Cancer is a significant contributor to mortality on a global scale. But what actually causes a cancer patient to die? Here, we summarize the elegant review “Why do cancer patients die?” from Boire and colleagues [1], highlighting severe acute events, systemic factors, and their underlying causes in this context.
Cancer metastasis is often cited as the primary cause of cancer-related mortality [2]. However, this term is over simplistic, not completely precise and not largely supported by published literature. While it is true that patients with metastatic cancer are more likely to die than those with locally confined disease, cancer is intriguingly complex and results in a variety of symptoms, including acute single events or patient deterioration through systemic (organ) dysfunction. To effectively mitigate the destructive impact of cancer, it is essential to gain a deeper understanding of the physiological responses involved and identify more precisely the various cancer-related causalities.
Most advanced cancers can be considered as a chronic and systemic disease. However, it is likely that up to half of the cancer-induced deaths are functionally related to severe events such as vascular coagulation and cardiac failure, obstruction of vital organs, bacterial infection, or paraneoplastic syndromes. For instance, patients with cancer have an elevated risk of thromboembolic events, which may lead acutely to fatal strokes or pulmonary emboli and chronically to coronary heart disease and, subsequently, heart failure. Furthermore, congestive heart failure may also occur due to excessive loss of cardiac muscle, a phenomenon associated with and often caused by cancer cachexia. In addition, growing tumours can impair vital organ function. This can particularly be observed in primary brain cancers, where uncontrolled growth increases intracranial pressure, which can ultimately cause irreversible brain damage. A similar phenomenon can be observed in the lung, where pulmonary metastases can reduce gas exchange, resulting in severe respiratory distress. Because cancer patients often have compromised immune systems, both from the disease itself and from cancer therapy, they are at an increased risk for bacterial, viral, or fungal infections that can cause life-threatening complications. Moreover, paraneoplastic syndromes can irreversibly damage critical organs as a consequence of tissue dysfunction in the surrounding area of the tumour. For example, an inappropriate production of pro-inflammatory cytokines, hormones, or antibodies can result in severe adverse effects, potentially leading to critical organ damage and ultimately, death. Despite the principle objective of cancer treatments to target tumour cells, almost every therapeutic agent has unwanted adverse effects, including acute neutropenia (potentially leading to bacterial sepsis) or platelet depletion, which can also be life-threatening in some cases.
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Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy. OPMD is caused by a short alanine expansion in the gene encoding for poly(A) binding protein nuclear 1 (PABPN1) forming insoluble nuclear aggregates. OPMD patients are predominantly heterozygous, and the knock-in Pabpn1+/A17 mouse, which expresses one copy of the expanded Pabpn1 gene under the PABPN1 promoter genetically, mimics OPMD. Insights into the A17/+ mouse model are necessary to evaluate its preclinical value and test therapeutics for OPMD. Here, we performed a natural disease history study for the A17/+ model.
We combined muscle force measurements of the tibialis anterior with magnetic resonance imaging (MRI) measurements of the calf muscles made in 4-, 8- and 12-month-old wild-type and A17/+ mice. These measures were complemented by muscle histopathology staining and image quantification to detect PABPN1 aggregates and to assess muscle wasting. Statistical significance between genotypes over the three time points was assessed using ANOVA or Student's t test.
PABPN1 nuclear aggregates were found in the 12-month-old A17/+ mice at similar quantities of ~2% across hindlimb muscles. We did not observe changes in muscle strength of the tibialis anterior in A17/+ mice. MRI analyses of hindlimb muscles revealed no metabolic difference, no fatty infiltration and limited muscle atrophy between A17/+ and +/+ mice. The plantaris muscle in A17/+ showed 30% atrophy at 12 months of age, which was corroborated by a 30% myofiber shift in the myosin heavy chain −2A to −2B ratio. Histopathologic staining did not reveal muscle wasting in the hindlimb muscles.
Despite the presence of PABPN1 insoluble aggregates in hindlimb muscles, muscle involvement in the 12-month-old A17/+ mice was limited. Our results query the usefulness of A17/+ hindlimb muscles for preclinical studies.
Fairman, C. M., Lønbro, S., Cardaci, T. D., VanderVeen, B. N., Nilsen, T. S., and Murphy, A. E. (2022) Muscle wasting in cancer: opportunities and challenges for exercise in clinical cancer trials. JCSM Communications, 5: 52–67, https://doi.org/10.1002/rco2.56.
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Loss of muscle mass and muscle strength are key characteristics of age-related muscle decline. Dietary protein is a key nutrient that supports optimal muscle health. However, there is a strong argument to reduce intake of animal protein for health and environmental reasons. The effects of vegetarian diets on determinants of muscle health are not clear. This systematic review aimed to investigate the impact of vegetarian diets on muscle mass and muscle strength.
A systematic literature search of the CINAHL, Medline, Scopus and Web of Science Core Collection databases, as well as the Cochrane Central Register of Controlled Trials, was conducted according to PRISMA guidelines. Studies reporting the effects of vegetarian diets on muscle mass and strength were analysed.
A total of three interventions and 11 observational studied were eligible to be included (n = 14) in this review. Five of the 12 studies that reported muscle mass found no difference in muscle mass between participants consuming an omnivorous versus vegetarian diet. One observational study reported higher muscle mass for vegetarians. Of the studies that reported muscle strength (n = 5), three reported no difference between participants consuming an omnivorous and vegetarian diet.
Half of the included studies reported no difference in muscle mass or strength between vegetarians and omnivores. Further high-quality studies are needed to better understand the relationship between vegetarian diets and determinants of muscle health.
Sarcopenia, the loss of muscle strength and mass with age, is a major cause of morbidity for older people. Dietary nitrate supplementation has been proposed as an intervention to improve skeletal muscle function via action as nitric oxide (NO) donors. However, the effect of nitrate supplementation on physical performance and muscle strength in older people is unclear. We aimed to systematically review evidence on whether dietary nitrate supplementation improves markers of muscle strength, muscle mass and physical performance in older people.
We conducted a systematic review of randomised controlled trials according to a prespecified protocol by two reviewers. We included interventional studies using dietary nitrate supplementation, mean participant age of >60 years, with or without muscle weakness. Outcomes of interest were physical performance, muscle strength and muscle mass. Risk of bias was assessed using a modified version of the Cochrane Risk of Bias tool. Results were grouped by intervention and outcome measures and were described by narrative synthesis.
Twenty-eight studies were included, with a size range of 8–72 participants. Intervention duration ranged from a single dose to 12 weeks. Seven studies were in healthy older people. Most studies had a high or unclear risk of bias; three had a low risk of bias. One-hundred-two outcomes were reported; 67 were related to physical performance, and 35 were related to muscle strength. No included study measured muscle mass. Thirty-three outcomes showed significant improvement, two showed significant worsening and 67 showed no statistically significant difference. Meta-analysis was not possible due to data heterogeneity. Subgroup analyses for different doses of nitrate (above or below 10 mmol nitrate per day), duration of treatment or specific commonly measured outcomes did not indicate any subgroup more likely to show positive results. The proportion of positive outcomes was similar in studies using beetroot extract, nitrate alone or exercise as a co-intervention.
Current evidence is insufficient to decide if dietary nitrate supplementation improves skeletal muscle function in older people. Future studies should be longer, larger and target older people with sarcopenia or frailty.
Cancer cachexia, systemic inflammation and muscle wasting are associated with poor survival in non–small cell lung cancer (NSCLC) patients (pts). We hypothesized whether neutrophil-to-lymphocyte ratio (NLR) and intramuscular adipose tissue/skeletal muscle index (IMAT/SMI) would predict prognosis in metastatic NSCLC (mNSCLC). In addition, we verified the role of a cancer cachexia questionnaire (EORTC-QLQ-CAX24) in the survival prediction.
We analysed a prospective cohort of 128 treatment-naive mNSCLC pts (April 2017 to May 2020). We evaluated QoL using the EORTC-QLQ-C30 and EORTC-QLQ-CAX24 scales. We used the baseline NLR as a surrogate of systemic inflammation. We did evaluate IMAT/SMI using baseline plain computed tomography imaging. Cox multivariate regression, including age, sex, ECOG-PS and histology as covariates, was performed.
Elevated NLR (hazard ratio [HR] 1.26, 95% confidence interval [CI]: 1.01–1.59, p = 0.038), IMAT/SMI ratio (HR 1.37, 95% CI: 1.03–1.84, p = 0.032) and high CAX24 scores for food aversion (HR 1.52, 95% CI: 1.13–2.03, p = 0.006) were associated with worse prognosis in mNSCLC. Indeed, higher ECOG-PS (Spearman rho = 0.208, p = 0.027), CAX24 scores for food aversion (Spearman rho = 0.197, p = 0.036), loss of control (Spearman rho = 0.212, p = 0.024) and eating and weight loss worry domains (Spearman rho = 0.219, p = 0.020) were associated with elevated NLR levels.
Elevated NLR, IMAT/SMI ratio and CAX24 score for food aversion are independently associated with worse survival in mNSCLC. These data underscored the importance of cachexia features as negative prognostic factors in mNSCLC and revealed the EORTC-QLQ-CAX24 questionnaire as a new tool for helping clinical decision-making.
Trial Registration: ClinicalTrials.gov identifier: NCT03960034 and NCT04306094
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