Dataset Information

Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

ABSTRACT:

Background

Cancer-associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C-reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer-associated WL (primary endpoint) and overall survival (OS, secondary endpoint).

Methods

The data set included a total of 12,253 patients at risk for cancer-associated WL. Patient-reported WL history (% in 6 months) and food intake (normal, moderately, or severely reduced) were measured in all patients; CRP (mg/L) and OS were measured in N = 4960 and N = 9952 patients, respectively. All measures were from a baseline assessment. Clinical variables potentially associated with WL and overall survival (OS) including age, sex, cancer diagnosis, disease stage, and performance status were evaluated using multinomial logistic regression MLR and Cox proportional hazards models, respectively.

Results

Patients had a mean weight change of -7.3% (±7.1), which was categorized as: ±2.4% (stable weight; 30.4%), 2.5-5.9% (19.7%), 6.0-10.0% (23.2%), 11.0-14.9% (12.0%), ≥15.0% (14.6%). Normal food intake, moderately, and severely reduced food intake occurred in 37.9%, 42.8%, and 19.4%, respectively. In MLR, severe WL (≥15%) (vs. stable weight) was more likely (P < 0.0001) if food intake was moderately [OR 6.28, 95% confidence interval (CI 5.28-7.47)] or severely reduced [OR 18.98 (95% CI 15.30-23.56)]. In subset analysis, adjusted for food intake, CRP was independently associated (P < 0.0001) with ≥15% WL [CRP 10-100 mg/L: OR 2.00, (95% CI 1.58-2.53)] and [CRP > 100 mg/L: OR 2.30 (95% CI 1.62-3.26)]. Diagnosis, stage, and performance status, but not age or sex, were significantly associated with WL. Median OS was 9.9 months (95% CI 9.5-10.3), with median follow-up of 39.7 months (95% CI 38.8-40.6). Moderately and severely reduced food intake and CRP independently predicted OS (P < 0.0001).

Conclusions

Modelling WL as the dependent variable is an approach that can help to identify clinical features and biomarkers associated with WL. Here, we identify criterion values for food intake impairment and CRP that may improve the diagnosis and classification of cancer-associated cachexia.

SUBMITTER: Martin L

PROVIDER: S-EPMC8517347 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

Martin Lisa L Muscaritoli Maurizio M Bourdel-Marchasson Isabelle I Kubrak Catherine C Laird Barry B Gagnon Bruno B Chasen Martin M Gioulbasanis Ioannis I Wallengren Ola O Voss Anne C AC Goldwasser Francois F Jagoe R Thomas RT Deans Chris C Bozzetti Federico F Strasser Florian F Thoresen Lene L Kazemi Sean S Baracos Vickie V Senesse Pierre P

Journal of cachexia, sarcopenia and muscle 20210827 5

<h4>Background</h4>Cancer-associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C-reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer-associated WL (primary endpoint) and overall survival (OS, sec ...[more]

PMID: 34448539

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Project description:Purpose: To investigate graded levels of low protien dites effects on hypothalamic gene expression pattern, RNA-seq was performed on hypothalamus of mice treated with different levels of low protein and normal protein under both 60% fat and 20% fat conditions. Methods: There were 8 diets in total, the fat content of first 4 diets were fixed at 60% fat level by energy and protein was varied from 1% to 20% (1%, 2.5%, 5% and 20% respectively) by energy (D14121903, D14121904, D14071601,D14071604), another 4 kinds of diets contained the same graded levels of protein content as the first 4 diets but fat contents were fixed at 20% by energy (D14121905, D14121906, D14071607, D14071610). The remaining energy was compensated of carbohydrate which included corn starch and maltodextrose. Casein was used as the protein source in all diets. To mimic the typical western diet a mix of cocoa butter, menhaden oil, sunflower oil, palm oil and coconut oil was used as the fat source and was designed to generate a 47.5: 36.8: 15.8 proportion of saturated, mono-unsaturated and polyunsaturated fats and 14.7: 1 proportion of n-6 and n-3 fatty acids, the proportions of different fat compositions didn’t change under two different 60% and 20% fat conditions. Sucrose and cellulose were fixed at 5% level by energy and standard vitamin and mineral mix were also added to all diets as well (Hu et al., 2018). The two series were isocaloric within each series. Diets can be ordered direct from research diets (https://researchdiets.com) using the diet codes provided. The hypothalamus of 6 individuals were collected for each diet group, 3 of which were pooled together as one sample, resulting in each group having 2 pooled samples of 3 hypothalamus. Hypothalamic RNA was extracted using Trizol method described in star methods in paper and then sent to Beijing Genomic Institute (BGI) for RNA sequencing. All RNA sequencing was measured by using the BGI-seq 500 sequencer. To determine the sequencing quality of each sample, FASTQ raw data files were measured by using fastQC (www.bioinformatics.bbsrc.ac.uk/projects/fastqc/) quality control tool, after confirmed sequencing quality of each sample, raw reads were aligned to the Mus musculus reference genome (GRCm38) using HISAT2-2.1.0 (Kim et al., 2015; Pertea et al., 2016) and Samtools-1.2 modules (Li et al., 2009), and then featureCounts (Liao et al., 2014) tool in Subread-5.0 (Liao et al., 2013) was used to get counts for each sample from BAM files which was obtained from alignment step. To exclude the low counts, only genes with counts per million (CPM) value > 1 were included in the further analysis. Counts were normalized by the trimmed means of M values (TMM normalization) (Robinson and Oshlack, 2010) method in the edgeR (Anders et al., 2013; Lund et al., 2012; McCarthy et al., 2012; Robinson et al., 2010; Robinson and Oshlack, 2010; Robinson and Smyth, 2007) package. To investigate different dietary protein contents under fixed two levels fat content effects on gene expression levels Generalized Linear Modelling (GLM) function in R-3.5.3 edgeR package was used, The GLM model used in this study were: ~P+F+P:F, which means regression against protein (P) and fat contents (F) of diets plus their interaction (P:F). If the interaction effect was not significant (p > 0.05), the interaction was not included in the analysis and a revised model (~P+F) was utilized (Hu et al., 2018). To explore significantly correlated genes with dietary protein content respectively under 60% fat and 20% fat conditions, Pearson correlation analysis was performed for normalized log counts of all genes by using Pearson correlation method in R-3.5.3. Then selected the significantly correlated genes with dietary protein content (GLM: p < 0.05) respectively in the GLM and Pearson correlation (Pearson: p < 0.05 for 60% fat and 20% fat conditions) analysis were loaded into the Ingenuity pathway analysis (IPA) program (Ingenuity Systems; http://www.ingenuity.com/) to observe the significantly affected pathways. Results: The most affected pathways by the dietary low protein included the mTOR signaling pathway, the hunger signaling pathway, eIF2a signaling pathway and regulation of eIF4 and p70S6K signaling pathway. In the hunger signal pathway, we found there were strong correlations for four key hunger signaling pathway genes Pomc, Cart, Npy and Agrp with the protein content in the diet across different protein content groups (from 1% protein to 20% protein group) with Pomc and Cart expression significantly reduced as protein level declined while Npy and Agrp expression increased as protein levels decreased.

Project description:BackgroundTo explore the association between cachexia, as defined by different diagnostic criteria, and the risk of mortality in individuals with cancer. We also examined which diagnostic criteria are more feasible and appropriate for cancer-associated cachexia in clinical practice.MethodsA multicentre cohort study was conducted, which involved 5769 participants with cancer. The diagnosis of cachexia was made by applying the initial Fearon criteria (with the appendicular skeletal muscle mass index [ASMI]) and six modified criteria: (1) evaluating the muscle mass through the mid-upper-arm muscle area (MAMA), (2) fat-free mass index (FFMI), (3) calf circumference (CC), (4) hand grip strength (HGS), (5) neutrophil-to-lymphocyte ratio (NLR) and (6) omission of reduced muscle mass. The correlations between cancer cachexia diagnosed by different definitions and survival were assessed using Kaplan-Meier analyses and multivariable-adjusted Cox models. The sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, AUC value, Youden index and weighted kappa coefficient were calculated for each set of criteria.ResultsThe final analysis included 5110 patients diagnosed with 15 different types of cancer, with a median age of 56. Out of these, 2490 (48.7%) were male. The prevalence of cancer cachexia based on the Fearon criteria was 26.5%, ranging from 21.8% to 32.2% with the six modified criteria. Following adjustment for age, sex, clinical stage and cancer site, cachexia defined by Fearon criteria was associated with a noteworthy increase in mortality (HR, 1.275; 95% CI, 1.136-1.430; p < 0.001), ranging from 1.237 (95% CI, 1.106-1.383; p < 0.001) to 1.382 (95% CI, 1.226-1.557; p < 0.001) by the six modified criteria. All six modified criteria presented adequate performance indicators (all p < 0.001), with sensitivity ranging from 82.4% (95% CI, 80.2%-84.3%) to 90.7% (95% CI, 89.0%-92.2%), specificity ranging from 86.9% (95% CI, 85.7%-87.9%) to 100.0% (95% CI, 99.9%-100.0%) and AUC ranging from 0.860 (95% CI, 0.850-0.869) to 0.932 (95% CI, 0.925-0.939). The modified criteria also showed strong (Fearon criteria with NLR: κ = 0.673, 95% CI, 0.651-0.695) to almost perfect (Fearon criteria without reduced muscle mass [RMM]: κ = 0.873, 95% CI, 0.857-0.888) consistency with the original Fearon criteria.ConclusionsCachexia defined by the Fearon criteria and the six modified criteria can predict the survival of cancer patients. All criteria provided a precise diagnosis and were feasible to use in clinical settings.

Dataset Information

Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

Background

Methods

Results

Conclusions

Publications

Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

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