Diagnostic criteria for cancer cachexia: reduced food intake and inflammation predict weight loss and survival in an international, multi-cohort analysis.

BACKGROUND: Cancer-associated weight loss (WL) associates with increased mortality. International consensus suggests that WL is driven by a variable combination of reduced food intake and/or altered metabolism, the latter often represented by the inflammatory biomarker C-reactive protein (CRP). We aggregated data from Canadian and European research studies to evaluate the associations of reduced food intake and CRP with cancer-associated WL (primary endpoint) and overall survival (OS, secondary endpoint). METHODS: The data set included a total of 12,253 patients at risk for cancer-associated WL. Patient-reported WL history (% in 6 months) and food intake (normal, moderately, or severely reduced) were measured in all patients; CRP (mg/L) and OS were measured in N = 4960 and N = 9952 patients, respectively. All measures were from a baseline assessment. Clinical variables potentially associated with WL and overall survival (OS) including age, sex, cancer diagnosis, disease stage, and performance status were evaluated using multinomial logistic regression MLR and Cox proportional hazards models, respectively. RESULTS: Patients had a mean weight change of -7.3% (±7.1), which was categorized as: ±2.4% (stable weight; 30.4%), 2.5-5.9% (19.7%), 6.0-10.0% (23.2%), 11.0-14.9% (12.0%), ≥15.0% (14.6%). Normal food intake, moderately, and severely reduced food intake occurred in 37.9%, 42.8%, and 19.4%, respectively. In MLR, severe WL (≥15%) (vs. stable weight) was more likely (P < 0.0001) if food intake was moderately [OR 6.28, 95% confidence interval (CI 5.28-7.47)] or severely reduced [OR 18.98 (95% CI 15.30-23.56)]. In subset analysis, adjusted for food intake, CRP was independently associated (P < 0.0001) with ≥15% WL [CRP 10-100 mg/L: OR 2.00, (95% CI 1.58-2.53)] and [CRP > 100 mg/L: OR 2.30 (95% CI 1.62-3.26)]. Diagnosis, stage, and performance status, but not age or sex, were significantly associated with WL. Median OS was 9.9 months (95% CI 9.5-10.3), with median follow-up of 39.7 months (95% CI 38.8-40.6). Moderately and severely reduced food intake and CRP independently predicted OS (P < 0.0001). CONCLUSIONS: Modelling WL as the dependent variable is an approach that can help to identify clinical features and biomarkers associated with WL. Here, we identify criterion values for food intake impairment and CRP that may improve the diagnosis and classification of cancer-associated cachexia.

Comparison of the anticatabolic effects of leucine and Ca-ß-hydroxy-ß-methylbutyrate in experimental models of cancer cachexia.

OBJECTIVE: Loss of skeletal muscle is the most debilitating feature of cancer cachexia, and there are few treatments available. The aim of this study was to compare the anticatabolic efficacy of L-leucine and the leucine metabolite ß-hydroxy-ß-methylbutyrate (Ca-HMB) on muscle protein metabolism, both in vitro and in vivo. METHODS: Studies were conducted in mice bearing the cachexia-inducing murine adenocarcinoma 16 tumor, and in murine C2 C12 myotubes exposed to proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. RESULTS: Both leucine and HMB were found to attenuate the increase in protein degradation and the decrease in protein synthesis in murine myotubes induced by proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. However, HMB was more potent than leucine, because HMB at 50 µM produced essentially the same effect as leucine at 1 mM. Both leucine and HMB reduced the activity of the ubiquitin-proteasome pathway as measured by the functional (chymotrypsin-like) enzyme activity of the proteasome in muscle lysates, as well as Western blot quantitation of protein levels of the structural/enzymatic proteasome subunits (20 S and 19 S) and the ubiquitin ligases (MuRF1 and MAFbx). In vivo studies in mice bearing the murine adenocarcinoma 16 tumor showed a low dose of Ca-HMB (0.25 g/kg) to be 60% more effective than leucine (1 g/kg) in attenuating loss of body weight over a 4-d period. CONCLUSION: These results favor the clinical feasibility of using Ca-HMB over high doses of leucine for the treatment of cancer cachexia.

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with a protein- and energy-dense nutritional supplement containing eicosapentaenoic acid.

BACKGROUND: Cancer-associated weight loss may be mediated by an inflammatory response to cancer. Eicosapentaenoic acid (EPA) may suppress this response. METHODS: Beginning no later than 2 weeks before surgery, patients with head and neck cancer and with weight loss, who were undergoing major resection with curative intent consumed a protein- and energy-dense nutritional supplement containing EPA from fish oil, in addition to usual diet or tube feed. RESULTS: Thirty-one subjects consumed an average of 1.8 containers/day before surgery and 1.5/day during hospitalization (per container: 300 kilocalories, 16 grams (g) protein, 1.08 g EPA). Seventy percent of subjects maintained or gained weight before hospital admission. Mean weight gain was 0.71 kg at admission and 0.66 kg at discharge. At discharge lean body mass increased by 3.20 kg (p < .001) and fat decreased by 3.19 kg (p < .001). CONCLUSIONS: An EPA-containing protein- and energy-dense nutritional supplement may help increase perioperative lean body mass in patients with head and neck cancer-related weight loss.

Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer.

PURPOSE: Hypogonadism has been linked with systemic inflammation and opioid use in males with advanced cancer. We aimed to investigate the interaction of gonadal status with systemic inflammation and opioids in determining nutritional status and prognosis in advanced pancreatic cancer. METHODS: One hundred and seventy-five patients (92 males, 83 postmenopausal females) with unresectable pancreatic cancer were studied. Serum sex steroids (total testosterone [TT], calculated free testosterone [cFT], oestradiol, sex hormone binding globulin), gonadotropins (follicle-stimulating hormone and luteinising hormone) and pro-inflammatory mediators (C-reactive protein [CRP], interleukin-6 [IL-6], soluble tumour necrosis factor receptor 75 [sTNFR75]) were measured, and nutritional assessment and opioid use recorded. RESULTS: Seventy-three percent of males were hypogonadal (by cFT definition). cFT correlated positively with BMI (r (2) =0.349; p< 0.001) and grip strength (r (2) = 0.229; p = 0.034) and inversely with weight loss (r (2) = -0.287; p = 0.007), CRP (r (2) = -0.426; p < 0.001) and IL-6 (r (2) = -0.303; p = 0.004). CRP (p= 0.007), opioid dosage (p = 0.009) and BMI (p = 0.005) were independent determinants of cFT on ANOVA. Hypogonadal males demonstrated worsened survival compared with eugonadal patients (TT: OR of death = 2.87; p < 0.001; cFT: OR = 2.26; p = 0.011). Furthermore, male opioid use was associated with decreased TT (p < 0.001) and cFT (p < 0.001) and worsened survival (OR = 1.96; p = 0.012). In contrast, 18% of postmenopausal females exhibited premenopausal ("hyperoestrogenic") oestradiol levels. Oestradiol correlated positively with sTNFR75 (r (2) = 0.299; p = 0.008). CRP (p < 0.001) was an independent determinant of oestradiol. Hyperoestrogenic females demonstrated worsened survival compared with eugonadal patients (OR = 2.43; p = 0.013). CONCLUSIONS: In males with pancreatic cancer, systemic inflammation and opioid use are associated with hypogonadism. Male hypogonadism and female hyperoestrogenism are associated with shortened survival in advanced pancreatic cancer.

Protein and ginger for the treatment of chemotherapy-induced delayed nausea.

BACKGROUND: Nausea that develops during the period that begins 24 hours after the administration of chemotherapy is called delayed nausea, and occurs in many patients with cancer. Meals high in protein decrease the nausea of motion sickness and pregnancy, possibly by reducing gastric dysrhythmias. Ginger also has antinausea properties. OBJECTIVES: To explore the use of protein meals with ginger for the treatment of the delayed nausea of chemotherapy. DESIGN: Twenty-eight (28) patients with cancer receiving chemotherapy for the first time were assigned to 1 of 3 groups. For 3 days beginning the day after their chemotherapy, Control Group patients continued with their normal diet, Protein Group patients consumed a protein drink and ginger twice daily, and High Protein Group patients consumed a protein drink with additional protein and ginger twice daily. OUTCOME MEASURES: Patients recorded in a diary each day whether they had experienced nausea, whether their nausea had been frequent, whether their nausea had been bothersome, and whether they had needed any antiemetic medication. Gastric myoelectrical activity was assessed in 5 patients before and after ingestion of a high protein meal and ginger. RESULTS: Reports of nausea, frequent nausea, and bothersome nausea were significantly less common among High Protein Group patients than among Control and Protein Group patients. Furthermore, significantly fewer patients in the High Protein Group used antiemetic medication. Differences between the Protein and Control groups were not statistically significant. In the 5 patients who had tests of gastric myoelectrical activity performed, a significant decrease in gastric dysrhythmia occurred after ingestion of the protein and ginger. CONCLUSIONS: High protein meals with ginger reduced the delayed nausea of chemotherapy and reduced use of antiemetic medications. Protein with ginger holds the potential of representing a novel, nutritionally based treatment for the delayed nausea of chemotherapy.

Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis.

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 (> 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. DESIGN: 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. 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, > 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. 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.

Agitation and depression in frail nursing home elderly patients with dementia: treatment characteristics and service use.

OBJECTIVE: The authors describe characteristics, treatment, and acute service use associated with agitation and depression in dementia. METHODS: Authors used retrospective chart review of symptoms, physician-level prescribing, and acute service use over 3 months for 2,487 physically frail older residents, including 1,836 with dementia, (mean age: 79.8 years) in 109 long-term care facilities, describing differences between uncomplicated dementia and three mutually exclusive subgroups of complicated dementia, including dementia with agitation-only, dementia with depression-only, and dementia with mixed agitation and depression. RESULTS: Compared with the other subgroups, frail elderly patients with dementia complicated by mixed agitation and depression have the highest rate of hospitalization, the greatest number of medical diagnoses, and the greatest medical severity, and they receive the greatest number of psychiatric medications. Depression in dementia (either alone or mixed with agitation) was associated with greater prevalence of pain. CONCLUSIONS: Dementia complicated by mixed agitation and depression accounts for over one-third of complicated dementia and is associated with multiple psychiatric and medical needs, intensive pharmacological treatment, and use of high-cost services. Research should target this complex, high-risk group to develop appropriate diagnostic criteria and effective treatment interventions.

Description of the National Pressure Ulcer Long-Term Care Study.

OBJECTIVES: To describe and provide baseline data from The National Pressure Ulcer Long-Term Care Study (NPULS). DESIGN: Retrospective cohort study of detailed resident characteristics, treatments, and outcomes using convenience sampling. SETTING: One hundred nine long-term care facilities throughout the United States. PARTICIPANTS: Two thousand four hundred twenty adult residents aged 18 and older, with a length of stay of 14 days or longer and who were at risk of developing a pressure ulcer, as defined by a Braden Scale for Predicting Pressure Sore Risk MEASUREMENTS: More than 500 characteristics were obtained for each resident over a 12-week period. This paper describes the NPULS database with respect to the resident (sex, age, diagnoses, severity of illness scores, Braden Scale score, activities of daily living, cognitive ability, mobility, bowel or bladder incontinence, laboratory values, nutritional assessment, and pressure ulcer assessment documentation), treatment (nutritional interventions, pressure relieving devices, incontinence interventions, protective devices, turning schedules, and pressure ulcer treatments), and outcome variables (pressure ulcer development and healing, pressure ulcer and systemic infection, changes in nutritional status, and discharge disposition) associated with pressure ulcers. Descriptive statistics and bivariate associations were used for preliminary analyses of resident, treatment, and outcome characteristics. RESULTS: The average age +/- standard deviation was 79.7 +/- 14.2; 70% of the residents were female. Fifty-three percent of residents (n = 1,293) were at risk of developing a pressure ulcer but never developed one during the study (Group 1), 19% developed a new pressure ulcer during the study (n = 457) (Group 2), 22% had an existing pressure ulcer (n = 534) (Group 3), and 6% had an existing pressure ulcer and developed a new ulcer during the study (n = 136) (Group 4). Residents who developed a new pressure ulcer (Group 2) were more likely to be female, older, cognitively impaired, and immobile than residents who had an existing pressure ulcer (Group 3). CONCLUSIONS: This baseline study describes the NPULS database with respect to the resident, treatment, and outcome variables associated with pressure ulcers. Future studies will focus on multivariate analyses for risk factor prediction of pressure ulcer development and pressure ulcer healing. Research-based pressure ulcer prevention and treatment protocols can then be developed.