Cancer cachexia

Studies demonstrate that obesity can increase tumor development. Botryosphaeran, a fungal (1!3)(1!6)-b-D-glucan, presents antimutagenic, antiproliferative and pro-apoptotic activities. This study evaluated the effects of botryosphaeran on tumor development and metabolic and hematological parameters in tumor-bearing obese and non-obese rats. Obesity was induced by a high-fat and high-sugar diet, while control rats received standard diet and water without sugar for 10 weeks. On 8th-week, Walker-256 tumor cells were inoculated in the rats, and treatment with botryosphaeran (12 mg/Kg b.w.) started. Groups:control tumor-CT, control tumor botryosphaeran-CTB, obese tumor-OT and obese tumor botryosphaeran-OTB. On 10th-week, tumor development, cachexia, metabolic and hematological parameters were analyzed. Tumor development and cachexia were significantly higher in the OT group compared to the CT group, and botryosphaeran attenuated these parameters. OT rats presented accumulation of adipose tissue, reduced muscle mass, glucose intolerance, insulin resistance, hyperglycemia, anemia, leukocytosis, and thrombocytopenia. Botryosphaeran corrected insulin resistance and hyperglycemia, modulated cholesterol levels, and increased leukocyte and lymphocytes in obese rats, which can be attributable to an inflammatory response against the Walker-256 tumor, contributing to a lower tumor development. Our data demonstrated that botryosphaeran was effective in attenuating tumor growth and in improving the metabolic and hematological profiles of the tumor-bearing rats, demonstrating its potential role in the cancer's management.

PURPOSE Internet fake information, parapharmacy and counterfeit drugs are a market of hundreds of billion dollars. Misleading internet data decrease patients' compliance to medical care, promote use of questionable and detrimental practices, and jeopardize patient outcome. This is particularly harmful among cancer patients, especially when pain and nutritional aspects are considered. Provision of Web recommendations for the general audience (patients, relatives, general population) from official medical-providers might be useful to outweigh the detrimental internet information produced by non-medical providers. METHODS 370 oncology and anesthesiology related societies were analyzed. Our objective was to evaluate the magnitude of web-recommendation for cancer cachexia and cancer pain for the general audience provided by official medical organizations' web sites at global level. RESULTS Magnitude of web-recommendations at global level was surprisingly scant both for coverage a...

Cancer cachexia is a common associate of cancer and has a negative impact on both patients' quality of life and overall survival. Nonetheless its management remains suboptimal in clinical practice. Provision of medical recommendations in websites is of extreme importance for medical decision making and translating evidence into clinical practice. Aim of the study: To scrutinize the magnitude, consistency and changes over time of cancer-cachexia recommendations for physicians on the Web among oncology related societies. Intercontinental, continental, national and socioeconomic variations were further analyzed. Material and methods: Web identification of oncology related societies and prospective analyses of relative Web guideline recommendations for physicians on cancer-cachexia at different time-points. Results: In June 2011, we scrutinized 144,000 Web pages. We identified 275 societies, of which 270 were eligible for analyses: 67 were international (African, American, Asian, European, Oceania and Intercontinental), 109 belonged to the top 10 countries with the highest development index and 94 pertained to 10 countries with a long lasting tradition in medical oncology. Conclusions: The magnitude of cancer cachexia recommendations for physicians on the Web at a global level was scant both for coverage and consistency, and at any time-point considered: 3.7% (10/270) in 2011 and 8.1% (22/270) in 2018. The proportion of societies giving evidence-based and updated recommendations for cancer cachexia for physicians was only 1.1% (3/270) in 2011 and 2.96% (8/270) in 2018. Continent, national highest developmental index, oncology tradition and economic-geographic areas were not found to influence Web guideline provision.

he became interested in the role of cytokines in the modulation of the host response and went to the Metabolic Research Laboratory, Radcliffe Infirmary, Oxford, UK, to work on the metabolic effects of tumor necrosis factor and interleukin-1. A t present he is Associate Professor of Biochemistry and Molecular Biology at the Faculty of Biology, University of Barcelona, where he is the leader of a research group interested in tumor-host interrelationships. Francisco J. Lopez-Soriano obtained his Doctorate from the University of Barcelona in 1987, investigating the role of amino acids in brown adipose tissue thermogenesis. Later, he undertook postdoctoral research in the Metabolic Research Laboratory, Radcliffe Infirmary, Ox- ford, UK, working on diferent aspects of cytokines during the perinatal period. In 1988 he was promoted to Associate Professor of Biochemistry and Molecular Biology in the University of Barcelona, where he is at present investigating the role of cytokines in muscle wasting and its relation with cachexia.

Cancer cachexia is a multi-factorial syndrome, which negatively affects quality of life, responsiveness to chemotherapy, and survival in advanced cancer patients. Our understanding of cachexia has grown greatly in recent years and the roles of many tumor-derived and host-derived compounds have been elucidated as mediators of cancer cachexia. However, cancer cachexia remains an unmet medical need and attempts towards a standard treatment guideline have been unsuccessful. This review covers the diagnosis, assessment, and treatment of cancer cachexia; the elements impeding the formulation of a standard management guideline; and future directions of research for the improvement and standardization of current treatment procedures.

Understanding the pathophysiology of cancer cachexia; Recognising the clinical and physical consequences and implications of cachexia; Understanding the metabolic pathways underlying cancer wasting and cachexia. 1. Malignancy 1.1. The wasting spectrum in cancer 2. Tumour burden, metabolic dysfunction and symptoms 2.1. Acute phase response 2.2. Hypermetabolism 2.3. Wasting, carbohydrate metabolism and energy expenditure 2.4. Wasting, protein metabolism and skeletal muscle 2.5. Wasting, lipid metabolism and adipose tissue 3. The impact of cancer wasting 4. Summary Cancer cachexia is a clinical syndrome as yet not totally understood; Muscle mass, adipose tissue, energy requirements and metabolic derangements are common; Cancer cachexia is associated with physical, symptomatic, metabolic and tumourassociated factors; Cachexia is prevalent and has profound adverse effects on patients' Quality of Life and survival; Evidence shows the need for the integration of nutrition as part of a team approach for cancer patients' treatment.

Chronic NP-1 administration reduces body weight and hepatic steatosis despite induction of tolerance in adiponectin gene transcription with respect to the acute actions of this drug. This study explored the hypothesis that NP-1 could exert these effects through mechanisms independent of adiponectin. To this aim, we took advantage of the Zucker (fa/fa) rat model, which exhibits obesity, fatty liver and elevated leptin and adiponectin levels. Body weight and food intake were reduced after chronic NP-1 treatment. Plasma TNFα concentrations were elevated but no increase in adiponectin was found. Even so, NP-1 ameliorated fatty liver and corrected dyslipidemia by mechanisms probably associated with reduced feeding, transcription of Cpt1 and down-regulation of Hmgcr-CoA expression. In brown fat tissue NP-1 increased Dnmt1 (inhibitor of Adipoq) while it reduced Ucp1 expression and heat production, which excludes thermogenesis as a mechanism of the NP-1 slimming effect. The anti-obesity act...

In cancer, more than 30% of patients die due to cachexia and more than 50% of patients with cancer die with cachexia being present. Patients with cancer cachexia frequently develop a chronic negative energy and protein balance driven by a combination of reduced food intake and metabolic change. Several studies have already demonstrated the usefulness of oral nutritional supplements (ONS) in managing malnutrition of cancer patients. Though increased energy intake is very important in managing cancer-related malnutrition, the source of this extra energy and the presence of anti-inflammatory and immunonutritional components may also play an important role. Here we present the study protocol of a randomized, open-label, multicentre clinical trial aimed to determine whether an ONS composed according to the needs of patients with malignant diseases an ONS composed according to the needs of patients with malignant diseases is more effective than a general product in improving the nutrition...

The CASC-IN score has been designed with two very clear objectives: first, as a means to quantitatively assess pre-cachexia in cancer patients, and second, as a tool to discriminate the patients where cachexia staging is relevant. From this point of view, the CASC-IN tool is tightly linked with the so-called CAchexia SCOre (CASCO) previously described 1 and validated 2 by our research team. The results presented here classify a population of cancer patients into non-cachectic, precachectic or cachectic. Patients and Methods: An observational prospective case-control study has been performed and a total of 179 carcinoma patients and 117 age-matched control subjects were included.

BackgroundNone of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects. The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models.MethodsIn order to achieve this goal, we included in the study one rat model (Yoshida AH‐130ascites hepatoma) and two mouse models (Lewis lung carcinoma and Colon26 carcinoma). The Animal cachexia score (ACASCO) includes five components: (a) body and muscle weight loss, (b) inflammation and metabolic disturbances, (c) physical performance, (d) anorexia, and (e) quality of life measured using discomfort symptoms and behavioral tests.ResultsUsing the ACASCO values, three cut‐off values were estimated by applying hierarchical cluster analysis. Four groups were originally described, one exactly below the observed mean, a second exactly over the mean, and two othe...

It is intimately known that well-ordered exercise training boosts muscle mass, physical performance and cause to health advantages including to control muscle mass in many pathological conditions, such as cancer, HIV, metabolic and neurodegenerative diseases[1-4]. As noted, Skeletal muscle wasting is critical problem, which occurs as part of cancer cachexia and a major cause of fatigue in patients[5,6]. Skeletal muscle wasting is induced by cancer even with normal energy intake and is not prevented by nutritional supplementation[6-8]. Muscle-wasting induced cancer is also associated with severe fatigue, which affects 70 100% of cancer patients[9,10]. Fatigue related to muscle wasting is a distressing symptom that negatively impacts on physical function and can lead to affected cancer patients changing their employment status and reducing their overall quality of life[11]. Although exercise training has been suggested as a promising countermeasure to prevent muscle wasting in cancer,...

It is intimately known that well-ordered exercise training boosts muscle mass, physical performance and cause to health advantages including to control muscle mass in many pathological conditions, such as cancer, HIV, metabolic and neurodegenerative diseases[1-4]. As noted, Skeletal muscle wasting is critical problem, which occurs as part of cancer cachexia and a major cause of fatigue in patients[5,6]. Skeletal muscle wasting is induced by cancer even with normal energy intake and is not prevented by nutritional supplementation[6-8]. Muscle-wasting induced cancer is also associated with severe fatigue, which affects 70 100% of cancer patients[9,10]. Fatigue related to muscle wasting is a distressing symptom that negatively impacts on physical function and can lead to affected cancer patients changing their employment status and reducing their overall quality of life[11]. Although exercise training has been suggested as a promising countermeasure to prevent muscle wasting in cancer,...

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice.MethodsIsoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes.ResultsMurine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced acti...

Complementary and alternative medicine is defined as "diagnosis, treatment and/or prevention which complements mainstream medicine by contributing to a common whole, by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks of medicine." 1 It comprises a confusingly large and heterogeneous array of techniques, with both therapeutic and diagnostic approaches (table 1).

Cancer cachexia (CC) is a multifactorial syndrome characterized by severe depletion of skeletal muscle, with or without fat loss. A majority of cancer patients with incurable cancer are affected with cachexia and it remains an unmet medical need. Gene expression changes at the transcriptional level have been studied for CC in both humans and rodents. However, post-transcriptional regulatory mechanisms likely play a role in CC and are not addressed in the literature on human subjects, and are the focus of this thesis. It is well known that the sex-specific expression of genes contributes to traits and phenotypes. The role of autosomal expression of genes and their regulation at a posttranscriptional level in skeletal muscle from cancer cachexia patients has not been explored to account for the sex-specific differences in cachexia prevalence or severity. I hypothesize that CC, a manifestation of the net effect of complex host-tumor interactions and underlying molecular mechanisms, involves dysregulation of miRNAs and splice variants in skeletal muscle contributing to the pathophysiology of CC in a sex-specific manner. The objectives of the thesis are (i) to profile miRNAs expressed in skeletal muscle biopsies and to identify Differentially Expressed (DE) miRNAs associated with human CC using Next Generation Sequencing (NGS), (ii) to profile Alternatively Spliced Genes (ASGs) from human skeletal muscle biopsies and to identify differentially expressed alternatively spliced genes (DASGs) associated with human CC using Human Transcriptome Array 2.0 (HTA 2.0) and (iii) to profile and identify sex-specific miRNAs and Differentially Expressed Isoform specific gene expression (DEI) for human CC. iii Study subjects were classified based on the international consensus definition and diagnostic criteria for CC. Forty-two cancer patients were classified into 22 cachectic cases and 20 non-cachectic cancer controls who had no weight loss over a period of six months compared to their pre-illness weight. For identifying sex-specific expression differences, 22 cases and 20 controls were further stratified by sex. Body composition analysis was carried out using computed tomography (CT) taken prior to surgery. Total RNA was isolated from rectus abdominis muscle and used for NGS and HTA 2.0 arrays. Representative signatures were validated using qRT-PCR for cross platform concordance. Partek Genomics Suite v6.6 and SPSS v16 were used for bioinformatics and statistical analyses, respectively. Ingenuity pathway analysis (IPA) was used to identify canonical pathways and network analysis for biological interpretation. 777 miRNAs were profiled and 82 miRNAs with read counts of ≥ 5 in 80% of samples were retained for analysis. Eight miRNAs were DE (up-regulated, fold change of ≥ 1.4 at p < 0.05). IPA identified pathways related to myogenesis and inflammation. qRT-PCR analysis of representative miRs showed a similar direction of effect (p < 0.05), as observed in NGS. 8960 ASGs were identified, of which 922 DASGs (772 upregulated, 150 down-regulated) were observed with > 1.4 fold change and p < 0.05. Representative DASGs validated by semi-quantitative RT-PCR confirmed the primary findings from the HTA 2.0. Identified DASGs were associated with myogenesis, adipogenesis, protein ubiquitination and inflammation. Up to 10% of the DASGs exhibited cassette exon (exon included or skipped) as a predominant form of AS event. Other forms of AS events such as intron retention and alternative promoters were also observed. Sex-specific expression was observed both at the miRNA and at the DEI iv levels. 10 upregulated miRNAs in males and 3 upregulated miRNAs in females were identified with ≥ 1.4 FC and p < 0.05. 1324 and 372 DEIs were identified in males and females, respectively. Pathways associated with skeletal muscle atrophy were predominant in males, whereas adipogenesis pathways were more common in females. Although the same upstream regulators were identified, their downstream targets were different between sexes. In all, my study has shown for the first time that posttranscriptional regulatory molecules are indeed associated with the pathophysiology of CC and are expressed in a sex-specific manner. This may potentially spur interests to address finer molecular mechanisms as an approach to personalized therapeutics development based on sex. Independent replications of the study findings are warranted. Functional characterization of the identified molecules may offer insights into their biological significance in cancer cachexia. v Preface This thesis is an original study conducted by Ashok Narasimhan. Human skeletal muscle biopsies were collected after obtaining written informed consent from patients and this was approved by the Conjoint Health Research Ethics Board at the University of Calgary (Ethics ID E-17213). Further, post-biopsy molecular profiling of samples and collection of patient information was conducted under ethics protocol ETH-21709, which was approved by Health Research Ethics Board of Alberta (HREBA)-Cancer Committee. Work from chapter 2 has been published in a peer-reviewed journal. The contributions from all the authors are listed below. Chapter 2-Small RNAome profiling from human skeletal muscle: Novel miRNAs and their targets associated with cancer cachexia

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer often accompanied by cachexia, a condition marked by physical decline, anorexia, and reduced quality of life. Cachexia varies in severity, categorized as precachexia, cachexia, and refractory cachexia, impacting patient survival and wellbeing. To explore cancer cachexia, we developed two experimental models using PDAC fragments from patients P08 and P12. Methods: Female BALB/c nude mice received subcutaneous transplants of PDAC xenografts from these patients. We rigorously assessed animal phenotypes, metabolism, and behavior during tumor progression to validate these cachexia models. Results: Each patient-derived xenograft (PDX) displayed a distinct cachexia pro le. Mice with P12-derived PDAC exhibited mild cachexia, showing reductions in muscle (15%) and brown adipose tissue (25%) mass, and decreased activity (35%), without signi cant weight loss or food intake changes. In contrast, P08-derived PDAC induced severe cachexia with pronounced losses in body weight (29%), muscle (38%), cardiac muscle (27%), and brown adipose tissue (60%), coupled with sustained strength decline (51%). Both models exhibited increased pro-in ammatory cytokine expression in tumor tissues and markers associated with muscle degradation. Conclusions: Our ndings highlight those mice with patient-derived PDAC xenotransplants represent robust models for studying the diverse cachexia pro les observed in patients. These models re ect the heterogeneity of PDAC cachexia and can distinguish between different stages. Importantly, they unveil potential biomarkers like IL-1β, IL-6, P2Y2 receptor, and ASS1, indicative of cachexia severity. The models highlight cachexia's complexity and underscore the importance of personalized approaches in cancer treatment. research regulatory platform of the Brazilian Ministry of Health (CAAE: 36005314.1.0000.5461). Experiments involving animals were performed under protocols approved by the Institutional Animal Care and Use Committee of the Institute of Chemistry of the University of Sao Paulo (CEUA: 132/2019).

Background: Early intervention against cachexia necessitates a predictive model. The aims of this study were to identify predictors of cachexia development and to create and evaluate accuracy of a predictive model based on these predictors. Methods: A secondary analysis of a prospective, observational, multicentre study was conducted. Patients, who attended a palliative care programme, had incurable cancer and did not have cachexia at baseline, were amenable to the analysis. Cachexia was defined as weight loss (WL) > 5% (6 months) or WL > 2% and body mass index< 20 kg/m 2. Clinical and demographic markers were evaluated as possible predictors with Cox analysis. A classification and regression tree analysis was used to create a model based on optimal combinations and cutoffs of significant predictors for cachexia development, and accuracy was evaluated with a calibration plot, Harrell's c-statistic and receiver operating characteristic curve analysis. Results: Six-hundred-twenty-eight patients were included in the analysis. Median age was 65 years (IQR 17), 359(57%) were female and median Karnofsky performance status was 70(IQR 10). Median follow-up was 109 days (IQR 108), and 159 (25%) patients developed cachexia. Initial WL, cancer type, appetite and chronic obstructive pulmonary disease were significant predictors (p ≤ 0.04). A five-level model was created with each level carrying an increasing risk of cachexia development. For Risk-level 1-patients (WL < 3%, breast or hematologic cancer and no or little appetite loss), median time to cachexia development was not reached, while Risk-level 5-patients (WL 3-5%) had a median time to cachexia development of 51 days. Accuracy of cachexia predictions at 3 months was 76%. Conclusion: Important predictors of cachexia have been identified and used to construct a predictive model of cancer cachexia.

Cachexia is one of the most common, related factors of malnutrition in cancer patients. Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at present. Current evidence is based on the intake of nutrients as supplements; however, the long-term and continuous intake of nutrients as food has the potential to be useful for the body. Therefore, in addition to conventional nutritional support, we believe that it is important for the dietitian to work with th...

BackgroundCancer cachexia is a multifactorial syndrome characterized by multiple metabolic dysfunctions. Besides the muscle, other organs such as the liver and the gut microbiota may also contribute to this syndrome. Indeed, the gut microbiota, an important regulator of the host metabolism, is altered in the C26 preclinical model of cancer cachexia. Interventions targeting the gut microbiota have shown benefits, but mechanisms underlying the host–microbiota crosstalk in this context are still poorly understood.MethodsTo explore this crosstalk, we combined proton nuclear magnetic resonance (1H‐NMR) metabolomics in multiple compartments with 16S rDNA sequencing. These analyses were complemented by molecular and biochemical analyses, as well as hepatic transcriptomics.Results1H‐NMR revealed major changes between control (CT) and cachectic (C26) mice in the four analysed compartments (i.e. caecal content, portal vein, liver, and vena cava). More specifically, glucose metabolism pathways...

BackgroundNone of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects. The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models.MethodsIn order to achieve this goal, we included in the study one rat model (Yoshida AH‐130ascites hepatoma) and two mouse models (Lewis lung carcinoma and Colon26 carcinoma). The Animal cachexia score (ACASCO) includes five components: (a) body and muscle weight loss, (b) inflammation and metabolic disturbances, (c) physical performance, (d) anorexia, and (e) quality of life measured using discomfort symptoms and behavioral tests.ResultsUsing the ACASCO values, three cut‐off values were estimated by applying hierarchical cluster analysis. Four groups were originally described, one exactly below the observed mean, a second exactly over the mean, and two othe...

≤ × ≤ 46), and severe cachexia (47 ≤ × ≤ 100). In addition, a simplified version of CASCO, MiniCASCO (MCASCO), was also presented and it contributes as a valid and easy-to-use tool for cachexia staging. Significant statistically correlations were found between CASCO and other validated indexes such as Eastern Cooperative Oncology Group (ECOG) and the subjective diagnosis of cachexia by specialized oncologists. A very significant estimated correlation between CASCO and MCASCO was found that suggests that MCASCO might constitute an easy and valid tool for the staging of the cachectic cancer patients. CASCO and MCASCO provide a new tool for the quantitative staging of cachectic cancer patients with a clear advantage over previous classifications.

Background & aims: Previous studies of our research group have shown that apoptosis is present in skeletal muscle of tumour-bearing animals subject to cachexia. For this reason we decided to investigate the apoptosis in skeletal muscle of cancer patients. Methods and results: In the present study, muscle biopsies from weight-losing patients with upper gastro-intestinal cancer showed a significant increase in muscle DNA fragmentation (three-fold), as compared with control subjects. The increase in DNA laddering was associated with an increase in poly(ADP-ribose) polymerase (PARP) cleavage (four-fold) as measured by western blotting. These two events indicate the presence of muscle apoptosis. These changes were associated with a decrease in MyoD protein content, suggesting important alterations in skeletal muscle physiology. Conclusions: The results presented therefore confirm that apoptosis is also present in human subjects undergoing cancer cachexia.

Objective To explore the correlation between macrophages and interleukin-10 (IL-10 in the peripheral blood of breast cancer (BC) patients and the diagnostic value of joint detection. Methods BC patients (n = 50) and healthy controls (n = 40) were prospectively recruited. The percentage of circulating cluster of differentiation 14 (CD 14) macrophage cells was analyzed by flow cytometry, and an enzyme-linked immunosorbent assay (ELISA) was used to detect IL-10 expression levels. Receiver operating characteristic (ROC) curves were used to verify the diagnostic value of the models based on the expression of CD14 macrophage cell populations and IL-10. In addition, the association between model expression and clinicopathological characteristics was investigated. Another 30 patients with BC and 30 with benign breast disease were selected to validate the IL-10 and CD14 macrophage joint detection model using the same method. Results CD14 macrophage and IL-10 expression levels in BC patients were higher than those in healthy controls (P < 0.05). The ROC curve showed that the area under the curve (AUC) of CD14+ macrophages combined with IL-10 was 0.830, the sensitivity was 72.0%, and the specificity was 87.5%. Its diagnostic efficiency was better than all other single and joint detections. Correlation analysis of clinicopathological features showed that IL-10 and CD14+ macrophage joint detection was significantly correlated with tumor size, tumor-node-metastasis (TNM) stage, and lymph node, estrogen receptor (ER), and Ki-67 expression (P < 0.05). The validation analysis results were consistent with the test results. Conclusion Peripheral blood macrophages can be an independent diagnostic marker for BC. Joint detection of CD14-macrophages and IL-10 suggests poor prognosis, which has unlimited potential to guide BC development and provides a new theory for studying tumor-associated macrophages in BC.

Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and is often treated with surgery and chemotherapy [1]. With the popularization and development of precision radiotherapy in recent years, radiotherapy has become an effective means to treat liver cancer [2]. However, the resistance of HCC cells to radiotherapy reduces the sensitivity and limits the wide application of radiotherapy. Finding biomarkers that are predictive of neoadjuvant therapy and have a prognostic effect on the overall survival is a research hotspot in the field of neoadjuvant therapy. Long noncoding RNAs (lncRNAs) are transcripts of more than 200 nucleotides Objective This study aims to investigate the effects of the long noncoding RNA (lncRNA) DRAIC on the proliferation, apoptosis, and radiosensitivity of hepatocellular carcinoma (HCC) cells and the molecular mechanisms involved. Methods Cancer tissues and their corresponding adjacent tissues from 30 patients with HCC were collected, and the expression levels of DRAIC and miR-223-3p were detected via RT-qPCR. DRAIC interference and miR-223-3p overexpression vectors were transfected into HepG2 cells. In addition, DRAIC and miR-223-3p interference vectors were co-transfected into HepG2 cells. The constructed cells were irradiated at 4 Gy. Cell colony formation assay, MTT assay, and flow cytometry were performed to detect the radiosensitivity, proliferation inhibition rate, and apoptosis rate of HepG2 cells, respectively. Dual luciferase reporter gene assay was performed to detect the targeted regulation of DRAIC on miR-223-3p expression. Results The expression level of DRAIC in HCC tissues was higher than that in paracancer tissues, whereas the expression level of miR-223-3p was lower in HCC tissues than that in paracancer tissues (P < 0.05). Inhibition of DRAIC expression or overexpression of miR-223-3p increased the proliferation inhibition and apoptosis rates of HepG2 cells (P < 0.05). After irradiation, cell survival fraction decreased and cell proliferation inhibition and apoptosis rates increased (P < 0.05). DRAIC targeted the regulation of miR-223-3p expression, and interference of miR-223-3p expression reversed the effects of inhibiting DRAIC expression on the proliferation, apoptosis, and radiosensitivity of HepG2 cells. Conclusion Inhibition of DRAIC expression can inhibit the proliferation of HepG2 cells, promote cell apoptosis, and enhance the radiosensitivity of cells via upregulation of miR-223-3p.

Cancer-related cachexia is highly prevalent in patients with advanced cancer, affecting approximately 50%-80% of patients and seriously interfering with active therapy, quality of life, and survival time. There are currently no effective treatments for cachexia. Therefore, new therapeutic strategies are required. In recent years, advances in understanding the mechanisms underlying cachexia have been made, and new drugs have been developed to combat cachexia muscle wasting and weight loss due to cancer. In this systematic review, we discuss these novel targets and drug treatments.

The cachexia syndrome is considered a chronic inflammatory degenerative deeply related with the increase of pro-inflammatory factors. The effect of pro-inflammatory factors, is counterbalanced by the effect of anti-inflammatory factors. In order to combat the inflammation in chronic disease, our group is currently adopting nutrition strategies in animal model of cancer cachexia. The effects of different nutrients compared to the damage caused by the syndrome of cancer cachexia are addressed in this review.

Cachexia is a prevalent muscle wasting syndrome among people with advanced cancer that profoundly impacts patient quality of life (QoL) and physical function. Exercise can improve QoL, physical function, and overall health in people with cancer and may be an important addition to treatment approaches for cancer cachexia. Greater understanding of patients’ perception of exercise can help elucidate the feasibility of implementing exercise interventions for cancer cachexia and facilitate the design of patient-centered interventions. We aimed to describe the perception of exercise in patients with advanced cancer and cachexia, and capture exercise motivators, barriers, and preferences, to inform the feasibility of exercise interventions. Individual interviews (n = 20) with patients with locally advanced or metastatic cancer with cachexia were conducted and analyzed using reflexive thematic analysis. Main themes from interviews were: 1) Life is disrupted by cancer and cachexia; 2) Exerci...

In the context of the management of the elderly patient with cancer, currently, a key topic may be expressed by sarcopenia. Sarcopenia in its various definitions and ambiguities in the older adult is always related to negative outcomes. A close correlation between sarcopenia and adverse outcomes such as treatment response or toxicity has also been shown in the patient with cancer. For these reasons, it becomes increasingly important to try to understand and therefore differentiate conditions such as the loss of muscle mass linked to normal aging, an independent pathological condition such as sarcopenia and finally a sometimes confusing pathologic condition called cachexia.

Walking at speeds less than the preferred walking speed (PWS) results in a greater oxygen cost of walking than walking at the PWS (Willis et al.). Furthermore, while walking at PWS carbohydrate (CHO) oxidation is minimized whereas fat oxidation is maximized. These data suggest PWS may be selected by an individual to maximize movement economy. Simultaneously describing the oxygen cost and kinematics of walking may help to further explain the relationship between PWS and walking economy. PURPOSE: To examine the oxygen cost and kinematics of walking as a function of walking speed. METHODS: After determining PWS subjects (6 male, 8 female) walked continuously on a treadmill at 3.2, 4.0, 4.8, 5.6, 6.4 and 7.2 km/hr. Walking speed was increased every 10 minutes. Metabolic data and 2-D video data were collected during the last 2 min at each walking speed. Metabolic variables analyzed were VO 2 , VCO 2 , RER and HR. Kinematic variables analyzed were step length (SL) and step rate (SR). Data were analyzed using a one way ANOVA with repeated measures (p<0.05, SPSS). RESULTS: PWS was 4.33 ± 0.56 km/hr. RER, HR, SL, and SR all increased significantly (p<0.05) with each increase in walking speed. VO 2 increased in a curvilinear fashion with increasing walking speed (p<0.05). The O 2 cost of walking was significantly higher at 3.2 km/hr than at walking speeds of 4.0, 4.8 and 5.6 km/hr (p<0.05). The O 2 cost of walking at 7.2 km/hr was significantly greater than at all other walking speeds (p<0.05). Contribution of fat as a fuel was significantly lower at the two greatest walking speeds (p<0.05), decreasing from 90 ± 8% at 3.2 km/hr to 62 ± 13% at 7.2 km/hr. The contribution of CHO as a fuel increased from 10 ± 8% at 3.2 km/hr to 43 ± 22 % at 7.2 km/hr. SL increased from 1.26 ± 0.60 m to 1.99 ± 0.19 m from 3.2 km/hr to7.2 km/hr. SR increased from 1.59 ± 0.03 to 2.26 ± 0.04 steps per second from 3.2 km/hr to 7.2 km/hr. CONCLUSION: The present kinematic measures of walking do not directly explain the greater oxygen cost of walking below PWS. However, further investigation may reveal the greater oxygen cost of walking below PWS may be partially explained the inefficiency of short SL. That is, individuals may not able to take advantage of the elastic properties of lower extremity muscles at slower speeds which require shorter step lengths.

BackgroundMost prognostic scoring systems for colorectal liver metastases (CRLMs) account for factors related to tumour biology. Little is known about the effects of the host phenotype to the tumour. Our objective was to delineate the relationship of systemic inflammation and body composition features [i.e. low skeletal muscle mass (sarcopenia) and low visceral adipose tissue (VAT)], two well‐described host phenotypes in cancer.MethodsClinical data and pre‐operative blood samples were collected from 99 patients who underwent resection of CRLM. Pre‐operative computed tomography scans were available for 97 patients; body composition was analysed at the L3 level, stratified for sex and age. Clinicopathological variables, serum C‐reactive protein (CRP), and various body composition variables were evaluated. Overall survival was evaluated as a function of these same variables in multivariate Cox regression analysis.ResultsSkeletal muscle was significantly correlated with VAT (r = 0.46, P...

BackgroundCachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients.Methods74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components.ResultsHigher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer p...

Liver and gastrointestinal tract S149 exposure on isolated colonocytes dose-dependently inhibited O 2 consumption. Last, we observed that nitric oxide impaired H 2 S detoxification by colonocytes. Conclusion: Our data show that H 2 S increases the expression of pro-inflammatory genes and reversibly affects mitochondrial metabolism while its detoxification is limited. From those results, it appears that increased colonocytes exposure to H 2 S during HPD may be deleterious for gut health.

Aims and background. The optimal treatment of cancer cachexia remains unknown. In this study, we compared the efficacy of three different treatment modalities in the management of cancer cachexia. Methods. Sixty-two assessable cachectic cancer patients were randomized to one of the following three arms: 1) megesterol acetate (MA) plus meloxicam (n = 23); 2) MA plus meloxicam plus oral eicosapentaenoic acid (EPA)-enriched nutritional supplement (n = 21); or 3) meloxicam plus oral EPA-enriched nutritional supplement (n = 18). Treatment duration was 3 months. Results. The treatment arms were well balanced at baseline. The primary efficacy (body weight and lean body mass) and secondary efficacy (body mass index, quality of life, and serum levels of IL-6 and TNF-α) parameters improved after treatment in all three arms. There were no statistically significant differences between treatment groups in the mean percentage changes in all efficacy parameters from baseline to end of study. Conclusions. MA plus meloxicam or EPA supplement plus meloxicam may be effective treatment options in the management of cancer cachexia. The combined use of these agents does not provide further advantages.

Multimodality treatments for patients with squamous cell head and neck cancer often produce significant mucositis and dysphagia, resulting in severe weight loss that requires nutritional support. Continuously progressing malnutrition is associated with shorter time to the development of complications, with shorter overall survival (OS), worse response to oncological treatment, deteriorating quality of life, and poorer performance status; moreover, cachexia strongly affects treatment tolerance. This article provides an overview of the methods of nutritional support for patients undergoing treatments for head and neck cancer: surgery, radiochemotherapy, and palliative care. Nowadays, nutritional therapy is a mandatory part of head and neck cancer management.

Physical activity is, among other things, characterized by an increased quality of life and several physiological positive results such as hypertrophy and counteracting atrophy. Cachexia has been proven to degradate muscle proteins and seems to be a death contributing factor during cancer.Cachectic muscles are resistant to anabolic effects, and this knowledge combined with the many proven positive outcomes on muscle hypertrophy by exercise led this study to investigate the previous studies conducted on this subject further. The Ubiquitin-Proteasome System (UPS) plays a significant role in protein degradation, more specifically the E3 ubiquitin ligases MuRF-1 (Muscle RING Finger protein-1) and MaFbx (Muscle atrophy F-box), which are FoxO (forkhead box-O) transcription factors. The UPS can be inhibited by substrates upregulated by physical activity, such as IGF-1 (Insulin-like Growth Factor-1) and PGC-1α (Peroxisome proliferatoractivated receptor gamma coactivator 1-alpha). In conclusion, there are a lot of pathways in both cancer cachexia and physical activity that border on each other, but the molecular mechanisms are complex and not always clear.

Studies demonstrate that obesity can increase tumor development. Botryosphaeran, a fungal (1!3)(1!6)-b-D-glucan, presents antimutagenic, antiproliferative and pro-apoptotic activities. This study evaluated the effects of botryosphaeran on tumor development and metabolic and hematological parameters in tumor-bearing obese and non-obese rats. Obesity was induced by a high-fat and high-sugar diet, while control rats received standard diet and water without sugar for 10 weeks. On 8th-week, Walker-256 tumor cells were inoculated in the rats, and treatment with botryosphaeran (12 mg/Kg b.w.) started. Groups:control tumor-CT, control tumor botryosphaeran-CTB, obese tumor-OT and obese tumor botryosphaeran-OTB. On 10th-week, tumor development, cachexia, metabolic and hematological parameters were analyzed. Tumor development and cachexia were significantly higher in the OT group compared to the CT group, and botryosphaeran attenuated these parameters. OT rats presented accumulation of adipose tissue, reduced muscle mass, glucose intolerance, insulin resistance, hyperglycemia, anemia, leukocytosis, and thrombocytopenia. Botryosphaeran corrected insulin resistance and hyperglycemia, modulated cholesterol levels, and increased leukocyte and lymphocytes in obese rats, which can be attributable to an inflammatory response against the Walker-256 tumor, contributing to a lower tumor development. Our data demonstrated that botryosphaeran was effective in attenuating tumor growth and in improving the metabolic and hematological profiles of the tumor-bearing rats, demonstrating its potential role in the cancer's management.

Studies demonstrate that obesity can increase tumor development. Botryosphaeran, a fungal (1!3)(1!6)-b-D-glucan, presents antimutagenic, antiproliferative and pro-apoptotic activities. This study evaluated the effects of botryosphaeran on tumor development and metabolic and hematological parameters in tumor-bearing obese and non-obese rats. Obesity was induced by a high-fat and high-sugar diet, while control rats received standard diet and water without sugar for 10 weeks. On 8th-week, Walker-256 tumor cells were inoculated in the rats, and treatment with botryosphaeran (12 mg/Kg b.w.) started. Groups:control tumor-CT, control tumor botryosphaeran-CTB, obese tumor-OT and obese tumor botryosphaeran-OTB. On 10th-week, tumor development, cachexia, metabolic and hematological parameters were analyzed. Tumor development and cachexia were significantly higher in the OT group compared to the CT group, and botryosphaeran attenuated these parameters. OT rats presented accumulation of adipose tissue, reduced muscle mass, glucose intolerance, insulin resistance, hyperglycemia, anemia, leukocytosis, and thrombocytopenia. Botryosphaeran corrected insulin resistance and hyperglycemia, modulated cholesterol levels, and increased leukocyte and lymphocytes in obese rats, which can be attributable to an inflammatory response against the Walker-256 tumor, contributing to a lower tumor development. Our data demonstrated that botryosphaeran was effective in attenuating tumor growth and in improving the metabolic and hematological profiles of the tumor-bearing rats, demonstrating its potential role in the cancer's management.

Background: C-terminal Agrin Fragment (CAF) has been proposed as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction. In patients with ischemic stroke muscle wasting is a common observation. We aimed to evaluate plasma level of total CAF and the sub-fragment AgrinC110 in relation to parameters for physical performance in patients during early rehabilitation after acute stroke. Methods: 101 patients with acute ischemic or haemorrhagic stroke (age 70±11 y, BMI 26.7±5.7 kg/m 2 , all mean ± SD) admitted to hospitalized rehabilitation centre and 15 healthy controls of similar age and BMI (64±8 y, 25.0±3.5) were studied. Base line (BL) physical examinations performed at admission (23±18 days after acute stroke) followed by follow up (FU) examinations (27±5 days, 50±18 days after acute stroke) included functional assessment (3 m walk test) and maximum hand grip testing and body composition analysis by bioelectrical impedance analysis (BIA). CAF concentrations were measured by Western blotting. Results: In patients serum levels of total CAF and AgrinC110 were elevated at admission and at discharge (total CAF 545.3± 175.2 and 541.8±159.9 pM; AgrinC110 405.5±133.0 and 417.4±127.5 pM, respectively) compared to healthy controls (total CAF 425.5 ± 77.0 pM, p<0.01, Agrin110 316.4 ± 59.6 pM, p<0.05). AgrinC110 and total CAF levels were associated with hand grip strength of the non-paretic arm (r=−0.207, p=0.0381 and r=−0.227, p=0.0227, respectively). Lower AgrinC110 and total CAF levels were associated with faster time in 3 m walk test (r=0.448, p=0.0147 and r= 0.445, p=0.0155, respectively) in patients who were able to complete the test (n=29). Total CAF and AgrinC110 serum levels were associated with BIA parameters of cellular integrity (reactance: r=0.345, p=0.0005 and r=0.332, p=0.0008, respectively and phase angle: r=0.392 and r=0.375, p≤ 0.0001 both, respectively). Conclusion: CAF serum levels were elevated at admission and remained high throughout the hospitalized rehabilitation period. CAF related to body composition and functional capacity during post-stroke rehabilitations. CAF serum levels may provide additional information to monitor muscle status and functional recovery in the early phase of post stroke rehabilitation.

Cancer is a global major public health problem, particularly in Western countries, where it represents the second leading cause of death after cardiovascular disease. Malnutrition is common in cancer patients and differs from starvation-related malnutrition, as it results from a combination of anorexia and metabolic dysregulation, caused by the tumor itself or by its treatment, and causing cachexia. Cancer-associated malnutrition can lead to several negative consequences, including poor prognosis, reduced survival, increased therapy toxicity, reduced tolerance and compliance to treatments, and diminished response to antineoplastic drugs. Guidelines issued by the Ministry of Health in 2017, the most recent ESPEN guidelines and the PreMiO study highlighted an inadequate nutritional support in cancer patients since their first visit, and recommended an optimization of the quality of life of cancer patients in each stage of the disease, also through specific nutritional interventions by...

BackgroundThe prevalence of nutritional derangements in patients with cancer is high. This survey assessed patients&#39; awareness of cancer‐related nutritional issues and evaluated how important they perceive the impact of nutrition on cancer and treatment to be.MethodsA structured questionnaire was developed to determine: presence of feeding problems, perception of nutrition importance, and perception of physicians&#39; approach to nutrition. The European Cancer Patient Coalition disseminated the questionnaire to its members in 10 countries. The Mediterranean cluster (Italy, Spain, and Greece) was analysed separately to further determine specific patterns in answers.ResultsIn total, 907 respondents completed the questionnaire (68.8% female participants; 51.7% with cancer; 48.3% cancer survivors; 59.3% diagnosed with cancer ≤3 years ago; 46.2% receiving treatment for &lt;1 year). Feeding problems during illness/therapy were experienced by 72.5% (628/867) of all respondents (Italian...

BackgroundCachexia has significant impact on the patients&#39; quality of life and prognosis. It is frequently observed in patients with cancer, especially in advanced stages, but prevalence data for the overall population are lacking. Good quality estimates of cancer cachexia in general and for each of the major cancer types would be highly relevant for potential treatment development efforts in this field. Both the USA and European Union (EU) have implemented special clinical development rules for such rare disorders what are called ‘orphan diseases’. The cut‐off level for a disease to be considered an orphan disease in the USA is 200 000 people (0.06% of the population) and EU is 5 per 10 000 people (0.05% of the population).MethodsFor this systematic review, we searched at PubMed (from inception to 31 January 2018) to identify clinical studies that assessed the prevalence of cachexia in cancer patients at risk. Studies reporting the prevalence of either cancer cachexia or wastin...

Background: Cachexia has a high prevalence in cancer patients and negatively impacts prognosis, quality of life (QOL), and tolerance/response to treatments. This study reports the results of three surveys designed to gain insights into cancer cachexia (CC) awareness, understanding, and treatment practices among health care professionals (HCPs). Methods: Surveys were conducted globally among HCPs involved in CC management. Topics evaluated included definitions and synonyms of CC, diagnosis and treatment practices, and goals and desired improvements of CC treatment. Results: In total, 742 HCPs from 14 different countries participated in the surveys. The majority (97%) of participants were medical oncologists or hematologists. CC was most frequently defined as weight loss (86%) and loss of appetite (46%). The terms loss of weight and decreased appetite (51% and 34%, respectively) were often provided as synonyms of CC. Almost half (46%) of the participants reported diagnosing CC and beginning treatment if a patient experienced a weight loss of 10%. However, 48% of the participants would wait until weight loss was !15% to diagnose CC and start treatment. HCPs also reported that 61%-77% of cancer patients do not receive any prescription medication for CC before Stage IV of disease is reached. Ability to promote weight gain was rated as the most important factor for selecting CC treatment. Key goals of treatment included ensuring that patients can cope with the cancer and treatment and have a QOL benefit. HCPs expressed desire for treatments with a more CC-specific mode of action and therapies that enhance QOL. Conclusions: These surveys underscore the need for increased awareness among HCPs of CC and its management.

On December 13th and 14th a group of scientists and clinicians met in Washington, DC, for the cachexia consensus conference. At the present time, there is no widely agreed upon operational definition of cachexia. The lack of a definition accepted by clinician and researchers has limited identification and treatment of cachectic patient as well as the development and approval of potential therapeutic agents. The definition that emerged is: ''cachexia, is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. While this definition has not been tested in epidemiological or intervention studies, a consensus operational definition provides an opportunity for increased research.