Functional Liver Imaging Score Derived from Gadoxetic Acid-enhanced MRI Predicts Cachexia and Prognosis in Hepatocellular Carcinoma Patients

Objective Cachexia occurs in approximately half of hepatocellular carcinoma(HCC)patients as the disease progresses and is correlated with a poor prognosis.Therefore,early identification of HCC patients at risk of developing cachexia and their prognosis is crucial.This study investigated the functional liver imaging score(FLIS)derived from gadoxetic acid-enhanced magnetic resonance imaging(MRI)to identify cachexia in HCC patients and their prognosis.Methods Pretreatment clinical and MRI data from 339 HCC patients who underwent gadoxetic acid-enhanced MRI scans were retrospectively collected.Patient weights were recorded for 6 months following the MRI scan to diagnose cachexia.The FLIS was calculated as the sum of the enhancement quality score,the excretion quality score,and the portal vein sign quality score.A Cox proportional hazards model was used to determine the significant factors affecting overall survival(OS).Multivariable logistic regression was then conducted to identify variables predicting cachexia in HCC patients,which were subsequently used to predict OS.Results Cox regression analysis revealed a significant association between cachexia and worse OS.Both FLIS(0–4 vs.5–6 points)(OR,9.20;95%CI:4.68–18.10;P<0.001)andα-fetoprotein>100 ng/mL(OR,4.08;95%CI:2.13–7.83;P<0.001)emerged as significant predictors of cachexia in patients with HCC.Furthermore,FLIS(0–4 vs.5–6 points)(HR,1.73;95%CI:1.19–2.51;P=0.004)was significantly associated with OS.Patients in the FLIS 0–4 points group had shorter OS than those in the FLIS 5–6 points group[20 months(95%CI,14.7–25.3)vs.43 months(95%CI,27.7–58.3);P=0.001].Conclusion Cachexia was associated with worse OS.The functional liver imaging score emerged as a significant predictor of cachexia in HCC patients and their prognosis.

Prognostic value of cachexia defined by the Asian Working Group for Cachexia criteria in patients with gastric cancer

Background:The Asian Working Group for Cachexia(AWGC)criteria are newly proposed diagnostic standards specifically designed for Asian populations.This research focused on validating the predictive value of the AWGC criteria for assessing the prognosis and medical burden of patients with gastric cancer.Methods:Cox proportional hazards analysis was conducted to evaluate the association between cachexia and overall survival.Logistic regression analysis was used to assess whether there was an independent association between cachexia and the 90-day mortality,the length of stay and the quality of life.Harrell’s concordance index was utilized to demonstrate the discriminative ability of different diagnostic criteria for cachexia.Results:AWGC-defined cachexia was an independent risk factor for a reduced overall survival in patients(HR=1.397,95%CI=1.209–1.615,P<0.001).The predictive accuracy of the AWGC criteria was markedly superior to that of the Fearon criteria(χ2=39.025 vs 13.877).Compared with Fearon standards,the AWGC criteria offered a 2.9%enhancement in clinical benefit(0.029,95%CI=0.048–0.008,P=0.005).Logistic regression analysis showed that only AWGC-defined cachexia was an independent risk factor for 90-day mortality(OR=2.142,95%CI=1.397–3.282,P<0.001)and prolonged hospitalization(OR=1.958,95%CI=1.587–2.416,P<0.001)in patients with gastric cancer,whereas cachexia defined by the Fearon criteria was not.Patients with AWGC-defined cachexia exhibited significant reductions in physical function,role function,emotional function,cognitive function,social functioning,and overall quality-of-life scores.Conversely,cachectic patients showed higher levels of fatigue,nausea and vomiting,pain,dyspnea,sleep disturbance,appetite loss,constipation,and financial difficulties.A multivariate logistic regression showed that patients with AWGC-defined cachexia had a 126.1%increased risk of impaired quality of life(OR=2.261,95%CI=1.859–2.749,P<0.001).Conclusions:The AWGC criteria are an effective tool for predicting adverse survival outcomes,90-day mortality,a prolonged hospital stay,and poorer quality of life in patients with gastric cancer.

Exploring the therapeutic effect of Xiaoyan d ecoction on lung cancer cachexia skeletal muscle atrophy based on L3-SMI

Background:Lung cancer cachexia has received widespread attention as one of the most common complications in patients with advanced lung cancer.As a multifactorial syndrome,lung cancer cachexia is characterized by a persistent decline in muscle mass that cannot be reversed by conventional nutrition Xiaoyan d ecoction can promote appetite and improve skeletal muscle mass in patients with lung cancer cachexia,while the third lumbar skeletal muscle index(L3-SMI)is able to determine whole-body skeletal muscle mass.To analyze the relationship between L3-SMI and hematological indexes and lung cancer cachexia,and to study the clinical efficacy of Xiaoyan decoction on skeletal muscle atrophy in lung cancer cachexia patients,with the aim of providing a reference basis for the early diagnosis and treatment of lung cancer cachexia patients and skeletal muscle atrophy.Methods:148 patients who were diagnosed with lung cancer in the Department of Oncology of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from January 2020 to December 2022 were included,and were divided into cachexia and non-cachexia groups according to the diagnostic criteria of cachexia,and analyzed the differences of hematological indexes and L3-SMI between cachexia patients and non-cachexia patients.And the patients with cachexia were divided into control group and treatment group,analyzed and compared the changes of body mass index(BMI),L 3-SMI,Karnofsky functional status score,albumin and other hematological indexes of the two groups before and after the treatment,and evaluated the safety of the Xiaoyan decoction in the treatment of cachexia.Results:A total of 148 lung cancer patients were included in this study,including 67 patients in the cachexia group and 81 patients in the non-cachexia group.According to the pre-treatment statistical analysis,the BMI of patients in the cachexia group was lower than that of patients in the non-cachexia group(P<0.05);among the biochemical function indexes,the proportions of creatinine(P<0.05),total protein(P<0.05),The levels of albumin in the cachexia group were significantly lower(P<0.05)compared to the non-cachexia group;in the cachexia group,both males and females had lower L3-SMIs than in the non-cachexia group(P<0.05).A total of 62 cases of lung cancer cachexia were studied,30 cases in the control group and 32 cases in the treatment group,according to statistical analysis,BMI was significantly different before and after treatment(P<0.05);L3-SMI was significantly different in the treatment group before and after treatment(P<0.05);Karnofsky significantly differed in the treatment group before and after treatment(P<0.05);and there was a significant difference in albumin before and after(P<0.05).Conclusion:Cachexia patients had significantly lower third lumbar skeletal muscle mass than non-cachexia patients,according to this study;Xiaoyan decoction was able to improve skeletal muscle mass,nutritional status as well as functional status of patients with cachexia in lung cancer,among others.

六君子汤改善肿瘤环境下C2C12成肌细胞分化的分子机制

目的研究六君子汤改善肿瘤环境下C2C12成肌细胞分化的分子机制,为健脾和胃法治疗肿瘤恶病质肌肉萎缩提供实验基础。方法诱导成肌细胞C2C12分化,倒置显微镜观察分化后肌管长度;成肌细胞C2C12与肺癌细胞Lewis共培养,分为空白组、模型组、叉头框蛋白O1(forkhead box protein O1,FoxO1)抑制剂组、六君子汤组、联合用药组,蛋白免疫印迹法(western blot,WB)检测C2C12细胞成肌分化抗原(myogenic differentiation antigen,MyoD)的表达及与过氧化物酶体增殖物受体γ辅助激活因子α(peroxisome proliferator-activated receptor gamma coactivator 1-alpha,PGC-1α)/FoxO1通路相关的蛋白表达;电子显微镜观察C2C12细胞线粒体数量及超微结构的变化;流式细胞术(flow cytometry,FCM)观测C2C12细胞线粒体膜电位的变化;实时荧光定量PCR(quantitative real-time PCR,qPCR)法检测C2C12细胞PGC-1α/FoxO1通路相关分子mRNA。结果C2C12细胞于分化48h肌管横径最长;与空白组比,模型组C2C12细胞MyoD蛋白表达明显减少(P<0.05),线粒体数量减少(P<0.05),线粒体双层膜皱曲不清晰甚至呈C形或基质肿胀,线粒体嵴数量减少、排列紊乱、断裂或溶解消失成空泡状,线粒体膜电位降低,细胞凋亡率显著升高(P<0.05),线粒体转录因子A(mitochondrial transcription factor A,tFAM)的mRNA表达明显降低(P<0.05),FoxO1蛋白表达明显增高,PGC-1α、脂肪和肥胖相关基因(fat mass and obesity-associated gene,FTO)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、tFAM蛋白表达明显减少(P<0.05);与模型组比较,六君子汤组C2C12细胞MyoD蛋白表达明显增高,FoxO1抑制剂组、六君子汤组、联合用药组中C2C12细胞线粒体数量显著增多(P<0.05),线粒体双层膜结构正常,线粒体膜电位升高,细胞凋亡率显著降低(P<0.05),联合用药组C2C12细胞mTOR和tFAM mRNA表达明显增加(P<0.05),FoxO1抑制剂组、六君子汤组及联合用药组中C2C12细胞FoxO1蛋白表达明显减少,PGC-1α、FTO、mTOR、tFAM蛋白表达明显增高(P<0.05);与六君子汤组比较,联合用药组C2C12细胞PGC-1α蛋白表达升高(P<0.05)。结论六君子汤通过调控PGC-1α/FoxO1信号通路,能维持线粒体功能,改善肿瘤环境下成肌细胞分化。

肿瘤患者食欲减退的中医治疗进展

食欲减退是肿瘤患者常见的、可严重降低生活质量、阻碍治疗效果的临床症状,故改善肿瘤患者食欲,从而改善患者生活状态,提高患者生活质量和治疗效果是医学学者孜孜以求的目标。近年来中医医家、学者在肿瘤患者食欲减退的中医治疗方面取得了一定的进展,认为中医治疗具有整体调节、效果优良、不良作用小等独特优点,易于为大众所接受,可为临床治疗提供新思路。

Cancer cachexia,mechanism and treatment

It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responsesto chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

Pancreatic cancer(PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies. Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta(TGF-β), myostatin and activin, IGF-1/PI3 K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3(IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6(IL-6), tumor necrosis factoralpha(TNF-α), and interferon gamma(INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.

Adipokines and ghrelin in gastric cancer cachexia

AIM:To investigate the roles of the adipocytokines,ghrelin and leptin in gastric cancer cachexia. METHODS:Resistin,ghrelin,leptin,adiponectin,insulin and insulin-like growth factor(IGF-Ⅰ),were measured in 30 healthy subjects,and 60 gastric cancer patients of which 30 suffered from cancer-induced cachexia and 30 served as a control group. The relationships between hormones,body mass index(BMI) loss ratio,age,gender,and Glasgow Prognostic Score(GPS) were investigated. RESULTS:Cachexia patients had higher tumor stage and GPS when compared with non-cachexia patients(P < 0.05). Ghrelin,resistin,leptin,adiponectin and IGF-Ⅰ,showed a significant correlation with BMI loss ratio and GPS(P < 0.05). A strong correlation was seen between GPS and BMI loss(R = -0.570,P < 0.0001). Multivariate analysis indicated that BMI loss was significantly independent as a predictor of ghrelin,resistin,leptin and IGF-Ⅰ(P < 0.05). Existence of an important significant relationship between resistin and insulin resistance was also noted. CONCLUSION:These results showed that serum ghrelin,leptin,adiponectin,and IGF-Ⅰ play important roles in cachexia-related gastric cancers. No relationshipwas found between resistin and cancer cachexia. Also,because of the correlation between these parameters and GPS,these parameters might be used as a predictor factor.

Frailty,sarcopenia and cachexia in heart failure patients:Different clinical entities of the same painting

Heart Failure(HF)in elderly patients is a systemic syndrome where advanced age,comorbidities with organ system deterioration,frailty and impaired cognition significantly impact outcome.Cardiac cachexia,sarcopenia and frailty despite overlap in definitions are different clinical entities that frequently coexist in HF patients.However,these co-factors often remain unaddressed,resulting in poor quality-of-life,prolonged physical disability and exercise intolerance and finally with higher rehospitalization rates and mortality.Strategy aim to increase muscle mass and muscle strength and delay the occurrence of frailty state appear essential in this regard.Common HF drugs therapy(b-blockers,angiotensinconverting enzyme inhibitors)and prescription of physical exercise program remain the cornerstone of therapeutic approach in HF patients with new promising data regarding nutritional supplementation.However,the treatment of all these conditions still remain debated and only a profound knowledge of the specific mechanisms and patterns of disease progression will allow to use the appropriate therapy in a given clinical setting.For all these reasons we briefly review current knowledge on frailty,sarcopenia and cachexia in HF patients with the attempt to define clinically significant degrees of multiorgan dysfunction,specific"red alert"thresholds in clinical practice and therapeutic approach.

Cachexia and pancreatic cancer: Are there treatment options?

Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients&#x02019; outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods.

Exosomal miR-155 from gastric cancer induces cancerassociated cachexia by suppressing adipogenesis and promoting brown adipose differentiation via C/EPBβ

Objective:The aim of this research was to identify whether exosomes were involved in impairing adipogenesis in cancer-associated cachexia(CAC)by detecting the adipodifferentiation capacity and the expressions of adipogenic proteins in gastric cancer(GC)-associated adipocytes.Methods:Western blotting and RT-PCR were used to investigate the expressions of C/EPBβ,C/EPBα,PPARγ,and UCP1 in adipose mesenchymal stem cells(A-MSCs)to evaluate the function of exosomal miR-155.BALB/c nude mice were intravenously injected in vivo with GC exosomes with different levels of miR-155 to determine changes in adipodifferentiation of A-MSCs.Results:Exosomes derived from GC cells suppressed adipogenesis in A-MSCs as characterized by decreased lipid droplets.Similarly,A-MSCs co-cultured with GC exosomes exhibited increased ATP production through brown adipose differentiation characterized by highly dense mitochondria and enhanced UCP1 expression(P<0.05).Mechanistically,exosomal miR-155 secreted from GC cells suppressed adipogenesis and promoted brown adipose differentiation by targeting C/EPBβ,accompanied by downregulated C/EPBαand PPARγand upregulated UCP1(P<0.05).Moreover,overexpression of miR-155 in GC exosomes improved CAC in vivo,which was characterized by fat loss,suppressed expressions of C/EPBβ,C/EPBα,and PPARγin A-MSCs,and high expression of UCP1(P<0.05).Decreasing the level of miR-155 in injected GC exosomes abrogated the improved CAC effects.Conclusions:GC exosomal miR-155 suppressed adipogenesis and enhanced brown adipose differentiation in A-MSCs by targeting C/EPBβof A-MSCs,which played a crucial role in CAC.

Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma

BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma(PDAC).The rapid disease progression and patient deterioration seems related to perineural invasion,but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied.As perineural invasion is difficult to be highlighted,a biomarker such as the neurotrophic factor Midkine(MK)which promotes the neuronal differentiation and the cell migration could be helpful.Also,Activin(ACV)has been described as cachexia related to PDAC.However,their role for assessing and predicting the disease course in daily practice is not known.AIM To assess the relationship between perineural invasion and cachexia and their biomarkers,MK and ACV,respectively,and their prognostic value.METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies.Patients with other causes of malnutrition were excluded.The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data.These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease.RESULTS The study comprised 114 patients with PDAC,125 controls and a supplementary group of 14 benign pancreatic tissue samples.ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls(63% vs 32% for ACV,P<0.001;47%vs 16%for MK,P<0.001),with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage(P=0.006),the presence of metastasis(P=0.04),perineural invasion(P=0.03)and diabetes(P=0.002),but with no influence on survival.No correlation between clinicopathological factors and ACV expression was noted.Cachexia,present in 19%of patients,was unrelated to ACV or MK level.Higher ACV expression was associated with a shorter survival(P=0.008).CONCLUSION The MK was a biomarker of perineural invasion,associated with tumor stage and diabetes,but without prognostic value as ACV.Cachexia was unrelated to perineural invasion,ACV level or survival.

Intervention of Mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts

AIM: To investigate the effect of Mirtazapine on tumor growth, food intake, body weight, and nutritional status in gemcitabine-induced mild cachexia. METHODS: Fourteen mice with subcutaneous xenografts of a pancreatic cancer cell line (SW1990) were randomly divided into Mirtazapine and control groups. Either Mirtazapine (10 mg/kg) or saline solution was orally fed to the mice every day after tumor implantation. A model of mild cachexia was then established in both groups by intraperitoneal injection of Gemcitabine (50 mg/kg) 10 d, 13 d, and 16 d after tumor implanta- tion. Tumor size, food intake, body weight, and nutritional status were measured during the experiment. All mice were sacrificed at day 28. RESULTS: (1) After 7 d of gemcitabine administration, body-weight losses of 5%-7% which suggested mild cachexia were measured; (2) No significant difference in tumor size was detected between the Mirtazapine and control groups (P > 0.05); and (3) During the entire experimental period, food intake and body weight were slightly greater for the Mirtazapine group compared with controls (although these differences were not statistically significant). After 21 d, mice in the Mirtazapine group consumed significantly more food than control mice (3.95 ± 0.14 g vs 3.54 ± 0.10 g, P = 0.004). After 25 d, mice in the Mirtazapine group were also significantly heavier than control mice (17.24 ± 0.53 g vs 18.05 ± 0.68 g, P = 0.014). CONCLUSION: Mild cachexia model was successfully established by gemcitabine in pancreatic tumor-bearing mice. Mirtazapine can improve gemcitabine-induced mild cachexia in pancreatic tumor-bearing mice. It was believed to provide a potential therapeutic perspective for further studies on cachexia.

Prognostic factors in heart failure patients with cardiac cachexia

Objective To clarify whether cardiac cachexia(CC)alters the prognostic impact of other general risk factors in patients with heart failure(HF).Methods This was an observational study.CC was defined as the combination of a body mass index of<20 kg/m^2 and at least one of the following biochemical abnormalities:C-reactive protein>5 mg/L;hemoglobin<12 g/dL;and/or albumin<3.2 g/d L.We divided 1608 hospitalized HF patients into a CC group(n=176,10.9%)and a non-CC group(n=1432,89.1%).The primary endpoints were cardiac event and all-cause death.Results The presence of CC showed significant interactions with other risk factors including cancer,estimated glomerular filtration rate(eGFR),and sodium in predicting these endpoints.Multiple Cox proportional analysis revealed that use of a blockers[hazard ratio(HR)=1.900,95%confidence interval(CI):1.045–3.455,P=0.035]and eGFR(HR=0.989,95%CI:0.980–0.998,P=0.018)were independent predictors of cardiac event in the CC group,while age(HR=1.020,95%CI:1.002–1.039,P=0.029)and hemoglobin(HR=0.844,95%CI:0.734–0.970,P=0.017)were independent predictors of all-cause death.The survival classification and regression tree analysis showed the optimal cut-off points for cardiac event(eGFR:59.9 m L/min per 1.73 m^2)and all-cause death(age,83 years old;hemoglobin,10.1 g/dL)in the CC group.Conclusions In predicting prognosis,CC showed interactions with several risk factors.Renal function,age,and hemoglobin were pivotal markers in HF patients with CC.

Gut microbiome and pancreatic cancer cachexia:An evolving relationship

Nearly 80% of patients with pancreatic ductal adenocarcinoma(PDAC)develop cachexia along their disease course.Cachexia is characterized by progressive weight loss,muscle wasting,and systemic inflammation and has been linked to poorer outcomes and impairments in quality of life.Management of PDAC cachexia has historically involved a multidisciplinary effort comprised of nutritional support,pancreatic enzyme replacement therapy,and/or pharmacologic interventions.Despite current interventions to mitigate PDAC cachexia,a significant proportion of patients continue to die from complications associated with cachexia underscoring the need for novel insights and treatments for this syndrome.We highlight the feasibility and effectiveness of a recent enteral feeding prospective trial at our institution to improve cachexia outcomes in patients with advanced PDAC.Additionally,we were among the first to characterize the stool microbiome composition in patients with advanced PDAC receiving enteral feeding for the treatment of cachexia.Novel insights into the relationship between enteral nutritional support,cachexia,and the gut microbiome are presented.These promising results are discussed in the context of a potential ability to modulate the stool microbiome as a new interventional strategy to mitigate PDAC cachexia.

Advances in the diagnosis and treatment of patients with cancer cachexia

Cachexia is a common complication with an incidence rate of 50%–80% in cancer patients. It is also responsible for 20% of mortality among these patients. Cachexia can significantly reduce the efficacy of antitumor therapies and increase treatment-related toxicity and adverse effects in cancer patients. This increases the symptom burden in patients, affects their quality of life, and ultimately shortens their survival time. The mechanism underlying the development of cachexia is complex and diverse and involves various factors and pathways, each playing an important role. Treatment approaches for cachexia are multimodal, including nutrition support therapy, appetite stimulants, and therapeutic drugs that specifically target the mechanism behind the disease. In recent years, we have gradually gained a better understanding of cachexia, and significant progress has been made in delineating molecular mechanisms, staging and diagnosis, and therapeutic drug treatment of cancer cachexia. This article reviews the research progress of cancer cachexia based on these contexts.

Advances in Immunonutrient Application to Treat Cancer Cachexia Syndrome

Cachexia is a multifactorial syndrome characterized by the loss of body weight,and has been observed in more than 50%of cancer patients.It arises as a result of anorexia and increased energy expenditure,leads to a reduced tolerance of cancer therapy and a reduced quality of life,resulting in a poorer prognosis and decreased survival.In the past few years,tremendous achievements have been made in cancer cachexia research.Systemic inflammation has been proven to play important roles in the etiology of cancer cachexia,leading to functional impairment and rapid deterioration,which suggests that anti-inflammatory agents may represent a promising strategy for cancer cachexia treatment.Thus,a variety of agents have been postulated to treat cachexia,with modulation of inflammation,the immune response,and reactive oxygen species being the most promising.Some immune-enhancing nutrients,‘immunonutrients’,such asω-3 fatty acids,arginine,nucleotides,L-carnitine,probiotics,phytochemicals,and specific minerals have been tested for their anti-inflammatory and anti-oxidative properties.They have also been used to treat,prevent or attenuate cancer cachexia in both experimental models and clinical trials.A number of studies on the use of immunonutrients for the treatment of cancer cachexia have been published over the past decade,with some promising results supporting the routine use of immune-enhancing formulas in patients with cachexia.However,the effects and efficacy of these substances have not been conclusively proven.In this review,we discuss recent studies on the molecular mechanisms underlying cancer cachexia and the application of several immunonutrients.

The rationale for preventing cancer cachexia：targeting excessive fatty acid oxidation

Cachexia commonly occurs at the terminal stage of cancer and has largely unclear molecular mechanisms.A recent study published in Nature Medicine,entitled "Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia," reveals that cachectic cancer cells can secrete multiple cytokines that induce excessive fatty acid oxidation,which is responsible for muscle loss in cancer cachexia.Inhibition of fatty acid oxidation using etomoxir can increase muscle mass and body weight in cancer cachexia animal models.The usage of stable cachexia animal models is also discussed in this research highlight.

Managing Cachexia and Improving Quality of Life in Cancer Patients Using Novel Nutritional Supplements: A PAN India Study

Cancer patients develop cachexia due to systemic inflammation, negative protein and energy balance. Esperer Onco Nutrition (EON) has come up with innovative nutritional supplements (EON Therapy) that help patients take the rigours of cancer therapy thereby improving prognosis and Quality of Life (QoL). This Post-marketing surveillance study was undertaken on 38 volunteers to assess the impact of EON therapy on cachexia and QoL of patients undergoing curative treatment. Body weight and biochemical parameters of the volunteers were recorded at each visit. Volunteers were assessed using ECOG Scale and Malnutrition Screening Tool (MST) to assess impact of nutritional supplements on QoL. Weight loss was observed in most of the patients for first two visits but the patients gained weight over subsequent visits and average weight at end of the study was higher than initial weight. At the end of study 22 of 38 volunteers gained weight and 7 volunteers maintained initial weight. The biochemical parameters either showed improvement or remained same. The QoL analysis indicated a marked improvement in physical wellness and nutritional status and no adverse effects were reported. In conclusion, the study underlines importance of research based on nutritional supplements for cancer patients for better disease management and prognosis.

Role of β-Hydroxy β-Methylbutyrate (HMB) in Cancer Cachexia/ Sarcopenia

Cancer cachexia is a complex multifactorial syndrome that has a substantial impact on the quality of life of cancer patients. Although some treatment options exist to counteract cachexia, very few options counteract sarcopenia (loss of muscle mass). HMB may be a viable component in multi-modal approaches targeting treatment of cancer cachexia/sarcopenia. Evidence suggests that HMB promotes myogenic events, suppresses proteasome activity, and activates protein synthesis. HMB also represses inflammation, reduces tumor growth, and increases lifespan.