Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia.

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCß) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.

Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Treatment of Cachexia in Gastric Cancer: Exploring the Use of Anti-Inflammatory Natural Products and Their Derivatives.

(1) Background: Gastric cancer is a significant cause of cancer-related mortality worldwide. Weight loss and malnutrition associated with cancer are linked with increased mortality rates and reduced quality of life. Cancer cachexia, characterised by the loss of skeletal muscle, is associated with approximately 20% of cancer-related deaths and differs from malnutrition in that it cannot be fully reversed by nutritional support alone. It is now recognised that the primary pathophysiological process underlying cancer cachexia is chronic inflammation leading to increased calorie consumption. Current treatments that focus on nutritional supplementation, psychological counselling, appetite stimulation and reducing inflammation are lacking in efficacy. This review focuses on the evidence supporting the potential roles of natural anti-inflammatory products and their derivatives including fatty acids, probiotics, amino acids, curcumin, fucoidan, epigallocatechin-3-gallate, ginger, resveratrol and Boswellia serrata in the management of gastric cancer cachexia. (2) Results: While natural anti-inflammatory products show promise in a number of in vitro and in vivo studies, there are only a small number of human studies available. Where present, the evidence base is heterogeneous, with varying study methodologies and outcomes. (3) Conclusions: Natural anti-inflammatory products represent a potential adjunctive therapy for gastric cancer cachexia. Further research, particularly well-designed clinical trials, is needed to elucidate their optimal role, dosing and safety profiles in the management of gastric cancer cachexia.

Effects of cancer-induced cachexia and administration of L-glutathione on the intestinal mucosa in rat.

Walker-256 tumor is an experimental model known to promote cachexia syndrome, oxidative stress, and systemic inflammation. This study evaluated the duodenal mucosa of rats with Walker-256 tumor administered with 1% L-glutathione, intending to evaluate the damage caused by cancer-associated cachexia in the gastrointestinal tract and the effects of antioxidant administration on mucosal protection. Twenty-four 55-day-old male Wistar rats were distributed into four groups: control (C); control administered with 1% L-glutathione (C-GSH); Walker-256 tumor (W) and Walker-256 tumor administered with 1% L-glutathione (W-GSH). After 14 days of treatment, the duodenum was harvested for morphometric analysis of the mucosa, proliferation, apoptosis, immunostaining of varicosities immunoreactive (IR) to vasoactive intestinal peptide (VIP) and 5-HT-IR cells, and quantification of mast cells and goblet cells. Walker-256 tumor-bearing rats showed cachexia syndrome, mucosal atrophy, reduced cell proliferation, reduced 5-HT-IR cells, and increased goblet cells and VIPergic varicosities, which were not reversed by L-glutathione. On the other hand, L-glutathione caused a reduction of cells in apoptosis and mast cell recruitment, demonstrating a partial recovery of the damage detected in the intestinal mucosa.

Taurine Rescues Cancer-induced Atrophy in Human Skeletal Muscle Cells via Ameliorating the Inflammatory Tumor Microenvironment.

BACKGROUND/AIM: Cancer cachexia is a wasting syndrome that has a devastating impact on the prognosis of patients with cancer. It is well-documented that pro-inflammatory cytokines are involved in the progression of this disorder. Therefore, this study was conducted to investigate the protective effect of taurine, an essential nonprotein amino acid with great anti-inflammatory properties, in attenuating muscle atrophy induced by cancer. MATERIALS AND METHODS: Conditioned media (CM) derived from T24 human bladder carcinoma cells with or without 5 mM taurine were incubated with human skeletal muscle cells (HSkMCs) and their differentiation was examined. The intracellular reactive oxygen species (ROS), morphology, and the catabolic pathway were monitored. RESULTS: T24-derived CM with high levels of TNF-α and IL-6 caused aberrant ROS accumulation and formation of atrophic myotubes by HSkMCs. In T24 cancer cells, taurine significantly inhibited the production of TNF-α and IL-6. In HSkMCs, taurine increased ROS clearance during differentiation and preserved the myotube differentiation ability impaired by the inflammatory tumor microenvironment. In addition, taurine ameliorated myotube atrophy by regulating the Akt/FoxO1/MuRF1 and MAFbx signaling pathways. CONCLUSION: Taurine rescues cancer-induced atrophy in human skeletal muscle cells by ameliorating the inflammatory tumor microenvironment. Taurine supplementation may be a promising approach for intervening with the progression of cancer cachexia.

IUPHAR ECR review: Cancer-related anorexia-cachexia in cancer patients: Pathophysiology and treatment.

Cancer-related anorexia-cachexia (CRAC) comprises one of the most common syndromes of advanced cancer patients. The prevalence of CRAC increases from 50% to 80% before death. CRAC is associated not only with impaired quality of life in patients and family members but also with shorter survival. The management of CRAC is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of CRAC. A multimodal strategy is the most effective way to treat anorexia-cachexia. Numerous medications have been suggested and used in clinical trials, while others are still being studied on experimental animals. These medications include branched-chain amino acids, eicosapentaenoic acid, thalidomide, cytokine inhibitors, steroids, antiserotoninergic medications, and appetite stimulants. The benefits of supportive care interventions and the advancement of exciting new pharmacological medicines for anorexia-cachexia are becoming more widely recognized. Health care professionals need to be aware of the psychosocial and biological effects of anorexia-cachexia, even though knowledge of the underlying molecular causes of the disorder has advanced significantly.

Second-Order Effects of Chemotherapy Pharmacodynamics and Pharmacokinetics on Tumor Regression and Cachexia.

Drug dose response curves are ubiquitous in cancer biology, but these curves are often used to measure differential response in first-order effects: the effectiveness of increasing the cumulative dose delivered. In contrast, second-order effects (the variance of drug dose) are often ignored. Knowledge of second-order effects may improve the design of chemotherapy scheduling protocols, leading to improvements in tumor response without changing the total dose delivered. By considering treatment schedules with identical cumulative dose delivered, we characterize differential treatment outcomes resulting from high variance schedules (e.g. high dose, low dose) and low variance schedules (constant dose). We extend a previous framework used to quantify second-order effects, known as antifragility theory, to investigate the role of drug pharmacokinetics. Using a simple one-compartment model, we find that high variance schedules are effective for a wide range of cumulative dose values. Next, using a mouse-parameterized two-compartment model of 5-fluorouracil, we show that schedule viability depends on initial tumor volume. Finally, we illustrate the trade-off between tumor response and lean mass preservation. Mathematical modeling indicates that high variance dose schedules provide a potential path forward in mitigating the risk of chemotherapy-associated cachexia by preserving lean mass without sacrificing tumor response.

Cancer cachexia reduces the efficacy of immune checkpoint inhibitors in cancer patients.

OBJECTIVE: Cachexia, a multifactorial syndrome, is frequently noticed in cancer patients. A recent study has shown inconsistent findings about the relationship between cachexia and the efficiency of immune checkpoint inhibitors (ICIs). To analyze this disparity, we did a meta-analysis. METHODS: From the beginning of each database to July 2023, literature describing the association between cachexia and prognosis of ICI-treated patients with solid malignancies was systematically searched in three online databases. Estimates were pooled, and 95% confidence intervals (CIs) were generated. RESULTS: We analyzed a total of 12 articles, which included data from 1407 patients. The combined results of our analysis showed that cancer patients with cachexia had significantly worse overall survival (HR = 1.88, 95% CI: 1.59-2.22, p < 0.001), progression-free survival (HR = 1.84, 95% CI: 1.59-2.12, p < 0.001), and time to treatment failure (HR = 2.15, 95% CI: 1.32-3.50, p = 0.002). These findings were consistent in both univariate and multivariate analyses. Additionally, while not statistically significant, we observed a trend towards a lower objective response rate in cancer patients with cachexia compared to those without cachexia (OR = 0.59, 95% CI: 0.32-1.09, p = 0.093). CONCLUSION: Poor survival in cachexia patients suggests a negative relationship between cachexia and ICI efficacy. In clinical practice, the existence of cachexia should be estimated to choose individuals who may benefit from ICIs.

R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. METHODS: Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. RESULTS: Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61 ± 1.82 vs. -4.48 ± 2.0 g, P = 0.0004) and CHX207 (-0.49 ± 0.33 vs. -2.49 ± 0.93 g, P = 0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7 ± 7.1% vs. -27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (-18.8 ± 49% vs. -69 ± 15.6%, P = 0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8 ± 42% vs. -49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. CONCLUSIONS: RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

Mirtazapine versus megestrol acetate in treatment of anorexia-cachexia in advanced cancer patients: a randomized, double-blind trial.

OBJECTIVE: Cancer-related anorexia-cachexia comprises one of the most common syndromes of advanced cancer patients. The management of cancer-related anorexia-cachexia is a great challenge in clinical practice. There are no definite practice guidelines yet for the prevention and treatment of cancer-related anorexia-cachexia. This study is considered to find out whether there is any role of mirtazapine in the improvement of anorexia in cancer patients. METHODS: A total of 80 cancer-anorexia patients were enrolled. Patients in the trial arm received the standard chemotherapy medication plus one tablet of mirtazapine 15 mg daily at night orally for 8 weeks starting from the day of an initial assessment. The control arm received the standard chemotherapy medication plus one tablet of megestrol acetate 160 mg daily orally for 8 weeks starting from the day of an initial assessment. Each patient was assessed by validated versions of Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale v 4 questionnaires. RESULTS: After 4 and 8 weeks each patient was evaluated again using the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale tool. The quality of life of each patient was assessed by European Organization for Research and Treatment QLQ-C30 v 3.0. After 4 to 8 weeks of treatment, the Functional Assessment of Anorexia/Cachexia Therapy Anorexia/Cachexia Sub Scale score in cancer anorexia patients in the mirtazapine improved anorexia significantly. However, the improvement after 4 to 8 weeks was not statistically significant when it was compared with the megestrol acetate (P > 0.05). CONCLUSIONS: Therefore, the findings of this study reveal that mirtazapine might be a potential alternative to megestrol acetate, as it has shown potential efficacy as like as megestrol acetate.

Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

Paeoniflorin alleviated muscle atrophy in cancer cachexia through inhibiting TLR4/NF-κB signaling and activating AKT/mTOR signaling.

Cancer cachexia is a progressive wasting syndrome, which is mainly characterized by systemic inflammatory response, weight loss, muscle atrophy, and fat loss. Paeoniflorin (Pae) is a natural compound extracted from the dried root of Paeonia lactiflora Pallas, which is featured in anti-inflammatory, antioxidant, and immunoregulatory pharmacological activities. While, the effects of Pae on cancer cachexia had not been reported before. In the present study, the effects of Pae on muscle atrophy in cancer cachexia were observed both in vitro and in vivo using C2C12 myotube atrophy cell model and C26 tumor-bearing cancer cachexia mice model. In the in vitro study, Pae could alleviate myotubes atrophy induced by conditioned medium of C26 colon cancer cells or LLC Lewis lung cancer cells by decreasing the expression of Atrogin-1 and inhibited the decrease of MHC and MyoD. In the in vivo study, Pae ameliorated weight loss and improved the decrease in cross-sectional area of muscle fibers and the impairment of muscle function in C26 tumor-bearing mice. The inhibition of TLR4/NF-κB pathway and the activation of AKT/mTOR pathway was observed both in C2C12 myotubes and C26 tumor-bearing mice treated by Pae, which might be the main basis of its ameliorating effects on muscle atrophy. In addition, Pae could inhibit the release of IL-6 from C26 tumor cells, which might also contribute to its ameliorating effects on muscle atrophy. Overall, Pae might be a promising candidate for the therapy of cancer cachexia.

Appetite and dietary intake endpoints in cancer cachexia clinical trials: Systematic Review 2 of the cachexia endpoints series.

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Should Cannabis be Used for Anorexia in Patients With Cancer?

Healthcare professionals are frequently asked about the benefits of cannabis for appetite or anorexia-cachexia syndrome. In popular culture, cannabis has a reputation of causing an increased hunger, slang termed "the munchies," so many patients consume this with the hope that it may improve the loss of appetite associated with serious illness such as cancer. There have only been a few randomized, controlled trials studying the controversial question as to if cannabis improves appetite. These studies are small and show no statistically significant benefit for appetite and one small study showed improvement of taste for foods. Due to regulation barriers, the studies have use synthetic products, not the products that represent what is more commonly used in the population, often whole flower smoked, vaporized or oral products. Despite the popularity of cannabis in culture, often touted as a panacea for all maladies, the evidence and education for several adverse effects and potential drug interactions have has yet to catch up with the cultural craze. International cannabis experts in the United States and Australia do not routinely certify patients for medical cannabis off trial for anorexia-cachexia, but one expert in Canada would consider use in selected cancer patients.

A dose-response meta-analysis of randomized clinical trials investigating the effects of omega-3 supplementation on body weight in patients with cancer cachexia.

BACKGROUND: Cachexia is one of the side effects of cancer diseases that can be reduced weight, and lower overall survival. Weight loss has been associated with adverse outcomes in both cancer patients and patients with benign diseases. There is no definitive treatment for fully reverse cachexia. studies showed higher levels of inflammatory markers in patient with cachectic cancer. Therefore, this study aimed to investigate the dose-response effects of omega-3 as an anti-inflammatory supplement on body weight in patients with cancer cachexia. METHODS: Online databases including PubMed, Scopus, and Web of Science were systematically searched by relevant keywords up to January 2022. Random effect analysis was applied to perform meta-analysis. Subgroup analyses were performed to find heterogeneity sources. Quality assessment was conducted using Revised Cochrane Collaboration's tool II. Trim and fill analysis were also carried out in case of the presence of publication bias. The certainty in the evaluations was assessed by the GRADE approach. RESULTS: Omega-3 supplementation resulted in a significant increase of body weight in patients with cancer cachexia when the age of study participants was ≥67 years and the baseline weight of them was ≤60 kg (WMD = 0.99; 95 % CI: 0.06, 1.92 and WMD = 1.22; 95 % CI: 0.14, 2.30, respectively). Also, there was a non-significant linear relationship between the dosage of omega-3 supplementation and body weight in patients with cancer cachexia. CONCLUSION: Omega-3 supplementation may be a promising agent to increase body weight in patients with cancer cachexia. Also, a non-significant linear relationship between the dosage of omega-3 supplementation and body weight was found in these patients.

Impacts of genetic polymorphisms and cancer cachexia on naldemedine pharmacokinetics and bowel movements in patients receiving opioid analgesics.

BACKGROUND/OBJECTIVES: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single-center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. METHODS: Forty-eight patients being treated with naldemedine for opioid-induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. RESULTS: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4ß-hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin-6 (IL-6) and acute-phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. CONCLUSION: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL-6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements.

Energy preservation for skeletal muscles: Shenqi Fuzheng injection prevents tissue wasting and restores bioenergetic profiles in a mouse model of chemotherapy-induced cachexia.

BACKGROUND: Energy deficiency is the characteristic of chemotherapy-induced cachexia (CIC) which is manifested by muscle wasting. glycolysis, tricarboxylic acid (TCA) cycle, and lipid metabolism are central to muscle bioenergy production, which is vulnerable to chemotherapy during cancer treatment. Recent investigations have spotlighted the potential of Shenqi Fuzheng injection (SQ), a Chinese proprietary medicine comprising Radix Codonopsis and Radix Astragali, in alleviating CIC. However, the specific effects of SQ on muscle energy metabolism remains less explored. PURPOSE AND METHODS: Here, we integrated transcriptomics, spatial metabolomics, gas chromatography-mass spectrometry targeted quantitative analysis, and transmission electron microscopy techniques, combined with Seahorse live-cell metabolic analysis to reveal the changes in genes and pathways related to energy metabolism in the CIC model and SQ's protective effects at molecular and functional levels. RESULTS: Our data showed that chemotherapeutic agents caused glycolysis imbalance, which further leads to metabolic derangements of TCA cycle intermediates. SQ maintained glycolysis balance by facilitating pyruvate fluxing to mitochondria for more efficient bioenergy production, which involved a dual effect on promoting functions of mitochondrial pyruvate dehydrogenase complexes and inhibiting lactate dehydrogenase for lactate production. As a result of the sustained pyruvate level achieved by SQ administration, glycolysis balance was maintained, which further led to the preservation of mitochondrial integrity and function of electron transport chain, thereby, ensuring the normal operation of the TCA cycle and the proper synthesis of adenosine triphosphate (ATP). The above results were further validated using the Seahorse live-cell assay. CONCLUSION: In conclusion, our study highlights SQ as a promising strategy for CIC management, emphasizing its ability to harmonize the homeostasis of the muscle bioenergetic profile. Beyond its therapeutic implications, this study also offers a novel perspective for the development of innovative treatments in the realm of herbal medicine.

Prognostic significance of the cachexia index in patients with unresectable advanced gastric cancer receiving palliative chemotherapy: a retrospective single-center study.

PURPOSE: To investigate the prognostic utility of the cachexia index (CXI) in unresectable advanced gastric cancer (UAGC). METHODS: The relationship between CXI and the outcomes was evaluated in 102 patients with UAGC who had received first-line palliative 5-fluorouracil-based chemotherapy between January 2012 and December 2021. RESULTS: The median survival time (MST) from first-line chemotherapy initiation was 16.2 months, and the cohort included 60 and 42 patients with high and low CXIs, respectively, based on the optimal CXI cutoff. The rates of patients with a performance status score of 0, recurrence, third-line chemotherapy, and all grade 3-4 side effects, including febrile neutropenia (FN), were significantly higher in the CXIhigh group than in the CXIlow group. The prognosis based on MST was significantly better in the CXIhigh group than in the CXIlow group (22.5 vs. 11.6 months, p < 0.001). According to a multivariate analysis, a low CXI and performance status score of 1-2 were poor prognostic factors. CONCLUSIONS: Patients with UAGC and a low CXI had poorer prognoses and more frequent grade 3-4 side effects, including FN, than those with a high CXI. Patients with UAGC and a low CXI should be carefully managed to control for side effects to receive subsequent treatment.

Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia.

Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.