Markers Of Cachexia Research Articles

The Effect of Resistance Training on Markers of Cachexia in Patients with Heart Failure: A Systematic Review and Meta‐Analysis

ABSTRACTBackgroundCachexia is a metabolic syndrome characterised by muscle wasting that is highly prevalent in subjects with heart failure (HF) and negatively affects physical function, quality of life, morbidity and mortality. Resistance training has been recently incorporated into cardiac rehabilitation exercise programmes to increase muscle strength in patients with HF. This systematic review and meta‐analysis aim to assess the effects of resistance training on markers of cachexia in patients with HF.MethodsFour electronic databases (MEDLINE, Embase, CENTRAL and CINAHL) were searched to identify randomised controlled trials (RCTs) evaluating the effects of resistance training‐only programmes on published criteria for cachexia assessment including muscle strength, body composition (e.g. lean mass/muscle mass) or biochemical markers of cachexia (e.g. inflammatory markers) in patients with HF. Studies were selected based on pre‐specified inclusion and exclusion criteria, with a risk of bias assessment carried out. Meta‐analyses of muscle strength outcomes were completed using RevMan 5.4.1.ResultsNine studies were included in this review. Pooled analysis of one repetition‐maximum strength test of the lower [SMD 0.67 (95% Cl – 0.12, 1.22) p‐value = 0.02] and upper extremities [SMD 1.20 (95% Cl – 0.62, 1.79) p‐value <0.0001] showed a significant increase in muscle strength associated with resistance training, which are both important indicators of physical function. Resistance training did not increase muscle strength during rapid movements measured via peak torque at 60, 90 or 180°/s. There were no significant results recorded for changes in body composition and biochemical markers of cachexia. There were inconsistent findings for the effect of resistance training on quality of life. No studies reported findings on measures of anorexia or fatigue.ConclusionsThe findings of this review reveal the potential benefits of resistance training in preserving and enhancing muscle strength in patients with HF who are at risk of cardiac cachexia. Despite inconclusive results on body composition and quality of life, the inclusion of resistance training in cardiac rehabilitation guidelines has the potential to address issues of muscle weakness and frailty. Specific resistance training protocol recommendations to prevent or treat the development of cachexia cannot be made without the publication of more robust RCTs, specifically examining cachectic patients with heart failure with careful assessment of clinical outcomes of markers of cachexia.

Doxorubicin causes cachexia, sarcopenia, and frailty characteristics in mice.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

Characterisation and Outcomes of Patients with Solid Organ Malignancies Admitted to the Intensive Care Unit: Mortality and Impact on Functional Status and Oncological Treatment.

Despite the increasing number of ICU admissions among patients with solid tumours, there is a lack of tools with which to identify patients who may benefit from critical support. We aim to characterize the clinical profile and outcomes of patients with solid malignancies admitted to the ICU. Retrospective observational study of patients with cancer non-electively admitted to the ICU of the Hospital Clinic of Barcelona (Spain) between January 2019 and December 2019. Data regarding patient and neoplasm characteristics, ICU admission features and outcomes were collected from medical records. 97 ICU admissions of 84 patients were analysed. Lung cancer (22.6%) was the most frequent neoplasm. Most of the patients had metastatic disease (79.5%) and were receiving oncological treatment (75%). The main reason for ICU admission was respiratory failure (38%). Intra-ICU and in-hospital mortality rates were 9.4% and 24%, respectively. Mortality rates at 1, 3 and 6 months were 19.6%, 36.1% and 53.6%. Liver metastasis, gastrointestinal cancer, hypoalbuminemia, elevated basal C-reactive protein, ECOG-PS greater than 2 at ICU admission, admission from ward and an APACHE II score over 14 were related to higher mortality. Functional status was severely affected at discharge, and oncological treatment was definitively discontinued in 40% of the patients. Medium-term mortality and functional deterioration of patients with solid cancers non-electively admitted to the ICU are high. Surrogate markers of cachexia, liver metastasis and poor ECOG-PS at ICU admission are risk factors for mortality.

Diet-induced obesity does not exacerbate cachexia in male mice bearing Lewis-lung carcinoma tumors.

Cachexia is a muscle-wasting syndrome commonly observed in patients with cancer, which can significantly worsen clinical outcomes. Because of a global rise in obesity, the coexistence of cachexia in obese individuals poses unique challenges, with the impact of excessive adiposity on cachexia severity and underlying pathophysiology not well defined. Understanding the interplay between cachexia and obesity is crucial for improving diagnosis and treatment strategies for these patients; therefore, the present study examined differences in cachexia between lean and obese mice bearing Lewis lung carcinoma (LLC) tumors. Nine-week-old, male C57Bl6J mice were placed on either a chow or a high-fat diet (HFD) for 9 wk. After the diet intervention, mice were inoculated with LLC or vehicle. Markers of cachexia, such as body and muscle loss, were noted in both chow and HFD groups with tumors. Tumor weight of HFD animals was greater than that of chow. LLC tumors reduced gastrocnemius, plantaris, and soleus mass, regardless of diet. The tibialis anterior and plantaris mass and cross-sectional area of type IIb/x fibers in the gastrocnemius were not different between HFD-chow, HFD-tumor, and chow-tumor. Using RNA sequencing (RNA-seq) of the plantaris muscle from chow-tumor and HFD-tumor groups, we identified ∼400 differentially expressed genes. Bioinformatic analysis identified changes in lipid metabolism, mitochondria, bioenergetics, and proteasome degradation. Atrophy was not greater despite larger tumor burden in animals fed an HFD, and RNA-seq data suggests that partial protection is mediated through differences in mitochondrial function and protein degradation, which may serve as future mechanistic targets.NEW & NOTEWORTHY This study provides timely information on the interaction between obesity and cancer cachexia. Lean and obese animals show signs of cachexia with reduced body weight, adipose tissue, and gastrocnemius muscle mass. There was not significant wasting in the tibialis anterior, plantaris, or fast twitch fibers in the gastrocnemius muscle of obese animals with tumors. RNA-seq analysis reveals that obese tumor bearing animals had differential expression of mitochondria- and degradation-related genes, which may direct future studies in mechanistic research.

SP5.7 Prognostic Value of ‘Cachexia Index’ in Patients with Colorectal Cancer Undergoing Surgical Resection

Abstract Aim Numerous phenotypical features of cachexia have been associated with poorer outcomes in patients with cancer. However, at present, very few of these markers are routinely considered during the shared decision-making process. This study aims to assess the prognostic value of a novel composite marker of cachexia, termed ‘Cachexia Index’, in patients with colorectal cancer. Method Consecutive patients who underwent resection of a newly diagnosed colorectal cancer, between Jan 2019 and December 2020, were identified from prospectively maintained databases across two sites. Cachexia index was calculated as (L3 skeletal muscle index) x (serum albumin) / (neutrophil-lymphocyte-ratio). The sex-stratified, cut-off values for cachexia index were determined using area under receiver operating characteristic curves (AUC) and Youden’s Index. The primary outcome of interest was overall survival. Results Overall 273 patients (53% male, median 67 years) underwent resection of a colon (n=178) or rectal (n=95) cancer across the study period. Optimum cut-off values for a low cachexia index were defined as &amp;lt;50 for males (AUC=0.792, sensitivity = 0.821, specificity = 0.727) or &amp;lt;35 for females (AUC=0.744, sensitivity = 0.700, specificity = 0.756). Patients with a low cachexia index were older (median 71 vs. 66 years, p=0.029) and had a higher proportion of cT4 (p=0.035) or cN1/2 tumours (p=0.044). Tumour site and ASA grade were comparable between groups. Following adjustment for confounders, using cox-multivariable regression, low cachexia index was associated with decreased overall survival (HR: 3.77, 95% CI: 1.93-7.37, p&amp;lt;0.001). Conclusion Cachexia index may be a clinically useful marker for poor prognosis in patients undergoing surgical resection of a colorectal cancer.

The effect of anamorelin (ONO-7643) on cachexia in cancer patients: Systematic review and meta-analysis of randomized controlled trials.

Cachexia is associated with increased morbidity and mortality rates in patients with cancer. This meta-analysis aims to explore the effect of anamorelin on cancer cachexia markers. We searched MEDLINE/PubMed, SCOPUS, and WOS from their inception until 5 June 2022. A systematic search was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We included trials investigating the effect of anamorelin on body weight, lean body mass, fat mass, insulin-like growth factor 1 (IGF-1), handgrip, quality of life insulin-like growth factor-binding protein 3 (IGFBP-3), and in patients with cancer. A random-effects model was run to pooled results. Five articles providing 1331 participants were analyzed in this study. Pooled analysis revealed a significant increase in body weight (weighted mean difference (WMD): 1.56 kg, 95% confidence interval (CI): 1.20, 1.92; I2= 0%), lean body mass (WMD: 1.36 kg, 95% CI: 0.85, 1.86; I2= 53.1%), fat mass (WMD: 1.02 kg, 95% CI: 0.51, 1.53; I2= 60.7%), IGF-1 (WMD: 51.16 ng/mL, 95% CI: 41.42, 60.90, I2= 0%), and IGFBP-3 (WMD: 0.43 μg/mL, 95% CI: 0.17, 0.68, I2= 98.6%). Results showed no significant increase in appetite when analysis run on all studies without considering different doses 0.29 (95% CI: -0.30, 0.89, I2= 73.8%), however, there was a significant increase in appetite without heterogeneity and inconsistency 0.59 (95% CI: 0.32, 0.86; I2= 0%) in the 100 mg/day group compared to anamorelin non-user. Patients with cancer who receive anamorelin as a treatment for cachexia showed a significant increase in body weight, lean body mass, fat mass, IGF-1, and IGFBP-3.

Abstract 361: PDK4 is dispensable for PDAC chachexia

Abstract Cachexia is an involuntary weight loss and muscle wasting that affects up to 80% of advanced cancer patients. It is an independent prognostic marker for response to treatment and overall survival and accounts for 20% of cancer-associated deaths. Skeletal muscles of cachectic patients manifest metabolic abnormalities, notably increased dependence on lipids as a source of energy at the expense of glucose. Pyruvate Dehydrogenase Kinase 4 (PDK4) is upregulated in the muscles of patients and mice with cancer cachexia. PDK4 inhibits the enzyme responsible for the conversion of pyruvate to acetyl coenzyme A which is further oxidized in the tricarboxylic acid cycle. As a result, lipids become the major substrate for oxidative metabolism at the expense of glucose. Recent reports suggested that PDK4 is responsible for metabolic dysregulation in cachexia, proposing PDK4 as a potential drug target. Here, we hypothesized that the deletion of PDK4 would protect against muscle wasting in an orthotopic model of pancreatic ductal adenocarcinoma (PDAC) by countering metabolic abnormalities driven by PDK4. Methods: 50,000 KPC (LSL-KrasG12D:LSL-Trp53R172H:Pdx1-Cre) cells were injected into the pancreas of male PDK4 knockout mice or wild-type controls. For each genotype, a sham surgery group without implantation was included. Body weight was measured at baseline and later every other day starting from day 7 after implantation. Body composition, i.e., lean and fat mass, was assessed at baseline and then once a week using EchoMRI. In-vivo muscle force production measured by the Aurora Scientific system and locomotor activity measured by Auto-Track were used as readouts of muscle function. Tissue was harvested at early and late stages of disease progression representing early and late cachexia. All measurements were normalized to initial body weight. Two-way ANOVA or Student’s t-test was used for statistical analysis as appropriate. Results: Consistent with previous results, PDAC cachexia induced an increase in the expression of PDK4 in muscle both at mRNA and protein. Expression of other members of the PDK family did not change with cachexia or genotype. Mice with KPC tumors produced less muscle force (-7%, p = 0.03), walked less distance (-30%), and had a longer resting time (17%), p &amp;lt; 0.05 without difference between genotypes. At euthanasia, both genotypes had similar tumor burdens (p &amp;gt;0.9) and exhibited similar degrees of muscle (-13 and -17%, p &amp;lt; 0.0001) and adipose tissue wasting (-50%, p &amp;lt; 0.0001). Deletion of PDK4 did not protect against induction of the muscle-specific E3 ubiquitin ligases in PDAC: FBXO32 and TRIM63 (10.7 fold and 13.6 fold on average, respectively, p &amp;lt; 0.01), molecular hallmarks of muscle atrophy. Overall, our work shows that the knockout of PDK4 does not protect against the development of PDAC cachexia suggesting that PDK4 might be a marker of cachexia but not necessarily a driving mechanism. Citation Format: Omnia U. Gaafer, Joseph Rupert, Joshua Huot, Daenique Jengelley, Andrea Bonetto, Leonidas Koniaris, Teresa Zimmers. PDK4 is dispensable for PDAC chachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 361.

Abstract 366: Utilizing epicardial fat thickness as an indicator of cardiac cachexia in resectable pancreatic ductal adenocarcinoma

Abstract Objective: Pancreatic adenocarcinoma (PDAC) is a highly aggressive malignancy with high mortality. A significant component of PDAC is cachexia, or cancer-related muscle wasting. While there are many studies analyzing skeletal muscle cachexia, there is limited data regarding cardiac muscle degradation (cardiac cachexia) in PDAC patients. Prior studies in heart failure patients have utilized epicardial fat thickness (EFT) as a marker for cardiac cachexia. The objective of this study was to determine if there is a relationship between skeletal muscle cachexia and cardiac cachexia in resectable PDAC patients. Methods: Adult patients with resectable PDAC from 2011-2021 were identified from a single institution. Patients were included in this study if they had available CT Chest and Abdominal scans of adequate quality within one year of their PDAC resection. Scans were acquired from various time points in the pre- and post-operative phases. The patient’s skeletal muscle index (SMI) at the L3 vertebral level was calculated using the software SliceOMatic. Using the SMI and the patient’s BMI, a determination of cachexia was made using criteria established by by Martin et al [2]. EFT was measured on the CT Chest scans by measuring the perpendicular distance of epicardial fat from the base of the right coronary artery the outer border of the epicardium on an axial view. Comparisons were made using t-test or Fisher's exact test with p-value of 0.05 for significance. Results: Overall, 22 patients met inclusion criteria. EFT was compared to SMI values across all patients and there was no correlation (R2=0.049). There was also no significant difference in EFT between cachectic and non-cachectic patients (2.52 cm vs .2.36 cm, p=0.42). Given the impact of obesity on visceral fat composition, we performed additional analysis after excluding patients with BMI &amp;gt; 25. In this subset, there was a significant difference in EFT between cachectic and non-cachectic patients (2.30 cm vs. 1.90 cm, p=0.03). Race was also a significant factor, with African American patients having lower EFT compared to Caucasians (1.57 cm vs. 2.31 cm, p=0.02). Conclusion: Although there was no direct correlation between EFT and skeletal muscle cachexia, EFT may be an important predictor of cachexia in PDAC patients with low to normal BMI. Furthermore, the racial difference in EFT demonstrates a possible disparity in cardiac cachexia and function. To establish this parameter as a marker of cachexia, the patient cohort will be expanded to include more time points and those with unresectable/metastatic disease. This will also need to be explored prospectively with functional imaging such as cardiac MRI to determine if there is a relationship between EFT and cardiac function. Citation Format: Vignesh Vudatha, Devon Freudenberger, Christopher Liu, Jose Trevino. Utilizing epicardial fat thickness as an indicator of cardiac cachexia in resectable pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 366.

The protective effect of cannabinoids against colorectal cancer cachexia through modulation of inflammation and immune responses

Cancer cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, and there are currently no FDA-approved medications. In the present study, upregulation of six cytokines was observed in serum samples from patients with colorectal cancer (CRC) and in mouse models. A negative correlation between the levels of the six cytokines and body mass index in CRC patients was seen. Gene Ontology analysis revealed that these cytokines were involved in regulating T cell proliferation. The infiltration of CD8+ T cells was found to be associated with muscle atrophy in mice with CRC. Adoptive transfer of CD8+ T cells isolated from CRC mice resulted in muscle wasting in recipients. The Genotype-Tissue Expression database showed that negative correlations between the expression of cachexia markers and cannabinoid receptor 2 (CB2) in human skeletal muscle tissues. Pharmacological treatment with Δ9-tetrahydrocannabinol (Δ9-THC), a selective CB2 agonist or overexpression of CB2 attenuated CRC-associated muscle atrophy. In contrast, knockout of CB2 with a CRISPR/Cas9-based strategy or depletion of CD8+ T cells in CRC mice abolished the Δ9-THC-mediated effects. This study demonstrates that cannabinoids ameliorate CD8+ T cell infiltration in CRC-associated skeletal muscle atrophy via a CB2-mediated pathway. Serum levels of the six-cytokine signature might serve as a potential biomarker to detect the therapeutic effects of cannabinoids in CRC-associated cachexia.

Targeting Gut Microbiota in Cancer Cachexia: Towards New Treatment Options.

Cancer cachexia is a complex multifactorial syndrome whose hallmarks are weight loss due to the wasting of muscle tissue with or without the loss of adipose tissue, anorexia, systemic inflammation, and multi-organ metabolic alterations, which negatively impact patients' response to anticancer treatments, quality of life, and overall survival. Despite its clinical relevance, cancer cachexia often remains an underestimated complication due to the lack of rigorous diagnostic and therapeutic pathways. A number of studies have shown alterations in gut microbiota diversity and composition in association with cancer cachexia markers and symptoms, thus supporting a central role for dysbiosis in the pathogenesis of this syndrome. Different tools of microbiota manipulation, including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation, have been investigated, demonstrating encouraging improvements in cachexia outcomes. Albeit pioneering, these studies pave the way for future research with the aim of exploring the role of gut microbiota in cancer cachexia more deeply and setting up effective microbiota-targeting interventions to be translated into clinical practice.

Babao Dan Alleviates Cancer Cachexia in Mice Via Inhibiting IL-6/STAT3 Signaling Pathway.

Cancer cachexia is a common but severe condition that causes muscle wasting, body weight loss, and progressive functional impairment, affecting over 50% of cancer patients. Currently, there are no effective treatments that can alleviate cachexia, and hence the discovery of new therapeutics that can effectively prevent or even reverse cancer cachexia is crucial. Babao Dan (BBD) is a Traditional Chinese Medicine (TCM) formula that has been used clinically in combating various cancers, however, its therapeutic potential in alleviating cancer cachexia remains unexplored. Our current study aims to determine the anti-cachectic effects of BBD treatment in alleviating cancer cachexia, as well as determining the underlying mechanisms involved. Mouse models of cancer cachexia were induced via implantation of CT26 colon adenocarcinoma cells, and the anti-cachectic effects and mechanisms of BBD were determined via examinations of body weight and muscle mass, as well as serum and muscle markers of cachexia and muscle atrophy. CT26 tumor implantation reduced in the rapid occurrence of cancer cachexia characterized by marked reductions in body weight and muscle mass, functional decrease in muscle function and accelerated deaths. BBD administration not only demonstrated robust anti-cachectic ability via preventing decreases in body weight, muscle mass, and muscle atrophy, but also markedly prolonged survival. The effects of BBD in alleviating cancer cachexia and its associated adverse effects were due to its ability in preventing the activation of IL-6/STAT3 signaling post-CT26 tumor implantation. Our findings demonstrated the robust ability of BBD in preventing cancer cachexia and alleviating the main cachexia-induced symptoms as well as prolonging survival via inhibiting activation of IL-6/STAT3 signaling pathway. Therefore, our study demonstrating the strong anti-cachectic effects of BBD in mice may provide a theoretical basis for the use of BBD as a safe and effective drug in the treatment of cancer cachexia.

Consensus Cachexia Criteria Are Independently Linked to Progression Free and Overall Survival in Multi-Site Analysis of Patients with Aggressive B-Cell Lymphomas Treated with CAR T-Cell Therapy

Background: Cachexia is a muscle wasting disorder present in 50% of cancer patients, 80% of advanced cancer patients, and is indirectly responsible for 20-30% of cancer-related mortality (von Haehling et al, JCSM. 2016). Prior studies have shown that cachexia is linked to poor treatment response and may be a proxy for an altered immune-state (Coss et al, CCR. 2018). While our pilot work suggested that serum-based cachexia markers are associated with poor survival after chimeric antigen T-cell receptor therapy (CART) (Roy et al., BrJH. 2022), the independent impact of cachexia, defined using consensus criteria, on short- and long-term outcomes after CART has not been explored. Our objective in this study was to evaluate whether consensus weight-based classifications of cachexia have an impact on short- and long-term outcomes after anti-CD19 CART in aggressive B-cell lymphomas. Methods: Adults with R/R aggressive B-cell NHL treated with anti-CD19 CART between 2015- 2020 from 13 academic centers in the US were identified. Demographic and clinical data were collected and analyzed as univariates via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression analyses assessed impact of significant covariates on survival with α = 0.05. Cachexia (>5% body weight loss (BWL) or 2% BWL with BMI < 20), pre-cachexia (0-5% BWL), and non-cachexia (no BWL) statuses were defined at apheresis using consensus weight-based criteria (Fearon et al., Lancet. 2011). Results: 433 patients had available weight and BMI data to establish cachexia status. Incidence of cachexia was 37%, pre-cachexia was 18%, and non-cachexia was 43%. Median follow up after CART was 12.4 mo for the entire cohort and 18 mo for survivors. There was no significant univariate association between cachexia and age, sex, performance status, co-morbidity index, CART product, LDH elevation, or IPI score. Significant univariate associations included cachexia patients were less likely to be on a clinical trial (p<0.001), more likely to have auto-transplant pre-CART (p<0.01), and more likely to have ABC cell of origin (p<0.05), while increased lines of pre-CART therapy also trended towards association (p=0.08). Amongst short-term outcomes, there was no association between cachexia and post-treatment cytokine release syndrome (p=0.93), neurotoxicity (ICANS) (p=0.20), infection (p=0.25), overall response at day 180 (p=0.91), complete response rate at day 180 (p=0.52), or advancement to post-CART salvage therapy (p=0.15). In survival analyses (Figure 1), patients with cachexia had decreased median progression free survival (mPFS) of 6.7 mo, compared with 13 mo for non-cachexia (HR 1.3 (95%CI 1.0 -1.8), p=0.04) and 23.4 mo for pre-cachexia (HR 1.5 (95%CI 1.0-2.2), p=0.03). Additionally, median overall survival (mOS) was 16.5 mo for cachectic patients, significantly lower compared to mOS of 29 mo for non-cachexia (HR 1.7 (95%CI 1.2 - 2.2), p=0.005) and a mOS that was not reached for pre-cachexia. In a multivariate analysis (Table 1), independent predictors of decreased mPFS were cachexia (HR 1.6 (95%CI 1.1 - 2.3), p = 0.02), number of pre-CART therapies (HR 1.2 (95%CI 1.0 - 1.3), p = 0.01), and elevated LDH at time of CART (HR 1.6 (95%CI 1.1 - 2.4), p = 0.01). Independent predictors of decreased mOS were cachexia (HR 1.9 (95%CI 1.2 - 2.9), p = 0.003), and number of pre-CART therapies (HR 1.2 (95%CI 1.0 - 1.4), p = 0.01). Conclusion: As durable remission rates remain close to 40%, improved predictors of survival post-CART treatment for lymphoma are needed. In this multi-site study, our findings suggest that cachexia, defined by weight-based criteria, should be included as a prognostic marker for CART. Our data also indicate that, amongst CART patients, the weight/BMI threshold for cachexia criteria (>5% BWL or 2% BWL with BMI < 20) is more prognostically relevant than pre-cachexia (0-5% BWL). While prior mechanistic studies show that cachexia is driven by an altered inflammatory state, our study expands upon this notion. Our data show that although patients with cachexia have similar initial response rates to non-cachectic patients, there may be a long-term dampened immune response in this population that ultimately impacts survival. Further study into cachexia-focused therapies is needed and specific investigation of the role of cachexia in immune evasion mechanisms may yield new targets. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cachexia is a risk factor for negative clinical and functional outcomes in patients receiving chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma.

Cachexia is a muscle-wasting syndrome that is known to impact the clinical course of several cancer populations but has not been specifically investigated in patients receiving chimeric antigen receptor T (CAR-T) cell therapy. In this study, we investigated the relationship between cachexia markers and several cancer and functional outcomes in a pilot population of aggressive B-cell non-Hodgkin lymphoma patients receiving CAR-T. We found that the prognostic nutritional index was linked to progression-free survival, overall survival, and disability-free survival, while several additional weight and serum-based markers of cachexia were also associated with negative outcomes. These data prompt further investigation of cachexia markers in populations receiving CAR-T cell therapy.

Moderate Intensity Endurance and Resistance Exercise Attenuates Cachexia in Tumor-bearing Mice.

Cancer cachexia encompasses several deleterious physiological alterations associated with functional impairments, poor quality of life, and increased mortality. The aim of this study was to examine the effects of chronic moderate intensity exercise training on markers of cachexia. Balb/c mice were randomly assigned to sedentary (SED) or exercise (EX) groups and EX mice were further randomly assigned to one of three exercise modalities (aerobic, resistance, combined). Cachexia was induced in SED animals inoculated with C26 cells, as evidenced by significant changes in numerous markers. All cachexia-related perturbations were significantly attenuated in EX versus SED animals. Systemic inflammation was significantly decreased in all EX groups, as evident by a normalization of spleen mass and plasma IL-6. Multiple moderate intensity exercise modalities can provide significant benefits in cachectic mice, and this may be due, at least in part, to decreased systemic inflammation.

Cachexia is an independent factor for negative clinical and functional outcomes in lymphoma patients receiving CART therapy.

e19504 Background: Cachexia is a known independent factor for negative outcomes in several cancer populations at early and late stages, but has not been in investigated in cancer patients receiving Chimeric Antigen Receptor T-cell therapy (CART). Our objective was to evaluate the relationship between cachexia and clinical and functional outcomes in patients with lymphoma receiving CART. Methods: Design: Retrospective cohort study including 70 adult patients with aggressive B-cell lymphomas (Diffuse Large B-cell or Mantle Cell Lymphoma) who received CART. Cachexia markers: body weight loss (BWL), BMI, albumin, creatinine, and neutrophil-to-lymphocyte ratio (NLR) – each captured at diagnosis, pre-collection, CART initiation, and through day 360 post-CART. Outcome measures: Primary outcomes: Disease relapse after CART and 90-day mortality. Secondary outcome: Need for rehabilitation services post-acute care (inpatient rehabilitation or home physical therapy). Statistical analyses: Linear regression modeling, area under the curve analysis, and multivariate modeling (any univariates with p &lt; 0.25). Co-variates: age, ECOG PS, IPI, cell of origin, MYC status, number of prior cancer therapies, time from diagnosis to CART, and need for bridging / steroid pre-CART. Results: In longitudinal modeling from diagnosis to day 360, CART patients who relapsed had linear associations over time with BWL since diagnosis (p &lt; 0.01), NLR (p &lt; 0.0001), creatinine (p = 0.045), and albumin (p &lt; 0.001). In univariate analyses (see table): at pre-collection, high NLR and BWL increased odds of relapse; at treatment, high NLR and CRP increased odds of mortality; and at D30, and BWL and high NLR increased odds of relapse and mortality, respectively. In multivariate analyses (see table, # = independent association), BWL and high NLR independently associated with relapse and mortality, respectively. Significant covariates included need for bridging (p = 0.02), steroid therapy pre-CART (p &lt; 0.01), and time from diagnosis to CART (p = 0.02). Secondarily, BWL and low albumin pre-CART increased odds of needing rehabilitation services, with BWL independently associating in multivariate models (OR = infinity, p &lt; 0.001). Conclusions: Cachexia markers, such as BWL from diagnosis and NLR, are candidate predictors of relapse and mortality after CART. Specific markers could also assign patients to neo/adjuvant rehabilitative and medical therapies targeted towards cachexia. Overall, this study suggests that cachexia may alter the clinical and functional trajectory of lymphoma patients receiving CART.[Table: see text]

Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy.

Simple SummaryThough patients with sensitizing epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer have been known to have rapid and durable responses to tyrosine kinase inhibitors, a subset of patients have inferior outcomes and may benefit from therapy escalation. Neutrophil-to-lymphocyte ratio (NLR) has been recognized as one indicator of poor prognosis in patients with various cancers, including non-small cell lung cancer. It is associated with cancer cachexia and treatment resistance. The aim of our study is to assess the serial predictive value of NLR and other markers of cachexia and chronic inflammation in the subset of patients with advanced non-small cell lung cancer who harbor the epidermal growth factor receptor mutation and who are undergoing treatment with tyrosine kinase inhibitor therapy.Background: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. Methods: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. Results: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282–7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063–1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. Conclusions: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.

Assessment of Cachexia Markers in the TCGA-LIHC Cohort of Patients with Hepatocellular Carcinoma

Abstract: &#x0D; Background: Cachexia, unintentional loss of muscle and fat, is frequent in patients with cancer. Cachexia, frequent with hepatocellular carcinoma, associates with decreased quality of life and survival. We sought to measure body composition changes in patients in the liver hepatocellular carcinoma (LIHC) cohort of The Cancer Genome Atlas (TCGA) preparatory to identifying tumor genomic characteristics associated with cachexia. &#x0D; &#x0D; Methods: Using CT scans from The Cancer Imaging Archive (TCIA), we measured changes in muscle area (SKMA) and height normalized skeletal muscle index (SKMI) between scans. Serum biomarkers, obtained from TCGA, and extracted data were assessed versus progression free survival (PFS) and overall survival (OS) using Spearman nonparametric correlation and log rank tests. &#x0D; &#x0D; Results: 43 patients of the LIHC cohort had two usable CT scans. 16 were female, mean age 63.4 ± 9.10 years (mean ± SD) and 27 were male, mean age 61.0 ± 15.5 years. SKMA, SKMI, and body weight were strongly correlated to male sex; conversely, platelet count was strongly correlated with female sex (r=0.400, p=0.01). We observed no correlations between change in SMA or SMKI and PFS or OS. However, variables of baseline SKMA (r=0.312, p=0.07), SKMI (r=0.312, p=0.07), patient weight (r=0.367, p=0.03), and body mass index (BMI) (r=.0404, p=0.02) correlated strongly with PFS. Serum platelet count was strongly negatively correlated with PFS (r=-0.401, p=0.02). Mutation count was strongly negatively correlated with OS (r=-0.311, p=0.04). &#x0D; &#x0D; Conclusion: This cohort is too small to draw general conclusions about body composition, muscle size, and survival. However, observing greater survival in patients with more muscle mass is consistent with studies of patients with advanced cancer showing increased risk of mortality with low muscle mass. Observing longer survival among patients with high starting BMI is consistent with prior studies in lung cancer. These results highlight the importance of body phenotype in prognosis of patients with hepatocellular carcinoma.

Effects Of Exercise Training On Cachexia In Mice Bearing The Colon-26 Carcinoma

Colorectal cancer (CRC) is the third most prevalent cancer in the U.S. and risk is increased by lifestyle factors such as poor diet and physical inactivity. Also, CRC patients are highly susceptible to developing cachexia, which is characterized by muscle wasting, fatigue, weakness, and immune function impairments, that lead to increased morbidity and mortality. Studies have shown that aerobic and resistance training, independently, can effectively attenuate the deleterious effects of cachexia, and though research on concurrent training is limited, studies are reporting that combined exercise positively affects muscle wasting. PURPOSE: The purpose of this study was to examine the effects of exercise training on markers of cachexia to determine if aerobic training (TM), resistance training (RT), or combined training (TM+RT) would be most effective. METHODS: Male Balb/c mice were randomly assigned to SED (n = 24) or EX (n = 36) groups. EX mice were further allocated to either TM (n = 12), RT (n = 12), or TM+RT (n = 12). After 5 weeks of EX, 12 SED and all EX mice were inoculated with C26 cells; EX continued for 3 additional weeks before mice were sacrificed. Cachexia was assessed via histochemical/biochemical analyses and forelimb grip strength. RESULTS: Cachexia was induced in Sed+Tumor, evidenced by significant changes in body mass (P < 0.05; -14%), gastrocnemius mass (P < 0.01; -16%), gastrocnemius cross sectional area (CSA) (P < 0.05; -35%), forelimb grip strength (P < 0.01; -18%), splenomegaly (P < 0.01; +83%), and plasma IL-6 (P < 0.01; +211%). Moreover, MHCIIa and IIb atrophied similarly in Sed+Tumor mice. All exercise groups had significant improvements in all examined markers of cachexia when compared to Sed+Tumor, with the exception of gastrocnemius mass (P > 0.05). Additionally, RT significantly improved relative grip strength versus all other groups (P < 0.05). Overall myofiber CSA increased significantly with all EX modes (P < 0.05). Finally, systemic inflammation was significantly decreased in all EX groups, as evident by decreases in spleen mass and plasma IL-6 (P < 0.01). CONCLUSIONS: These data support past literature in that exercise provides significant benefit to cachectic mice, and this may be due, in part, to decreased systemic inflammation. Specifically, RT, alone and with TM, provided the most benefit.

A multi‐targeted treatment approach to cancer cachexia: Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT) trial

AbstractBackgroundCancer cachexia is a condition often seen at diagnosis, throughout anti‐cancer treatments and in end‐stage non‐small‐cell lung cancer patients.Methods and resultsParticipants with late‐stage non‐small‐cell lung cancer and cachexia (defined as ≥5% weight loss within 12 months) were randomly assigned 1:2 to 2.09 g of eicosapentaenoic acid (EPA) and 300 mg of cyclo‐oxygenase‐2 inhibitor celecoxib orally once daily vs. same dosing of EPA, celecoxib, plus two sessions per week of progressive resistance training and 20 g of oral essential amino acids high in leucine in a split dose over 3 days, after each session. Primary endpoint was the acceptability of the earlier multi‐targeted approach. Main secondary endpoints included change in body weight and fat‐free mass, by bioelectric impedance analysis and total quadriceps muscle volume by magnetic resonance imaging over 20 weeks. Sixty‐nine patients were screened resulting in 20 patients being enrolled. Acceptability scored high, with 4.5/5 (Arm A) and 5/5 (Arm B) for EPA and 5/5 for celecoxib within both arms and 4.8/5 for progressive resistance training sessions and 4.5/5 for essential amino acids within Arm B, all at Week 20. Results showed a net gain in bioelectric impedance analysis fat‐free mass of +1.3 kg, n = 2 (Arm A), compared with +0.7 kg, n = 7 (Arm B) at Week 12, and —1.5 kg, n = 2 (Arm A), compared with —1.7 kg, n = 4 (Arm B) at Week 20. Trends in efficacy in terms of improvement and/or stability in cachexia markers were seen within magnetic resonance imaging muscle volume, albumin, and C‐reactive protein levels within both arms. There were no exercise‐related adverse events, with one possible related adverse event of asymptomatic atrial fibrillation in one participant within Arm A.ConclusionsNon‐small‐cell lung cancer cachectic patients are willing to be enrolled onto a multi‐targeted treatment regimen and may benefit from cachexia symptom management even during the late/refractory stage.

PF716 CLINICAL IMPACT OF PROGNOSTIC NUTRITIONAL INDEX IN DIFFUSE LARGE B CELL LYMPHOMA

Please indicate where the abstract has been published before: Annals of HematologyBackground:Cachexia is an indicator of tumor progression in patients with malignancy. Cachectic patients exhibit intolerance and a reduced response to antitumor therapy, and have an unfavorable prognosis. An international consensus proposed diagnostic criteria for cancer cachexia including weight loss, low body mass index (BMI), and/or presence of sarcopenia. Other potential biomarkers (e.g., albumin, C‐reactive protein, pro‐inflammatory cytokines, and microRNAs) and scoring systems (e.g., cachexia score [CASCO], Glasgow prognostic score [GPS], prognostic nutritional index [PNI]) have also been studied to diagnose cancer cachexia and assess its severity.Aims:In this study, we assessed the associations among PNI, other clinical outcomes, and survival in patients with DLBCL. Then we sought valid cachexia markers with prognostic significance and designed a novel model to improve the prognostic ability of well‐known clinical indices for patients with DLBCL.Methods:A total of 228 DLBCL patients treated with first‐line R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively reviewed. PNI was calculated as 10 × serum levels of albumin (g/dL) + 0.005 × absolute lymphocyte count (/mm3). Patients were categorized into low‐ and high‐PNI groups based on a cut‐off value of 40. The nomogram for predicting overall survival (OS) was constructed using a Cox regression model. PNI was positively correlated with skeletal muscle index, body mass index, and serum levels of albumin.Results:The low‐PNI group had a lower complete response rate (60.3% vs. 87.6%), increased treatment‐related toxicity, and more frequent treatment discontinuation (43.5% vs. 8.8%) than the high‐PNI group. The median OS was shorter in the low‐PNI group than the high‐PNI group (15.6 months vs. not reached; p &lt; 0.001, Figure.1). Multivariate Cox regression analyses showed that PNI, sarcopenia, and the international prognostic index (IPI) were independent prognostic factors for OS. The nomogram developed using this regression model showed excellent discriminatory ability for predicting OS (c‐index, 0.80) compared to the IPI alone (c‐index, 0.75).Summary/Conclusion:This study supports the results of a previous study [29], whereby low PNI is an independent poor prognostic factor in patients with DLBCL treated with first‐line R‐CHOP immunochemotherapy. In addition, we newly found that treatment‐related toxicity and early discontinuation of treatment occurred more frequently in DLBCL patients with low PNI. We anticipate that the new prognostic nomogram developed using PNI, SMI, and IPI may help to realize individualized therapy that considers both the disease characteristics and the patient's tolerance to treatment in patients with DLBCL. This will be validated externally in a future study.image