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Cancer Cachexia and Related Metabolic Dysfunction.
Fonseca, GWPD, Farkas, J, Dora, E, von Haehling, S, Lainscak, M
International journal of molecular sciences. 2020;(7)
Abstract
Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer-dependent on the underlying type of cancer-and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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2.
Investigational drugs for the treatment of cancer cachexia: a focus on phase I and phase II clinical trials.
Molfino, A, Amabile, MI, Giorgi, A, Monti, M, D'Andrea, V, Muscaritoli, M
Expert opinion on investigational drugs. 2019;(8):733-740
Abstract
Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue. Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life. Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.
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3.
Nonparathyroid Hypercalcemia.
Goltzman, D
Frontiers of hormone research. 2019;:77-90
Abstract
Primary hyperparathyroidism is among the most common causes of hypercalcemia. However, ingestion of medication, including hydrochlorathiazide, lithium, and foscarnet, excessive vitamin A ingestion, endocrinopathies such as hyperthyroidism, adrenal insufficiency, and acromegaly, abnormal nutrient intake such as parenteral nutrition in preterm infants and milk-alkali syndrome, and prolonged immobilization have all been associated with hypercalcemia. The most common cause of nonparathyroid hypercalcemia is neoplasia. Hypercalcemia is generally due to the secretion of parathyroid hormone (PTH)-related peptide (PTHrP) by a wide variety of nonmetastatic solid tumors, including squamous cell tumors but also hematologic tumors. PTHrP, although encoded by a distinct gene, shares amino acid sequence homology with PTH in the amino-terminal domain, which allows it to cross-react at a common G protein receptor, the type 1 PTH/PTHrP receptor (PTHR1), resulting in similar skeletal effects and effects on calcium and phosphorus metabolism. Increased PTHrP action with hypercalcemia may be seen in the benign disease Jansen's metaphyseal chondrodysplasia due to a gain-of-function mutation in PTHR1. Another humoral factor, 1,25-dihyroxyvitamin D [1,25(OH)2D] may be produced by lymphomas, but also by benign granulomatous disorders and may also cause hypercalcemia when its metabolism is genetically impaired. Vitamin D intoxication may cause hypercalcemia due to overproduction of the metabolite, 25 hydroxyvitamin D, apparently in the absence of conversion to 1,25(OH)2D. Malignancies metastatic to bone or arising in bone (such as multiple myeloma) may produce a variety of growth factors and cytokines, in addition to PTHrP, which can contribute to tumor growth as well as osteolysis and hypercalcemia.
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4.
Protective Effects of Omega-3 Fatty Acids in Cancer-Related Complications.
Freitas, RDS, Campos, MM
Nutrients. 2019;(5)
Abstract
Omega-3 polyunsaturated fatty acids (PUFAs) are considered immunonutrients and are commonly used in the nutritional therapy of cancer patients due to their ample biological effects. Omega-3 PUFAs play essential roles in cell signaling and in the cell structure and fluidity of membranes. They participate in the resolution of inflammation and have anti-inflammatory and antinociceptive effects. Additionally, they can act as agonists of G protein-coupled receptors, namely, GPR40/FFA1 and GPR120/FFA4. Cancer patients undergo complications, such as anorexia-cachexia syndrome, pain, depression, and paraneoplastic syndromes. Interestingly, the 2017 European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines for cancer patients only discuss the use of omega-3 PUFAs for cancer-cachexia treatment, leaving aside other cancer-related complications that could potentially be managed by omega-3 PUFA supplementation. This critical review aimed to discuss the effects and the possible underlying mechanisms of omega-3 PUFA supplementation in cancer-related complications. Data compilation in this critical review indicates that further investigation is still required to assess the factual benefits of omega-3 PUFA supplementation in cancer-associated illnesses. Nevertheless, preclinical evidence reveals that omega-3 PUFAs and their metabolites might modulate pivotal pathways underlying complications secondary to cancer, indicating that this is a promising field of knowledge to be explored.
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5.
Medical Cannabinoids for Cancer Cachexia: A Systematic Review and Meta-Analysis.
Wang, J, Wang, Y, Tong, M, Pan, H, Li, D
BioMed research international. 2019;:2864384
Abstract
OBJECTIVES Cancer cachexia (CCA) is an intractable and ineffective metabolic syndrome that attacks 50-80% of cancer patients. It reduces patient's life quality, affects the efficacy of treatment, and then increases their mortality; however, there are no established therapeutic strategies for CCA in the world. In this study, we assess the positive and negative effects of cannabinoid in the treatment of CCA. METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Web of Science, and PubMed up to December 2017. RESULTS Of the 256 screened studies, three studies with a total of 592 participants were included. Compared with placebo, cannabinoid increased the appetite (MD 0.27, 95% CI -0.51 to 1.04; n= 3) but failed to improve the overall quality of life (QOL; MD -12.39, 95% CI [-24.21 to -0.57; n = 2), and a total of 441 patients had 607 adverse events (AEs; 496 in the cannabinoid group and 111 in the placebo group). CONCLUSIONS Our analysis showed cannabinoid is effective in increasing appetite in cancer patients. However, it declines the quality of life, which may be due to the side effects of cannabinoid.
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6.
Extra-Skeletal Effects of Vitamin D.
Bouillon, R
Frontiers of hormone research. 2018;:72-88
Abstract
There are very solid data to confirm that the vitamin D endocrine system is important not only for calcium transport or bone homeostasis but also for operational functions in most cells of the body. Preclinical studies convincingly demonstrated coherent actions of the vitamin D endocrine system on the proliferation/differentiation of most cells (and thus possibly on the evolution of cancer). The most plausible target tissues include skeletal and cardiac muscle, all immune cells, many cells involved in cardiovascular homeostasis, brain cells, and reproductive tissues. These data have been generated in models of (near) total absence of vitamin D action or when exposed to very high concentrations of the active hormone, 1,25-dihydroxyvitamin D or its analogs. In humans, observational data frequently demonstrate a link between poor vitamin D status and a large number of major human diseases such as cancer, muscle weakness and falls, infections or autoimmune diseases, hypertension and cardiovascular risks and events, obesity, diabetes and all aspects of the metabolic syndrome, and other health problems. Intervention studies so far have not convincingly demonstrated a positive effect on such extra-skeletal health outcomes. A very large number of ongoing studies (about 3,000), however, should help to clarify the role of vitamin D on the musculoskeletal system and on global health.
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7.
How much does reduced food intake contribute to cancer-associated weight loss?
Martin, L, Kubrak, C
Current opinion in supportive and palliative care. 2018;(4):410-419
Abstract
PURPOSE OF REVIEW An international consensus group defined cancer cachexia as a syndrome of involuntary weight loss, characterized by loss of skeletal muscle (with or without fat loss), which is driven by a variable combination of reduced food intake and altered metabolism.This review presents recent studies that evaluated the contribution of reduced food intake to cancer-associated weight loss. RECENT FINDINGS Four studies examined food intake in relation to weight loss. Heterogeneity among studies rendered aggregation and interpretation of results challenging. Despite these limitations, reduced food intake had consistent significant, independent associations with weight loss. However, reduced food intake did not explain all the variation in weight loss; and limited data suggests factors related to alterations in metabolism (e.g. increased resting energy expenditure, systemic inflammation) are also contributing to weight loss. SUMMARY Reduced food intake is a significant contributor to cancer-associated weight loss. Understanding the magnitude of the association between food intake and weight loss may improve when it is possible to account for alterations in metabolism. Efforts to align clinical assessments of food intake to reduce heterogeneity are needed.