 12(2), 329; https://doi.org/10.3390/cancers12020329 - 01 Feb 2020
Abstract
Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro [...] Read more.
Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Upregulation of ZIP14 and Altered Zinc Homeostasis in Muscles in Pancreatic Cancer Cachexia
Cancers 2020, 12(1), 3; https://doi.org/10.3390/cancers12010003 - 18 Dec 2019
Cited by 2
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer type in which the mortality rate approaches the incidence rate. More than 85% of PDAC patients experience a profound loss of muscle mass and function, known as cachexia. PDAC patients with this condition suffer from decreased tolerance to anti-cancer therapies and often succumb to premature death due to respiratory and cardiac muscle wasting. Yet, there are no approved therapies available to alleviate cachexia. We previously found that upregulation of the metal ion transporter, Zip14, and altered zinc homeostasis are critical mediators of cachexia in metastatic colon, lung, and breast cancer models. Here, we show that a similar mechanism is likely driving the development of cachexia in PDAC. In two independent experimental metastasis models generated from the murine PDAC cell lines, Pan02 and FC1242, we observed aberrant Zip14 expression and increased zinc ion levels in cachectic muscles. Moreover, in advanced PDAC patients, high levels of ZIP14 in muscles correlated with the presence of cachexia. These studies underscore the importance of altered ZIP14 function in PDAC-associated cachexia development and highlight a potential therapeutic opportunity for improving the quality of life and prolonging survival in PDAC patients. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Deterioration in Muscle Mass and Physical Function Differs According to Weight Loss History in Cancer Cachexia
Cancers 2019, 11(12), 1925; https://doi.org/10.3390/cancers11121925 - 03 Dec 2019
Cited by 2
Abstract
Background: Muscle mass and physical function (PF) are common co-primary endpoints in cancer cachexia trials, but there is a lack of data on how these outcomes interact over time. The aim of this secondary analysis of data from a trial investigating multimodal intervention [...] Read more.
Background: Muscle mass and physical function (PF) are common co-primary endpoints in cancer cachexia trials, but there is a lack of data on how these outcomes interact over time. The aim of this secondary analysis of data from a trial investigating multimodal intervention for cancer cachexia (ClinicalTrials.gov: NCT01419145) is to explore whether changes in muscle mass and PF are associated with weight loss and cachexia status at baseline. Methods: Secondary analysis was conducted using data from a phase II randomized controlled trial including 46 patients with stage III–IV non-small cell lung cancer (n = 26) or inoperable pancreatic cancer (n = 20) due to commence chemotherapy. Cachexia status at baseline was classified according to international consensus. Muscle mass (assessed using computed tomography (CT)) and PF outcomes, i.e., Karnofsky performance status (KPS), self-reported PF (self-PF), handgrip strength (HGS), 6-minute walk test (6MWT), and physical activity (PA), were measured at baseline and after six weeks. Results: When compared according to cachexia status at baseline, patients with no/pre-cachexia had a mean loss of muscle mass (−5.3 cm2, p = 0.020) but no statistically significant change in PF outcomes. Patients with cachexia also lost muscle mass but to a lesser extent (−2.8 cm2, p = 0.146), but demonstrated a statistically significant decline in PF; KPS (−3.8 points, p = 0.030), self-PF (−8.8 points, p = 0.027), and HGS (−2.7 kg, p = 0.026). Conclusions: Weight loss history and cachexia status at baseline are of importance if one aims to detect changes in PF outcomes in cancer cachexia trials. To improve the use of co-primary endpoints that include PF in future trials, outcomes that have the potential to detect change relative to weight loss should be investigated further. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
IL-8 Released from Human Pancreatic Cancer and Tumor-Associated Stromal Cells Signals through a CXCR2-ERK1/2 Axis to Induce Muscle Atrophy
Cancers 2019, 11(12), 1863; https://doi.org/10.3390/cancers11121863 - 25 Nov 2019
Cited by 4
Abstract
Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected [...] Read more.
Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Blocking Activin Receptor Ligands Is Not Sufficient to Rescue Cancer-Associated Gut Microbiota—A Role for Gut Microbial Flagellin in Colorectal Cancer and Cachexia?
Cancers 2019, 11(11), 1799; https://doi.org/10.3390/cancers11111799 - 15 Nov 2019
Cited by 2
Abstract
Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC [...] Read more.
Colorectal cancer (CRC) and cachexia are associated with the gut microbiota and microbial surface molecules. We characterized the CRC-associated microbiota and investigated whether cachexia affects the microbiota composition. Further, we examined the possible relationship between the microbial surface molecule flagellin and CRC. CRC cells (C26) were inoculated into mice. Activin receptor (ACVR) ligands were blocked, either before tumor formation or before and after, to increase muscle mass and prevent muscle loss. The effects of flagellin on C26-cells were studied in vitro. The occurrence of similar phenomena were studied in murine and human tumors. Cancer modulated the gut microbiota without consistent effects of blocking the ACVR ligands. However, continued treatment for muscle loss modified the association between microbiota and weight loss. Several abundant microbial taxa in cancer were flagellated. Exposure of C26-cells to flagellin increased IL6 and CCL2/MCP-1 mRNA and IL6 excretion. Murine C26 tumors expressed more IL6 and CCL2/MCP-1 mRNA than C26-cells, and human CRC tumors expressed more CCL2/MCP-1 than healthy colon sites. Additionally, flagellin decreased caspase-1 activity and the production of reactive oxygen species, and increased cytotoxicity in C26-cells. Conditioned media from flagellin-treated C26-cells deteriorated C2C12-myotubes and decreased their number. In conclusion, cancer increased flagellated microbes that may promote CRC survival and cachexia by inducing inflammatory proteins such as MCP-1. Cancer-associated gut microbiota could not be rescued by blocking ACVR ligands. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessFeature PaperArticle
Cachectic Body Composition and Inflammatory Markers Portend a Poor Prognosis in Patients with Locally Advanced Pancreatic Cancer Treated with Chemoradiation
Cancers 2019, 11(11), 1655; https://doi.org/10.3390/cancers11111655 - 26 Oct 2019
Cited by 4
Abstract
Background: Patients with pancreatic cancer often develop cancer cachexia, a complex multifactorial syndrome with weight loss, muscle wasting and adipose tissue depletion with systemic inflammation causing physical impairment. In patients with locally advanced pancreatic cancer (LAPC) neoadjuvant treatment is routinely performed to allow [...] Read more.
Background: Patients with pancreatic cancer often develop cancer cachexia, a complex multifactorial syndrome with weight loss, muscle wasting and adipose tissue depletion with systemic inflammation causing physical impairment. In patients with locally advanced pancreatic cancer (LAPC) neoadjuvant treatment is routinely performed to allow a subsequent resection. Herein, we assess body composition and laboratory markers for cancer cachexia both before and after neoadjuvant chemoradiation (CRT). Methods: Subcutaneous fat (SCF), visceral fat (VF), skeletal muscle (SM), weight and laboratory parameters were determined longitudinally in 141 LAPC patients treated with neoadjuvant CRT. Changes during CRT were statistically analyzed and correlated with outcome and Kaplan–Meier curves were plotted. Different prognostic factors linked to cachexia were assessed by uni- and multivariable cox proportional hazards models. Results: There was a significant decrease in weight as well as SCF, VF and SM during CRT. The laboratory parameter C-reactive protein (CRP) increased significantly, whereas there was a significant decrease in leukocyte count, hemoglobin, albumin and cholinesterase as well as in the tumor marker CA 19.9. Cachectic weight loss, sarcopenia, reductions in body compartments SCF, VF and SM, and changes in laboratory markers as well as resection affected survival in univariable analysis. In multivariable analysis, weight loss >5% (HR 2.8), reduction in SM >5% (HR 5.5), an increase in CRP (HR 2.2) or CA 19.9 (HR 1.9), and resection (HR 0.4) remained independently associated with survival, whereas classical cachexia and sarcopenia did not. Interestingly, the subgroup of patients with cachectic weight loss >5% or SM reduction >5% during CRT did not benefit from resection (median survival 12 vs. 27 months). Conclusions: Persistent weight loss and muscle depletion during CRT as well as systemic inflammation after CRT impacted survival more than cachexia or sarcopenia according classical definitions. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Plasma Metabolomics Identifies Lipid and Amino Acid Markers of Weight Loss in Patients with Upper Gastrointestinal Cancer
Cancers 2019, 11(10), 1594; https://doi.org/10.3390/cancers11101594 - 19 Oct 2019
Cited by 1
Abstract
Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The ‘omics’ technologies allow us the opportunity to study the end points [...] Read more.
Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The ‘omics’ technologies allow us the opportunity to study the end points of many biological processes. Among these, blood-based metabolomics is a promising method to investigate the pathophysiology of human cancer cachexia and identify candidate biomarkers. In this study, we performed liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of cancer-associated weight loss. Non-selected patients undergoing surgery with curative intent for upper gastrointestinal cancer were recruited. Fasting plasma samples were taken at induction of anaesthesia. LC/MS analysis showed that 6 metabolites were highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, L-Proline, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16:1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight-stable samples (<5%weight loss) between predicted and actual weight change (r = 0.976, p = 0.0014). Overall, 40 metabolites were associated with ≥5% weight loss. This study provides biological validation of the consensus definition of cancer cachexia (Fearon et al.) and provides feasible candidate markers for further investigation in early diagnosis and the assessment of therapeutic intervention. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice
Cancers 2019, 11(10), 1541; https://doi.org/10.3390/cancers11101541 - 12 Oct 2019
Cited by 4
Abstract
Physical activity improves the prognosis of cancer patients, partly by contrasting the associated muscle wasting (cachexia), through still unknown mechanisms. We asked whether aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor [...] Read more.
Physical activity improves the prognosis of cancer patients, partly by contrasting the associated muscle wasting (cachexia), through still unknown mechanisms. We asked whether aerobic exercise causes secretion by skeletal muscles of proteins (myokines) that may contrast cachexia. Media conditioned by peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α)-expressing myotubes, reproducing some metabolic adaptations of aerobic exercise, as increased mitochondrial biogenesis and oxidative phosphorylation, restrained constitutively active Forkhead box-containing subfamily O3 (caFoxO3)-induced proteolysis. Microarray analysis identified amphiregulin (AREG), natriuretic peptide precursor B (NppB), musclin and fibroblast growth factor 18 (FGF18) as myokines highly induced by PGC1α. Notably, only musclin tended to be low in muscle of mice with a rare human renal carcinoma; it was reduced in plasma and in muscles of C26-bearing mice and in atrophying myotubes, where PGC1α expression is impaired. Therefore, we electroporated the Tibialis Anterior (TA) of C26-bearing mice with musclin or (its receptor) natriuretic peptide receptor 3 (Npr3)-encoding plasmids and found a preserved fiber area, as a result of restrained proteolysis. Musclin knockout (KO) mice lose more muscle tissue during growth of two distinct cachexia-causing tumors. Running protected C26-bearing mice from cachexia, not changing tumor growth, and rescued the C26-induced downregulation of musclin in muscles and plasma. Musclin expression did not change in overloaded plantaris of mice, recapitulating partially muscle adaptations to anaerobic exercise. Musclin might, therefore, be beneficial to cancer patients who cannot exercise and are at risk of cachexia and may help to explain how aerobic exercise alleviates cancer-induced muscle wasting. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Assessing Cachexia Acutely after Autologous Stem Cell Transplant
Cancers 2019, 11(9), 1300; https://doi.org/10.3390/cancers11091300 - 04 Sep 2019
Abstract
Autologous hematopoietic stem cell transplantation (AHCT) is an accepted strategy for various hematologic malignancies that can lead to functional impairment, fatigue, muscle wasting, and reduced quality of life (QOL). In cancer cachexia, these symptoms are associated with inflammation, hypermetabolism, and decreased anabolic hormones. [...] Read more.
Autologous hematopoietic stem cell transplantation (AHCT) is an accepted strategy for various hematologic malignancies that can lead to functional impairment, fatigue, muscle wasting, and reduced quality of life (QOL). In cancer cachexia, these symptoms are associated with inflammation, hypermetabolism, and decreased anabolic hormones. The relative significance of these factors soon after AHCT setting is unclear. The purpose of this study was to characterize the acute effects of AHCT on physical function, body composition, QOL, energy expenditure, cytokines, and testosterone. Outcomes were assessed before (PRE) and 30 ± 10 days after (FU) AHCT in patients with multiple myeloma (n = 15) and non-Hodgkin lymphoma (n = 6). Six-minute walk test (6MWT; p = 0.014), lean mass (p = 0.002), and fat mass (p = 0.02) decreased; nausea and fatigue increased at FU (both p = 0.039). Recent weight change and steroid exposure were predictors of reduced aerobic capacity (p < 0.001). There were no significant changes in interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), energy expenditure, or bioavailable testosterone. Alterations in cytokines, energy expenditure, and testosterone were not associated with functional impairment acutely following AHCT. Recent history of weight loss and steroid exposure were predictors of worse physical function after AHCT, suggesting that targeting nutritional status and myopathy may be viable strategies to mitigate these effects. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle
Cancers 2019, 11(9), 1264; https://doi.org/10.3390/cancers11091264 - 28 Aug 2019
Cited by 4
Abstract
Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle [...] Read more.
Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Tumor Transcriptome Reveals High Expression of IL-8 in Non-Small Cell Lung Cancer Patients with Low Pectoralis Muscle Area and Reduced Survival
Cancers 2019, 11(9), 1251; https://doi.org/10.3390/cancers11091251 - 26 Aug 2019
Cited by 4
Abstract
Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data [...] Read more.
Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and tenth thoracic (T10) vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, interleukin (IL)-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL-6, CSF3, and IL-8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL-8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL-8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these upregulated genes, IL-8 expression in NSCLC tissues was associated with worse prognosis, and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Treatment with Soluble Activin Receptor Type IIB Alters Metabolic Response in Chemotherapy-Induced Cachexia
Cancers 2019, 11(9), 1222; https://doi.org/10.3390/cancers11091222 - 21 Aug 2019
Cited by 2
Abstract
Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from [...] Read more.
Some chemotherapeutic agents have been shown to lead to the severe wasting syndrome known as cachexia resulting in dramatic losses of both skeletal muscle and adipose tissue. Previous studies have shown that chemotherapy-induced cachexia is characterized by unique metabolic alterations. Recent results from our laboratory and others have shown that the use of ACVR2B/Fc, a soluble form of the activin receptor 2B (ACVR2B), can mitigate muscle wasting induced by chemotherapy, although the underlying mechanisms responsible for such protective effects are unclear. In order to understand the biochemical mechanisms through which ACVR2B/Fc functions, we employed a comprehensive, multi-platform metabolomics approach. Using both nuclear magnetic resonance (NMR) and mass-spectrometry (MS), we profiled the metabolome of both serum and muscle tissue from four groups of mice including (1) vehicle, (2) the chemotherapeutic agent, Folfiri, (3) ACVR2B/Fc alone, and (4) combined treatment with both Folfiri and ACVR2B/Fc. The metabolic profiles demonstrated large effects with Folfiri treatment and much weaker effects with ACVR2B/Fc treatment. Interestingly, a number of significant effects were observed in the co-treatment group, with the addition of ACVR2B/Fc providing some level of rescue to the perturbations induced by Folfiri alone. The most prominent of these were a normalization of systemic glucose and lipid metabolism. Identification of these pathways provides important insights into the mechanism by which ACVR2B/Fc protects against chemotherapy-induced cachexia. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Rapid Depletions of Subcutaneous Fat Mass and Skeletal Muscle Mass Predict Worse Survival in Patients with Hepatocellular Carcinoma Treated with Sorafenib
Cancers 2019, 11(8), 1206; https://doi.org/10.3390/cancers11081206 - 19 Aug 2019
Cited by 5
Abstract
The aim of this study was to investigate whether rapid depletions of fat mass and skeletal muscle mass predict mortality in hepatocellular carcinoma (HCC) patients treated with sorafenib. This retrospective study evaluated 61 HCC patients. The cross-sectional areas of visceral and subcutaneous fat [...] Read more.
The aim of this study was to investigate whether rapid depletions of fat mass and skeletal muscle mass predict mortality in hepatocellular carcinoma (HCC) patients treated with sorafenib. This retrospective study evaluated 61 HCC patients. The cross-sectional areas of visceral and subcutaneous fat mass and skeletal muscle mass were measured by computed tomography, from which the visceral fat mass index (VFMI), subcutaneous fat mass index (SFMI), and skeletal muscle index (L3SMI) were obtained. The relative changes in these indices per 120 days (ΔVFMI, ΔSFMI, and ΔL3SMI) before and after sorafenib treatment were calculated in each patient. Patients within the 20th percentile cutoffs for these indices were classified into the rapid depletion (RD) group. Kaplan–Meier analysis revealed that with respect to ΔL3SMI (p = 0.0101) and ΔSFMI (p = 0.0027), the RD group had a significantly poorer survival. Multivariate analysis using the Cox proportional-hazards model also demonstrated that ΔL3SMI (≤−5.73 vs. >−5.73; hazard ratio [HR]: 4.010, 95% confidence interval [CI]: 1.799–8.938, p = < 0.001) and ΔSFMI (≤−5.33 vs. >−5.33; HR: 4.109, 95% CI: 1.967–8.584, p = < 0.001) were independent predictors. Rapid depletions of subcutaneous fat mass and skeletal muscle mass after the introduction of sorafenib indicate a poor prognosis. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Chronic Treatment with Multi-Kinase Inhibitors Causes Differential Toxicities on Skeletal and Cardiac Muscles
Cancers 2019, 11(4), 571; https://doi.org/10.3390/cancers11040571 - 23 Apr 2019
Cited by 4
Abstract
Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid [...] Read more.
Despite recent progress, chemotherapy remains the preferred treatment for cancer. We have shown a link between anticancer drugs and the development of cachexia, i.e., body wasting accompanied by muscle loss. The multi-kinase inhibitors (MKIs) regorafenib and sorafenib, used as second-line treatment for solid tumors, are frequently accompanied by several side effects, including loss of muscle mass and strength. In the present study we aimed to investigate the molecular mechanisms associated with the occurrence of muscle toxicities in in vivo conditions. Hence, we treated 8-week old healthy CD2F1 male mice with MKIs for up to six weeks and observed decreased skeletal and cardiac muscle mass, consistent with muscle weakness. Modulation of ERK1/2 and GSK3β, as well as increased expression of markers of autophagy, previously associated with muscle atrophy conditions, were shown in skeletal muscle upon treatment with either drug. MKIs also promoted cardiac abnormalities consistent with reduced left ventricular mass, internal diameter, posterior wall thickness and stroke volume, despite unchanged overall function. Notably, different signaling pathways were affected in the heart, including reduced expression of mitochondrial proteins, and elevated AKT, GSK3β, mTOR, MEK1/2 and ERK1/2 phosphorylation. Combined, our data demonstrate detrimental effects on skeletal and cardiac muscle in association with chronic administration of MKIs, although different mechanisms would seem to contribute to the cachectic phenotype in the two tissues. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessArticle
Moderate Exercise Improves Experimental Cancer Cachexia by Modulating the Redox Homeostasis
Cancers 2019, 11(3), 285; https://doi.org/10.3390/cancers11030285 - 28 Feb 2019
Cited by 6
Abstract
Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study [...] Read more.
Cachexia is a debilitating syndrome that complicates the management of cancer patients. Muscle wasting, one of the main features of cachexia, is associated with hyper-activation of protein degradative pathways and altered mitochondrial function that could both result from impaired redox homeostasis. This study aimed to investigate the contribution of oxidative stress to cancer-induced cachexia in the presence or in the absence of moderate exercise training. Mice bearing the colon C26 carcinoma, either sedentary or exercised, were used. The former showed muscle wasting and redox imbalance, with the activation of an antioxidant response and with upregulation of markers of proteasome-dependent protein degradation and autophagy. Moderate exercise was able to relieve muscle wasting and prevented the loss of muscle strength; such a pattern was associated with reduced levels of Reactive Oxygen Species (ROS), carbonylated proteins and markers of autophagy and with improved antioxidant capacity. The muscle of sedentary tumor hosts also showed increased levels of molecular markers of mitophagy and reduced mitochondrial mass. Conversely, exercise in the C26 hosts led to increased mitochondrial mass. In conclusion, moderate exercise could be an effective non-pharmacological approach to prevent muscle wasting in cancer patients, decreasing muscle protein catabolism and oxidative stress and preserving mitochondria. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Review

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Open AccessReview
Systemic Actions of Breast Cancer Facilitate Functional Limitations
Cancers 2020, 12(1), 194; https://doi.org/10.3390/cancers12010194 - 13 Jan 2020
Cited by 1
Abstract
Breast cancer is a disease of a specific organ, but its effects are felt throughout the body. The systemic effects of breast cancer can lead to functional limitations in patients who suffer from muscle weakness, fatigue, pain, fibromyalgia, or many other dysfunctions, which [...] Read more.
Breast cancer is a disease of a specific organ, but its effects are felt throughout the body. The systemic effects of breast cancer can lead to functional limitations in patients who suffer from muscle weakness, fatigue, pain, fibromyalgia, or many other dysfunctions, which hasten cancer-associated death. Mechanistic studies have identified quite a few molecular defects in skeletal muscles that are associated with functional limitations in breast cancer. These include circulating cytokines such as TNF-α, IL-1, IL-6, and TGF-β altering the levels or function of myogenic molecules including PAX7, MyoD, and microRNAs through transcriptional regulators such as NF-κB, STAT3, and SMADs. Molecular defects in breast cancer may also include reduced muscle mitochondrial content and increased extracellular matrix deposition leading to energy imbalance and skeletal muscle fibrosis. This review highlights recent evidence that breast cancer-associated molecular defects mechanistically contribute to functional limitations and further provides insights into therapeutic interventions in managing functional limitations, which in turn may help to improve quality of life in breast cancer patients. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessReview
ER Stress and Unfolded Protein Response in Cancer Cachexia
Cancers 2019, 11(12), 1929; https://doi.org/10.3390/cancers11121929 - 03 Dec 2019
Cited by 6
Abstract
Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin [...] Read more.
Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin resistance, dysfunctional mitochondria, oxidative stress, and heightened activation of ubiquitin-proteasome system and macroautophagy. Accumulating evidence suggests that deviant regulation of an array of signaling pathways engenders cancer cachexia where the human body is sustained in an incessant self-consuming catabolic state. Recent studies have further suggested that several components of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle of animal models and muscle biopsies of cachectic cancer patients. However, the exact role of ER stress and the individual arms of the UPR in the regulation of skeletal muscle mass in various catabolic states including cancer has just begun to be elucidated. This review provides a succinct overview of emerging roles of ER stress and the UPR in cancer-induced skeletal muscle wasting. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessFeature PaperReview
Cachexia and Sarcopenia in Older Adults with Cancer: A Comprehensive Review
Cancers 2019, 11(12), 1861; https://doi.org/10.3390/cancers11121861 - 25 Nov 2019
Cited by 12
Abstract
Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic [...] Read more.
Cancer cachexia is a syndrome characterized by weight loss with accompanying loss of muscle and/or fat mass and leads to impaired patient function and physical performance and is associated with a poor prognosis. It is prevalent in older adults with cancer; age-associated physiologic muscle wasting and weakness, also known as sarcopenia, can compound deficits associated with cancer cachexia in older adults and makes studying this condition more complex in this population. Multiple measurement options are available to assess the older patient with cancer and cachexia and/or sarcopenia including anthropometric measures, imaging modalities such as Dual X-ray absorptiometry (DEXA) and Computed Tomography (CT), muscular strength and physical performance testing, and patient-reported outcomes (PROs). A geriatric assessment (GA) is a useful tool when studying the older patient with cachexia given its comprehensive ability to capture aging-sensitive PROs. Interventions focused on nutrition and increasing physical activity may improve outcomes in older adults with cachexia. Efforts to develop targeted pharmacologic therapies with cachexia have not been successful thus far. Formal treatment guidelines, an updated consensus definition for cancer cachexia and the development of a widely adapted assessment tool, much like the GA utilized in geriatric oncology, could help advance the field of cancer cachexia over the next decade. Full article
(This article belongs to the Special Issue Cancer Cachexia)
Open AccessReview
The Relationship between Imaging-Based Body Composition Analysis and the Systemic Inflammatory Response in Patients with Cancer: A Systematic Review
Cancers 2019, 11(9), 1304; https://doi.org/10.3390/cancers11091304 - 04 Sep 2019
Cited by 3
Abstract
Background and aim: Cancer is the second leading cause of death globally. Nutritional status (cachexia) and systemic inflammation play a significant role in predicting cancer outcome. The aim of the present review was to examine the relationship between imaging-based body composition and systemic [...] Read more.
Background and aim: Cancer is the second leading cause of death globally. Nutritional status (cachexia) and systemic inflammation play a significant role in predicting cancer outcome. The aim of the present review was to examine the relationship between imaging-based body composition and systemic inflammation in patients with cancer. Methods: MEDLINE, EMBASE, Cochrane Library and Google Scholar were searched up to 31 March 2019 for published articles using MESH terms cancer, body composition, systemic inflammation, Dual energy X-ray absorptiometry (DEXA), magnetic resonance imaging (MRI), ultrasound sonography (USS) and computed tomography (CT). Studies performed in adult patients with cancer describing the relationship between imaging-based body composition and measures of the systemic inflammatory response were included in this review. Results: The literature search retrieved 807 studies and 23 met the final eligibility criteria and consisted of prospective and retrospective cohort studies comprising 11,474 patients. CT was the most common imaging modality used (20 studies) and primary operable (16 studies) and colorectal cancer (10 studies) were the most commonly studied cancers. Low skeletal muscle index (SMI) and systemic inflammation were consistently associated; both had a prognostic value and this relationship between low SMI and systemic inflammation was confirmed in four longitudinal studies. There was also evidence that skeletal muscle density (SMD) and systemic inflammation were associated (9 studies). Discussion: The majority of studies examining the relationship between CT based body composition and systemic inflammation were in primary operable diseases and in patients with colorectal cancer. These studies showed that there was a consistent association between low skeletal muscle mass and the presence of a systemic inflammatory response. These findings have important implications for the definition of cancer cachexia and its treatment. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessReview
Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins—An Emerging Mechanism of Cancer-Induced Cachexia
Cancers 2019, 11(9), 1272; https://doi.org/10.3390/cancers11091272 - 30 Aug 2019
Cited by 1
Abstract
Cancer-associated cachexia (cancer cachexia) is a major contributor to the modality and mortality of a wide variety of solid tumors. It is estimated that cachexia inflicts approximately ~60% of all cancer patients and is the immediate cause of ~30% of all cancer-related death. [...] Read more.
Cancer-associated cachexia (cancer cachexia) is a major contributor to the modality and mortality of a wide variety of solid tumors. It is estimated that cachexia inflicts approximately ~60% of all cancer patients and is the immediate cause of ~30% of all cancer-related death. However, there is no established treatment of this disorder due to the poor understanding of its underlying etiology. The key manifestations of cancer cachexia are systemic inflammation and progressive loss of skeletal muscle mass and function (muscle wasting). A number of inflammatory cytokines and members of the TGFβ superfamily that promote muscle protein degradation have been implicated as mediators of muscle wasting. However, clinical trials targeting some of the identified mediators have not yielded satisfactory results. Thus, the root cause of the muscle wasting associated with cancer cachexia remains to be identified. This review focuses on recent progress of laboratory studies in the understanding of the molecular mechanisms of cancer cachexia that centers on the role of systemic activation of Toll-like receptor 4 (TLR4) by cancer-released Hsp70 and Hsp90 in the development and progression of muscle wasting, and the downstream signaling pathways that activate muscle protein degradation through the ubiquitin–proteasome and the autophagy–lysosome pathways in response to TLR4 activation. Verification of these findings in humans could lead to etiology-based therapies of cancer cachexia by targeting multiple steps in this signaling cascade. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Open AccessReview
Pretreatment Cancer-Related Cognitive Impairment—Mechanisms and Outlook
Cancers 2019, 11(5), 687; https://doi.org/10.3390/cancers11050687 - 16 May 2019
Cited by 13
Abstract
Cognitive changes are common in patients with active cancer and during its remission. This has largely been blamed on therapy-related toxicities and diagnosis-related stress, with little attention paid to the biological impact of cancer itself. A plethora of clinical studies demonstrates that cancer [...] Read more.
Cognitive changes are common in patients with active cancer and during its remission. This has largely been blamed on therapy-related toxicities and diagnosis-related stress, with little attention paid to the biological impact of cancer itself. A plethora of clinical studies demonstrates that cancer patients experience cognitive impairment during and after treatment. However, recent studies show that a significant portion of patients with non-central nervous system (CNS) tumors experience cognitive decline prior to treatment, suggesting a role for tumor-derived factors in modulating cognition and behavior. Cancer-related cognitive impairment (CRCI) negatively impacts a patient’s quality of life, reduces occupational and social functioning, and increases morbidity and mortality. Furthermore, patients with cancer cachexia frequently experience a stark neurocognitive decline, suggesting peripheral tumors exert an enduring toll on the brain during this chronic paraneoplastic syndrome. However, the scarcity of research on cognitive impairment in non-CNS cancers makes it difficult to isolate psychosocial, genetic, behavioral, and pathophysiological factors in CRCI. Furthermore, clinical models of CRCI are frequently confounded by complicated drug regimens that inherently affect neurocognitive processes. The severity of CRCI varies considerably amongst patients and highlights its multifactorial nature. Untangling the biological aspects of CRCI from genetic, psychosocial, and behavioral factors is non-trivial, yet vital in understanding the pathogenesis of CRCI and discovering means for therapeutic intervention. Recent evidence demonstrating the ability of peripheral tumors to alter CNS pathways in murine models is compelling, and it allows researchers to isolate the underlying biological mechanisms from the confounding psychosocial stressors found in the clinic. This review summarizes the state of the science of CRCI independent of treatment and focuses on biological mechanisms in which peripheral cancers modulate the CNS. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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Other

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Open AccessPerspective
Theoretical and Practical Implications of Treating Cachexia in Advanced Lung Cancer Patients
Cancers 2019, 11(11), 1619; https://doi.org/10.3390/cancers11111619 - 23 Oct 2019
Abstract
Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape is changing rapidly as a result of the positive impact of effective inhibitors of [...] Read more.
Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape is changing rapidly as a result of the positive impact of effective inhibitors of tumor driver mutations, and the more recent discovery that immune modulation with anti-PD-1/PD-L1 monoclonal antibodies results in tumor regression and prolonged survival. While a relatively small subset of lung cancer patients are candidates for inhibitors of driver mutations, the majority of advanced lung cancer patients are candidates for an immunotherapy regimen. Many of these patients have cachexia, which is associated with increased cancer therapy toxicity and possibly reduced responsiveness to immunotherapy. Two ongoing cachexia trials, one testing a ghrelin analogue and the other testing a multimodal strategy, have endpoints which assess clinical benefit—weight gain and relief of anorexia/cachexia symptoms. Provided that the trial objectives are achieved, these treatment strategies will provide a way to relieve suffering and distress for cachectic cancer patients. While awaiting the results of these trials, it would be reasonable to consider designing studies testing cachexia treatments combined with first-line immunotherapy and chemotherapy–immunotherapy in stage IV lung cancer patients, with enhanced overall survival being one of the endpoints. Full article
(This article belongs to the Special Issue Cancer Cachexia)
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