Alessio Molfino

Omega-3 fatty acids in cancer.

Purpose of reviewSignificant achievements have been obtained in cancer treatment, but the clinical relevance of drug approach in daily practice remains questionable due to the high costs, limited efficacy, and negligible influence on quality of life. A new concept is emerging which is based on the early combination of chemotherapy and nutrition therapy. Recent findingsInflammation dictates tumour initiation, progression and growth. Omega-3 fatty acids exert anti-inflammatory effects, and therefore recent studies investigated their role in cancer prevention, in cancer cachexia treatment and in enhancement of antitumour therapies. Limited evidence suggests a role for omega-3 fatty acid supplementation in cancer prevention, but they have been shown to preserve muscle mass and function in cancer patients even during active treatment. During chemotherapy, omega-3 fatty acids may contribute to a reduced inflammatory response, but whether cancer treatment toxicity can be prevented remains to be assessed. Finally, small studies showed that omega-3 fatty acids increase response rate to chemotherapy. SummaryCombination of chemotherapy and omega-3 supplementation appears an effective strategy to enhance the clinical outcome of cancer patients in their curative and palliative clinical trajectory.

Anorexia in Hemodialysis Patients: The Possible Role of Des-Acyl Ghrelin

Background: Anorexia is frequently found in end-stage renal disease and is a reliable predictor of morbidity and mortality in hemodialysis (HD) patients. The pathogenesis of anorexia is complex and the appetite-modulating hormone ghrelin could be involved. Two forms of circulating ghrelin have been described: acylated ghrelin (<10% of circulating ghrelin) which promotes food intake, and des-acyl ghrelin which induces a negative energy balance. The aim of this cross-sectional study is to clarify whether anorexia and body weight change in HD patients relate to plasma des-acyl ghrelin levels. Methods: 34 HD patients and 15 healthy controls were studied. The presence of anorexia was assessed by a questionnaire. Serum des-acyl ghrelin was measured in HD patients and in 15 body mass index-, sex- and age-matched controls by ELISA. Energy intake was assessed by a 3-day dietary diary, and fat-free mass (FFM) was evaluated by body impedance analysis. Data have been statistically analyzed and are presented as mean ± SD. Results: 14 patients (41%) were found to be anorexic, and 20 patients (59%) non-anorexic. Energy intake (kcal/day) was significantly lower in anorexic than in non-anorexic patients (1,682 ± 241 vs. 1,972.50 ± 490; p < 0.05). FFM (%) was lower in anorexic than in non-anorexic patients (65.8 ± 4.4 vs. 70.9 ± 8.7; p = 0.05). Plasma des-acyl ghrelin levels (fmol/ml) were significantly higher in HD patients than in controls (214.88 ± 154.24 vs. 128.93 ± 51.07; p < 0.05), and in anorexic HD patients than in non-anorexic (301.7 ± 162.4 vs. 159.1 ± 115.5; p < 0.01). Conclusion: Anorexia is highly prevalent among HD patients and des-acyl ghrelin could be involved in its pathogenesis.

Body mass index is related to autonomic nervous system activity as measured by heart rate variability

Autonomic nervous system activity is involved in body weight regulation. We assessed whether the body mass index (BMI) is related to the autonomic nervous system activity as assessed by heart rate variability (HRV). Twenty-five adult normotensive, euglycemic healthy males (M) and females (F) were studied (M/F=13/12). BMI was assessed in each individual. HRV was assessed and the domains of low frequencies (LF, index of the sympathetic modulation) and high frequencies (HF, index of the parasympathetic modulation) were measured. Data were statistically analyzed and are presented as mean±s.d. Mean BMI did not correlate with either HF or LF. It inversely related to HF (r=−0.50, P<0.01), whereas its relationship with LF was marginally significant (r=−0.39, P=0.05). The HF in individuals with BMI <20 kg/m2 was significantly higher from those measured in the remaining subjects (P<0.05). The results support the role of parasympathetic activity in influencing BMI through likely modulation of body weight.

The “parallel pathway”: a novel nutritional and metabolic approach to cancer patients

Cancer-associated malnutrition results from a deadly combination of anorexia, which leads to reduced food intake, and derangements of host metabolism inducing body weight loss, and hindering its reversal with nutrient supplementation. Cancer patients often experience both anorexia and weight loss, contributing to the onset of the clinical feature named as anorexia–cachexia syndrome. This condition has a negative impact upon patients’ nutritional status. The pathogenesis of the anorexia–cachexia syndrome is multifactorial, and is related to: tumour-derived factors, host-derived factors inducing metabolic derangements, and side effects of anticancer therapies. In addition, the lack of awareness of cancer patients’ nutritional issues and status by many oncologists, frequently results in progressive weight loss going undiagnosed until it becomes severe. The critical involvement of host inflammatory response in the development of weight loss, and, in particular, lean body mass depletion, limits the response to the provision of standard nutrition support. A novel nutritional and metabolic approach, named “parallel pathway”, has been devised that may help maintain or improve nutritional status, and prevent or delay the onset of cancer cachexia. Such an approach may improve tolerance to aggressive anticancer therapies, and ameliorate the functional capacity and quality of life even in advanced disease stages. The “parallel pathway” implies a multiprofessional and multimodal approach aimed at ensuring early, appropriate and continuous nutritional and metabolic support to cancer patients in any phase of their cancer journey.

Malnutrition and wasting in renal disease.

Purpose of reviewMalnutrition and accelerated catabolism frequently complicate chronic kidney disease and end-stage renal disease. This review provides an update on the recent advances in the understanding of the mechanisms underlying protein–energy wasting, both in experimental and human models, and on the currently available therapeutic approaches. Recent findingsIncreased levels of circulating cytokines, metabolic acidosis, oxidative stress and insulin resistance all appear to be variably implicated in muscle protein breakdown during end-stage renal disease and dialysis. The individual role of each component in the pathogenesis of chronic kidney disease-related wasting is still unclear, but recent clinical data show a positive relationship between inflammation and muscle protein catabolism as a major contributing factor. SummaryThe basis for appropriate therapeutic approaches to protein–energy wasting in chronic kidney disease and end-stage renal disease relies entirely on the understanding of its pathophysiology. Our knowledge of the pathogenesis of malnutrition and hypercatabolism in renal disease is still limited and mostly based on experimental data, but the currently available evidence suggests that multimodal preventive and therapeutic strategies should be entertained.

The Role for Dietary Omega-3 Fatty Acids Supplementation in Older Adults

Optimal nutrition is one of the most important determinants of healthier ageing, reducing the risk of disability, maintaining mental and physical functions, and thus preserving and ensuring a better quality of life. Dietary intake and nutrient absorption decline with age, thus increasing the risk of malnutrition, morbidity and mortality. Specific nutrients, particularly long-chain omega-3 polyunsaturated fatty acids (PUFAs), might have the potential of preventing and reducing co-morbidities in older adults. Omega-3 PUFAs are able to modulate inflammation, hyperlipidemia, platelet aggregation, and hypertension. Different mechanisms contribute to these effects, including conditioning cell membrane function and composition, eicosanoid production, and gene expression. The present review analyzes the influence of omega-3 PUFAs status and intake on brain function, cardiovascular system, immune function, muscle performance and bone health in older adults. Omega-3 FAs may have substantial benefits in reducing the risk of cognitive decline in older people. The available data encourage higher intakes of omega-3 PUFAs in the diet or via specific supplements. More studies are needed to confirm the role of omega-3 FAs in maintaining bone health and preventing the loss of muscle mass and function associated with ageing. In summary, omega-3 PUFAs are now identified as potential key nutrients, safe and effective in the treatment and prevention of several negative consequences of ageing.

Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism.

BACKGROUND Reduced circulating and tissue carnitine levels, possibly leading to impaired mitochondrial function, have been postulated to be involved in the pathogenesis of insulin resistance. However, whether L-carnitine administration may improve insulin sensitivity in patients with impaired fasting glucose (IFG) or type 2 diabetes mellitus (DM-2) is still controversial. The aim of the study was to explore the role of L-carnitine supplementation in influencing insulin sensitivity. METHODS A randomized controlled study involving adult outpatients was designed. Adult patients referred to the outpatient clinic and within 10 days of the diagnosis of IFG or DM-2 were consecutively enrolled. Exclusion criteria were concomitant antidiabetic therapy and modifications of lifestyle during the previous 4 weeks. Patients were randomly assigned to receive a hypocaloric diet for 10 days (group C; n = 8) or the same dietetic regimen in addition to oral L-carnitine (2 g twice daily) supplementation (group LC; n = 8). Oral glucose tolerance test (OGTT), fasting plasma insulin levels, and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed at the beginning and end of the study. Data were statistically analyzed using the Student t test for paired and unpaired data. RESULTS OGTT at 2 hours improved in both groups. Only in the L-carnitine-supplemented group did plasma insulin levels and HOMA-IR significantly decrease when compared to baseline values. CONCLUSIONS Considering the role of caloric restriction in increasing the intestinal uptake of carnitine, the results suggest that oral L-carnitine administration, when associated with a hypocaloric feeding regimen, improves insulin resistance and may represent an adjunctive treatment for IFG and DM-2.

Novel therapeutic options for cachexia and sarcopenia

ABSTRACT Introduction: Cachexia and sarcopenia are conditions phenotypically characterized by muscle loss and represent a factor of poor prognosis, increasing patients’ morbidity and mortality. Cachectic and sarcopenic patients often suffer from low quality of life, presenting lower muscle strength and appetite loss, which makes research on novel treatment strategies to ameliorate clinical response including patient’s symptoms, the objective of scientific interest. Areas covered: This article covers recent developments in the area of cachexia and sarcopenia treatment and therapeutic interventions, targeting central nervous system involvement, key inflammatory and muscle-specific metabolic pathways. Expert opinion: A number of promising agents have being evaluated, such as enobosarm, a selected androgen receptor modulator, and anamorelin, a ghrelin agonist which have been recently studied in phase III trials. These and other agents (i.e., infliximab, tocilizumab, MABp1, bimagrumab) have shown significant impact on reversal of skeletal muscle loss, but limited effect on physical function. In the last few years advancement in the number and type of potential treatments for cachexia and sarcopenia have been obtained and we have now available more data on measurable effects of several drugs on patients’ nutritional and metabolic parameters and outcomes.

Antimyopathic effects of carnitine and nicotine

Purpose of reviewThe clinical course of most chronic diseases is associated with declined energy intake and nutrient-resistant progressive myopathy, characterized by accelerated proteolysis and impaired function. This anorexia/cachexia syndrome leads to deterioration of quality of life, and increased morbidity and mortality. The clinical efficacy of currently available therapeutic strategies is limited and more effective treatments are needed. Recent findingsChronic systemic inflammation, triggered and sustained by cytokines, and increased oxidative stress contribute to the pathogenesis of the anorexia/cachexia syndrome. Carnitine and nicotine have recently been tested as immunomodulating and antioxidant agents. In particular, carnitine supplementation has been shown to reduce chronic inflammation and oxidative stress in hemodialysis patients and, in cancer patients, yielding to reduced fatigue and improved outcome. Nicotine is able to induce the anti-inflammatory activity of the vagus nerve. In animal models of sepsis and cancer, the nicotine-induced supplementation resulted in better protection of nutritional status and improved survival. SummaryIn the continuous effort to develop more efficacious strategies against the anorexia/cachexia syndrome, carnitine and nicotine may represent a further therapeutic tool. More clinical studies are needed, however, before their use can be routinely suggested.

Nutritional and metabolic support in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease and the most devastating neurodegenerative disorder. ALS is characterized by progressive paralysis and respiratory failure leading to death within 3 to 5 years after its onset. Protein-energy malnutrition is a frequent finding in ALS. The pathogenesis of protein-energy malnutrition in ALS is multifactorial. Muscle atrophy, hypophagia, dysphagia, and hypermetabolism play a role in determining the deterioration of nutritional status. A multidisciplinary approach is crucial to set an appropriate plan for metabolic and nutritional support in ALS. Nutritional management incorporates a continuous assessment and implementation of dietary modifications throughout the duration of the disease. The nutritional and metabolic approaches to ALS should start when the diagnosis of ALS is made and should become an integral part of the continuous care to the patient, including nutritional surveillance, dietary counseling, management of dysphagia, and enteral nutrition when needed. Parenteral nutrition is rarely indicated. Standard polymeric enteral formulas are routinely used, usually providing 25 to 30 kcal/kg and protein 0.8 to 1.2 g /kg per day. The use of fiber-enriched formulas may help prevent constipation. However, considering the complex metabolic abnormalities of ALS, standard and/or fiber-enriched formulas might not be sufficient to achieve optimal metabolic and nutritional support. Based on the most recent clinical and experimental evidence, it is tempting to hypothesize that personalized nutritional support including specific nutritional substrates could act on disease progression and improve the quality of life and the response to the few and yet scarcely effective, currently available pharmacologic therapies.