Longitudinal characterisation of cachexia in patients undergoing surgical resection for cancer

PURPOSE OF REVIEW: The complexity of the cancer cachexia phenotype has undoubtedly hindered researchers' understanding of this devastating syndrome. The presence and magnitude of host-tumour interactions are rarely considered during clinical decision-making within the current staging paradigm. Furthermore, treatment options for those patients who are identified as suffering from cancer cachexia remain extremely limited.RECENT FINDINGS: Previous attempts to characterise cachexia have largely focussed on individual surrogate disease markers, often studied across a limited timeframe. While the adverse prognostic value of clinical and biochemical features is evident, the relationships between these are less clear. Investigation of patients with earlier-stage disease could allow researchers to identify markers of cachexia that precede the refractory stage of the wasting process. Appreciation of the cachectic phenotype within 'curative' populations may aid our understanding of the syndrome's genesis and provide potential routes for prevention, rather than treatment.SUMMARY: Holistic, longitudinal characterisation of cancer cachexia, across all at-risk and affected populations, is of vital importance for future research in the field. This paper presents the protocol for an observational study aiming to create a robust and holistic characterisation of surgical patients with, or at risk of, cancer cachexia.</p

Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients

Background&nbsp; In order to grow the potential therapeutic armamentarium in the cachexia domain of supportive oncology, there is a pressing need to develop suitable biomarkers and potential drug targets. This pilot study evaluated several potential candidate biomarkers in skeletal muscle biopsies from a cohort of upper gastrointestinal cancer (UGIC) patients.&nbsp; Methods&nbsp; One hundred seven patients (15 weight-stable healthy controls (HC) and 92 UGIC patients) were recruited. Mean (standard deviation) weight-loss of UGIC patients was 8.1 (9.3\%). Cachexia was defined as weight-loss &ge;5\%. Rectus&thinsp;abdominis muscle was obtained at surgery and was analysed by western blotting or quantitative real-time&ndash;polymerase chain reaction. Candidate markers were selected according to previous literature and included Akt and phosphorylated Akt (pAkt, n&thinsp;=&thinsp;52), forkhead box O transcription factors (n&thinsp;=&thinsp;59), ubiquitin E3 ligases (n&thinsp;=&thinsp;59, control of muscle anabolism/catabolism), BNIP3 and GABARAPL1 (n&thinsp;=&thinsp;59, as markers of autophagy), myosin heavy-chain (MyHC, n&thinsp;=&thinsp;54), dystrophin (n&thinsp;=&thinsp;39), &beta;-dystroglycan (n&thinsp;=&thinsp;52), and &beta;-sarcoglycan (n&thinsp;=&thinsp;52, as markers of structural alteration in a muscle). Patients were followed up for an average of 1255&thinsp;days (range 581&ndash;1955&thinsp;days) or until death. Patients were grouped accordingly and analysed by (i) all cancer patients vs. HC; (ii) cachectic vs. non-cachectic cancer patients; and (iii) cancer patients surviving &le;1 vs. {\textgreater}1&thinsp;year post operatively.&nbsp; Results&nbsp; Cancer compared with HC patients had reduced mean (standard deviation) total Akt protein [0.49 (0.31) vs. 0.89 (0.17), P&thinsp;=&thinsp;0.001], increased ratio of phosphorylated to total Akt [1.33 (1.04) vs. 0.32 (0.21), P&thinsp;=&thinsp;0.002] and increased expression of GABARAPL1 [1.60 (0.76) vs. 1.10 (0.57), P&thinsp;=&thinsp;0.024]. &beta;-Dystroglycan levels were higher in cachectic compared with non-cachectic cancer patients [1.01 (0.16) vs. 0.87 (0.20), P&thinsp;=&thinsp;0.007]. Survival was shortened in patients with low compared with high MyHC levels (median 316 vs. 1326&thinsp;days, P&thinsp;=&thinsp;0.023) and dystrophin levels (median 341 vs. 660&thinsp;days, P&thinsp;=&thinsp;0.008).&nbsp; Conclusions&nbsp; The present study has identified intramuscular protein level of &beta;-dystroglycan as a potential biomarker of cancer cachexia. Changes in the structural elements of muscle (MyHC or dystrophin) appear to be survival biomarkers

The Emerging Role of Intelectin-1 in Cancer

Background: Intelectin (ITLN) is an adipokine with two homologs—ITLN1 and ITLN2—that has various physiological functions. Studies analyzing the relationship between ITLN and cancer are focused on ITLN1; the available literature on ITLN2 and cancer is limited. This review aims to evaluate the role of ITLN1 in cancer without imposing any inclusion criteria, to examine pro- and anticancer roles for ITLN1 and to discuss whether the relationship between ITLN and cancer is mediated by obesity. Findings: Overall, ITLN1 level was highly variable in cancer patients but different from healthy individuals. Compared with control groups, patients with gastrointestinal and prostate cancer showed increased concentrations of circulating ITLN1, while patients with gynecological, breast, bladder, and renal cancer had lower ITLN1 levels. Several studies also evaluated tissue and tumor expression of ITLN1. In gastrointestinal cancer, ITLN1 was increased in tumor tissue compared with adjacent healthy tissue and elevated in the visceral adipose tissue of patients compared with controls. Consequently, the high levels of circulating ITLN1 might be determined by the tumor and by the cancer-associated weight loss in gastrointestinal cancer. ITLN1 can activate the phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathway. The improper regulation of this pathway may contribute to a series of cellular events that favor tumor development and progression. Obesity has been linked with an increased risk of developing some cancers. Indeed, low circulating ITLN1 levels may be a marker of the metabolic effects of obesity, rather than obesity per se, and might contribute to a deregulation of the PI3K/Akt pathway. Conclusions: ITLN1 could be associated with cancer formation and progression. Since circulating ITLN1 levels are highly variable and differ between cancer types, the local tumor production of ITLN1 could be more relevant in determining malignant behavior. Future research should aim to identify the source of ITLN1 variability, to understand the differences in ITLN1 between distinct tumor types, and to further explore the signaling pathways through which this adipokine influences cancer biology

Gene ontology (GO)-driven inference of candidate proteomic markers associated with muscle atrophy conditions

Skeletal muscle homeostasis is essential for the maintenance of a healthy and active lifestyle. Imbalance in muscle homeostasis has significant consequences such as atrophy, loss of muscle mass, and progressive loss of functions. Aging-related muscle wasting, sarcopenia, and atrophy as a consequence of disease, such as cachexia, reduce the quality of life, increase morbidity and result in an overall poor prognosis. Investigating the muscle proteome related to muscle atrophy diseases has a great potential for diagnostic medicine to identify (i) potential protein biomarkers, and (ii) biological processes and functions common or unique to muscle wasting, cachexia, sarcopenia, and aging alone. We conducted a meta-analysis using gene ontology (GO) analysis of 24 human proteomic studies using tissue samples (skeletal muscle and adipose biopsies) and/or biofluids (serum, plasma, urine). Whilst there were few similarities in protein directionality across studies, biological processes common to conditions were identified. Here we demonstrate that the GO analysis of published human proteomics data can identify processes not revealed by single studies. We recommend the integration of proteomics data from tissue samples and biofluids to yield a comprehensive overview of the human skeletal muscle proteome. This will facilitate the identification of biomarkers and potential pathways of muscle-wasting conditions for use in clinics

A systematic review and Bayesian meta-analysis assessing intelectin-1 in cancer patients and healthy individuals

Background: Intelectin-1 (ITLN1) is an adipokine with multiple physiological functions, including a role in tumour formation and development. Previous research reported variable ITLN1 levels for cancer patients and healthy individuals. This study aimed to compare ITLN1 concentrations between controls and cancer patients and to determine the adipokine’s physiological level. Methods: Five databases were searched in January 2022 for studies that measured the level of ITLN1 in adults that were healthy or diagnosed with any type of cancer. After title, abstract and full-text screening, the methodological quality of the studies was assessed. The extracted data were meta-analysed using the R language and Bayesian statistical techniques. Results: Overall, 15 studies compared circulating ITLN1 levels between healthy individuals (n=3424) and cancer patients (n=1538), but no differences were observed between these studies. ITLN1 was not different between groups in an analysis that evaluated high-quality studies only (n=5). The meta-analysis indicated considerably higher ITLN1 levels in gastrointestinal (i.e., colorectal, pancreatic, gastric) cancer compared to controls, while the other cancer types did not demonstrate differences between groups. The mean ITLN1 level of healthy individuals was 234 ± 21ng/ml (n=136), while the average value in high-quality studies (n=52) was 257 ± 31ng/ml. Conclusion: Different types of cancer showed different circulating ITLN1 patterns. Circulating ITLN1 concentration was higher in gastrointestinal cancer compared to controls, with strong support from the meta-analytical model. Our analysis also determined the mean ITLN1 level in healthy individuals; this is a crucial starting point for understanding how this cytokine associates with diseases. Two-thirds of the studies were of low methodological quality and thus, future work in this field must focus on improved methods. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=303406, identifier CRD42022303406