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

The tip of the iceberg: a giant pelvic atypical lipoma presenting as a sciatic hernia

BACKGROUND: This case report highlights two unusual surgical phenomena: lipoma-like well-differentiated liposarcomas and sciatic hernias. It illustrates the need to be aware that hernias may not always simply contain intra-abdominal viscera. CASE PRESENTATION: A 36 year old woman presented with an expanding, yet reducible, right gluteal mass, indicative of a sciatic hernia. However, magnetic resonance imaging demonstrated a large intra- and extra-pelvic fatty mass traversing the greater sciatic foramen. The tumour was surgically removed through an abdomino-perineal approach. Subsequent pathological examination revealed an atypical lipomatous tumour (synonym: lipoma-like well-differentiated liposarcoma). The patient remains free from recurrence two years following her surgery. CONCLUSION: The presence of a gluteal mass should always suggest the possibility of a sciatic hernia. However, in this case, the hernia consisted of an atypical lipoma spanning the greater sciatic foramen. Although lipoma-like well-differentiated liposarcomas have only a low potential for recurrence, the variable nature of fatty tumours demands that patients require regular clinical and radiological review

Adipose depot gene expression identifies intelectin-1 as potential mediator of the metabolic response to cancer and cachexia

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

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

Validated screening tools for the assessment of cachexia, sarcopenia, and malnutrition: a systematic review

Background: There is great overlap between the presentation of cachexia, sarcopenia, and malnutrition. Distinguishing between these conditions would allow for better targeted treatment for patients. Objectives: The aim was to systematically review validated screening tools for cachexia, sarcopenia, and malnutrition in adults and, if a combined tool is absent, make suggestions for the generation of a novel screening tool. Design: A systematic search was performed in Ovid Medline, EMBASE, CINAHL, and Web of Science. Two reviewers performed data extraction independently. Each tool was judged for validity against a reference method. Psychometric evaluation was performed as was appraisal of the tools' ability to assess the patient against consensus definitions. Results: Thirty-eight studies described 22 validated screening tools. The Cachexia score (CASCO) was the only validated screening tool for cachexia and performed well against the consensus definition. Two tools assessed sarcopenia [the Short Portable Sarcopenia Measure (SPSM) and the SARC-F (Strength, Assistance with walking, Rise from a chair, Climb stairs, and Falls)] and scored well against the 1998 Baumgartner definition. The SPSM required large amounts of equipment, and the SARC-F had a low sensitivity. Nineteen tools screened for malnutrition. The 3-Minute Nutrition Score performed best, meeting consensus definition criteria (European Society for Clinical Nutrition and Metabolism) and having a sensitivity and specificity of >80%. No tool contained all of the currently accepted components to screen for all 3 conditions. Only 3 tools were validated against cross-sectional imaging, a clinical tool that is gaining wider interest in body-composition analysis. Conclusions: No single validated screening tool can be implemented for the simultaneous assessment of cachexia, sarcopenia, and malnutrition. The development of a tool that encompasses consensus definition criteria and directs clinicians toward the underlying diagnosis would be optimal to target treatment and improve outcomes. We propose that tool should incorporate a stepwise assessment of nutritional status, oral intake, disease status, age, muscle mass and function, and metabolic derangement