Cachexia In Cancer Patients Research Articles

Report of Objective Clinical Responses of Cancer Patients to Pharmaceutical-grade Synthetic Cannabidiol

Cannabinoids are widely used in the management of pain, nausea and cachexia in cancer patients. However, there has been no objective clinical evidence of any anticancer activity yet. The aim of this study was to assess the effects of pharmaceutical-grade synthetic cannabidiol on a range of cancer patients. We analysed the data routinely collected, as part of our treatment program, in 119 cancer patients over a four-year period. Clinical responses were seen in 92% of the 119 cases with solid tumours including a reduction in circulating tumour cells in many cases and in other cases, a reduction in tumour size, as shown by repeat scans. No side-effects of any kind were observed when using pharmaceutical grade synthetic cannabidiol. Pharmaceutical-grade synthetic cannabidiol is a candidate for treating breast cancer and glioma patients.

Twist1 Activation in Muscle Progenitor Cells Causes Muscle Loss Akin to Cancer Cachexia

Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a marked increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Finally, both genetic and pharmacological inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.

Abstract A40: Twist1 activation in muscle progenitor cells during development or adulthood causes severe muscle loss reminiscent of human cancer cachexia

Abstract Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a massive increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Both genetic and pharmacologic inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients. Citation Format: Parash Parajuli, Santosh Kumar, Audrey Loumaye, Purba Singh, Sailaja Eragamreddy, Thien Ly Nguyen, Seval Ozkan, Mohammed S. Razzaqe, Céline Prunier, Jean-Paul Thissen, Azeddine Atfi. Twist1 activation in muscle progenitor cells during development or adulthood causes severe muscle loss reminiscent of human cancer cachexia [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A40.

A novel herbal formula, SGE, induces endoplasmic reticulum stress-mediated cancer cell death and alleviates cachexia symptoms induced by colon-26 adenocarcinoma.

Cachexia in cancer patients, characterized by marked involuntary weight loss and impaired physical function, is associated with a poor prognosis in response to conventional treatment and with an increase in cancer-related mortality. Prevention of skeletal muscle loss under cancer-induced cachexia via inhibition of pro-cachectic factors, as well as a reduction in tumor mass, has been considered reasonable pharmacological and nutritional interventions to treat cancer patients. In this study, we constructed a novel herbal formula, SGE, which contains Ginseng Radix alba, Atractylodis Rhizoma alba, and Hoelen, examined its anti-cancer and anti-cachexia efficacies. In in vitro experiments, SGE induced death of CT-26 murine colon carcinoma cells via endoplasmic reticulum stress, and suppressed the production of inflammatory cytokines in Raw 264.7 murine macrophage-like cells. In addition, SGE treatment attenuated CT-26-induced C2C12 skeletal muscle cell atrophy as well as CT-26-induced reduction in lipid accumulation in 3T3-L1 adipocyte. In CT-26 tumor-bearing mice, daily oral administration of 10 and 50 mg/kg SGE remarkably attenuated the cachexia-related symptoms, including body weight and muscle loss, compared with saline treatment, while food intake was not affected. These data collectively suggest that SGE is beneficial as an anti-cancer adjuvant to treat cancer patients with severe weight loss.

Abstract A017: Optimization of a cachexia animal model for efficacy evaluation of candidates

Abstract Cachexia-anorexia syndrome, which is called cancer cachexia, is a common and important indicator of cancer and occurs in 30% to 80% of cancer patients. Cancer cachexia is characterized by a severe progressive body wasting, accompanied by loss of adipose tissue and skeletal muscle mass. The presence of cachexia is associated with a worsened prognosis and contributes to up to 20% of cancer deaths. In most cases, cancer cachexia patients clinically show anorexia caused through a complex system of hormones and neuropeptides. To investigate efficacy in development of new medicine, an optimized animal model is essentially required. Although several cancer cachexia animal models have been established, we focused on developing a better animal model particularly for efficacy evaluation with advanced bioimaging evaluation methods. First of all, we confirmed that an appropriate mouse strain is CDF1 in comparison with DBA1 and Balb/c after xenografting of Colon26. As the second step, we checked cell numbers with pattern of tumor growth. In human clinics, cure of cancer cachexia is usually performed with surgical removal of tumor. To make the animal model similar to clinical circumstances, we tested recovery time and pattern after removal of tumor. With optimized mouse model we tested efficacy of anticancer drug Megace 200 mg/kg as a positive control. In addition, we applied advanced bioimaging equipment such as MRI and CT to visualize actual tumor and fat with body composition. We expect that optimized animal model of cancer cachexia will prepare the way for more accurate efficacy test in preclinical state to go to a clinical trial. Citation Format: Jiyeong Bae, Ig Jun Cho, Jung Hyu Shin, Hyung Soo Yuh, Hyung Ho Moon, Hye Lim Lee, Yeong Nang Jo, Yeon Ju Park, Woo Sung Choi, Byung Hwa Hyun. Optimization of a cachexia animal model for efficacy evaluation of candidates [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A017.

Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia.

BackgroundCachexia is a multifactorial metabolic syndrome with high morbidity and mortality in patients with advanced cancer. The diagnosis of cancer cachexia depends on objective measures of clinical symptoms and a history of weight loss, which lag behind disease progression and have limited utility for the early diagnosis of cancer cachexia. In this study, we performed a nuclear magnetic resonance‐based metabolomics analysis to reveal the metabolic profile of cancer cachexia and establish a diagnostic model.MethodsEighty‐four cancer cachexia patients, 33 pre‐cachectic patients, 105 weight‐stable cancer patients, and 74 healthy controls were included in the training and validation sets. Comparative analysis was used to elucidate the distinct metabolites of cancer cachexia, while metabolic pathway analysis was employed to elucidate reprogramming pathways. Random forest, logistic regression, and receiver operating characteristic analyses were used to select and validate the biomarker metabolites and establish a diagnostic model.ResultsForty‐six cancer cachexia patients, 22 pre‐cachectic patients, 68 weight‐stable cancer patients, and 48 healthy controls were included in the training set, and 38 cancer cachexia patients, 11 pre‐cachectic patients, 37 weight‐stable cancer patients, and 26 healthy controls were included in the validation set. All four groups were age‐matched and sex‐matched in the training set. Metabolomics analysis showed a clear separation of the four groups. Overall, 45 metabolites and 18 metabolic pathways were associated with cancer cachexia. Using random forest analysis, 15 of these metabolites were identified as highly discriminating between disease states. Logistic regression and receiver operating characteristic analyses were used to create a distinct diagnostic model with an area under the curve of 0.991 based on three metabolites. The diagnostic equation was Logit(P) = −400.53 – 481.88 × log(Carnosine) −239.02 × log(Leucine) + 383.92 × log(Phenyl acetate), and the result showed 94.64% accuracy in the validation set.ConclusionsThis metabolomics study revealed a distinct metabolic profile of cancer cachexia and established and validated a diagnostic model. This research provided a feasible diagnostic tool for identifying at‐risk populations through the detection of serum metabolites.

Lipases and lipid droplet-associated protein expression in subcutaneous white adipose tissue of cachectic patients with cancer

BackgroundCancer cachexia is a multifactorial metabolic syndrome characterized by marked loss of adipose tissue and skeletal muscle. Fat loss from adipose tissue in cancer cachexia is partly the result of increased lipolysis. Despite the growing amount of studies focused on elucidating the mechanisms through which lipolysis-related proteins regulate the lipolytic process, there are scarce data concerning that profile in the adipose tissue of cancer cachectic patients. Considering its fundamental importance, it was our main purpose to characterize the expression of the lipolysis-related proteins in the white adipose tissue of cachectic cancer patients.MethodsPatients from the University Hospital were divided into three groups: control, cancer cachexia (CC), and weight-stable cancer patients (WSC). To gain greater insight into adipose tissue wasting during cancer cachexia progression, we have also analyzed an experimental model of cachexia (Walker 256 carcinosarcoma). Animals were divided into: control, intermediate cachexia (IC) and terminal cachexia (TC). Subcutaneous white adipose tissue of patients and epidydimal white adipose tissue of animals were investigated regarding molecular aspects by determining the protein content and gene expression of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), perilipin 1, leptin, adiponectin, visfatin, and tumour necrosis factor alpha (TNF-alpha).ResultsWe found augmented lipolysis in CC associated with increased HSL expression, as well as upregulation of ATGL expression and reduction in perilipin 1 content. In IC, there was an imbalance in the secretion of pro- and anti-inflammatory factors. The alterations at the end-stage of cachexia were even more profound, and there was a reduction in the expression of almost all proteins analyzed in the animals.ConclusionsOur findings show that cachexia induces important morphological, molecular, and humoral alterations in the white adipose tissue, which are specific to the stage of the syndrome.

Abstract 447: ZAG promotes cachexia-associated white adipose tissue browning and energy wastage

Abstract Cancer cachexia is a complex condition of tissue wasting that affects up to 80% of cancer patients. To date, there is no effective treatment for cachexia due to the complex nature of this condition. Energy wasting in cachexia is caused by excessive lipid and protein turnover in the body, browning of white adipose tissue (WAT), and futile metabolic cycling such as glucose recycling between the liver and tumor. Therefore, identifying and inhibiting factors that promote WAT browning, and glucose and lipid recycling can reduce energy wasting and ameliorate cachexia in cancer patients. Zinc-α2-glycoprotein (ZAG), a lipid mobilizing factor secreted by multiple cancers, has been shown to promote lipolysis and inhibit lipogenesis in WAT. However, whether ZAG plays any role beyond lipolysis and participates in other energy wasting mechanisms of cachexia such as glucose and lipid recycling, and WAT browning has not been explored. Our initial studies indicate that while ZAG is highly expressed in the heart, kidney, and liver of wild-type mice, the basal expression of ZAG is very low in WAT at both the mRNA and protein levels. To investigate the metabolic functions of ZAG in vivo, ZAG-expressing 293 cells were implanted subcutaneously in athymic nude mice, and analyzed them after 3 and 6 weeks. We detected a 3-fold increase in the circulating plasma levels of ZAG. Importantly, the increase in ZAG levels was associated with a decrease in body weight gain without any differences in food consumption and physical activity. Morphological examination of eFAT pads of ZAG-cell implanted mice showed smaller size compared to controls. In addition, histological examination of eFAT showed cell shrinkage and almost complete depletion of fat stores, suggesting enhanced lipolysis in the WAT. Notably, ZAG induced the expression of beige, mitochondrial, and thermogenesis genes at mRNA level in the eFAT. Moreover, the expression of brown adipocyte-specific thermogenic genes such as Ebf2, Prdm16, PGC1α, UCP1, SRC1 and IRF4 were strongly induced at the protein level in eWAT of ZAG-cell implanted mice suggesting that ZAG causes WAT browning. Furthermore, metabolic analysis revealed increased O2 consumption and heat production in ZAG-cell implanted mice compared to controls indicating increased total body energy expenditure. ZAG-cell implanted mice also displayed reduced respiratory exchange ratio indicating increased consumption of lipids. Overall, our findings suggest that ZAG functions beyond lipolysis and causes significant energy wasting by causing WAT browning and promoting glucose and lipid catabolism in the beige cells. These findings suggest that ZAG plays a predominant role in the development of cachexia, and thus, may represent a novel therapeutic target to block energy wasting and delay or prevent cachexia in cancer patients. Citation Format: Sawsan Elattar, Satyanarayana Ande. ZAG promotes cachexia-associated white adipose tissue browning and energy wastage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 447. doi:10.1158/1538-7445.AM2017-447

Cachexia in Cancer Patients

Cachexia in Cancer Patients

Elevated MCP-1 is associated with cancer cachexia in patients with pancreatic ductal adenocarcinoma

Elevated MCP-1 is associated with cancer cachexia in patients with pancreatic ductal adenocarcinoma

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study.

BackgroundCancer cachexia (cancer‐induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age‐related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early.MethodsWe used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH‐MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy.ResultsWe quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age‐related muscle loss (aka age‐related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration.ConclusionsThe work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature.

Differences in Symptom Burden Among Cancer Patients With Different Stages of Cachexia

ContextCancer patients with cachexia may suffer from significant burden of symptoms and it can severely impair patients' quality of life. However, only few studies have targeted the symptom burden in cancer cachexia patients, and whether the symptom burden differed in different cachexia stages is still unclear. ObjectivesThe aims of this study were to evaluate the symptom burden in cancer cachexia patients and to compare the severity and occurrence rates of symptoms among cancer patients with non-cachexia, pre-cachexia, cachexia, and refractory cachexia. MethodsAdvanced cancer patients (n = 306) were included in this cross-sectional study. Patients were divided into four groups, based on the cachexia stages of the international consensus. The M.D. Anderson Symptom Inventory added with eight more cachexia-specific symptoms were evaluated in our patients. Differences in symptom severity and occurrence rates among the four groups were compared using one-way ANOVA or Kruskal-Wallis test analyses. ResultsLack of appetite, disturbed sleep, fatigue, lack of energy, and distress were the symptoms with highest occurrence rates and severity scores in all four groups and were exacerbated by the severity of cachexia stages. After confounders were adjusted for, significant differences were seen in symptoms of pain, fatigue, disturbed sleep, remembering problems, lack of appetite, dry mouth, vomiting, numbness, feeling dizzy, early satiety, lack of energy, tastes/smell changes, and diarrhea. ConclusionThis study identified higher symptom burden in cancer patients with cachexia and it increased with the stages of cachexia, which emphasized the importance of screening in multiple co-occurring symptoms for cachexia patients.

Effects of Serum Leptin and Resistin Levels on Cancer Cachexia in Patients With Advanced-Stage Non–Small Cell Lung Cancer

Introduction:Cancer cachexia is one of the most frequent effects of malignancy, is often associated with poor prognosis, and may account for up to 20% of cancer deaths. The aim of our study was to evaluate the relationship of cancer cachexia and serum levels of resistin and leptin in patients with advanced non–small cell lung cancer.Methods:A total of 67 chemotherapy-naïve patients with advanced-stage non–small cell cancer and a control group containing 20 healthy individuals without a known chronic disease were enrolled in this study. All individuals in the control group were age and sex matched. Demographic, anthropometric, laboratory data and serum levels of adipokines were measured for 2 groups. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Survival among various factors was calculated using the log-rank test.Results:Patients presented significantly higher serum resistin (P = .0001) and lower serum leptin levels (P = .025) than the control group. Lower serum levels of leptin were correlated with overall survival (P = .011).Conclusions:Serum leptin and resistin levels play key role as proinflammatory cytokines in lung cancer and cancer cachexia; however, their use as diagnostic or prognostic markers is not possible yet, and further large-scale studies are required to confirm our findings.

P1.06-010 Analysis of the Incidence of Cancer Cachexia in Patients with Advanced Lung Cancer at Referral to a Dietitian

Lung cancer is the second most common cancer diagnosed in men and women in the UK with a very poor 5 year survival (10%). There is a lack of robust data on the stage of cachexia in which patients with lung cancer present. The severity of cachexia can influence overall outcomes and a patient’s quality of life. Refractory (irreversible) cachexia indicates a poor prognosis. We reviewed all patients diagnosed with metastatic primary lung cancer that were referred to the Macmillan Oncology Dietitians over a 4 year period at the Royal Surrey County Hospital. Reasons for referral commonly included: weight loss, glycemic control in diabetes, decreased oral intake and food texture modification. We compared self-reported usual body weight (UBW) to weight at referral. Patients were defined as cachectic if weight loss was >5% and refractory cachexia if survival was <90 days from dietitian review. 310 patients with incurable lung cancer were reviewed by the dietitian. Mean age was 68.8 (range 36-89). 42% were female, 58% were male. Mean weight loss was 10%. 76% of patients had lost >5% of usual body weight. Mean pre-cancer body mass index (BMI) was 26.9 (kg/m2), mean BMI at referral was 23.0 (kg/m2). Median survival of non-cachectic and cachectic cohorts were different (299 vs 188 days respectively, p=0.0078). 24% (73 patients) had refractory cachexia. Our study shows cachexia is very common (76%) in lung cancer and affects survival. A quarter of patients had refractory cachexia. BMI is an insensitive measure of weight loss. Early symptom control improves survival in lung cancer and this data suggests patients are routinely being referred too late to a dietitian. Cachexia in lung cancer is a significant clinical problem. Could upfront assessment of cachexia improve outcome in patients with advanced lung cancer? We propose to investigate this further.

Body composition indices and tissue loss in patients with resectable gastric adenocarcinoma

AbstractBackgroundBody composition analyses from computed tomography (CT) scans have been used to assess cachexia in cancer patients. We investigated body composition indices, tissue change and treatment outcome in patients with resectable gastric adenocarcinoma.MethodsA cohort analysis of all patients treated with curative intent for gastric adenocarcinoma in two Scandinavian university hospitals from 2008–2011 was performed (n=137). Body composition analyses were performed on CT images taken for routine diagnostics and staging. Both preoperative single scans and repeat CT examinations were analyzed.ResultsPerioperative chemotherapy was given to 58 (42.3%) patients. Forty patients (29.2%) suffered severe postoperative complications and 70 (51.1%) patients died within three years. There was a significant reduction in patients' lean tissue during neoadjuvant chemotherapy (p=0.001). There was no association between skeletal muscle tissue index and postoperative complications. Poorer survival was observed in patients with preoperative skeletal muscle tissue index within the lowermost quartile, independent of tumor characteristics and neoadjuvant treatment (HR=1.91, 95% CI 1.11–3.28, p=0.019).ConclusionsPatients lost lean tissue during neoadjuvant treatment for gastric adenocarcinoma. Low preoperative skeletal muscle index was not associated with postoperative complications, but strongly associated with poorer survival.

Worse Preoperative Status Based on Inflammation and Host Immunity Is a Risk Factor for Surgical Site Infections in Colorectal Cancer Surgery.

The modified Glasgow Prognostic Score (mGPS) is an inflammation-based measure of malnutrition that reflects a state of cachexia in cancer patients. We evaluated mGPS as an index to predict surgical site infection (SSI) incidence in patients undergoing colorectal cancer surgery. We retrospectively analyzed 351 patients who underwent colon cancer resection. Factors correlated with the incidence of SSIs were identified by logistic analysis and stepwise selection. SSIs were observed in 32 patients, with an incidence of 9.1%. Univariate logistic analysis revealed mGPS (Score 2), laparotomy, resection of other organs, colostomy, excessive blood loss (>423 mL), long duration of surgery (>279 minutes), pulmonary dysfunction, prognostic nutritional index (PNI) ≤40, neutrophil lymphocyte ratio (NLR)(>4), and controlling nutritional status (CONUT) ≥2 to be associated with an increased incidence of SSIs. Multivariate analysis with variables selected by the stepwise procedure also revealed mGPS (Score 2) (Odds ratio (OR) =3.55, 95% Confidence interval (CI) 1.30-9.56; p=0.01), colostomy (OR=6.56, 95%CI 1.60-31.38; p=0.01), excessive blood loss (OR=3.20, 95%CI 1.23-8.42; p=0.02), and NLR (>4)(OR=3.24, 95%CI 1.31-8.17; p=0.01) to be independent risk factors. mGPS is an independent risk factor for SSIs. Our results suggest that cachexia before surgery in patients with colorectal cancer might predict the incidence of SSIs.

Metabolic Changes During Cancer Cachexia Pathogenesis.

Wasting of adipose tissue and skeletal muscle is a hallmark of metastatic cancer and a major cause of death. Like patients with cachexia caused by other chronic infections or inflammatory diseases, the cancer subject manifests both malnutrition and metabolic stress. Both carbohydrate utilization and amino acid incorporation are decreased in the muscles of cancer cachexia patients. Cancer cells affect host metabolism in two ways: (a) their own metabolism of nutrients into other metabolites and (b) circulating factors they secrete or induce the host to secrete. Accelerated glycolysis and lactate production, i.e., the Warburg effect and the resultant increase in Cori cycle activity, are the most widely discussed metabolic effects. Meanwhile, although a large number of pro-cachexia circulating factors have been found, such as TNFa, IL-6, myostatin, and PTHrp, none have been shown to be a dominant factor that can be targeted singly to treat cancer cachexia in humans. It is possible that given the complex multifactorial nature of the cachexia secretome, and the personalized differences between cancer patients, targeting any single circulating factor would always be insufficient to treat cachexia for all patients. Here we review the metabolic changes that occur in response to tumor growth and tumor-secreted factors during cachexia.

IS THE GLASGOW PROGNOSTIC SCORE A USEFUL TOOL FOR DIAGNOSIS OF CANCER CACHEXIA?

Background: Cancer cachexia is characterized as a multi-factorial syndrome, identified by the continuing decline of skeletal muscle mass where nutritional support does not completely reverse the effects. Finding a cure for cachexia will impact cancer patients’ worldwide, improving quality of life and potentially increasing survival in response to standard care. In turn, an accurate diagnostic tool would assist in the identification and translation of therapeutic targets to the clinic. The Glasgow Prognostic Score (GPS), is determined from combining circulating albumin and C-reactive protein (CRP) concentrations to form a score of 0 (normal) and 1 or 2 (abnormal) (albumin 10mg/L=1). The GPS has been used as an indicator in various cancer types, due to the presence of systemic inflammation, but not in cancer cachexia. The GPS has been validated in a wide range of clinical situation for a systemic inflammatory response so it may be beneficial in assessing the prognosis of cancer cachexia patients. Method/Design:A retrospective cohort study was conducted to assess the GPS as a valuable tool for diagnosing cancer cachexia. The relationship between BMI and the GPS was examined, along with other parameters for controls and cases. Clinical audit data was collected for 357 participants, 185 cases and 172 controls. Results: The GPS was abnormal (2; with albumin 10mg/L) in 123 (66.5%) cases and in 13 (7.6) controls. The GPS scored was also abnormal (1; with albumin 10 mg/L) in 53 (28.6%) cases and 89 (51.7%) controls. It was normal (0) in 9 (4.9%) cases and in 70 (40.7%) controls. There was a significant correlation between the GPS and a decrease in BMI as P value was 0.019. Conclusion: The GPS could be a useful indicator for the onset of cancer cachexia as advanced cancer is usually associated with a marked systemic inflammatory response which is manifested by an increase in CRP which led to a decrease in albumin. It would be beneficial to investigate if the GPS could be used for early diagnosis of cancer cachexia so it must be included in the basic assessment for all patients with cancer.

Altered mitochondrial quality control signaling in muscle of old gastric cancer patients with cachexia

Mitochondrial dysfunction is involved in the loss of muscle featuring both aging and cancer cachexia (CC). Whether mitochondrial quality control (MQC) is altered in skeletal myocytes of old patients with CC is unclear. The present investigation therefore sought to preliminarily characterize MQC pathways in muscle of old gastric cancer patients with cachexia. The study followed a case-control cross-sectional design. Intraoperative biopsies of the rectus abdominis muscle were obtained from 18 patients with gastric adenocarcinoma (nine with CC and nine non-cachectic) and nine controls, and assayed for the expression of a set of MQC mediators. The mitofusin 2 expression was reduced in cancer patients compared with controls, independent of CC. Fission protein 1 was instead up-regulated in CC patients relative to the other groups. The mitophagy regulators PTEN-induced putative kinase 1 and Parkin were both down-regulated in cancer patients compared with controls. The ratio between the protein content of the lipidated and non-lipidated forms of microtubule-associated protein 1 light chain 3B was lower in CC patients relative to controls and non-cachectic cancer patients. Finally, the expression of autophagy-associated protein 7, lysosome-associated membrane protein 2, peroxisome proliferator-activated receptor-γ coactivator-1α, and mitochondrial transcription factor A was unvarying among groups. Collectively, our findings indicate that, in old patients with gastric cancer, cachexia is associated with derangements of the muscular MQC axis at several checkpoints: mitochondrial dynamics, mitochondrial tagging for disposal, and mitophagy signaling. Further investigations are needed to corroborate these preliminary findings and determine whether MQC pathways may become target for future interventions.

Use of routinely available clinical, nutritional, and functional criteria to classify cachexia in advanced cancer patients

Cachexia is a highly prevalent syndrome in cancer and chronic diseases. However, due to the heterogeneous features of cancer cachexia, its identification and classification challenge clinical practitioners. To determine the clinical relevance of a cancer cachexia classification system in advanced cancer patients. Beginning with the four-stage classification system proposed for cachexia [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca) and refractory cachexia (RCa)], we assigned patients to these cachexia stages according to five classification criteria available in clinical practice: 1) biochemistry (high C-reactive protein or leukocytes, or hypoalbuminemia, or anemia), 2) food intake (normal/decreased), weight loss: 3) moderate (≤5%) or 4) significant (>5%/past six months) and 5) performance status (Eastern Cooperative Oncology Group Performance Status≥3). We then determined if symptom severity, body composition changes, functional levels, hospitalizations and survival rates varied significantly across cachexia stages. Two-hundred and ninety-seven advanced cancer patients with primary gastrointestinal and lung tumors were included. Patients were classified into Ca (36%), PCa and RCa (21%, respectively) and NCa (15%). Significant (p<0.05) differences were observed among cachexia stages for most of the outcome measures (symptoms, body composition, handgrip strength, emergency room visits and length of hospital stays) according to cachexia severity. Survival also differed between cachexia stages (except between PCa and Ca). Five clinical criteria can be used to stage cancer cachexia patients and predict important clinical, nutritional and functional outcomes. The lack of statistical difference between PCa and Ca in almost all clinical outcomes examined suggests either that the PCa group includes patients already affected by early cachexia or that more precise criteria are needed to differentiate PCa from Ca patients. More studies are required to validate these findings.