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Abstract

Cachexia is a progressive deterioration of body habitus associated with certain chronic diseases (e.g., cancer, chronic obstructive pulmonary disease, chronic heart failure, and chronic kidney disease). The aim of this article is to describe the prevalence and impact of cachexia (and precachexia) in such patients. Owing to the wide spectrum of clinical presentation and lack of an 'all-inclusive' definition, it is difficult to estimate the true prevalence of cachexia. Perhaps 2% of the population suffer from precachexia (characterized by weight loss in association with a chronic disease). The significant increase in obesity of the general population (which can mask significant muscle wasting) confounds such simple estimates of the true prevalence of cachexia. In contrast, a multidimensional characterization of the cachectic state (including weight loss, reduced food intake, and systemic inflammation) may be more meaningful in terms of altered clinical outcomes. Such a multidimensional view of cachexia has been shown to impact on patients' survival and quality of life and therefore constitutes a major public health issue. There is a high prevalence of (pre)cachexia in patients with chronic diseases. The cachexia syndrome is probably less frequent but has a significant impact in terms of morbidity and mortality.

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... Непреднамеренное снижение массы тела часто встречается в клинической практике, сопровождая течение многих заболеваний. Кахексия как комплексный метаболический синдром развивается при большинстве хронических соматических патологий, таких как хроническая сердечная недостаточность (ХСН), хроническая болезнь почек (ХБП), сахарный диабет, хроническая обструктивная болезнь легких (ХОБЛ), синдром приобретенного иммунодефицита (СПИД), ревматоидный артрит, болезнь Альцгеймера и другие, и, конечно, при онкологических заболеваниях [4,5]. Кахексия может развиваться при опухолях любой локализации. ...
... Чаще развитие этого синдрома наблюдается при опухолях верхних отделов ЖКТ, легкого, молочной железы, головы и шеи [6]. Известно, что даже незначительное снижение веса у пациентов определяет неблагоприятный прогноз основного заболевания, снижает эффективность проводимой терапии и является мощным предиктором высокой смертности [5,[7][8][9]. В частности, у хирургических пациентов недостаточное питание приводит к существенному увеличению частоты послеоперационных осложнений, в том числе инфекционных, увеличению сроков госпитализации и летальных исходов [10]. ...
Article
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The relevance of cachexia syndrome is determined by its high prevalence in clinical practice. It accompanies the course of not only oncological diseases, but also the majority of chronic somatic pathologies, such as chronic heart failure, renal failure, diabetes mellitus, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, rheumatoid arthritis, Alzheimers disease and others. It is known that even a slight weight loss in patients can determine an unfavorable prognosis of the underlying disease and reduce the effectiveness of therapy, and sometimes it becomes the direct cause of death of the patient. Cachexia is a complex metabolic syndrome, which is based on a violation of the central regulation of metabolism. The dangerous combination of decreased appetite (anorexia) and increased metabolism is the result of an imbalance in energy exchange. Treatment of cachexia syndrome is ineffective and limited in means. Given the progressive and irreversible nature of this syndrome, early diagnosis and prevention of its development are the primary task of the doctor. The article describes the main pathogenetic aspects of the development of cachexia syndrome. They can be common in different diseases. The article discusses the difficulties of diagnosing cachexia syndrome, the possibilities and prospects of treatment.
... Cancer cachexia is a syndrome characterized by unintentional loss of fat and skeletal muscle tissue (19) that affects 50% of patients (18,62). Patients with solid tumors are most likely to experience muscle atrophy, particularly in advanced stages (44). ...
... Mitochondrial content, ROS production, and mitochondrial respiration with murine CM. Recent reports have suggested a role for oxidant stress in the atrophic effect of tumor-related factors (3,16,20,33,62). Thus, we examined the effects of CM on mitochondrial content and ROS production. ...
Article
Factors secreted from tumors/tumor cells are hypothesized to cause skeletal muscle wasting in cancer patients. We examined whether cancer cells secrete factors to promote atrophy by evaluating the effects of conditioned media (CM) from murine lung cancer cells and primary cultures of human lung tumor cells on cultured myotubes. We evaluated murine Lewis lung carcinoma (LLC) and KRAS G12D cells, and primary cell lines derived from tumor biopsies from patients with lung cancer (hTCM; n=6). In all experiments, serum content was matched across treatment groups. We hypothesized that CM from murine and human tumor cells would reduce myotube myosin content, decrease mitochondrial content and increase mitochondrial reactive oxygen species production (ROS). Treatment of myotubes differentiated for 7 days with CM from LLC and KRAS G12D cells did not alter any of these variables. Effects of murine tumor cell CM were observed when myotubes differentiated for 4 days were treated with tumor cell CM and compared to undiluted differentiation media. However, these effects were not apparent if tumor cell CM treatments were compared to control cell CM or dilution controls. Finally, CM from human lung tumor primary cell lines did not modify myosin content or mitochondrial content or ROS production compared to either undiluted differentiated media, control cell CM or dilution controls. Our results do not support the hypothesis that factors released from cultured lung cancer/tumor cells promote myotube wasting or mitochondrial abnormalities, but cannot dismiss the possibility that these cells could secrete such factors in vivo within the native tumor microenvironment.
... Cancer kills nearly 600,000 Americans annually, equating to approximately 1500 deaths every day (Society, 2012). Fifty percent of all cancer patients experience cachexia, a severe wasting syndrome that includes loss of muscle mass, weakness and fatigue (Tan and Fearon, 2008;Fearon et al., 2011). Cachexia is unresponsive to nutritional interventions, and limits the response to cancer treatments . ...
... Although studies are ongoing, we currently know that malignant tumors alter their surrounding environment via tumor-derived and host-derived paracrine factors, which promote cachexia and may also lead to mitochondrial dysfunction. Some recent studies found evidence of mitochondrial dysfunction in cachexia, which may contribute to muscle pathology (Tan and Fearon, 2008;Constantinou et al., 2011;Fearon et al., 2011;Julienne et al., 2012Julienne et al., , 2014Wang et al., 2012;White et al., 2012;Dumas et al., 2013;Fontes-Oliveira et al., 2013;Tzika et al., 2013). ...
... Cancer cachexia is a debilitating condition correlated with several types of malignant cancers and is associated with poor response to treatment and decreased survival rates [4][5][6][7][8][9]. Since cachexia is a common side effect of cancer and to chemotherapy treatment, one may wonder whether or not the activated molecular mechanisms that induce muscle loss are similar. ...
Article
Although chemotherapy is a standard treatment for cancer, it comes with significant side effects. In particular, certain agents can induce severe muscle loss, known as cachexia, worsening patient quality of life and treatment outcomes. 5-fluorouracil, an anti-cancer agent used to treat several cancers, has been shown to cause muscle loss. Experimental data indicates a non-linear dose-dependence for muscle loss in mice treated with daily or week-day schedules. We present a mathematical model of chemotherapy-induced muscle wasting that captures this non-linear dose-dependence. Area-under-the-curve metrics are proposed to quantify the treatment's effects on lean mass and tumour control. Model simulations are used to explore alternate dosing schedules, aging effects, and morphine use in chemotherapy treatment with the aim of better protecting lean mass while actively targeting the tumour, ultimately leading to improved personalization of treatment planning and improved patient quality of life.
... DRM is a common issue in the inhospital setting (32-34%) and the outpatient setting (39%) (1,11,12). Approximately 20% of cancer patients die from the consequences of DRM, rather than from the primary disease itself (13,14). Usually, DRM cannot completely be reversed with a conventional diet and requires artificial nutritional therapy. ...
Article
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Disease-related malnutrition is highly prevalent among cancer patients, with 40–80% suffering from it during the course of their disease. Malnutrition is associated with numerous negative outcomes such as: longer hospital stays, increased morbidity and mortality rates, delayed wound healing, as well as decreased muscle function, autonomy and quality of life. In cancer patients, malnutrition negatively affects treatment tolerance (including anti-cancer drugs, surgery, chemo- and radiotherapy), increases side effects, causes adverse reactions, treatment interruptions, postoperative complications and higher readmission rates. Conversely, anti-cancer treatments are also known to affect body composition and impair nutritional status. Tailoring early nutritional therapy to patients' needs has been shown to prevent, treat and limit the negative consequences of malnutrition and is likely to improve overall prognosis. As the optimisation of treatment outcomes is top priority and evidence for nutritional therapy is growing, it is increasingly recognized as a significant intervention and an autonomous component of multimodal cancer care. The proactive implementation of nutritional screening and assessment is essential for patients suffering from cancer - given the interaction of clinical, metabolic, pharmacological factors with systemic inflammation; and suppressed appetite with accelerated muscle protein catabolism. At the same time, a nutritional care plan must be established, and adequate individualized nutritional intervention started rapidly. Screening tools for nutritional risk should be validated, standardized, non-invasive, quick and easy-to-use in daily clinical practice. Such tools must be able to identify patients who are already malnourished, as well as those at risk for malnutrition, in order to prevent or treat malnutrition and reduce negative outcomes. This review investigates the predictive value of commonly used screening tools, as well as the sensitivity and specificity of their individual components for improving clinical outcomes in oncologic populations. Healthcare professionals' awareness of malnutrition in cancer patients and the pertinence of early nutritional screening must be raised in order to plan the best possible intervention and follow-up during the patients' ordeal with the disease.
... The concomitant onset of cardiac disease is critical because heart dysfunction hinders optimal management of cancer treatment, especially where aggressive therapies are employed. A vicious circle may therefore develop where cachexia induces HF and HF exacerbates global cachexia [12][13][14][15][16]. ...
Article
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Since it came into being as a discipline, cardio-oncology has focused on the prevention and treatment of cardiotoxicity induced by antitumor chemotherapy and radiotherapy. Over time, it has been proved that even more detrimental is the direct effect generated by cancer cells that release pro-cachectic factors in the bloodstream. Secreted molecules target different organs at a distance, including the heart. Inflammatory and neuronal modulators released by the tumor bulk, either as free molecules or through exosomes, contribute to the pathogenesis of cardiac disease. Progressive cancer causes cachexia and severe cardiac muscle wasting accompanied by cardiomyocyte atrophy, tissue fibrosis, and several functional impairments up to heart failure. The molecular mechanisms responsible for such a cardiac muscle wasting have been partially elucidated in animal models, but minimally investigated in humans, although severe cardiac dysfunction exacerbates global cachexia and hampers efficient anti-cancer treatments. This review provides an overview of cancer-induced structural cardiac and functional damage, drawing on both clinical and scientific research. We start by looking at the pathophysiological mechanisms and evolving epidemiology and go on to discuss prevention, diagnosis, and a multimodal policy of intervention aimed at providing overall prognosis and global care for patients. Despite much interest in the cardiotoxicity of cancer therapies, the direct tumor effect on the heart remains poorly explored. There is still a lack of diagnostic criteria for the identification of the early stages of cardiac disease in cancer patients, while the possibilities that there are for effective prevention are largely underestimated. Research on innovative therapies has claimed considerable advances in preclinical studies, but none of the molecular targets suitable for clinical application has been approved for therapy. These issues are critically discussed here.
... Cachexia, which affects up to 80% of patients with advanced cancer [8], is also associated with decreased quality of life, poor response to chemotherapy, and has been implicated as the cause of death as many as 20% of cancer patients [9][10][11]. Furthermore it has been established that the development of cachexia symptoms is associated with a decreased overall survival [3,6,12,13], and poor outcomes following surgery or targeted therapy for ccRCC [14][15][16][17]. ...
Article
Full-text available
Clear cell renal carcinoma (ccRCC) is frequently associated with cachexia which is itself associated with decreased survival and quality of life. We examined relationships among body phenotype, tumor gene expression, and survival. Demographic, clinical, computed tomography (CT) scans and tumor RNASeq for 217 ccRCC patients were acquired from the Cancer Imaging Archive and The Cancer Genome Atlas (TCGA). Skeletal muscle and fat masses measured from CT scans and tumor cytokine gene expression were compared with survival by univariate and multivariate analysis. Patients in the lowest skeletal muscle mass (SKM) quartile had significantly shorter overall survival versus the top three SKM quartiles. Patients who fell into the lowest quartiles for visceral adipose mass (VAT) and subcutaneous adipose mass (SCAT) also demonstrated significantly shorter overall survival. Multiple tumor cytokines correlated with mortality, most strongly interleukin-6 (IL-6); high IL-6 expression was associated with significantly decreased survival. The combination of low SKM/high IL-6 was associated with significantly lower overall survival compared to high SKM/low IL-6 expression (26.1 months vs. not reached; p < 0.001) and an increased risk of mortality (HR = 5.95; 95% CI = 2.86–12.38). In conclusion, tumor cytokine expression, body composition, and survival are closely related, with low SKM/high IL-6 expression portending worse prognosis in ccRCC.
... Cachexia leads to progressive functional impairment 3 . Up to 20 per cent of all cancer-associated deaths may be attributed to cachexia, through the sequelae of immobility and cardiac or respiratory failure 2,4 . We have shown that skeletal muscle wasting is associated with poor outcome in patients with colorectal and hepatopancreatobiliary malignancies [5][6][7][8] . ...
Article
Full-text available
Cancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.
... Cachexia as a complex metabolic syndrome is accompanied by a significant weight loss and mostly characterized by a decreased muscle mass. Beside the marked weight loss with muscle and adipose mass wasting, anorexia, asthenia, fatigue, hypothalamic appetite control modification, intestinal malabsorption, nausea, profound endocrine alteration and metabolic chaos are frequently reported in patients with cancer cachexia [4]. Roberts et al. [5] demonstrated that cancer cachexia directly impacts functional capacity by muscle atrophy and contractile dysfunction. ...
Article
PURPOSE: Although growing evidence underlines the benefits of physical activity as supportive intervention for cancer patients, sparse data are available for exercise in patients with advanced disease stages, in particular for gastrointestinal cancer (GIC) patients who experience specific disease-associated limitations. Thus, the aim of this study is to evaluate the effects of home-based moderate intensity exercise on functional capacity, activities of daily living (ADL) and body composition in patients with advanced GIC during first-line chemotherapy. METHODS: Participants (GIC, UICC III-IV; n = 44) were randomly assigned to home-based physical activity programme of 150 min moderate walking per week or a control group (CG). Functional status (SPPB: gait speed, balance, lower extremity muscle strength), postural sway, chemotherapy-induced peripheral neuropathy, nutritional state (Mini Nutritional Assessment, MNA) and lean body mass were assessed according to established recommendations. All tests were performed before chemotherapy (T0), after two chemotherapy cycles (T1) and after 12 weeks (T2). RESULTS: SPPB changes from T1 to T2 differed between groups with a comparably greater decrease in the CG (p < .05), but no changes or group differences over the whole study period (T0 to T2) were found. Exercise improved postural sway (T0 to T1; T0 toT2) and lean body mass (T1 to T2; T0 to T2) compared to the control group (p < .05). Gait speed, peripheral neuropathy and strength did not differ between groups (p > .05). CONCLUSIONS: Our results indicate that a home-based physical activity improves postural sway and body composition and might stabilize functional capacity in patients with advanced GIC during chemotherapy. Although the other outcomes did not differ between groups, aforementioned effects might contribute to a maintenance of independency in ADL and a better treatment tolerance and thus enhance patients' quality of life.
... Уменьшение силы скелетных мышц приводит к снижению скорости ходьбы, функционального статуса, что сказывается на качестве жизни человека и в конечном счете к таким последствиям неподвижности, как тромбоз, пневмония, дыхательная недостаточность [19,20]. ...
... Cachexia associated with somatic disorders such as cancer 8 and chronic kidney disorder 9 is also associated with changes in inflammatory markers and cytokines, in particular elevated levels of interleukin (IL) 1 and 6, and tumor necrosis factor (TNF)  have been well documented 10,11 . ...
Article
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Anorexia nervosa (AN) is a severe psychiatric disorder with high mortality and relapse rates. Even though changes in inflammatory markers and cytokines are known to accompany cachexia associated with somatic disorders such as cancer and chronic kidney disorder, studies on inflammatory markers in AN are rare and typically include few individuals. Here, we utilize an Olink Proteomics inflammatory panel to explore the concentrations of 92 preselected inflammation-related proteins in plasma samples from women with active AN (N=113), recovered from AN (AN-REC, N=113), and normal weight healthy controls (N=114). After correction for multiple testing, twenty-five proteins differed significantly between the AN group and controls (lower levels: ADA, CCL19, CD40, CD5, CD8A, CSF1, CXCL1, CXCL5, HGF, IL10RB, IL12B, 1L18R1, LAP TGFß1, MCP3, OSM, TGFα, TNFRSF9, TNFS14 and TRANCE; higher levels: CCL11, CCL25, CST5, DNER, LIFR and OPG). Although more than half of these differences (N=15) were present in the comparison between AN and AN-REC, no significant differences were seen between AN-REC and controls. Furthermore, twenty-five proteins correlated positively with BMI (ADA, AXIN1, CASP8, CD5, CD40, CSF1, CXCL1, CXCL5, EN-RAGE, HGF, IL6, IL10RB, IL12B, IL18, IL18R1, LAP TGFß1, OSM, SIRT2, STAMBP, TGFα, TNFRSF9, TNFS14, TRANCE, TRAIL and VEGFA) and four proteins correlated negatively with BMI (CCL11, CCL25, CCL28 and DNER). These results suggest that a dysregulated inflammatory status is associated with AN, but, importantly, seem to be confined to the acute illness state.
... It cannot be reversed by conventional nutritional support and leads to progressive functional impairment [1,2]. Nearly half of all cancer patients are faced with cachexia in the course of their disease, and it is the cause of death in up to 20 percent [3][4][5]. Catabolic cytokines and patient-related factors such as age are key pathogenic mechanisms underlying cancer cachexia [6][7][8]. Catabolic pro-inflammatory cytokines associated with cancer cachexia include interleukin-6 (IL-6), interleukin-1 beta (IL-1B), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) [7,9]. ...
Article
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Caloric restriction increases lifespan and healthspan, and limits age-associated muscle wasting. In this study, we investigate the impact of 30% caloric restriction (CR) in a murine cancer cachexia model. Forty CD2F1 mice were allocated as C26 tumor-bearing (TB) + ad libitum food intake (dietary reference intake [DRI]), TB CR, non-TB (NTB) CR, or NTB matched intake (MI). TB groups were inoculated subcutaneously with 0.5x10⁶ C26 cells 14 days after initiating CR. Bodyweight, food intake, and grip-strength were recorded periodically. Gastrocnemius (GCM) and tibialis anterior (TA) muscles were resected and weighed 3 weeks after tumor inoculation. mRNA expression of MuRF1, Atrogin-1, myogenin, and MyoD was determined. At tumor inoculation, the mean body weight of TB CR was 88.6% of initial body weight and remained stable until sacrifice. TB DRI showed wasting before sacrifice. TB groups experienced muscle wasting compared with NTB MI. Grip-strength change was less severe in TB CR. Expression of MuRF1, Atrogin-1, and MyoD was similar between TB DRI and both CR groups. Expression of myogenin was increased in CR groups. In conclusion, caloric restriction limits loss of muscle strength but has no impact on muscle mass despite significant loss of body weight in an experimental cancerassociated cachexia model.
... It is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient's quality of life, and it is also associated with a low response to chemotherapy and leads to a decrease in survival [3][4][5]. ...
Article
Full-text available
Cachexia is an extremely serious syndrome which occurs in most patients with different cancers, and it is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient’s quality of life, and it is also associated with a low response to chemotherapy leading to a decrease in survival. Despite this, cachexia is still underestimated and often untreated. New research is needed in this area to understand this complex phenomenon and ultimately find treatment methods and therapeutic targets. The skeletal muscle can act as an endocrine organ. Signaling between muscles and other systems is done through myokines, cytokines, and proteins produced and released by myocytes. In this review, we would like to draw attention to some of the most important myokines that could have potential as biomarkers and therapeutic targets: myostatin, irisin, myonectin, decorin, fibroblast growth factor 21, interleukin-6, interleukin-8, and interleukin-15.
... In cancer patients, there is, generally, weight loss, which has been attributed normally to the diminution of skeletal muscle as a response to the overactivation of proteolysis together with the reduction in proteins synthesis (Tan & Fearon, 2008). This phenomenon is known as cachexia Cid-Gallegos, M. S. et al. ...
Article
Resumen Introducción: El diagnóstico del cáncer de colon suele realizarse de forma tardía, por lo que suelen buscarse varias opciones para su prevención. Para esto, los modelos in vivo resultan una opción para la evaluación de agentes quimiopreventivos. Estos modelos se basan principalmente en la inducción y promoción de la carcinogénesis; sin embargo, tardan mucho tiempo. Este trabajo tuvo como objetivo evaluar y proponer un modelo de carcinogénesis con manifestación tumoral en menos tiempo, para comprobar la eficacia de compuestos quimiopreventivos. Método: Se indujo carcinogénesis de colon en tres grupos (n = 7) de ratones macho BALB/c con azoximetano (AOM) y dextran sulfato de sodio (DSS). El daño se evaluó 14 semanas después de la inducción. Los protocolos fueron los siguientes: 1) P1: dos inyecciones de AOM y dos ciclos de Protocol for short-term tumor development, as an option for the study of chemopreventive agentsDSS al 1.5 % durante cinco días, con tres días de descanso entre ciclos; 2) P2: una inyección de AOM y dos ciclos de DSS al 2 % durante siete días, con cinco días de descanso, y 3) P3: una inyección de AOM y dos ciclos de DSS al 2 % durante cuatro días, con cuatro días de reposo. Se utilizó control negativo en paralelo, P0: con una inyección de solución salina y agua ad libitum. Se determinó peso, índice de actividad de la enfermedad (DAI), supervivencia, incidencia de tumores, lípidos y oxidación de proteínas. Resultados: P2 mostró mayor severidad en los signos evaluados (100 % de incidencia de tumores, peso/longitud de colon 101.68 ± 2.99 mg/cm), con baja supervivencia (43 %); P1 presentó menor mortalidad (14 %) y 83 % de incidencia de tumores, sin diferencia significativa con P2. P3 desarrolló la enfermedad, pero en menor grado (33 % incidencia de tumores). Además, los tres protocolos mostraron oxidación de lípidos (0.4-0.58 ng/μg de proteína) y proteínas (0.6-1 ng/μg de proteína). Los protocolos de inducción P1 y P3 presentaron menor mortalidad, pérdida de peso y DAI aceptable, relación peso/longitud de colon superior al control negativo y presencia de tumores. Discusión o Conclusión: El uso de AOM (10mg/kg) combinado con DSS (1.5-2 %) son modelos adecuados para evaluar el efecto carcinogénico de compuestos de interés, signos de inflamación, oxidación de lípidos y proteínas, y un número de supervivencia necesario para realizar el análisis estadístico que conduzca a conclusiones certeras. Por tanto, P1 y P3 son protocolos que pueden utilizarse con resultados satisfactorios para los ensayos de quimioprevención. Abstract Introduction: Colon cancer diagnosis is usually performed late; so, it is necessary to search for
... Cancer cachexia is a comorbid disorder that affects over 50% of all patients with cancer and is estimated to have a 20%-60% 1-year mortality among all cancer types. 2 Weight loss as an indicator of cachexia is highest among patients with gastrointestinal (GI) cancers followed by lung and other respiratory cancers. 3 Other symptoms of cachexia, in addition to unintentional weight loss, may include fatigue, anorexia, sarcopenia, increased inflammatory markers, decreased muscle strength, and lean muscle mass depletion with or without loss of fat mass. 4 Cachexia often progresses as a result of cancer metabolism and chemotherapy, which contribute to systemic inflammation, physical obstruction (eg, esophageal cancer, intestinal cancer), and pain. ...
Article
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Few studies have examined the possibility that cachexia may affect men and women differently. This pilot study assessed gender differences in body composition in stomach, colorectal, and biliary cancer patients with cachexia. A sample of 38 participants (Female: Male = 17:21, mean age 57.4 years) were included if they were undergoing chemotherapy and experienced weight loss of 5% or more over a 6‐month period. Bioelectrical impedance analysis (BIA) was applied to measure body composition. Phase angle (PA) and levels of extra‐/intracellular water (ECW; ICW) were determined. Data were analyzed first by gender and then compared to age‐ and gender‐matched healthy controls from the NHANES‐III dataset. PA was lower (P < .01) in both genders compared with healthy controls, and PA was lower in female patients compared with male patients (P = .03). Male cancer patients with lower PA also had lower ICW levels compared with healthy controls (r = .98, P < .01). For female patients, PA and ICW were negatively correlated (r = .897, P < .01). A lower ECW/ICW ratio was highly correlated (r = .969 for men, r = .639 for women) with increased PA in cancer patients. ICW changes are gender‐specific in patients with GI cancer. ECW/ICW ratios and PA may be suitable surrogate markers for gender‐specific changes in cell composition and health status. Body composition may be gender dependent in patients with gastrointestinal cancer and require differential diagnosis and treatment approaches. Determination of sarcopenia and cachexia should utilize changes in intracellular/extracellular water ratio in addition to phase angle dependent of gender.
... Cachexia as a complex metabolic syndrome is accompanied by a significant weight loss and mostly characterized by a decreased muscle mass. Beside the marked weight loss with muscle and adipose mass wasting, anorexia, asthenia, fatigue, hypothalamic appetite control modification, intestinal malabsorption, nausea, profound endocrine alteration and metabolic chaos are frequently reported in patients with cancer cachexia [4]. Roberts et al. [5] demonstrated that cancer cachexia directly impacts functional capacity by muscle atrophy and contractile dysfunction. ...
Article
Full-text available
Purpose Although growing evidence underlines the benefits of physical activity as supportive intervention for cancer patients, sparse data are available for exercise in patients with advanced disease stages, in particular for gastrointestinal cancer (GIC) patients who experience specific disease-associated limitations. Thus, the aim of this study is to evaluate the effects of home-based moderate intensity exercise on functional capacity, activities of daily living (ADL) and body composition in patients with advanced GIC during first-line chemotherapy. Methods Participants (GIC,UICC III-IV;n=44) were randomly assigned to home-based physical activity program of 150 minutes moderate walking per week or a control group (CG). Functional status (SPPB: gait speed, balance, lower extremity muscle strength), postural sway, chemotherapy-induced peripheral neuropathy, nutritional state (Mini Nutritional Assessment; MNA) and lean body mass were assessed according to established recommendations. All tests were performed before chemotherapy (T0), after two chemotherapy-cycles (T1) and after 12 weeks (T2). Results SPPB changes from T1 to T2 differed between groups with a comparably greater decrease in the CG (p<.05), but no changes or group differences over the whole study period (T0 toT2) were found. Exercise improved postural sway (T0 toT1;T0 toT2) and lean body mass (T1 toT2;T0 toT2) compared to the control group (p<.05). Gait speed, peripheral neuropathy and strength did not differ between groups (p>.05). Conclusions Our results indicate that a home-based physical activity improves postural sway and body composition and might stabilize functional capacity in patients with advanced GIC during chemotherapy. Although the other outcomes did not differ between groups, aforementioned effects might contribute to a maintenance of independency in ADL and a better treatment tolerance and thus enhance patients' quality of life.
... Cachexia is a multifactorial metabolic syndrome characterised by the dramatic loss of skeletal muscle mass, which is often accompanied by fat loss [1]. It is a devastating consequence seen in patients with acquired immune deficiency syndrome [2], burns [3], cancers [4,5], chronic obstructive pulmonary disease [6], chronic heart [7] and renal failures [8], diabetes [9], and sepsis [10][11][12]. During these disorders, the basal energy expenditure increases, which enhances the fat and protein catabolism primarily from the energy reserve organs and thus leads to wasting [8]. ...
Article
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Clinical management of cancer-associated cachexia, a multi-organ wasting syndrome, has been challenging without effective treatment strategies. An effective treatment that directly targets cancer-induced wasting is desperately needed to improve the quality of life and the survival of cancer patients. Recently, an antibiotic SFX was shown to have anti-tumour and anti-metastatic effects in mouse models of breast cancer. Hence, in this study, we examined the efficacy of SFX in the treatment of cancer-induced cachexia. C26 cachexic mice models were administered with SFX, and the tumour volume and body weight were regularly measured. Blood glucose, skeletal muscles, and adipose tissue were examined at the endpoint. Contrary to a previous study, SFX did not reduce the tumour volume in mice bearing C26 cells. Administration of SFX neither revealed any survival benefit nor rescued C26 cachectic mice from muscle wasting. Interestingly, SFX administration partially rescued (~10%) tumour-induced weight loss by preserving both the subcutaneous and intestinal fat mass. Together, these results suggest that the administration of SFX could partially rescue cancer-induced weight loss by inhibiting lipolysis. As anti-cachexia therapies are scarce, the results could facilitate the design of combinatorial therapies involving SFX, standard-of-care chemotherapeutics, and drugs that inhibit muscle atrophy for the treatment of cancer cachexia.
Article
Objective In this study, we investigated the muscle function of patients with haematological malignancy and healthy controls and examined the effect of cachexia on muscle function. Methods Seventy‐one patients with haematological malignancy, hospitalised for chemotherapy, and 71 healthy controls underwent examination of skeletal muscle mass (SMM; total body and upper and lower limbs), handgrip strength and isometric knee extensor strength. Patients with haematological malignancy were divided into three groups based on Glasgow Prognostic Score: non‐cachexia (n = 31), pre‐cachexia (n = 23) and cachexia (n = 17) groups. The evaluation items were compared among the groups. Results Patients with haematological malignancy had lower SMM of the total body and lower limbs, handgrip strength and isometric knee extensor strength than healthy controls. There was no significant difference in SMM of the upper limbs among the groups. When classifying patients with haematological malignancy according to GPS, there was no significant difference among the three groups for any of the evaluation items. Conclusions In patients with haematological malignancy, although significant muscle wasting and weakness were observed in the lower limbs, the effect of cachexia was minimal. The reduction in muscle function involved disuse syndrome, which accompanied a decline in physical activity.
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Purpose The aim of this study was to investigate the effects of creatine supplementation on muscle wasting in Walker-256 tumor-bearing rats. Methods Wistar rats were randomly assigned into three groups (n = 10/group): control (C), tumor bearing (T), and tumor bearing supplemented with creatine (TCr). Creatine was provided in drinking water for a total of 21 days. After 11 days of supplementation, tumor cells were implanted subcutaneously into T and TCr groups. The animals’ weight, food and water intake were evaluated along the experimental protocol. After 10 days of tumor implantation (21 total), animals were euthanized for inflammatory state and skeletal muscle cross-sectional area measurements. Skeletal muscle components of ubiquitin–proteasome pathways were also evaluated using real-time PCR and immunoblotting. Results The results showed that creatine supplementation protected tumor-bearing rats against body weight loss and skeletal muscle atrophy. Creatine intake promoted lower levels of plasma TNF-α and IL-6 and smaller spleen morphology changes such as reduced size of white pulp and lymphoid follicle compared to tumor-bearing rats. In addition, creatine prevented increased levels of skeletal muscle Atrogin-1 and MuRF-1, key regulators of muscle atrophy. Conclusion Creatine supplementation prevents skeletal muscle atrophy by attenuating tumor-induced pro-inflammatory environment, a condition that minimizes Atrogin-1 and MuRF-1-dependent proteolysis.
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Background Cachexia is associated with increased mortality risk among chronic obstructive pulmonary disease (COPD) patients. However, low body mass index (BMI) as opposed to cachexia is often used, particularly when calculating the BODE (BMI, Obstruction, Dyspnea and Exercise) index. For this reason, we examined mortality using a consensus definition and a weight-loss definition of cachexia among COPD cases and compared two new COPD severity indices with BODE. Methods In the current report, the consensus definition for cachexia incorporated weight-loss > 5% in 12-months or low BMI in addition to 3/5 of decreased muscle strength, fatigue, anorexia, low FFMI and inflammation. The weight-loss definition incorporated weight-loss > 5% or weight-loss > 2% (if low BMI) in 12-months. The low BMI component in BODE was replaced with the consensus definition to create the CODE (Consensus cachexia, Obstruction, Dyspnea and Exercise) index and the weight-loss definition to create the WODE (Weight loss, Obstruction, Dyspnea and Exercise) index. Mortality was assessed using Kaplan-Meier survival and Cox Regression. Performance of models was compared using C-statistics. Results Among 1483 COPD cases, the prevalences of cachexia by the consensus and weight-loss definitions were 4.7 and 10.4%, respectively. Cachectic patients had a greater than three-fold increased mortality by either the consensus or the weight-loss definition of cachexia independent of BMI and lung function. The CODE index predicted mortality slightly more accurately than the BODE and WODE indices. Conclusions Cachexia is associated with increased mortality among COPD patients. Monitoring cachexia using weight-loss criteria is relatively simple and predictive of mortality among COPD cases who may be missed if only low BMI is used. Electronic supplementary material The online version of this article (10.1186/s12931-019-1073-3) contains supplementary material, which is available to authorized users.
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Background Cognitive impairment and poor oral health are common problems in older adults and are associated with malnutrition. However, it is unclear how they are related to cachexia in community-dwelling older adults. The aim of this study was to examine the relationships among cachexia, cognitive function, and oral health in community-dwelling older adults. Methods This study is a secondary analysis of a data-set. Data were collected in the community setting on older adults who applied for government-funded long-term care services in Hong Kong in 2017. Subjects were community-dwelling and aged ≥60 years. The outcome variable was cachexia. The predictors were cognitive function and oral health. The covariates included demographics and comorbidities associated with cachexia or malnutrition. Path analysis was employed to examine the associations among cachexia, cognitive function, and oral health using the software SAS/STAT and Mplus. Results This analysis included 12,940 subjects. The prevalence of cachexia was 1.3%. Cognitive function was also found to have a direct effect on the oral health indicators of chewing problems (OR=1.073, p<0.001), brushing teeth problems (OR=1.349, p<0.001), and swallowing problems (coeff.=0.177, p<0.001). Oral health indicators with a direct effect on cachexia included dry mouth (OR=1.250, p<0.001), brushing teeth problems (OR = 1.185, p<0.01), and swallowing problems (OR=1.231, p<0.001). Cognitive function had no significant direct effect, but had a significant indirect effect on cachexia (OR=1.100, p<0.001) which is mediated by brushing teeth problems (OR=1.052, p<0.001) and swallowing problems (OR=1.038, p<0.001). Conclusion Cognitive impairment causes cachexia indirectly through poor oral health. This study recommends adding cognitive function when screening community-dwelling older adults for cachexia. Health policymakers should stress regular oral health screening and interventions, and encourage increased utilization of oral health services by community-dwelling older adults with cognitive problems.
Article
Cancer cachexia is a complicated disorder of extreme, progressive skeletal muscle.wasting. It is directed by metabolic alterations and systemic inflammation dysregulation. Numerous studies have demonstrated that increased systemic inflammation promotes this type of cachexia and have suggested that cytokines are implicated in the skeletal muscle loss. Exercise is firmly established as an anti-inflammatory therapy that can attenuate or even reverse the process of muscle wasting in cancer cachexia. The interleukin IL-6 is generally considered to be a key player in the development of the microenvironment of malignancy; it promotes tumor growth and metastasis by acting as a bridge between chronic inflammation and cancerous tissue and it also induces skeletal muscle atrophy and protein breakdown. Paradoxically, a beneficial role for IL-6 has also been identified recently, and that is its status as a "founding member" of the myokine class of proteins. Skeletal muscle is an important source of circulating IL-6 in persons who participate in exercise training. IL-6 acts as an anti-inflammatory myokine by inhibiting TNF-α and improving glucose uptake through the stimulation of AMPK signaling. This review discusses the action of IL-6 in skeletal muscle tissue dysfunction and the role of IL-6 as an "exercise factor" that modulates the immune system. This review also sheds light on the main considerations related to the treatment of muscle wasting in cancer cachexia.
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Aim: To evaluate whether cardiac muscle area and radiation attenuation, determined using pre-chemotherapy computed tomography (CT), are associated with therapeutic response and overall survival (OS) in chemotherapy-treated advanced pancreatic cancer (APC) patients. Materials and methods: Ninety-eight chemotherapy-treated APC patients who underwent pre-chemotherapy CT between 2009 and 2018 were considered. Left ventricular muscle area (LVMA) and left ventricular muscle radiation attenuation (LVMRA) were measured using pre-chemotherapy arterial-phase CT. OS and progression-free survival (PFS) were analysed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to analyse potential factors affecting OS and PFS. Results: Patients with low LVMRA, low LVMA at baseline CT, and multiple metastases had a significantly shorter median OS than patients with high LVMRA, high LVMA, and without multiple metastases (8.8 versus 14 months, p=0.017; 12.2 versus 18.1 months, p=0.038; 7.3 versus 13.5 months, p<0.001, respectively). Patients with low LVMRA and distant metastasis had a shorter median PFS than patients with high LVMRA and those without distant metastasis (4.9 versus 8.3 months, p=0.032; 5.4 versus 9.9 months, p=0.002, respectively). Moreover, the mean LVMRA was the highest in the partial response group (p=0.028). Conclusion: LVMRA could well predict PFS and OS in chemotherapy-treated APC patients.
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Background By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. Methods We performed a retrospective review of 53 patients with advanced PDAC on 5‐fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. Results Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat‐Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5–17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1–2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT‐based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. Conclusions Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first‐line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.
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Abstract Cancer cachexia is the loss of lean muscle mass with or without loss of fat mass that is often highlighted by a progressive loss of skeletal muscle mass and function. The mechanisms behind the cachexia‐related loss of skeletal muscle are poorly understood, including cachexia‐related muscle functional impairments. Existing models have revealed some potential mechanisms, but appear limited to how the cancer develops and the type of tumors that form. We studied the C57BL6/J (B6) ApcMin/+ Tg::Fabp1‐Cre TG::PIK3ca* (CANCER) mouse. In this model, mice develop highly aggressive intestinal cancers. We tested whether CANCER mice develop cancer cachexia, if muscle function is altered and if sex differences are present. Both female and male mice, B6 (CONTROL) and CANCER mice, were analyzed to determine body weight, hindlimb muscle mass, protein concentration, specific force, and fatigability. Female CANCER mice had reduced body weight and hindlimb muscle mass compared with female CONTROL mice, but lacked changes in protein concentration and specific force. Male CANCER mice had reduced protein concentration and reduced specific force, but lacked altered body weight and muscle mass. There were no changes in fatigability in either group. Our study demonstrates that CANCER mice present an early stage of cachexia, have reduced specific force in male CANCER mice and develop a sex‐dependent cachexia phenotype. However, CANCER mice lack certain aspects of the syndrome seen in the human scenario and, therefore, using the CANCER mice as a preclinical model does not seem sufficient in order to maximize the translation of preclinical findings to humans.
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Background: Unintentional weight loss is a major problem for patients with gastrointestinal (GI) cancers because it affects treatment, survival outcomes, and quality of life. To date, little is known about the trajectory of weight loss and the relationship between baseline body mass index (BMI), location of the cancer, and outcomes. The aims of this study were to investigate patterns of weight loss over time in patients with GI cancer according to BMI groups (low, normal, and high) and location of cancer. Methods: We examined de-identified electronic medical record data of 801 adults (>21 years) with GI cancer using ICD-9 codes (150-159). Descriptive statistics and linear mixed models were used to examine unintentional weight loss over time by BMI group (low, normal, and high) and to determine the effect of primary cancer site and patient characteristics on weight loss. Results: The mean age of patients was 66.5 ± 11.9 years (21-95 years), with 58% male and 86% White. Mean weight loss over 3 years was 21.39 kg. At the first observation point, 7.8% were in the low BMI group, 30.1% were in the normal, and 62% were in the high group. At the end of observation, a majority of deaths (35.5%) occurred in the low BMI group (BMI < 20 kg/m2 ). Significant weight loss was observed in patients with gastric (t = -5.11, P < 0.001), oesophageal (t = -4.18, P < 0.001), and pancreatic (35.8%, t = -3.58, P < 0.001) cancers. Predictors of weight change were gender (F = 64.93, P < 0.001), cancer stage (F = 7.28, P < 0.001), and site by days (F = 8.24, P < 0.001). Weight loss rates were similar among the three BMI groups, but patterns were different based on primary cancer type as a function of days within each group. Conclusions: Weight loss in patients with GI cancers has implications for survival. Patients with upper GI cancers experienced more weight loss and decreased survival rates compared with patients with lower GI cancers. Patients with a combination of upper GI cancer (oesophagogastric or pancreatic) and low baseline BMI had the fewest survival days and worst patient outcomes. Early intervention for weight management plays a critical role for improving the health outcomes and fatality rates of these patients.
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Background Unintentional weight loss in older people has been linked to increased risk of mortality. We aimed to investigate common medical conditions and lifestyle factors, including body fat distribution, as potential determinants of recent and prospective unintentional weight loss in early old age. Methods From the Medical Research Council (MRC) National Survey of Health and Development (NSHD), we included a total of 2234 study members aged 60–64 with information on unintentional weight loss in 2006–2010. Of these, 2136 also had information on unintentional weight loss recorded in 2015. Logistic regression was conducted to examine the associations between medical conditions, lifestyle, and body fat distribution at age 60–64 and unintentional weight loss at age 60–64 and 69. Results A total of 109 of 2234 study members had unintentional weight loss at ages 60–64, and 166 of 2136 at age 69. Never smoking was associated with lower risk of unintentional weight loss at age 60–64 (OR = 0.29, 95%CI = 0.12–0.68 compared to current smokers), and this association remained when adjusted for other determinants. Greater waist-hip ratio (OR = 0.95, 95%CI = 0.91–0.99) and body fat-lean mass ratio (OR = 0.96, 95%CI = 0.94–0.99) were associated with less likelihood of unintentional weight loss at age 60–64. Never smoking and greater hip circumference at age 60–64 were associated with lower odds of unintentional weight loss at age 69. Conclusions Smoking status and body fat distribution may help identify those at risk of unintentional weight loss in early old age. Their benefit in interventions to prevent age-associated weight loss needs to be further investigated.
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Cancer cachexia, characterized by continuous muscle wasting, is a key determinant of cancer‐related death; however, there are few medical treatments to combat it. Myostatin (MSTN)/ growth differentiation factor 8 (GDF8), which is a member of the TGF‐β family, is secreted in an inactivated form non‐covalently bound to the prodomain, negatively regulating the skeletal muscle mass. Therefore, inhibition of MSTN signaling is expected to serve a therapeutic target for intractable muscle wasting diseases. Here, we evaluated the inhibitory effect of peptide‐2, an inhibitory core of mouse MSTN prodomain, on MSTN signaling. Peptide‐2 selectively suppressed the MSTN signal although it had no effect on the activin signal. In contrast, peptide‐2 slightly inhibited the GDF‐11 signaling pathway, which is strongly related to the MSTN signaling pathway. Furthermore, we found that the intramuscular administration of peptide‐2 to tumor‐implanted C57BL/6 mice alleviated muscle wasting in cancer cachexia. Although, peptide‐2 was unable to improve the loss of heart weight and fat mass when cancer cachexia model mice were injected with it, peptide‐2 increased the gastrocnemius muscle weight and muscle cross section area resulted in the enhanced grip strength in cancer cachexia mice. Consequently, the model mice treated with peptide‐2 could survive longer than those that did not undergo this treatment. Our results suggest that peptide‐2 might be a novel therapeutic candidate to suppress muscle wasting in cancer cachexia.
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Nutrition and diet play a major role in cancer. Malnutrition and weight loss often contribute to the death of cancer patients. Nutritional abnormalities in cancer are unique and are a result of abnormal anatomic and physiologic circumstances. Factors that contribute to this are cancer cachexia, abnormalities in metabolism, and the cytokine milieu. Because of these abnormalities, surgery in cancer patients can be problematic. It is important to perform a formal nutritional assessment on patients with cancer and develop unique treatment plans to address deficiencies in the perioperative setting. Additionally, special nutritional considerations must be made to address malignancies affecting specific organ sites.
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Purpose: To determine the role of mammalian target of rapamycin (mTORC1) activation and catabolic markers in resistance training's (RT) anti-atrophy effect during cachexia-induced muscle loss. Methods: Myofiber atrophy was induced by injecting Walker 256 tumor cells into rats exposed or not exposed to the RT protocol of ladder climbing. The role of RT-induced anabolic stimulation was investigated in tumor-bearing rats with the mTORC1 inhibitor rapamycin, and cross-sectional areas of skeletal muscle were evaluated to identify atrophy or hypertrophy. Components of the mTORC1 and ubiquitin-proteasome pathways were assessed by real-time PCR or immunoblotting. Results: While RT prevented myofiber atrophy and impaired the strength of tumor-bearing rats, in healthy rats it promoted activated mTORC1, as demonstrated by p70S6K's increased phosphorylation and myofiber's enlarged cross-sectional area. However, RT promoted no changes in the ratio of p70S6K to phospho-p70S6K protein expression while prevented myofiber atrophy in tumor-bearing rats. Beyond that, treatment with rapamycin did not preclude RT's preventive effect on myofiber atrophy in tumor-bearing rats. Thus, RT's ability to prevent cancer-induced myofiber atrophy seems to be independent of mTORC1's and p70S6K's activation. Indeed, RT's preventive effect on cancer-induced myofiber atrophy was associated with its capacity to attenuate elevated TNF-α and IL-6 as well as to prevent oxidative damage in muscles and an elevated abundance of atrogin-1. Conclusion: By inducing attenuated myofiber atrophy independent of mTORC1's signaling activation, RT prevents muscle atrophy during cancer by reducing inflammation, oxidative damage, and atrogin-1 expression.
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Relationship between BMI and all-cause mortality in patients with hypertension remains controversial. This study aimed to evaluate the time-varying association between BMI in patients with hypertension and all-cause mortality. This population-based cohort study included 212,394 Chinese adults with hypertension from 2007 to 2015 and was followed up until death, loss-to-follow-up, or December 31, 2018. According to the World Health Organization criteria for Asians, BMI was categorized into five groups: underweight (BMI < 18.5 kg/m²), normal weight (18.5–22.9 kg/m²), overweight (23–24.9 kg/m²), class I obesity (25–29.9 kg/m²) and class II obesity (BMI ≥ 30 kg/m²). Cox model was used to estimate the time-varying association of BMI on the risk of mortality by including the interaction term between BMI and time using restricted cubic spline. Compared with normal weight, underweight and class II obesity were associated with higher mortality (Hazard ratio [HRs] at 1 and 10 years of follow-up: 1.51 [95% CI: 1.39–1.65], and 1.27 (1.15–1.41) for underweight, respectively; 1.08 (0.96–1.21), and 1.16 (1.03–1.30) for class II obesity, respectively). However, overweight and class I obesity were associated with lower mortality, although the protective effects gradually attenuated over time (HRs at 1 and 10 years of follow-up: 0.85 (0.81–0.90), and 0.96 (0.91–1.02) for overweight, respectively; 0.80 (0.76–0.84), and 1.04 (0.99–1.10) for class I obesity, respectively). We found increased mortality among hypertensive patients with underweight and class II obesity while decreased mortality with overweight and class I obesity was observed during the first 5 years of follow-up. Management efforts for hypertension may target controlling body weight in a reasonable range for patients, and probably more attention should be given to underweight patients.
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Malnutrition, sarcopenia, frailty and cachexia are different conditions but have overlapping characteristics and consequences for older adults. These conditions are especially prevalent in hospitalised patients affecting almost two thirds of older adults. They can often be hidden conditions; hence multidisciplinary awareness is needed for optimal identification and management. This chapter provides an overview of the definitions of each of these syndromes, its detrimental impact on health outcomes of older adults and tips for clinical practice implementation.
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Background: Cancer cachexia syndrome (CCS) is an adverse prognostic factor in cancer patients undergoing chemotherapy or surgical procedures. We performed a prospective study to investigate the effect of CCS on treatment outcomes in patients with non-oncogene driven metastatic non-small cell lung cancer (NSCLC) undergoing therapy with programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors. Methods: Patients were categorized as having cancer cachexia if they had weight loss >5% in the last 6 months prior to immunotherapy (I-O) initiation or any degree of weight loss >2% and body mass index (BMI) <20 kg/m2 or skeletal muscle index at the level of third lumbar vertebra (LSMI) <55 cm2/m2 for males and <39 cm2/m2 for females. LSMI was calculated using computed tomography (CT) scans of the abdomen at the beginning of I-O and every 3 months thereafter. Results: Eighty-three patients were included in the analysis and the prevalence of cancer cachexia at the beginning of I-O was 51.8%. The presence of CCS was associated with inferior response rates to ICIs (P≤0.001) and consisted an independent predictor of increased probability for developing disease progression as best response to treatment, OR =8.11 (95% CI: 2.95-22.40, P≤0.001). In the multivariate analysis, the presence of baseline cancer cachexia consisted an independent predictor for inferior survival, HR =2.52 (95% CI: 1.40-2.55, P=0.002). Reduction of LSMI >5% during treatment did not affect overall survival (OS; P=0.40). Conclusions: CCS is associated with reduced PD-1/PD-L1 inhibitor efficacy in NSCLC patients and should constitute an additional stratification factor in future I-O clinical trials. Further research at a translational and molecular level is required to decipher the mechanisms of interrelation of metabolic deregulation and suppression of antitumor immunity.
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Aim To describe and synthesise experiences of food and mealtimes from the perspective of patients with chronic life-limiting disease. Design A mixed-method systematic review. Data Sources The databases Academic Search Complete, CINAHL, Nursing and Allied Health Database, PsycINFO, PubMed, Soc Index and Web of Science Core Collection were searched (January 2000 to March 2019). Review Methods Out of 3151 identified articles, 24 were included for appraisal and synthesis, using a data based convergent design. Results Four themes were derived: ‘understanding hampered eating—perhaps it is best to let nature run its course’; ‘food and meals evoke distress—reducing joy, testing interim ways’; ‘struggling with food and meals—eating to please others and to postpone death’; and ‘food and meals as caring and love—flanked by social disconnecting’. Conclusion For patients with chronic life-limiting disease, food entailed potential to remain healthy, improve well-being and prolong life. Meanwhile, eating difficulties were experienced as fundamentally affecting social life and interactions; consequently, joy around food and meals was lost.
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Cachexia is a multifactorial syndrome characterized by skeletal muscle loss, with or without adipose atrophy, irreversible through nutritional support, in the context of systemic inflammation and metabolic disorders. It is mediated by inflammatory reaction and affects almost 50% of all cancer patients, due to prominent systemic inflammation associated with the disease. The comprehension of the molecular mechanisms that are implicated in cancer cachexia sheds light on its pathogenesis and lays the foundations for the discovery of new therapeutic targets and biomarkers. Recently, ncRNAs, like microRNAs as well as lncRNAs and circRNAs seem to regulate pathways that are implicated in cancer cachexia pathogenesis, as it has been observed in animal models and in cancer cachexia patients, highlighting their therapeutic potential. Moreover, increasing evidence highlights the involvement of circulating and exosomal ncRNAs in the activation and maintenance of systemic inflammation in cancer and cancer-associated cachexia. In that context, the present review focuses on the clinical significance of ncRNAs in cancer-associated cachexia.
Article
Background Pancreatic ductal adenocarcinoma (PDAC) has the worst survival of common cancers, partly because there are no reliable early detection tests. Unintentional weight loss (≥ 5% decrease from baseline) has been linked to PDAC, but the frequency and severity of weight loss using objective measures, and its relationship to prognosis, have not been well characterized.Methods We identified 390 patients with PDAC (all stages) and two or more prediagnosis weights in the electronic medical record. Percentage weight loss in the 365 and 180 days preceding diagnosis was calculated. Results were compared with raw weights of age- and sex-matched non-cancer controls (n = 780). Odds ratios for PDAC were calculated using conditional logistic regression. Cox proportional hazards models were used for survival.ResultsWithin 1 year of diagnosis, more PDAC patients lost ≥ 5% weight relative to controls (74.9% vs. 11.2%; p < 0.001), with a median weight loss of 14.2 versus 2.9 lbs. The odds ratio for PDAC comparing weight loss within 1 year of 5 to < 10% was 10.30 (p < 0.001) and 77.82 for ≥ 10% (p < 0.001), compared with stable weight. Weight loss prior to diagnosis was also associated with early-stage PDAC. PDAC cases with ≥ 10% prediagnosis weight loss had worse survival compared with stable weights (hazard ratio [HR] 1.60; p = 0.01). Greater prediagnosis weight loss was associated with poor survival after pancreatectomy (5 to < 10% vs. < 5%, HR 2.40, p = 0.03; ≥ 10% vs. < 5%, HR 2.59, p = 0.03).Conclusions Diagnosis of PDAC is preceded by unintentional weight loss in the majority of patients, even at an early stage. Greater prediagnosis weight loss severity is also associated with poor postoperative survival.
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Sarcopenia, cachexia, and atrophy due to inactivity and disease states are characterized by a loss of skeletal muscle mass, often accompanied by reduced levels of anabolic hormones (e.g. testosterone). These conditions are associated with an increase in mortality, hospitalization and worsening in quality of life. Both physical exercise (EX) and anabolic-androgenic steroid (AAS) administration can improve the prognosis of patients as they increase physical functionality. However, there is a gap in the literature as to the impact of these therapies on the gains in strength and muscle mass and their implications for patient safety. Accordingly, we performed a random-effects meta-analysis to elucidate the effects of AAS and/or EX interventions on lean body mass (LBM) and muscle strength in conditions involving muscle loss. A systematic search for relevant clinical trials was conducted in MEDLINE, EMBASE, SCOPUS, Web of Science, and SPORTDiscus. Comparisons included AAS vs. Control, EX vs. Control, AAS vs. EX, AAS + EX vs. AAS and AAS + EX vs. EX. A total of 1114 individuals were analyzed. AAS increased LBM (effect size [ES]: 0.46; 95% CI: 0.25, 0.68, P = 0.00) and muscle strength (ES: 0.31; 95% CI: 0.08, 0.53, P = 0.01) when compared to a control group. EX promoted an increase in muscular strength (ES: 0.89; 95% CI: 0.53, 1.25, P = 0.00), with no effect on LBM when compared to the control group (ES: 0.15; 95% CI:-0.07, 0.38, P = 0.17). AAS did not demonstrate statistically significant differences when compared to EX for LBM and muscle strength. The combination of EX + AAS promoted a greater increase in LBM and muscular strength when compared to AAS or EX in isolation. Qualitatively, AAS administration had relatively few side effects. Significant heterogeneity was found in some analyses, which may be explained by the use of different AAS types and EX protocols. Our findings suggest that AAS administration in cachectic and sarcopenic conditions may be a viable interventional strategy to enhance muscle function when exercise is not a possible approach. Moreover, combining AAS with exercise may enhance positive outcomes in this population.
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Aims and objectives: To explore partners’ experiences of everyday life in caring for a dying person with eating deficiencies at home. Background: When a dying person receives care at home, eating deficiencies can influence everyday life for family members, who often take responsibility for the provision of food and meals. The literature reveals this to be emotionally stressful. Partners of dying persons are challenged both as caregivers and as partners who will soon lose their life companion. There is a need for studies that provide enhanced understanding about the influence of dying persons’ eating deficiencies on their partners, from the perspective of everyday life. Design: A qualitative design was chosen to obtain experience-based knowledge of relevance for the clinical context of palliative home care. Methods: Nine people were purposefully selected and interviewed three– six months after the death of their partner. Data collection and analysis were guided by an interpretive descriptive method. Results. The partners described experiences of how eating deficiencies brought about changes in the participants’ everyday lives. Two patterns of experiences were identified: the challenge of doing the best for their dying partner around matters involving food and mealtimes, and experiences of striving to maintain ordinariness, including holding on to social values around food, despite experiences of unfamiliarity when the dying partners’ habits were changed. Conclusion: Living close to a person who has eating deficiencies at the end of life is challenging, both from a caring perspective and for personal well-being. Relevance to clinical practice: The findings can assist palliative home care teams and other healthcare professionals to give support that goes beyond giving practical advice about food. Initiating talk about the current situation around food and meals at home, by posing questions and opening the way for conversations, is suggested.
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Background: Patients with gastric cancer have an increased nutritional risk and experience a significant skeletal muscle loss after surgery. We aimed to determine whether muscle loss during the first postoperative year and preoperative nutritional status are indicators for predicting prognosis. Methods: From a gastric cancer registry, a total of 958 patients who received curative gastrectomy followed by chemotherapy for stage 2 and 3 gastric cancer and survived longer than 1 year were investigated. Clinical and laboratory data were collected. Skeletal muscle index (SMI) was assessed based on the muscle area at the L3 level on abdominal computed tomography. Results: Preoperative nutritional risk index (NRI) and postoperative decrement of SMI (dSMI) were significantly associated with overall survival (hazards ratio: 0.976 [95% CI: 0.962-0.991] and 1.060 [95% CI: 1.035-1.085], respectively) in a multivariate Cox regression analysis. Recurrence, tumor stage, comorbidity index were also significant prognostic indicators. Kaplan-Meier analyses exhibited that patients with higher NRI had a significantly longer survival than those with lower NRI (5-year overall survival: 75.8% vs. 63.0%, P < 0.001). In addition, a significantly better prognosis was observed in a patient group with less decrease of SMI (5-year overall survival: 75.7% vs. 66.2%, P = 0.009). A logistic regression analysis demonstrated that the performance of preoperative NRI and dSMI in mortality prediction was quite significant (AUC: 0.63, P < 0.001) and the combination of clinical factors enhanced the predictive accuracy to the AUC of 0.90 (P < 0.001). This prognostic relevance of NRI and dSMI was maintained in patients experiencing tumor recurrence and highlighted in those with stage 3 gastric adenocarcinoma. Conclusions: Preoperative NRI is a predictor of overall survival in stage 2 or 3 gastric cancer patients and skeletal muscle loss during the first postoperative year was significantly associated with the prognosis regardless of relapse in stage 3 tumors. These factors could be valuable adjuncts for accurate prediction of prognosis in gastric cancer patients.
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Background: Interferon-induced protein with tetratricopeptide repeat 2 (IFIT2) is a reported metastasis suppressor in oral squamous cell carcinoma (OSCC). Metastases and cachexia may coexist. The effect of cancer metastasis on cancer cachexia is largely unknown. We aimed to address this gap in knowledge by characterizing the cachectic phenotype of an IFIT2-depleted metastatic OSCC mouse model. Methods: Genetically engineered and xenograft tumour models were used to explore the effect of IFIT2-depleted metastatic OSCC on cancer cachexia. Muscle and organ weight changes, tumour burden, inflammatory cytokine profiles, body composition, food intake, serum albumin and C-reactive protein (CRP) levels, and survival were assessed. The activation of the IL6/p38 pathway in atrophied muscle was measured. Results: IFIT2-depleted metastatic tumours caused marked body weight loss (-18.2% vs. initial body weight, P < 0.001) and a poor survival rate (P < 0.01). Skeletal muscles were markedly smaller in IFIT2-depleted metastatic tumour-bearing mice (quadriceps: -28.7%, gastrocnemius: -29.4%, and tibialis: -24.3%, all P < 0.001). Tumour-derived circulating granulocyte-macrophage colony-stimulating factor (+772.2-fold, P < 0.05), GROα (+1283.7-fold, P < 0.05), IL6 (+245.8-fold, P < 0.001), IL8 (+616.9-fold, P < 0.001), IL18 (+24-fold, P < 0.05), IP10 (+18.8-fold, P < 0.001), CCL2 (+439.2-fold, P < 0.001), CCL22 (+9.1-fold, P < 0.01) and tumour necrosis factor α (+196.8-fold, P < 0.05) were elevated in IFIT2-depleted metastatic tumour-bearing mice. Murine granulocyte colony-stimulating factor (+61.4-fold, P < 0.001) and IL6 (+110.9-fold, P < 0.01) levels were significantly increased in IFIT2-depleted metastatic tumour-bearing mice. Serum CRP level (+82.1%, P < 0.05) was significantly increased in cachectic shIFIT2 mice. Serum albumin level (-26.7%, P < 0.01) was significantly decreased in cachectic shIFIT2 mice. An assessment of body composition revealed decreased fat (-81%, P < 0.001) and lean tissue (-21.7%, P < 0.01), which was consistent with the reduced food intake (-19.3%, P < 0.05). Muscle loss was accompanied by a smaller muscle cross-sectional area (-23.3%, P < 0.05). Muscle atrophy of cachectic IFIT2-depleted metastatic tumour-bearing mice (i.v.-shIFIT2 group) was associated with elevated IL6 (+2.7-fold, P < 0.05), phospho-p38 (+2.8-fold, P < 0.05), and atrogin-1 levels (+2.3-fold, P < 0.05) in the skeletal muscle. Neutralization of IL6 rescued shIFIT2 conditioned medium-induced myotube atrophy (+24.6%, P < 0.01). Conclusions: Our results suggest that the development of shIFIT2 metastatic OSCC lesions promotes IL6 production and is accompanied by the loss of fat and lean tissue, anorexia, and muscle atrophy. This model is appropriate for the study of OSCC cachexia, especially in linking metastasis with cachexia.
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Muscle wasting in cancer is associated with deficits in protein synthesis, yet, the mechanisms underlying this anabolic impairment remain poorly understood. The capacity for protein synthesis is mainly determined by the abundance of muscle ribosomes, which is in turn regulated by transcription of the ribosomal (r)RNA genes (rDNA). In this study, we investigated whether muscle loss in a preclinical model of ovarian cancer is associated with a reduction in ribosomal capacity and was a consequence of impaired rDNA transcription. Tumor bearing resulted in a significant loss in gastrocnemius muscle weight and protein synthesis capacity, and was consistent with a significant reduction in rDNA transcription and ribosomal capacity. Despite the induction of the ribophagy receptor NUFIP1 mRNA and the loss of NUFIP1 protein, in vitro studies revealed that while inhibition of autophagy rescued NUFIP1, it did not prevent the loss of rRNA. Electrophoretic analysis of rRNA fragmentation from both in vivo and in vitro models showed no evidence of endonucleolytic cleavage, suggesting that rRNA degradation may not play a major role in modulating muscle ribosome abundance. Our results indicate that in this model of ovarian cancer‐induced cachexia, the ability of skeletal muscle to synthesize protein is compromised by a reduction in rDNA transcription and consequently a lower ribosomal capacity. Thus, impaired ribosomal production appears to play a key role in the anabolic deficits associated with muscle wasting in cancer cachexia.
Chapter
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Purpose Multiple myeloma (MM), a clonal plasma cell malignancy, composes around 10% of hematologic malignancies. Though recent advances in treatment have dramatically improved MM survival, some aggressive courses of disease and dismal outcomes still exist. Low body weight, undernutrition, and cachexia are noted at MM diagnosis. We aim to evaluate the impact of low body mass index (BMI) and undernutrition in MM patients. Methods We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2006 and October 31, 2018. Being underweight is defined as having a BMI of under 18.5 kg/m². The patient’s baseline characteristics, including BMI, serum albumin level, and comorbidities, etc., were recorded. The primary endpoint of the study was all-cause mortality. A Cox regression model was used to estimate the risk factors of mortality. Results A total of 378 newly diagnosed MM patients were enrolled in this study. The median age of the patients was 69. Thirty patients (7.9%) were underweight at diagnosis. The median overall survival was 1.3 years (95% CI 0.3–5.7) and 5.0 years (95% CI 3.1–5.9) for patients with low BMI and for patients with normal or higher BMI, respectively. In the multivariate analysis, low BMI (95% CI 1.07–4.44), ECOG ≥2 (95% CI 1.02–2.89), hypoalbuminemia (95% CI 1.21–4.01), high LDH (95% CI 1.22–3.49), and light chain ratio > 100 (95% CI 1.06–2.77) were independent risk factors of mortality. Conclusion MM patients who were underweight, with hypoalbuminemia, poor performance status, higher LDH, and light chain ratio > 100 were associated with poor overall survival.
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Purpose of Review Cardiovascular disease is the leading cause of death in the United States. Obese patients are at an increased risk of cardiovascular disease and weight loss can attenuate the risk. Cancer is the second leading cause of death and commonly associated with weight loss. This review focuses on the complex interaction between body weight, cardiovascular disease, and a cancer diagnosis. Recent Findings The cancer-associated mortality rate has steadily decreased over the last decade. Patients are living longer. Therefore, nonmalignant conditions, such as cardiovascular disease, have assumed an increased importance in cancer survivors. Moreover, patients with cancer are at an especially high risk for cardiovascular disease, due to side effects of various treatments and overlapping risk factors for both malignancy and heart disease. In cancers with a high likelihood of survival or cure, cardiovascular screening, risk factor modification, and attentive treatment of cardiovascular problems should be vigilantly pursued. Summary Like all individuals, patients with cancer should strive to maintain a healthy weight and participate in regular physical activity, with a goal to optimize cardiac health and health span. Weight loss has a cardioprotective effect in cancer survivors without obvious cancer progression. The notion that cardiac health is a low priority for cancer survivors, particularly for patients with a favorable prognosis, is not true. However, in advanced stages of cancer or with highly lethal cancers, weight loss is associated with poor outcomes and nutritional support to optimize nutritional status and maintain body weight should be prioritized.
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Thesis
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Elements of malnutrition-inflammation complex syndrome (MICS) may blunt the responsiveness of anemia of end-stage renal disease (ESRD) to recombinant human erythropoietin (EPO). The authors examined cross-sectional associations between the required dose of EPO within a 13-week interval as prescribed by practicing nephrologists who were blind to the study and several laboratory values known to be related to nutrition and/or inflammation, as well as the malnutrition-inflammation score (MIS), which is a fully quantitative assessment tool based on the subjective global assessment of nutrition. A total of 339 maintenance hemodialysis (MHD) outpatients, including 181 men, who were aged 54.7 +/- 14.5 years (mean +/- SD), who had undergone dialysis for 36.3 +/- 33.2 months, were selected randomly from 7 DaVita dialysis units in Los Angeles South/East Bay area. The average weekly dose of administered recombinant human EPO within a 13-week interval was 217 +/- 187 U/kg. Patients were receiving intravenous iron supplementation (iron gluconate or dextran) averaging 39.5 +/- 47.5 mg/wk. The MIS and serum concentrations of high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor-alpha, and lactate dehydrogenase had positive correlation with required EPO dose and EPO responsiveness index (EPO divided by hemoglobin), whereas serum total iron binding capacity (TIBC), prealbumin and total cholesterol, as well as blood lymphocyte count had statistically significant but negative correlations with indices of refractory anemia. Most correlations remained significant even after multivariate adjustment for case-mix and anemia factors and other relevant covariates. Similar associations were noticed across EPO per body weight tertiles via analysis of variance and after estimating odds ratio for higher versus lower tertile via logistic regression after same case-mix adjustment. The existence of elements of MICS as indicated by a high MIS and increased levels of proinflammatory cytokines such as IL-6 as well as decreased nutritional values such as low serum concentrations of total cholesterol, prealbumin, and TIBC correlates with EPO hyporesponsiveness in MHD patients.
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Markers of malnutrition-inflammation complex syndrome (MICS) are reported to predict mortality and hospitalization in maintenance haemodialysis (MHD) patients. However, it is not clear which one is a more sensitive and stronger predictor of outcome. We examined the utility of 10 markers of MICS as predictors of prospective mortality and hospitalization, which included malnutrition-inflammation score (MIS), a fully quantitative score adopted from subjective global assessment, and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), albumin, pre-albumin, total iron binding capacity, creatinine, total cholesterol and normalized protein nitrogen appearance. A cohort of 378 MHD patients, who were randomly selected from eight DaVita dialysis facilities in the South Bay Los Angeles area, was studied. Patients, aged 54.5+/-14.7 years, included 53% men, 47% Hispanics, 30% African-Americans and 55% diabetics, who had undergone MHD for 37+/-34 months. Over a 12-month follow-up, 39 patients died and 208 were hospitalized at least once. Multivariate Cox and Poisson models that included 11 covariates [gender, age, race, ethnicity, diabetes, dialysis vintage, Charlson co-morbidity index (CCI), insurance status, Kt/V, body mass index and history of cardiovascular disease] were explored for the highest quartiles of inflammatory markers or the lowest quartiles of nutritional markers. The magnitude of relative risk of death and hospitalization was greatest for MIS, CRP and IL-6. In extended multivariate models that included all 10 MICS markers and 11 additional covariates simultaneously, CRP, MIS and CCI were the only consistent predictors of mortality and hospitalization, and their outcome predictabilities were superior to serum albumin. The MIS appears to be a useful, short-term tool to risk-stratify MHD patients and may circumvent the need for measuring inflammatory markers such as CRP or IL-6.
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To examine whether weight loss at presentation influences outcome in patients who received chemotherapy for lung cancer or mesothelioma. Multivariate analysis of prospectively collected data 1994-2001. Data were available for age, gender, performance status, histology, stage, response, toxicity, progression-free and overall survival. The outcomes of patients with or without weight loss treated with chemotherapy for small cell lung cancer (SCLC; n=290), stages III and IV non-small-cell lung cancer (NSCLC; n=418), or mesothelioma (n=72) were compared. Weight loss was reported by 59, 58 and 76% of patients with SCLC, NSCLC and mesothelioma, respectively. Patients with weight loss and NSCLC (P=0.003) or mesothelioma (P=0.05) more frequently failed to complete at least three cycles of chemotherapy. Anaemia as a toxicity occurred significantly more frequently in NSCLC patients with weight loss (P=0.0003). The incidence of other toxicities was not significantly affected by weight loss. NSCLC patients with weight loss had fewer symptomatic responses (P=0.001). Mesothelioma patients with weight loss had fewer symptomatic (P=0.03) and objective responses (P=0.05). Weight loss was an independent predictor of shorter overall survival for patients with SCLC (P=0.003, relative risk (RR)=1.5), NSCLC (P=0.009, RR=1.33) and mesothelioma (P=0.03, RR=1.92) and an independent predictor of progression-free survival in patients with SCLC (P=0.01, RR=1.43). In conclusion, weight loss as a symptom of lung cancer predicts for toxicity from treatment and shorter survival.
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Prospective data to support the hypothesis that corticosteroids are a significant cause of muscle weakness in patients with chronic obstructive pulmonary disease (COPD) are lacking. The authors studied respiratory and quadriceps muscle function, using both volitional techniques and magnetic nerve stimulation, as well as measuring metabolic parameters during incremental cycle ergometry, in 25 stable COPD patients. The forced expiratory volume in one second was 37.6 +/- 21.4% predicted, before and after a 2-week course of o.d. prednisolone 30 mg. Quadriceps strength was also assessed in 15 control patients on two occasions. Only two patients met the British Thoracic Society definition of steroid responsiveness. There was no change either in sniff transdiaphragmatic pressure (pre: 96.8 +/- 19.7 cmH2O; post: 98.6 +/- 22.4 cmH2O) or in twitch transdiaphragmatic pressure elicited by bilateral anterolateral magnetic phrenic-nerve stimulation (pre: 16.8 +/- 9.1 cmH2O; post: 17.9 +/- 10 cmH2O). Quadriceps twitch force did not change significantly either in the steroid group (pre: 9.5 +/- 3.1 kg; post: 8.9 +/- 3.7 kg) or in the control patients (pre: 8.1 +/- 2.7 kg; post: 7.9 +/- 2.2 kg). There were no changes in either peak or isotime ventilatory and metabolic parameters during exercise. In conclusion, in stable patients with chronic obstructive pulmonary disease, a 2-week course of 30 mg prednisolone daily does not cause significant skeletal muscle dysfunction or alter metabolic parameters during exercise.
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To estimate the incidence and direct medical costs for fatal and non-fatal fall injuries among US adults aged >or=65 years in 2000, for three treatment settings stratified by age, sex, body region, and type of injury. Incidence data came from the 2000 National Vital Statistics System, 2001 National Electronic Injury Surveillance System-All Injury Program, 2000 Health Care Utilization Program National Inpatient Sample, and 1999 Medical Expenditure Panel Survey. Costs for fatal falls came from Incidence and economic burden of injuries in the United States; costs for non-fatal falls were based on claims from the 1998 and 1999 Medicare fee-for-service 5% Standard Analytical Files. A case crossover approach was used to compare the monthly costs before and after the fall. In 2000, there were almost 10 300 fatal and 2.6 million medically treated non-fatal fall related injuries. Direct medical costs totaled 0.2 billion dollars for fatal and 19 billion dollars for non-fatal injuries. Of the non-fatal injury costs, 63% (12 billion dollars ) were for hospitalizations, 21% (4 billion dollars) were for emergency department visits, and 16% (3 billion dollars) were for treatment in outpatient settings. Medical expenditures for women, who comprised 58% of the older adult population, were 2-3 times higher than for men for all medical treatment settings. Fractures accounted for just 35% of non-fatal injuries but 61% of costs. Fall related injuries among older adults, especially among older women, are associated with substantial economic costs. Implementing effective intervention strategies could appreciably decrease the incidence and healthcare costs of these injuries.
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This review will update clinicians and basic scientists who are interested in the clinical relevance and molecular mechanism of uremic cachexia. Recent studies that examine the role of cytokines and hypothalamic neuropeptides are emphasized. A current hypothesis of the cause of cachexia in chronic illness is that proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and leptin, act on the central nervous system to alter the release and function of several key neurotransmitters, thereby altering both appetite and metabolic rate. Proinflammatory cytokines also activate the transcription factor nuclear factor-kappaB, resulting in decreased protein synthesis, and activate the ubiquitin-mediated proteolytic system, which is the major system involved in increased protein degradation. This review highlights the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and the potential of peripheral administration of melanocortin-4 receptor antagonists as a novel therapeutic approach.
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Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
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Background: Survival studies have consistently shown significantly greater mortality rates in underweight and normal-weight patients with chronic obstructive pulmonary disease (COPD) than in overweight and obese COPD patients. Objective: To compare the contributions of low fat-free mass and low fat mass to mortality, we assessed the association between body composition and mortality in COPD. Design: We studied 412 patients with moderate-to-severe COPD [Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stages II–IV, forced expiratory volume in 1 s of 36 ± 14% of predicted (range: 19–70%). Body composition was assessed by using single-frequency bioelectrical impedance. Body mass index, fat-free mass index, fat mass index, and skeletal muscle index were calculated and related to recently developed reference values. COPD patients were stratified into defined categories of tissue-depletion pattern. Overall mortality was assessed at the end of follow-up. Results: Semistarvation and muscle atrophy were equally distributed among disease stages, but the highest prevalence of cachexia was seen in GOLD stage IV. Forty-six percent of the patients (n = 189) died during a maximum follow-up of 5 y. Cox regression models, with and without adjustment for disease severity, showed that fat-free mass index (relative risk: 0.90; 95% CI: 0.84, 0.96; P = 0.003) was an independent predictor of survival, but fat mass index was not. Kaplan-Meier and Cox regression plots for cachexia and muscle atrophy did not differ significantly. Conclusions: Fat-free mass is an independent predictor of mortality irrespective of fat mass. This study supports the inclusion of body-composition assessment as a systemic marker of disease severity in COPD staging.
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Background: Cancer cachexia is a multifactorial syndrome that is poorly defined. Objective: Our objective was to evaluate whether a 3-factor profile incorporating weight loss (≥10%), low food intake (≤1500 kcal/d), and systemic inflammation (C-reactive protein ≥ 10 mg/L) might relate better to the adverse functional aspects of cachexia and to a patient’s overall prognosis than will weight loss alone. Design: One hundred seventy weight-losing (≥5%) patients with advanced pancreatic cancer were screened for nutritional status, functional status, performance score, health status, and quality of life. Patients were followed for a minimum of 6 mo, and survival was noted. Patients were characterized by using the individual factors, ≥2 factors, or all 3 factors. Results: Weight loss alone did not define a population that differed in functional aspects of self-reported quality of life or health status and differed only in objective factors of physical function. The 3-factor profile identified both reduced subjective and objective function. In the overall population, the 3 factors, ≥2 factors, and individual profile factors (except weight loss) all carried adverse prognostic significance (P < 0.01). Subgroup analysis showed that the 3-factor profile carried adverse prognostic significance in localized (hazard ratio: 4.9; P < 0.001) but not in metastatic disease. Conclusions: Weight loss alone does not identify the full effect of cachexia on physical function and is not a prognostic variable. The 3-factor profile (weight loss, reduced food intake, and systemic inflammation) identifies patients with both adverse function and prognosis. Shortened survival applies particularly to cachectic patients with localized disease, thereby reinforcing the need for early intervention.
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The prognostic effect of weight loss prior to chemotherapy was analyzedusing data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
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The prognostic effect of weight loss prior to chemotherapy was analyzed using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group. The frequency of weight loss ranged from 31 percent for favorable non-Hodgkin's lymphoma to 87 percent in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Chemotherapy response rates were lower in the patients with weight loss, but only in patients with breast cancer was this difference significant. Decreasing weight was correlated with decreasing performance status except for patients with pancreatic and gastric cancer. Within performance status categories, weight loss was associated with decreased median survival. The frequency of weight loss increased with increasing number of anatomic sites involved with metastases, but within categories of anatomic involvement, weight loss was associated with decreased median survival. These observations emphasize the prognostic effect of weight loss, especially in patients with a favorable performance status or a limited anatomic involvement with tumor.
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Wasting in chronic heart failure (CHF) has long been known but is little investigated. We sought to find out whether the cachectic state in CHF provides additional prognostic information about all-cause mortality. Between June, 1993, and May, 1995, we studied 171 consecutive patients with CHF (mean age 60 years [SD 11; range 27-86]; 17 female). We assessed exercise capacity (peak oxygen consumption; mean 17.5 mL kg-1 min-1 [6.7]), functional status (New York Heart Association [NYHA] class: 21 class I, 63 class II, 68 class III, 19 class IV), and left-ventricular ejection fraction (mean 30% [SD 15]; n = 115). The cachectic status was defined prospectively as a non-intentional documented weight loss of at least 7.5% of previous normal weight (28 patients; range 9-36% or 6-30 kg) during at least 6 months. The Cox proportional-hazards model was used to assess the association of variables with survival, and Kaplan-Meier cumulative survival plots were constructed to estimate the influence of risk factors. At the end of follow-up in November, 1996, 49 patients had died (after a mean 324 days [SD 283]). The mean follow-up of the survivors was 834 days (SD 186; range 549-1269). The cachectic state was predictive of 18-month mortality independent of age, NYHA class, left-ventricular ejection fraction, and peak oxygen consumption. Mortality in the cachectic patients (n = 28) was 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months. Patients who had a peak oxygen consumption below 14 mL kg-1 min-1 (n = 53) had mortality at 3, 6, 12, and 18 months of 19%, 30%, 40%, and 51%. 18-month survival was 23% (95% CI 0-46) for the 13 patients with both of these risk factors (cachexia and low peak oxygen consumption) compared with 93% (88-98) in those (n = 103) with neither risk factor (p < 0.0001). The cachectic state is a strong independent risk factor for mortality in patients with CHF. Combined with a low peak oxygen consumption, it identifies a subset of patients at extremely high risk of death. Assessment of cachexia should be included in transplant programmes and studies that investigate the effect of interventions by survival analyses.
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Despite a general recognition that treatment of end-stage renal disease (ESRD) has become a large-scale undertaking, the size of the treated population and the associated costs are not well quantified. This report combines data available from a variety of sources and places the current (midyear 2001) estimated global maintenance dialysis population at just over 1.1 million patients. The size of this population has been expanding at a rate of 7% per year. Total therapy cost per patient per year in the United States is approximately 66,000 dollars. Assuming that this figure is a reasonable global average, the annual worldwide cost of maintenance ESRD therapy in the year 2001, excluding renal transplantation, will be between 70 and 75 billion US dollars. If current trends in ESRD prevalence continue, as seems probable, the ESRD population will exceed 2 million patients by the year 2010. The care of this group represents a major societal commitment: the aggregate cost of treating ESRD during the coming decade will exceed 1 trillion dollars, a thought-provoking sum by any economic metric.
Article
Mutations in Notch3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an inherited small vessel disease leading to subcortical strokes and vascular dementia. The phenotypic presentation is variable but remarkable for a high frequency of migraine with aura. Magnetic resonance images show a microangiopathic pattern of lesions. Prominent involvement of the temporopolar white matter and involvement of the temporopolar arcuate fibers are conspicuous findings seen in many patients. The underlying angiopathy is characterized by a unique type of ultrastructural basal lamina deposits and by degeneration of vascular smooth muscle cells which are the major source of Notch3 expression. In line with these findings there is evidence for a functional impairment of vascular smooth muscle cells. CADASIL has opened a new perspective in studying basic mechanisms of vessel wall degeneration and ischemic tissue damage related to small vessel disease.
Article
Weight loss and muscle wasting adversely affect morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Maintenance systemic glucocorticosteroids, prescribed in a substantial number of patients, further contribute to muscle weakness. We investigated the efficacy of oral nutritional supplementation therapy in depleted patients with COPD. The therapy consisted of daily two to three oral liquid nutritional supplements (mean +/- standard deviation: 2812 +/- 523 kJ/24 h) incorporated into an 8-wk inpatient pulmonary rehabilitation program in 64 (49 men) depleted patients with COPD. Endpoints were body weight, fat-free mass by bioelectrical impedance analysis, respiratory and peripheral muscle function (maximal inspiratory mouth pressure and handgrip strength, respectively), exercise performance (incremental bicycle ergometry), and disease-specific health status by St. George's Respiratory Questionnaire. Forty-eight percent of the patients were treated with low-dose oral glucocorticosteroids as maintenance medication (dose equivalent to 7.6 +/- 2.5 mg of methylprednisolone per day). Increases in body weight (2.1 +/- 2.1 kg, P < 0.001) and fat-free mass (1.1 +/- 2.0 kg, P < 0.001) were seen. Further, maximal inspiratory mouth pressure (4 +/- 10 cm of H(2)O, P = 0.001), handgrip strength (1.2 +/- 3.1 kg, P = 0.004), and peak workload (7 +/- 11 W, P = 0.001) significantly improved. Clinically significant improvements in the items symptoms (9 +/- 16 points, P < 0.001) and impact (4 +/- 15 points, P = 0.043) of St. George's Respiratory Questionnaire were achieved. Oral glucocorticosteroid treatment significantly impaired the response to nutritional supplementation therapy with respect to maximal inspiratory mouth pressure, peak workload, and St. George's Respiratory Questionnaire symptom score. Nutritional supplementation therapy implemented in a pulmonary rehabilitation program was effective in depleted patients with COPD. However, oral glucocorticosteroid treatment attenuated the anabolic response to nutritional supplementation.
Article
Weight loss in chronic heart failure is linked to impaired survival. We aimed to assess the frequency of weight loss in patients with this disease, whether the degree of weight loss predicts mortality, and whether weight loss can be prevented by angiotensin-converting-enzyme (ACE) inhibitors. We investigated weight changes in 1929 patients from the SOLVD trial who had chronic heart failure, were free of oedema at baseline, and survived for at least 4 months after trial entry. Meanfollow-up was 35 months (SD 13). We analysed the effect of weight loss at cutpoints of 5%, 7.5%, 10%, 15% (a priori), and 6% (post hoc) to identify which one best predicted outcome. To validate results, we analysed data for 619 patients in the V-HeFT II trial. 817 (42%) patients in the SOLVD trial had weight loss from baseline of 5% or more. At 8 months follow-up, all cutpoints for weight loss were significantly associated with impaired survival after adjustment for age, sex, New York Heart Association class, left ventricular ejection fraction, and treatment allocation. Weight loss of 6% or more at any time during follow-up was the strongest predictor of impaired survival (adjusted hazard ratio 2.10, 95% CI 1.77-2.49; p<0.0001). Patients on the ACE inhibitor enalapril had a lower hazard of 6% or more weight loss than did those not taking the drug (adjusted reduction 19%, p=0.0054). Results from analyses of V-HeFT II data lent support to our findings. Weight loss occurs frequently in patients with chronic heart disease, its reversal is rare, and when present, it is independently linked to impaired survival. Weight loss of more than 6% should be used to define the presence of cachexia in patients with chronic heart failure. In chronic heart failure, treatment with an ACE inhibitor reduces the risk of weight loss.
Article
Clinically significant involuntary weight loss (IWL) is defined as a loss of 4.5 kg or > 5% of the usual body weight over a period of 6 - 12 months, especially when progressive. Weight loss of > 10% of normal body weight is considered to represent protein-energy malnutrition (PEM). Despite progress in our understanding of the aetiology and pathophysiology of IWL and PEM, these conditions remain frequent and serious problems in several high-risk populations in both acute and long-term care facilities. In patients with IWL and PEM, nonhealing wounds signal a catabolic process that requires prompt nutritional intervention. Aggressive nutritional therapy that provides adequate protein, calories and micronutrients, combined with an anabolic agent such as oxandrolone, may provide the most optimal environment for restoration of lean body mass and body weight and in turn, promote wound healing. More research, however, is needed to define optimal nutritional and anabolic therapies for these patients given the associated high morbidity and cost of care.
Article
Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.
Article
High morbidity and mortality of maintenance dialysis patients have led to an increase in interest in outcome research in an attempt to identify causes for this adverse outcome. It has been proposed that a substantial amount of this risk can be explained by protein energy malnutrition, chronic inflammation, or concurrent combination of both, known as malnutrition-inflammation complex syndrome (MICS). Elements of overnutrition, such as increased weight or high serum cholesterol levels, which are deleterious in the general population, paradoxically are protective in dialysis patients. Conversely, a low body mass index and low serum levels of cholesterol, creatinine, and possibly homocysteine are risk factors for poor outcome in dialysis-dependent populations. These reverse or paradoxical relationships between nutritional markers and outcome are referred to as reverse epidemiology. The MICS appears to be a main contributor to the reverse epidemiology and poor outcome. Mortality is the most definitive and objective clinical outcome, whereas hospitalization and quality of life (QoL) are additional relevant but somewhat less objective outcome measures in dialysis populations. A systematic classification of outcome measures and their related epidemiologic and statistical assessment tools in dialysis patients are reviewed. The effect of MICS on outcome can be examined by epidemiologic studies that are based on large samples of dialysis patients, use multivariate techniques, and, as long as they follow strict methodologic requirements, provide an invaluable economical alternative to expensive clinical trials.
Article
To determine health care costs associated with pressure ulcers, ulcers of the lower limbs, other chronic ulcers, and venous leg ulcers from the New Mexico Medicaid fee-for-service program perspective. Retrospective analysis of claims database Physician visit, hospital, and prescription costs were determined for New Mexico Medicaid patients with a primary and/or secondary diagnosis of 1 of 4 identified categories of skin ulcers from January 1, 1994, through December 31, 1998. Costs were determined in terms of mean and median annual cost per patient and total costs per year. Zero dollar claims were included within the cost calculations. All costs are expressed in 2000-dollar values. Mean annual physician visit costs per patient ranged from $71 (standard deviation [SD] = $60) for venous leg ulcers in 1998 to $520 (SD = $1228) for pressure ulcers in 1996. Mean annual hospital costs per patient ranged from $266 (SD = $348) for other chronic ulcers in 1998 to $15,760 (SD = $30,706) for pressure ulcers in 1998. Mean annual prescription costs per patient ranged from $145 (SD = $282) for other chronic ulcers in 1998 to $654 (SD = $1488) for pressure ulcers in 1994. The New Mexico Medicaid fee-for-service system incurred a total cost of approximately $11.6 million (in 2000 dollars) from 1994 through 1998 for the treatment of the 4 categories of skin ulcers studied. The data showed that the majority of wounds were coded as pressure ulcers, which had the highest associated costs.
Article
This study evaluated the effects of body weight on both generic and disease-specific health-related quality of life (HRQoL) of patients with COPD. A total of 83 patients with stable COPD were enrolled (mean age: 74.6 yr, mean FEV1: 1.29 L). Patients were divided into two groups according to body mass index (BMI) (UW group: BMI < or = 20, NW group: 20 < BMI < or = 26). The degree of dyspnea and both disease-specific and generic HRQoL were compared between the two groups. An oxygen cost diagram (OCD) was used to assess the degree of dyspnea and St. George's Respiratory Questionnaire (SGRQ) and Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) were used for HRQoL evaluation. The OCD was significantly lower in the UW group. Compared with the NW group, the UW group showed significant deterioration in the total score and three subscales of SGRQ. SF-36 also showed significantly worse scores for the parameters of physical functioning, role emotional, bodily pain, and general health. The results of stepwise multiple regression analysis showed that OCD, FEV1, %pred. BMI were independent variables in the total score on SGRQ. The results of stepwise multiple regression analysis also showed that OCD was an independent variable for four of eight components of SF-36, while BMI was three of eight components of SF-36. In conclusion, low body weight in patients with COPD is related to a worsening of dyspnea and deterioration of both generic and disease-specific HRQoL. The present results also indicate that nutritional intervention may be important for improving dyspnea and HRQoL in patients with COPD.
Article
Malnutrition is frequent in cancer. The objective of this study was to determine the prevalence, in Spain, of malnutrition in cancer patients with advanced disease and to assess the therapeutic focus. A total of 781 patients were evaluated to determine individual nutritional status using the Scored Patient Generated-Subjective Global Assessment (Scored PG-SGA) questionnaire. Almost 60% of the patients included were receiving cancer treatment. Patients with the highest weight loss were those with tumours of oesophagus (57%), stomach (50%) and larynx (47%). Serious eating problems were encountered by 68% of the patients; the principal problem being anorexia (42.2%). The median number of symptoms impeding food intake was 2. According to the Scored PG-SGA, 52% of the patients were moderately or severely malnourished and 97.6% required some form of nutritional intervention/recommendation. (a) the majority of patients in the study needed nutritional intervention; (b) more than 50% had moderate or severe malnutrition; (c) the Scored PG-SGA is a useful and simple tool for evaluating nutritional status and contains additional information on nutritional recommendations; (d) nutritional evaluation of the cancer patients needs to be improved so as to offer better treatment of symptoms and to improve the patient's quality of life.
Article
Survival studies have consistently shown significantly greater mortality rates in underweight and normal-weight patients with chronic obstructive pulmonary disease (COPD) than in overweight and obese COPD patients. To compare the contributions of low fat-free mass and low fat mass to mortality, we assessed the association between body composition and mortality in COPD. We studied 412 patients with moderate-to-severe COPD [Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) stages II-IV, forced expiratory volume in 1 s of 36 +/- 14% of predicted (range: 19-70%). Body composition was assessed by using single-frequency bioelectrical impedance. Body mass index, fat-free mass index, fat mass index, and skeletal muscle index were calculated and related to recently developed reference values. COPD patients were stratified into defined categories of tissue-depletion pattern. Overall mortality was assessed at the end of follow-up. Semistarvation and muscle atrophy were equally distributed among disease stages, but the highest prevalence of cachexia was seen in GOLD stage IV. Forty-six percent of the patients (n = 189) died during a maximum follow-up of 5 y. Cox regression models, with and without adjustment for disease severity, showed that fat-free mass index (relative risk: 0.90; 95% CI: 0.84, 0.96; P = 0.003) was an independent predictor of survival, but fat mass index was not. Kaplan-Meier and Cox regression plots for cachexia and muscle atrophy did not differ significantly. Fat-free mass is an independent predictor of mortality irrespective of fat mass. This study supports the inclusion of body-composition assessment as a systemic marker of disease severity in COPD staging.
Article
Studies have shown a high prevalence of weight loss in older adults is associated with an increased risk of death. We investigated this in a population-based study. Persons living in Beaver Dam, Wisconsin, participated in a baseline examination between 1988 and 1990 (n=4926). A medical examination and standardized questionnaire were administered. Weight loss was defined as percent loss in body weight from highest lifetime weight to measured weight at baseline. Weight loss was associated with older age, higher rates of diseases such as diabetes, and lower baseline levels of blood pressure and serum total cholesterol. After controlling for age, medical, and lifestyle factors, both men and women had higher mortality rates over a 10+ year period for increasing categories of weight loss (hazard ratio [ 95% CI]: 1.16 [1.06, 1.27] for men and 1.23 [1.13, 1.34] for women). Increased mortality rates with increasing weight loss was shown in stratified analyses of age, body mass index (BMI) at highest weight, smoking, and disease status, but did not always reach statistical significance. Persons on weight loss diets within the year prior to baseline did not have increased mortality with increasing weight loss. The strong association between weight loss (likely involuntary) and mortality may be a useful way of estimating overall risks to longevity in populations.
Article
Several recent clinical trials using single modalities to correct the conventional cardiovascular risk factors in patients with chronic kidney disease (CKD) or to improve dialysis dose and techniques in maintenance dialysis patients have failed despite the high rate of cardiovascular mortality in these individuals. Protein-energy malnutrition and inflammation, two relatively common and concurrent conditions in CKD patients, have been implicated as the main cause of poor short-term survival in this population. The "malnutrition-inflammation-cachexia syndrome" (MICS) appears to be the main cause of worsening atherosclerotic cardiovascular disease in the CKD population. The MICS is associated with low serum cholesterol and homocysteine levels and leads to "cachexia in slow motion." Hence a reverse epidemiology of cardiovascular risk factors is observed in dialysis patients with a paradoxical association of obesity, hypercholesterolemia, and hyperhomocysteinemia with better survival. Correction of MICS can potentially ameliorate the cardiovascular epidemic in CKD patients. Because MICS is multifactorial, its correction will require an integral approach rather than a single intervention. The ongoing obsession with conventional cardiovascular risk factors largely reflecting overnutrition in a population that suffers from the short-term consequences of undernutrition and excessive inflammation may well be fruitless. Clinical trials focusing on the causes and consequences of MICS and its modulation using nutritional interventions may be the key to improving survival in these individuals.
Article
The present study focuses on the prevalence of nutritional depletion in relation to functional performance, airflow limitation, experienced dyspnoea and health status in a large multi-center out-patient population with chronic obstructive pulmonary disease (COPD). In 39 out-patient centers in The Netherlands, 389 patients with moderate to severe COPD (217 men) were recruited. The study evaluated on the baseline characteristics of the COSMIC study. Measurements included body composition by bioelectrical impedance analysis, dyspnoea by MRC-score, peripheral muscle function by isometric handgrip strength and disease-specific health status by St. George Respiratory Questionnaire. The prevalence of nutritional depletion (defined as body mass index (BMI)<or=21 kg/m2 and/or fat-free mass index (FFMI)<or=15 (females) or <or=16 (males) kg/m2) was high (27%). Prevalence of normal BMI and low FFMI was 15%, and of low BMI and low FFMI 11%. The prevalence of low BMI as well as low FFMI was significantly higher in female than in male COPD patients, 18% and 40% vs. 10% and 20%, respectively (both P<0.01). No differences in FEV1%predicted, dyspnoea score and health status were observed between depleted and non-depleted COPD patients. Multiple linear regression analysis in the total group showed that handgrip strength correlated with FFMI after correction for sex distribution and age, but not FEV1%predicted. The prevalence of nutritional depletion was high in a large out-patient COPD population in The Netherlands, especially in female COPD patients. Depletion of FFM was associated with impaired peripheral muscle strength, independent of disease severity.
Article
Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.
Article
Cancer cachexia is a multifactorial syndrome that is poorly defined. Our objective was to evaluate whether a 3-factor profile incorporating weight loss (> or = 10%), low food intake (< or = 1500 kcal/d), and systemic inflammation (C-reactive protein > or = 10 mg/L) might relate better to the adverse functional aspects of cachexia and to a patient's overall prognosis than will weight loss alone. One hundred seventy weight-losing (> or = 5%) patients with advanced pancreatic cancer were screened for nutritional status, functional status, performance score, health status, and quality of life. Patients were followed for a minimum of 6 mo, and survival was noted. Patients were characterized by using the individual factors, > or = 2 factors, or all 3 factors. Weight loss alone did not define a population that differed in functional aspects of self-reported quality of life or health status and differed only in objective factors of physical function. The 3-factor profile identified both reduced subjective and objective function. In the overall population, the 3 factors, > or = 2 factors, and individual profile factors (except weight loss) all carried adverse prognostic significance (P < 0.01). Subgroup analysis showed that the 3-factor profile carried adverse prognostic significance in localized (hazard ratio: 4.9; P < 0.001) but not in metastatic disease. Weight loss alone does not identify the full effect of cachexia on physical function and is not a prognostic variable. The 3-factor profile (weight loss, reduced food intake, and systemic inflammation) identifies patients with both adverse function and prognosis. Shortened survival applies particularly to cachectic patients with localized disease, thereby reinforcing the need for early intervention.
Article
Chronic heart failure is a complex catabolic state that carries a devastating prognosis. The transition from stable disease to cardiac cachexia is not well understood. Mechanisms that maintain the wasting process involve neurohormones and pro-inflammatory cytokines, which contribute to an imbalance in anabolic and catabolic pathways. A decrease in food intake alone rarely triggers the development of a wasting process, but dietary deficiencies in micronutrients and macronutrients contribute to the progression of the disease. Malabsorption from the gut as a result of bowel wall edema and decreased bowel perfusion also plays an important role. This article describes the complex interplay of hormonal systems in energy balance in patients with chronic heart failure as well as other factors such as malabsorption and dietary deficiencies that contribute to the wasting process. Finally, therapeutic approaches are discussed. These include dietary advice, ongoing studies, and future possibilities.
Article
Background: In patients with chronic obstructive pulmonary disease (COPD) weight loss frequently occurs that may ultimately lead to cachexia as a serious co-morbidity, indicating severely impaired functional capacity, health status and increased mortality. Increased energy expenditure due to mechanic and metabolic inefficiency and systemic inflammation are determinants of a hypermetabolic state that is not balanced by dietary intake. Anorexia may importantly contribute to weight loss in COPD, however, the association between immune and hormonal derangement and altered appetite has not been studied in detail. Aim: The aim of the present study was to investigate whether anorexia in COPD is related to inflammation and hormonal derangement in association to weight loss. Methods: We prospectively enrolled 103 consecutive patients with COPD (age 59.8+/-1.3 years, 35% female, mean FEV1 38.3+/-1.7%) in comparison to healthy controls of similar age (n=15). Results: In 34 patients (33%) cachexia was diagnosed (weight loss >7.5%, BMI < or = 24 kg/m2). Cachectic COPD patients had lower BMI (19.0+/-0.5 vs 25.6+/-0.7 kg/m2) and impaired lung function (FEV1 31+/-2% vs 42+/-2%, FVC 51+/-3 vs 59+/-3%, both p<0.001). Inflammatory immune activation (IL-6 and IL-6/IL-10 ratio) was significantly higher in cachectic COPD patients. Analysis of the extent of anorexia (visual analogue scale) revealed that cachectic COPD patients had significantly decreased subjective desire to eat compared to non-cachectic patients (3.5+/-0.3 vs 6.3+/-0.2, p<0.001). Patients with COPD and cachexia showed evidence of acquired GH resistance (decreased IGF-1/GH ratio) and insulin resistance (HOMA). Anorexia showed a direct correlation with the IGF-1/GH ratio (r=0.34, p<0.05) and was further related to BMI and % weight loss (both p<0.001). Conclusion: In COPD anorexia relates to hormonal derangement and inflammatory immune activation. Anorexia contributes to development of cachexia. The concept of appetite stimulating therapy emerges as a novel therapeutic option in cachectic COPD patients.