Explore the vast range of titles available.

Background Muscle wasting during cancer cachexia is mediated by protein degradation via autophagy and ubiquitin‐linked proteolysis. These processes are sensitive to changes in intracellular pH ([pH]i) and reactive oxygen species, which in skeletal muscle are partly regulated by histidyl dipeptides, such as carnosine. These dipeptides, synthesized by the enzyme carnosine synthase (CARNS), remove lipid peroxidation‐derived aldehydes, and buffer [pH]i. Nevertheless, their role in muscle wasting has not been studied. Methods Histidyl dipeptides in the rectus abdominis (RA) muscle and red blood cells (RBCs) of male and female controls (n = 37), weight stable (WS: n = 35), and weight losing (WL; n = 30) upper gastrointestinal cancer (UGIC) patients, were profiled by LC–MS/MS. Expression of enzymes and amino acid transporters, involved in carnosine homeostasis, was measured by Western blotting and RT‐PCR. Skeletal muscle myotubes were treated with Lewis lung carcinoma conditioned medium (LLC CM), and β‐alanine to study the effects of enhancing carnosine production on muscle wasting. Results Carnosine was the predominant dipeptide present in the RA muscle. In controls, carnosine levels were higher in men (7.87 ± 1.98 nmol/mg tissue) compared with women (4.73 ± 1.26 nmol/mg tissue; P = 0.002). In men, carnosine was significantly reduced in both the WS (5.92 ± 2.04 nmol/mg tissue, P = 0.009) and WL (6.15 ± 1.90 nmol/mg tissue; P = 0.030) UGIC patients, compared with controls. In women, carnosine was decreased in the WL UGIC (3.42 ± 1.33 nmol/mg tissue; P = 0.050), compared with WS UGIC patients (4.58 ± 1.57 nmol/mg tissue), and controls (P = 0.025). Carnosine was significantly reduced in the combined WL UGIC patients (5.12 ± 2.15 nmol/mg tissue) compared with controls (6.21 ± 2.24 nmol/mg tissue; P = 0.045). Carnosine was also significantly reduced in the RBCs of WL UGIC patients (0.32 ± 0.24 pmol/mg protein), compared with controls (0.49 ± 0.31 pmol/mg protein, P = 0.037) and WS UGIC patients (0.51 ± 0.40 pmol/mg protein, P = 0.042). Depletion of carnosine diminished the aldehyde‐removing ability in the muscle of WL UGIC patients. Carnosine levels were positively associated with decreases in skeletal muscle index in the WL UGIC patients. CARNS expression was decreased in the muscle of WL UGIC patients and myotubes treated with LLC‐CM. Treatment with β‐alanine, a carnosine precursor, enhanced endogenous carnosine production and decreased ubiquitin‐linked protein degradation in LLC‐CM treated myotubes. Conclusions Depletion of carnosine could contribute to muscle wasting in cancer patients by lowering the aldehyde quenching abilities. Synthesis of carnosine by CARNS in myotubes is particularly affected by tumour derived factors and could contribute to carnosine depletion in WL UGIC patients. Increasing carnosine in skeletal muscle may be an effective therapeutic intervention to prevent muscle wasting in cancer patients.

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40–628). Forty‐nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24‐h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Background Cancer cachexia is a poorly understood metabolic consequence of cancer. During cachexia, different adipose depots demonstrate differential wasting rates. Animal models suggest adipose tissue may be a key driver of muscle wasting through fat–muscle crosstalk, but human studies in this area are lacking. We performed global gene expression profiling of visceral (VAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls. Methods Cachexia was defined as >2% weight loss plus low computed tomography‐muscularity. Biopsies of SAT and VAT were taken from patients undergoing resection for oesophago‐gastric cancer, and healthy controls (n = 16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S microarray and data analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated‐t‐statistic approaches. Category enrichment analysis was used with a tissue‐specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. Enzyme‐linked immunosorbent assay (ELISA) for intelectin‐1 was performed on all VAT samples. The previously‐described cohort plus 12 additional patients from each group also had plasma I = intelectin‐1 ELISA carried out. Results In VAT vs. SAT comparisons, there were 2101, 1722, and 1659 significantly regulated genes in the cachectic, weight stable, and control groups, respectively. There were 2200 significantly regulated genes from VAT in cachectic patients compared with controls. Genes involving inflammation were enriched in cancer and control VAT vs. SAT, although different genes contributed to enrichment in each group. Energy metabolism, fat browning (e.g. uncoupling protein 1), and adipogenesis genes were down‐regulated in cancer VAT (P = 0.043, P = 5.4 × 10−6 and P = 1 × 10−6 respectively). The gene showing the largest difference in expression was ITLN1, the gene that encodes for intelectin‐1 (false discovery rate‐corrected P = 0.0001), a novel adipocytokine associated with weight loss in other contexts. Conclusions SAT and VAT have unique gene expression signatures in cancer and cachexia. VAT is metabolically active in cancer, and intelectin‐1 may be a target for therapeutic manipulation. VAT may play a fundamental role in cachexia, but the down‐regulation of energy metabolism genes implies a limited role for fat browning in cachectic patients, in contrast to pre‐clinical models.

[...]it will highlight the emerging importance of host phenotyping in the delivery of modern oncological care. In the Dolan study, measures of BC were still weakly associated with overall survival even after stratification of patients in to different SI groups. [...]in the van Dijk study, a composite host phenotype consisting of adverse BC and SI was shown to have an additive and synergistic deleterious effect on survival (HR of death >4) and was also statistically independent of the Fong clinical prognostic score (a 5‐point score that assesses nodal status of the primary tumour, the disease‐free interval, the size and number of secondary hepatic tumours, and the preoperative serum CEA level). Despite the apparent separation of survival impact, interestingly, the presence of SI still appears to be correlated with worsened BC. [...]the relationship between BC and SI in cancer appears to be a complex one, for which direct causality is difficult to prove. [...]attempts at standardization of language, as well as technique, would also be beneficial.

Background Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/− computerized tomography‐defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype Methods A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform. Results Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle‐specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P < 0.05). Conclusions The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro‐inflammatory cytokines and the renin–angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

Urine is an ideal medium in which to focus diagnostic cancer research due to the non-invasive nature and ease of sampling. Many large-scale proteomic studies have shown that urine is unexpectedly complex. We hypothesised that novel diagnostic cancer biomarkers could be discovered using a comparative proteomic analysis of pre-existing data. We assembled a database of 100 published datasets of 5,620 urinary proteins, as well as 46 datasets of 8,620 non-redundant proteins derived from kidney and blood proteome analyses. The data were then used to either subtract or compare molecules from a novel urinary proteome profiling dataset that we generated. We identified 1,161 unique proteins in samples from either cancer-bearing or healthy subjects. Subtractive analysis yielded a subset of 44 proteins that were found uniquely in urine from cancer patients, 30 of which were linked previously to cancer. In conclusion, this approach is useful in discovering novel biomarkers in tissues where unrelated profiling data is available. Only a limited disease-specific novel dataset is required to define new targets or substantiate previous findings. We have shared this discovery platform in the form of our Large Scale Screening Resource database, accessible through the Proteomic Analysis DataBase portal (www.PADB.org).

Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.

Cancer cachexia is an unmet clinical need that affects more than 50% of patients with cancer. The systemic inflammatory response, which is mediated by a network of cytokines, has an established role in the genesis and maintenance of cancer as well as in cachexia; yet, the specific role of the cytokine milieu in cachexia requires elucidation. This systematic review aims to examine the relationship between cytokines and the cachexia syndrome in patients with incurable cancer. The databases MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, and Web of Science were searched for studies published between 01/01/2004 and 06/01/2020. Included studies measured cytokines and their relationship with cachexia and related symptoms/signs in adults with incurable cancer. After title screening (n = 5202), the s (n = 1264) and the full‐text studies (n = 322) were reviewed independently by two authors. The quality assessment of the selected papers was conducted using the modified Downs and Black checklist. Overall, 1277 patients with incurable cancer and 155 healthy controls were analysed in the 17 eligible studies. The mean age of the patients was 64 ± 15 (mean ± standard deviation). Only 34% of included participants were female. The included studies were assessed as moderate‐quality to high‐quality evidence (mean quality score: 7.8; range: 5–10). A total of 31 cytokines were examined in this review, of which interleukin‐6 (IL‐6, 14 studies) and tumour necrosis factor‐α (TNF‐α, 12 studies) were the most common. The definitions of cachexia and the weight‐loss thresholds were highly variable across studies. Although the data could not be meta‐analysed due to the high degree of methodological heterogeneity, the findings were discussed in a systematic manner. IL‐6, TNF‐α, and IL‐8 were greater in cachectic patients compared with healthy individuals. Also, IL‐6 levels were higher in cachectic participants as opposed to non‐cachectic patients. Leptin, interferon‐γ, IL‐1β, IL‐10, adiponectin, and ghrelin did not demonstrate any significant difference between groups when individuals with cancer cachexia were compared against non‐cachectic patients or healthy participants. These findings suggest that a network of cytokines, commonly IL‐6, TNF‐α, and IL‐8, are associated with the development of cachexia. Yet, this relationship is not proven to be causative and future studies should opt for longitudinal designs with consistent methodological approaches, as well as adequate techniques for analysing and reporting the results.

Research interests In his own words, Ken wrote that his research focus was “a multidisciplinary approach to the understanding of the mediators and mechanisms of wasting in cancer cachexia”, and that he aimed to perform studies in human integrative physiology that “extend from the molecular level to whole body metabolic studies”. Since his passing, further tributes have been paid in Ken's honour, including the inception of the Ken Fearon oral presentation prize at the ERAS Society UK Conference, and the “Meet the Mentors” session at the excellently titled Ken Fearon Career Café at the Cachexia Conference. [...]Ken was an exceptional person who was able to traverse successfully the worlds of surgery and science.