Transcriptional landscape of skeletal muscle in cancer patients.

The purpose of these guidelines is to provide dietitians in Australia with a user-friendly summary of the evidence to support the nutritional management of adult patients with cancer cachexia. This best available evidence is presented and used as a basis for providing recommendations about clinical practice. The clinical questions were as follows: How should patients be identified for referral to the dietitian in order to maximise nutritional intervention opportunities? How should nutritional status be assessed? What are the goals of nutrition intervention for patients with cancer cachexia? What is the nutrition prescription to achieve these goals? Should eicosapentaenoic acid be included in the prescription? What are effective methods of implementation to ensure positive outcomes? Does nutrition intervention improve outcomes in patients with cancer cachexia? This document is a general guide to appropriate practice to be followed only subject to the dietitian's judgement in each individual case. The guidelines are designed to provide information to assist decision-making and are based on the best information available at the date of compilation. The guidelines recommend intensive nutrition therapy. This has potential resource implications that may include additional staff, change to staff roles and increased use of high/protein energy supplements if they are considered. Therefore, in applying the guidelines these potential organisational and cost barriers need to be considered. These guidelines for practice are provided with the express understanding that they do not establish or specify particular standards of care, whether legal, medical or other.

Expression of NF-κB and IκB proteins in skeletal muscle of gastric cancer patients

Cancer cachexia is associated with marked alterations in skeletal muscle protein metabolism that lead to muscle wasting and, in some cases, death. The inflammatory response elicited by cancer is a likely, if not primary, mediator of these alterations. This review focuses on the possible relationship between inflammatory signaling and altered amino acid metabolism in cancer. Loss of skeletal muscle in cancer patients can potentially be due to anorexia and early satiety, reduced muscle protein synthesis, and/or increased muscle protein breakdown. Inflammation has been associated with each of these mechanisms. Effects on appetite appear to be mediated by the melanocortin system in the hypothalamus. Studies in animal models of cachexia suggest that modulation of orexigenic and anorexigenic pathways in this system may improve nutrient consumption. Inflammatory cytokines such as IL-6 and TNF-alpha are likely to contribute to the effects of inflammation on muscle protein metabolism through several pathways. Limited studies in humans suggest that targeted anti-inflammatory and nutritional interventions may ameliorate the net catabolic effect on skeletal muscle protein metabolism. Future studies of the precise mechanism of muscle protein loss, as well as novel or combination therapies to inhibit inflammation and promote anabolism, are warranted.

Cancer anorexia and cachexia

Biomarkers and mechanisms associated with cancer-induced cardiac cachexia: A systematic review.

Participation in cancer cachexia clinical trials requires a defined weight loss (WL) over time. A loss in skeletal muscle mass, measured by cross-sectional computed tomography (CT) image analysis, represents a possible alternative. Our aim was to compare WL versus muscle loss in patients who were screened to participate in a cancer cachexia clinical trial. This was a single-center, retrospective analysis in metastatic colorectal cancer patients screened for an interventional cancer cachexia trial requiring a ≥5% WL over the preceding 6months. Concurrent CT images obtained as part of standard oncology care were analyzed for changes in total muscle and fat (visceral, subcutaneous, and total). Of patients screened (n=36), 3 (8%) enrolled in the trial, 17 (47%) were excluded due to insufficient WL (<5%), 3 (8%) were excluded due to excessive WL (>20%), and 16 (44%) met inclusion criteria for WL. Patients who met screening criteria for WL (5-20%) had a mean±SD of 7.7±8.7% muscle loss, 24.4±37.5% visceral adipose loss, 21.6±22.3% subcutaneous adipose loss, and 22.1±24.7% total adipose loss. Patients excluded due to insufficient WL had 2±6.4% muscle loss, but a gain of 8.5±39.8% visceral adipose, and 4.2±28.2% subcutaneous adipose loss and 0.8±28.4% total adipose loss. Of the patients excluded due to WL <5% (n=17), 7 (41%) had a skeletal muscle loss >5%. Defining cancer cachexia by WL over time may be limited as it does not capture skeletal muscle loss. Cross-sectional CT body composition analysis may improve early detection of muscle loss and patient participation in future cancer cachexia clinical trials.

Cytokines: the mother of catabolic mediators!

Is Weight Loss a Loss of Chance in Patients Receiving Chemoradiotherapy?

ESPEN Guidelines on Enteral Nutrition: Non-surgical oncology

Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia.Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia.Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss.Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.

Introduction: Cancer cachexia (CC) is a major contributor to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). It is characterized by loss of skeletal muscle (SM) tissue with or without adipose tissue loss. This analysis reports on the characteristics and outcomes of patients recruited into the prospective TRACERx study, who presented with or subsequently developed features of CC during follow-up. Approach: Using longitudinal CT imaging, total, subcutaneous and visceral adipose tissue (TAT, SAT, VAT) and SM volumes were manually quantified at the 3rd lumbar vertebrae level. Body weight was measured every 3-6 months and grouped according to BMI-adjusted weight loss grades. Multi-region primary tumour tissue was collected at the time of surgical resection and subjected to whole exome and RNA sequencing. Results: Patients in the TRACERx 421 cohort who presented with low SAT volume at diagnosis, represented by the lower 20% percentile of the cohort, had significantly shorter lung-cancer specific survival (LCSS) and overall survival (OS) compared with patients in the 80% percentile (3-y LCSS 61% vs 81%, p&amp;lt;0.001; 3-y OS 57% vs 69%, p=0.02). Patients presenting with low VAT had a significantly shorter LCSS (3-y-LCSS 66% vs 79%, p=0.01), but not OS (3-y OS 60% vs 69%). Low SM volume was not associated with LCSS or OS. However, loss of SM volume of ≥20% between diagnosis and disease relapse was associated with significantly reduced LCSS and OS (3-y LCSS 30% vs 49%, p=0.02; 3-y OS 26% vs 45%, p=0.03). Based on a multivariable model, low SAT volume at diagnosis and SM loss were independent prognostic factors for LCSS, but not OS. In addition, BMI-adjusted weight loss was associated with shorter OS and LCSS (3-y OS 7% for patients with weight loss grade 4 vs 54% in patients with stable weight, p&amp;lt;0.001 [LCSS 8% vs 61%, p&amp;lt;0.001]). Preliminary genomic data from patients with disease recurrence and with (n=47) or without (n=107) features of CC, defined as SAT or muscle loss &amp;gt;20% or weight loss grade 4, demonstrated distinct copy number alteration and differential gene expression profiles. Conclusion: In patients with early-stage NSCLC, both altered body composition and weight loss in keeping with CC was associated with poor survival outcomes. In particular, low SAT volume at diagnosis and loss of SM between diagnosis and relapse were independent prognostic factors for LCSS. Ongoing analyses in TRACERx will continue to investigate the potential tumour-intrinsic mediators of CC. Citation Format: Othman Al-Sawaf, Marcin Skrzypski, Jakob Weiss, Takahiro Karasaki, Nicolai Juul Birkbak, Francisco Zambrana, Alexander Frankell, Thomas B. Watkins, Carlos Martinez Ruiz, Selvaraju Veeriah, Cristina Naceur-Lombardelli, TRACERx Consortium, Nicholas McGranahan, Hugo Aerts, Charles Swanton, Mariam Jamal-Hanjani. Features of cancer cachexia in non-small cell lung cancer: Insights from the prospective TRACERx study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5818.

Thirty percent of cancer patients (up to 80% in some forms of cancer) suffer from cachexia syndrome, which is characterised by weight loss, muscle loss, loss of fatty tissue, inflammation and decreased appetite. Eventually 20-60% of patients actually die from the effects of cachexia and not the tumour. With the assistance of CT scans, this research mapped the level of muscle and fatty tissue loss in cancer patients. The body composition of a patient appears to be just as important for their prognosis and survival as the characteristics of the tumour. Currently, in most medical care only the tumour characteristics are used when determining prognosis and treatment. With the results of this research, cancer patients can be more precisely examined in order to possibly receive more appropriate treatment. Additionally, this research showed that cancer patients with cachexia are able to produce protein from food. For a long time this was thought to be impossible. This insight offers possibilities to treat cachexia with food and nutritional supplements. Lastly, the protein production of pancreatic tumours and different organs was measured. It appears that the protein production of the tumour is much lower than the protein production of healthy organs. Therefore, the common assumption that the tumour is responsible for the weight and muscle loss in cancer patients because it “eats” the patient’s nutrients appears to be false. Financed by the Dutch Research Council (NOW)

Cachexia in pancreatic cancer: new treatment options and measures of success

Background/Objectives: Cancer cachexia (CC) is a prevalent and debilitating syndrome in cancer patients, characterized by severe muscle and weight loss, leading to increased mortality and reduced quality of life. Despite the significant impact, effective treatments are lacking due to an incomplete understanding of its underlying mechanisms. In this study, we aim to develop drugs that ameliorate the inhibition of muscle differentiation induced by CC. We established an advanced, high-content phenotypic screening system using the serum of cancer patients and identified potential compounds. Methods: We used cancer patients' sera as pathophysiological stimuli in our screening system to evaluate their effects on muscle atrophy and differentiation. Various histone deacetylase (HDAC) inhibitors were tested for their efficacy. The system's translational relevance was validated by comparing results with clinical data and in vivo cachexia models. Results: Using our screening system, we evaluated several cancer patients' sera and found that they reflect clinical features of cancer cachexia. In addition, HDAC inhibitors, particularly those with broad-spectrum inhibition, showed promise as agents to ameliorate the inhibition of muscle differentiation induced by CC sera. This system's findings were consistent with clinical and in vivo data, highlighting its potential for identifying new drugs. Conclusions: The high-content phenotypic screening system effectively mimics some key aspects of CC pathophysiology on skeletal muscle, providing a valuable tool for drug discovery and understanding CC mechanisms. The translational relevance of our system offers a promising avenue for therapeutic advancements in the management of cancer cachexia, with the potential to improve patient outcomes and quality of life.

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