Inflammatory Cachexia Research Articles

Tocilizumab for advanced non-small cell lung cancer with concomitant inflammatory cachexia: A single-centre study.

2647 Background: Cancer cachexia significantly contributes to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Inflammatory pathways mediated by interleukin-6 play a crucial role in the development of cancer cachexia. This study aimed to investigate the use of tocilizumab, an anti-interleukin-6 receptor inhibitor, in the management of NSCLC with coexisting inflammatory cachexia. Methods: Data were collected from patients with NSCLC and concurrent inflammatory cachexia who received either tocilizumab plus anti-tumour therapy or anti-tumour therapy alone. The primary endpoints were overall survival (OS) and improved modified Glasgow Prognostic Score (mGPS) at week 12, while secondary endpoints included changes from baseline over 12 weeks in body weight, albumin, C-reactive protein and mGPS. Qualitative improvements in patient self-rated appetite and fatigue were reported as exploratory analysis. Results: The study included 49 patients diagnosed with NSCLC and coexisting inflammatory cachexia, of which 26 received tocilizumab in combination with anti-tumour therapy, and 23 received anti-tumour therapy alone. The tocilizumab group demonstrated a significantly longer median OS compared to the control group (15.1 vs. 3.2 months; hazard ratio 0.18, 95% confidence interval 0.08-0.38; p < 0.001). The rate of patients surviving with mGPS improvement at week 12 was significantly higher in the tocilizumab group than in the control group (OR 168.7, 95% CI 16.3-1746.5; p < 0.001). Over the 12-week period, significant improvements were observed in body weight, albumin, C-reactive protein, and mGPS in the tocilizumab group compared to the control group. Additionally, the tocilizumab group displayed significantly higher rates of improvement in appetite and fatigue. The incidence of grade 3 or higher adverse events was 34.6% in the tocilizumab group compared to 78.3% in the control group. Tocilizumab-related adverse events were observed in three patients (11.5%), including two cases of neutropenia and one case of skin and subcutaneous tissue infection. Conclusions: Tocilizumab demonstrated significant benefits in survival and various clinical parameters, including body weight, albumin, C-reactive protein, mGPS, and symptom burden in patients with NSCLC and concurrent inflammatory cachexia. Given the existing unmet medical need for effective interventions for cancer cachexia, tocilizumab may be considered as a potential treatment option.

Renal Rehabilitation: Present and Future Perspectives.

Chronic kidney disease (CKD) is a global health problem. In patients with CKD, exercise endurance is decreased, especially as renal dysfunction advances. This is due to the combined effects of protein-energy wasting, uremic acidosis, and inflammatory cachexia, which lead to sarcopenia and are aggravated by a sedentary lifestyle, resulting in a progressive downward spiral of deconditioning. Renal rehabilitation (RR) is a coordinated, multifaceted intervention designed to optimize a patient's physical, psychological, and social functioning, as well as to stabilize, slow, or even reverse the progression of renal deterioration, improving exercise tolerance and preventing the onset and worsening of heart failure, thereby reducing morbidity and mortality. This review focused on the history and benefits of RR in patients with CKD. Based on current evidence, RR is an effective, feasible, and safe secondary prevention strategy in CKD. RR is a promising model for a new field of rehabilitation. Therefore, efforts to increase RR implementation rates are urgently needed.

Lenalidomide in cancer cachexia: a randomized trial of an anticancer drug applied for anti‐cachexia

AbstractBackgroundCancer cachexia (CC) impacts quality of life, physical function, anticancer treatment response, and survival. Inflammation is a prominent pathomechanism of CC. This small‐scale study sets out to investigate the immunomodulatory drug lenalidomide in inflammatory CC in a randomized, double‐blind, placebo‐controlled trial.MethodsPatients with advanced solid malignancies, documented weight loss, no or unchanged anticancer treatment, and C‐reactive protein > 30 mg/L were included. In a 2:2:1 randomization, patients received either lenalidomide 25 mg once daily or C‐reactive protein‐guided dose, starting with 5 mg lenalidomide once daily or placebo once a day for 8 weeks. Dose adaption and safety were assessed twice a week. Treatment response was defined as an increase of lean body mass of more than 2% in a lower lumbar computed tomography and an increase in dynamometer‐assessed handgrip strength of 4 kg. Secondary endpoints included adverse events, C‐reactive protein response, nutritional intake, and symptoms.ResultsOf 24 eligible patients, 16 were included (25% female). At baseline, the mean age was 67 (range 51–88) years, and mean body weight was 64.7 kg (range 39.8–87.2 kg). Five were diagnosed with mesothelioma, two with non‐small‐cell lung cancer, two with renal cell carcinoma, two with neuroendocrine tumours, and five with other malignancies. Mean survival was 43 days. Eleven adverse events (four of which were severe) were recorded with a probable link to study participation. Nine patients completed the study. No participant showed a treatment response. C‐reactive protein‐guided dosing did not result in lower doses of lenalidomide. Lean body mass decreased less in the treatment groups. For the lenalidomide and placebo groups respectively, handgrip strength decreased by 2.3 vs. 5.5 kg, nutritional intake decreased by 249 vs. 32 kcal/day, and C‐reactive protein increased by 35 mg/dL vs. decreased by 17 mg/dL. The study was closed prematurely due to slow accrual and the need for concurrent anticancer treatments.ConclusionsNo treatment response on muscle mass and muscle strength was observed with lenalidomide. Because of several limiting factors, including low recruitment caused in part by an ambitious study design and concomitant anticancer treatment, this study did not generate adequate data to draw reliable conclusions.

IGF-1 and IGFBP-3 in Inflammatory Cachexia.

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic–growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic–GH–IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis. Day 8 onwards of CFA administration, rats were injected daily with agmatine for next 7days, and arthritis score, body weights and food intake were monitored daily (g). Since cachexia is known to produce severe inflammation, malnutrition and inhibition of albumin gene expression, we have also monitored the total proteins, albumin, TNF-α and IL-6 levels in arthritic rats and its modulation by agmatine. In the present study, CFA treated rats showed a progressive reduction in both food intake and body weight. In addition analysis of blood serum of arthritis animals showed a significant reduction in proteins and albumin and significant elevation in tumor necrosis factor (TNF)-α and Interleukins (IL)-6. Chronic agmatine (20-40mg/kg, ip) treatment not only attenuated the signs of arthritis but also reverses anorexia and body weight loss in CFA treated rats. In addition, agmatine restored total protein and albumin and reduces TNF-α and IL-6 levels in arthritis rats. These results suggest that agmatine administration can prevent the body weights loss and symptoms of arthritis via inhibition of inflammatory cytokines.

Malvidin-3-O-β glucoside, major grape anthocyanin, inhibits human macrophage-derived inflammatory mediators and decreases clinical scores in arthritic rats

Polyphenolic anthocyanins are major colorful compounds in red fruits, known to prevent cardiovascular and other diseases. Grape polyphenols are a mixture of various molecules and their exact contribution to above bioactivities remains to be clarified. In the present study, we first analyzed the effect of purified grape-derived compounds on human peripheral blood mononuclear cell (PBMC) survival, proliferation, as well as for their ability to inhibit the activation of human normal macrophages. Data indicated that malvidin-3-O-β glucoside (Malβg), the major grape anthocyanin, is bioactive with no toxicity on human PBMC. Malβg decreased the transcription of genes encoding inflammatory mediators, confirmed by the inhibition of TNFα, IL1, IL-6 and iNOS-derived nitric oxide (NO) secretion from activated macrophages. As Malβg also inhibited inflammatory response of rat macrophages, we investigated the anti-inflammatory potential of Malβg in chronic rat adjuvant-induced arthritis (AIA). Malβg significantly diminished inflammatory cachexia and arthritic paw scores in AIA rats at both therapeutic and preventive levels. In vivo effects of Malβg correlated with down-regulation of NO generation from AIA rats’ peritoneal macrophages ex vivo. These data indicate that Malβg, major grape anthocyanin, is a potent anti-inflammatory agent in vitro and in vivo, without detectable toxic effect.

Oxidative state of the liver of rats with adjuvant-induced arthritis

Adjuvant-induced arthritis is an experimental immunopathology in rats that is often used as a model for studying autoimmune chronic inflammation and inflammatory cachexia. In these animals oxidative stress is quite pronounced in the articular inflammation sites. The purpose of this study was to evaluate oxidative stress in the liver of arthritic rats in which morphological and metabolic alterations have been reported to occur. Oxidative injury parameters, levels and production of reactive oxygen species (ROS), and antioxidant parameters were measured in the total liver homogenate and in subcellular fractions, namely cytosol, mitochondria, and peroxisomes. Arthritic rats presented higher levels of ROS than controls in the total homogenate (46% higher) and in all subcellular fractions (51, 38, and 55% higher for mitochondria, peroxisome, and cytosol, respectively). Arthritic rats also presented higher levels of protein carbonyl groups in the total homogenate (75%) and in all subcellular fractions (189, 227, and 260%, respectively, for mitochondria, peroxisomes, and cytosol). The TBARS levels of arthritic rats were more elevated in the total homogenate (36%), mitochondria (20%), and peroxisomes (16%). Arthritic rats also presented higher levels of NO markers in the peroxisomes (112%) and in the cytosol (35%). The catalase activity of all cell compartments was strongly diminished (between 77 and 87%) by arthritis, and glutathione peroxidase activities were diminished in the mitochondria (33.7%) and cytosol (41%). The cytosolic glucose-6-phosphate dehydrogenase activity, on the other hand, was increased (62.9%), the same happening with inducible peroxisomal NO synthase (119.3%). The superoxide dismutase and glutathione reductase activities were not affected. The GSH content was diminished by arthritis in all cellular compartments (50 to 59% diminution). The results reveal that the liver of rats with adjuvant-induced arthritis presents a pronounced oxidative stress and that, in consequence, injury to lipids and proteins is highly significant. The higher ROS content of the liver of arthritic rats seems to be the consequence of both a stimulated pro-oxidant system and a deficient antioxidant defense with a predominance of the latter as indicated by the strongly diminished activities of catalase and glutathione peroxidase.

Pharmacological modulation by celecoxib of cachexia associated with experimental arthritis and atherosclerosis in rabbits

Non-steroidal anti-inflammatory drugs improve inflammatory cachexia in several conditions. Thus, we have explored inhibition of cyclooxygenase-2 (COX-2) in an experimental model of rheumatoid cachexia in rabbits. Chronic arthritis was induced in immunized rabbits by repeated intra-articular injections of ovalbumin. To increase the degree of systemic inflammation and also to induce atherosclerotic lesions, the animals were fed a hyperlipidaemic diet (2% cholesterol and 6% peanut oil) and were given an endothelial injury of the femoral artery. Rabbits were randomized to receive the COX-2 inhibitor celecoxib (10 mg·kg⁻¹ ·day⁻¹) or no treatment. After 4 weeks, sera, peripheral mononuclear cells and vessel specimens were collected. Inhibition of COX-2 by celecoxib modulated the systemic inflammatory response and increased total cholesterol and triglyceride levels. Celecoxib also minimized weight loss and prevented serum albumin fall. At a vascular level, celecoxib reduced COX-2 protein in the femoral arterial wall, but did not modify size or the macrophage infiltration of femoral lesions nor the percentage of rabbits with spontaneous aortic plaques. Our animal model induced a severe inflammatory cachexia, comparable to that of persistently active rheumatoid arthritis. The inhibition of COX-2 by celecoxib improves this state, suggesting that COX products play an important role in its development, without affecting the development or the progression of vascular lesions. Overall, these results suggest that celecoxib might be considered as a new therapeutic tool for the treatment of rheumatoid cachexia.

Copper chelation with tetrathiomolybdate suppresses adjuvant-induced arthritis and inflammation-associated cachexia in rats

Tetrathiomolybdate (TM), a drug developed for Wilson's disease, produces an anti-angiogenic and anti-inflammatory effect by reducing systemic copper levels. TM therapy has proved effective in inhibiting the growth of tumors in animal tumor models and in cancer patients. We have hypothesized that TM may be used for the therapy of rheumatoid arthritis and have examined the efficacy of TM on adjuvant-induced arthritis in the rat, which is a model of acute inflammatory arthritis and inflammatory cachexia. TM delayed the onset of and suppressed the severity of clinical arthritis on both paw volume and the arthritis score. Histological examination demonstrated that TM significantly reduces the synovial hyperplasia and inflammatory cell invasion in joint tissues. Interestingly, TM can inhibit the expression of vascular endothelial growth factor in serum synovial tissues, especially in endothelial cells and macrophages. Moreover, the extent of pannus formation, which leads to bone destruction, is correlated with the content of vascular endothelial growth factor in the serum. There was no mortality in TM-treated rat abnormalities. TM also suppressed inflammatory cachexia. We suggest that copper deficiency induced by TM is a potent approach both to inhibit the progression of rheumatoid arthritis with minimal adverse effects and to improve the well-being of rheumatoid arthritis patients.

Adjuvant arthritis as a model of inflammatory cachexia.

To determine whether adjuvant arthritis (AA) leads to changes in body composition and cytokine production similar to those seen in patients with rheumatoid arthritis. AA was induced in Lewis rats using Freund's complete adjuvant. Body cell mass was measured by determining the concentration of total exchangeable potassium using 42K gavage. Splenocyte production of interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) was measured by bioassay. Weight and food intake were also measured. Animals that developed AA lost 6% of their body weight by the onset of clinically evident arthritis (day 14; P < 0.01) and lost 20% by the end of the inflammatory phase of AA (day 28; P < 0.0001). Body cell mass fell 24.7 +/- 8.6% (mean +/- SEM) in animals with AA, but did not change significantly in controls (increase of 6.3 +/- 7.9%) (P < 0.03). Pair-fed animals lost one-fourth of the weight lost by the animals with AA (P < 0.01), indicating that anorexia alone does not explain inflammatory cachexia. Weight loss was correlated with TNF alpha production by spleen mononuclear cells (r = 0.68, P < 0.007), and a weaker correlation was seen with IL-1 production (r = 0.45, P < 0.04). AA in rats is a useful model of inflammatory cachexia that mimics the human pathophysiology in important ways, and is consistent with cytokine-driven cachexia in chronic inflammatory arthritis.