Development of Pharmacotherapies for the Treatment of Sarcopenia.

Sarcopenia, the associated loss of skeletal muscle mass and strength and impaired physical function seen with aging, is a growing, global public health challenge in need of accepted, proven treatments that address the needs of a broad range of older adults. While exercise, primarily resistance training, and increased dietary protein have been shown to delay and even reverse losses in muscle mass, strength and physical function seen with aging, proven treatments that are accessible globally, cost effective and sustainable by patients are needed. While no drug has yet demonstrated the substantial safety and clinical value needed to be the first pharmacological therapy registered for muscle wasting or sarcopenia, the field is active. Several approaches to treating the muscle loss and subsequent functional decline are being studied in a variety of patient populations across every continent. We provide a review of the leading programs and approaches and available findings from recent studies. In addition, we briefly discuss several related issues needed to facilitate the development of a safe and efficacious pharmacotherapeutic that could be used as part of a treatment plan for older men and women with sarcopenia.

Associations between human leukocyte antigen, PTPN22, CTLA4 genotypes and rheumatoid arthritis phenotypes of autoantibody status, age at diagnosis and erosions in a large cohort study.

BACKGROUND: HLA-DRB1 shared epitope (HLA-SE), PTPN22 and CTLA4 alleles are associated with cyclic citrullinated peptide (CCP) and rheumatoid arthritis (RA). OBJECTIVE: We examined associations between HLA-SE, PTPN22, CTLA4 genotypes and RA phenotypes in a large cohort to (a) replicate prior associations with CCP status, and (b) determine associations with radiographic erosions and age of diagnosis. METHODS: A total of 689 RA patients from the Brigham RA Sequential Study (BRASS) were genotyped for HLA-SE, PTPN22 (rs2476601) and CTLA4 (rs3087243). Association between genotypes and CCP, rheumatoid factor (RF) erosive phenotypes and age at diagnosis were assessed with multivariable models adjusting for age, sex and disease duration. Novel causal pathway analysis was used to test the hypothesis that genetic risk factors and CCP are in the causal pathway for predicting erosions. RESULTS: In multivariable analysis, presence of any HLA-SE was strongly associated with CCP+ (odds ratio (OR) 3.05, 95% CI 2.18-4.25), and RF+ (OR 2.53, 95% CI 1.83-3.5) phenotypes; presence of any PTPN22 T allele was associated with CCP+ (OR 1.81, 95% CI 1.24-2.66) and RF+ phenotypes (OR 1.84, 95% CI 1.27-2.66). CTLA4 was not associated with CCP or RF phenotypes. While HLA-SE was associated with erosive RA phenotype (OR 1.52, 95% CI 1.01-2.17), this was no longer significant after conditioning on CCP. PTPN22 and CTLA4 were not associated with erosive phenotype. Presence of any HLA-SE was associated with an average 3.6 years earlier diagnosis compared with absence of HLA-SE (41.3 vs 44.9 years, p = 0.002) and PTPN22 was associated with a 4.2 years earlier age of diagnosis (39.5 vs 43.6 years, p = 0.002). CTLA4 genotypes were not associated with age at diagnosis of RA. CONCLUSIONS: In this large clinical cohort, we replicated the association between HLA-SE and PTPN22, but not CTLA4 with CCP+ and RF+ phenotypes. We also found evidence for associations between HLA-SE, and PTPN22 and earlier age at diagnosis. Since HLA-SE is associated with erosive phenotype in unconditional analysis, but is not significant after conditioning on CCP, this suggests that CCP is in the causal pathway for predicting erosive phenotype.

Implications of ICD-10 for Sarcopenia Clinical Practice and Clinical Trials: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Establishment of an ICD-10-CM code for sarcopenia in 2016 was an important step towards reaching international consensus on the need for a nosological framework of age-related skeletal muscle decline. The International Conference on Frailty and Sarcopenia Research Task Force met in April 2017 to discuss the meaning, significance, and barriers to the implementation of the new code as well as strategies to accelerate development of new therapies. Analyses by the Sarcopenia Definitions and Outcomes Consortium are underway to develop quantitative definitions of sarcopenia. A consensus conference is planned to evaluate this analysis. The Task Force also discussed lessons learned from sarcopenia trials that could be applied to future trials, as well as lessons from the osteoporosis field, a clinical condition with many constructs similar to sarcopenia and for which ad hoc treatments have been developed and approved by regulatory agencies.

Rheumatoid cachexia: cytokine-driven hypermetabolism accompanying reduced body cell mass in chronic inflammation.

The cytokines IL-1 beta and TNF-alpha cause cachexia and hypermetabolism in animal models, but their role in human inflammation remains controversial. The relationship between in vitro cytokine production and metabolism was examined in 23 adults with RA and 23 healthy control subjects matched on age, sex, race, and weight. Body composition was measured by multicompartmental analysis of body cell mass, water, fat, and bone mass. Resting energy expenditure (REE) was measured by indirect calorimetry. Cytokine production by PBMC was measured by radioimmunoassay. Usual energy intake, physical activity, disability scores, medication use, and other confounders were also measured. Body cell mass was 13% lower (P < 0.00001), REE was 12% higher (P < 0.008), and physical activity was much lower (P < 0.001) in subjects with RA. Production of TNF-alpha was higher in RA than controls, both before and after stimulation with endotoxin (P < 0.05), while production of IL-1 beta was higher with endotoxin stimulation (P < 0.01). In multivariate analysis, cytokine production was directly associated with REE (P < 0.001) in patients but not in controls. While energy and protein intake were similar in the two groups and exceeded the Recommended Dietary Allowances, energy intake in subjects with RA was inversely associated with IL-1 beta production (P < 0.005). In this study we conclude that: loss of body cell mass is common in RA; cytokine production in RA is associated with altered energy metabolism and intake, despite a theoretically adequate diet; and TNF-alpha and IL-1 beta modulate energy metabolism and body composition in RA.

Resistance training alters cytokine gene expression in skeletal muscle of adults with type 2 diabetes.

Resistance training results in muscle hypertrophy and improves glycemic control in patients with type 2 diabetes. Whether resistance training modulates inflammation in muscles of diabetic patients remains unknown. We examined the expression of genes encoding the cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) as well as the pan-leukocyte marker CD18. Thirty men and women (67+/-7 years) were randomized to either 16 weeks of resistance training and usual diabetes care (EX) or to usual diabetes care only (CON). Muscle biopsies were obtained from the vastus lateralis muscle prior to the 16-week intervention, and 72 h following the maximal strength test post-intervention. Fiber cross-sectional area (CSA) was determined following ATPase staining. Cytokine and CD18 transcript levels were assessed by real-time PCR. Resistance training increased CSA of type I and II fibers (both P <0.05) and IL-1beta transcript levels (P = 0.05). TNF-alpha (P<0.05) and TGF-beta1 transcripts (P<0.05) increased over time in the EX group, but these increases did not differ from those in the CON group. In both groups, the increase in CD18 transcripts remained minimal. The two groups differ by the relationship between changes in CD18 and changes in cytokine transcripts, suggesting that resistance training affects the source of cytokines in muscle. Our studies establish that resistance training in older adults with type 2 diabetes results in muscle fiber hypertrophy, despite a greater accumulation of inflammatory cytokine transcripts in muscle.

Sarcopenia Trials in Specific Diseases: Report by the International Conference on Frailty and Sarcopenia Research Task Force.

Muscle atrophy occurs as a consequence of a number of conditions, including cancer, chronic obstructive pulmonary disease (COPD), diabetes mellitus, heart failure, and other chronic diseases, where it is generally a predictor of poor survival. It also occurs as a consequence of disuse and an age-related loss of muscle mass and strength (sarcopenia). The aims of the 2016, International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force were to examine how these specific chronic conditions have been employed in treatment trials thus far and how future trials using these patient groups might be designed for efficient identification of effective sarcopenia interventions. Functional limitations assessed as gait speed, distance walked over a set time period, or other attributes of physical performance have been suggested as outcome measures in sarcopenia trials. Indeed, such measures have already been used successfully in a number of trials aimed at preventing disability in older adults.

Malnutrition among hospitalized patients. A problem of physician awareness.

Between 25% and 50% of patients admitted to an acute medical service are malnourished. Physicians are often unaware which patients are admitted at nutritional risk and make no attempt to arrest further nutritional decline until a dramatic deterioration has occurred. We studied all patients admitted to an acute medical ward service before and after their physicians were taught to recognize nutritional deficiency early and to intervene appropriately. During the initial period, the house staff correctly identified two (12.5%) of 16 patients as being malnourished. During the posteducation period, physicians correctly identified all 14 patients admitted at nutritional risk (100%), using a simple screening device that required only routine admission data. In all cases, the appropriate nutritional intervention was subsequently made. Results were further validated using a pretest and posttest, showing a significant improvement in nutritional knowledge. We conclude that physicians are not presently being taught to recognize malnutrition, that such malnutrition is latrogenically worsened in the hospital, and that physician education can effectively correct this problem.

Pneumothorax due to nasogastric feeding tubes. Report of four cases, review of the literature, and recommendations for prevention.

Intrapulmonary placement of small-bore nasogastric feeding tubes caused pneumothoraces in four patients. Review of the literature discloses another 106 cases of the same complication. Risk factors for intrapulmonary complications include endotracheal intubation or tracheostomy (60% of reported cases [95% confidence interval, 44% to 80%]), and altered mental status (36% of reported cases [95% confidence interval, 24% to 53%]). We propose a simple, two-step method of feeding tube insertion designed to prevent such complications in high-risk patients.

PHARMACOLOGICAL INTERVENTIONS IN FRAILTY AND SARCOPENIA: REPORT BY THE INTERNATIONAL CONFERENCE ON FRAILTY AND SARCOPENIA RESEARCH TASK FORCE.

Sarcopenia and frailty often co-exist and both have physical function impairment as a core component. Yet despite the urgency of the problem, the development of pharmaceutical therapies for sarcopenia and frailty has lagged, in part because of the lack of consensus definitions for the two conditions. A task force of clinical and basic researchers, leaders from the pharmaceutical and nutritional industries, and representatives from non-profit organizations was established in 2012 with the aim of addressing specific issues affecting research and clinical activities on frailty and sarcopenia. The task force came together on April 22, 2015 in Boston, Massachusetts, prior to the International Conference on Frailty and Sarcopenia Research (ICFSR). The theme of this meeting was to discuss challenges related to drugs designed to target the biology of frailty and sarcopenia as well as more general questions about designing efficient drug trials for these conditions. The present article reports the results of the task force's deliberations based on available evidence and preliminary results of ongoing activities. Overall, the lack of a consensus definition for sarcopenia and frailty was felt as still present and severely limiting advancements in the field. However, agreement appears to be emerging that low mass alone provides insufficient clinical relevance if not combined with muscle weakness and/or functional impairment. In the next future, it will be important to build consensus on clinically meaningful functional outcomes and test/validate them in long-term observational studies.

Elevated resting energy expenditure among HIV-seropositive persons receiving highly active antiretroviral therapy.

OBJECTIVES: To ascertain the relationships between resting energy expenditure (REE), HIV RNA in plasma, and highly active antiretroviral therapy (HAART). DESIGN: Cross-sectional analysis using data of a large cohort study of nutrition in relation to HIV disease. METHODS: HIV RNA in plasma, REE, fat-free mass (FFM), and medication regimens were assessed at 530 visits among 372 participants in a cohort study of HIV-seropositive men and women. RESULTS: HIV RNA in plasma was directly correlated with REE. After adjustment for FFM, age, CD4 cell count and HAART use, there was an increase in REE of 90 kJ/day per log10 copies/ml increase in HIV RNA [95% confidence interval (CI) 16-164; P = 0.02). HAART use had an independent effect on REE. In patients reporting HAART use, adjusted REE was 339 kJ/day higher than in those not reporting HAART use (95% CI 177-501; P = 0.0001). CONCLUSIONS: Viral load and HAART appear to exert independent effects on REE. Although HAART may decrease metabolic rate by lowering viral burden, it appears to increase metabolic demands through some mechanism(s) independent of its effect on viral burden. This may result in elevated REE despite control of viral replication.

A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution.

OBJECTIVE: Body fat redistribution ('lipodystrophy'), with gain in abdominal and trunk fat, and decline in facial and limb fat, is a newly recognized problem in patients with HIV infection that has been linked to use of HIV-1 protease inhibitors. Increased abdominal fat may predispose these patients to hypertension, diabetes, and coronary artery disease. At this time no effective treatment is available. We examined whether exercise training could reduce trunk fat in men with fat redistribution. DESIGN: Open-label pilot study. METHODS: Ten men with increasing abdominal girth participated in a 16 week pilot study of progressive resistance training with an aerobic component. They trained in a community health club three times per week. Total body lean and fat mass, and trunk fat mass, were assessed by dual-energy x-ray absorptiometry (DXA). RESULTS: After 16 weeks of exercise, strength increased for three of the four exercises tested (leg press + 13% [p < 0.02], leg extension + 19% [p < 0.03], seated row + 7% [p < 0.13], chest press + 18% [p < 0.0051). There was a significant decline in total body fat by 1.5 kg (= 2.1 percentage points, p < 0.01); most of the decline in body fat occurred in trunk fat, which decreased by 1.1 kg (p < 0.03). Weight, lean mass (+ 1.1 + 2.6 kg, p = 0.23), and bone mineral density measured by DXA did not change. No adverse effects were seen from the training. CONCLUSIONS: Exercise training may reduce trunk fat mass in HIV-positive men with fat redistribution. Controls trials of this approach are warranted.

Short-term progressive resistance training increases strength and lean body mass in adults infected with human immunodeficiency virus.

BACKGROUND: To assess the efficacy of progressive resistance training (PRT) in increasing strength and lean body mass (LBM) in HIV-infected adults. METHODS: Twenty-five adults with HIV infection were trained using a highly intensive PRT regimen for 8 weeks, followed by an additional 8 weeks of observation under ad libitum physical activity conditions. RESULTS: Twenty-four of the 25 patients completed the first phase of the study. They had significant increases in strength on all four exercises tested (P < 0.0001), and an increase in LBM of 1.75 +/- 1.94 kg (mean +/- SD, P < 0.0002), with a concomitant decline in fat of 0.92 +/- 2.22 kg (P < 0.05), and no significant change in weight or bone mineral content. Twenty-one of the patients returned for follow-up 8 weeks after completing the PRT. Compared with their baseline values, their mean lean mass remained 1.40 +/- 1.8 kg higher (P < 0.003). Among those who continued to train to some extent, lean mass increased by a mean of 1.1 +/- 1.6 kg (n = 9, P < 0.05 versus end of PRT), whereas those who did no further training showed an increase in lean mass of 0.28 +/- 1.4 kg (n = 12, P = NS versus end of PRT). The difference between the two groups was not, however, significant (P = 0.25). Among six patients with AIDS wasting, the increase in LBM was larger than among non-wasted patients (2.8 versus 1.4 kg, P < 0.06), and there was an increase in both weight (+3.9 versus -0.2 kg, P < 0.002) and fat mass (+ 0.95 versus -1.5 kg, P < 0.002) at 8 weeks, which persisted at 16 weeks (weight: +4.0 versus -1.6 kg, P < 0.0002; fat: +1.6 versus -1.9 kg, P < 0.01). CONCLUSION: This preliminary study suggests that short-term, high intensity PRT can significantly increase LBM and strength in HIV infection, and may be used as an alternative or adjunct to pharmacological anabolic treatments in this disease.

The relationship between growth hormone kinetics and sarcopenia in postmenopausal women: the role of fat mass and leptin.

Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean +/- SD age, 66.9 +/- 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = 0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.

Applications of bioelectrical impedance analysis for body composition to epidemiologic studies.

Bioelectrical impedance analysis (BIA) is a promising tool in the evaluation of body composition in large population studies because it is fast, is inexpensive, and does not require extensive operator training or cross-validation. The empiric nature of the relation between resistance and reactance measured by BIA and body composition has led to the development of equations that translate the raw data into liters of body water or kilograms of fat-free mass (FFM) or fat mass. These equations may not be easily transferred from one population to another if the populations differ significantly in important determinants of body composition such as age, obesity, and illness. I review two recent studies from the Framingham Heart Study in which BIA was first compared with dual-energy X-ray absorptiometry (DXA) as a validation technique, and then compared with the body mass index (BMI, in kg/m2) as an alternative estimate of body fat. BIA was a good predictor of DXA-derived FFM (r = 0.85-0.88, P < 0.001) and was superior to BMI as an estimator of body fat.

Catabolic effects of high-dose corticosteroids persist despite therapeutic benefit in rheumatoid arthritis.

Although corticosteroids (CS) cause nitrogen wasting in healthy humans, it is not known whether the salutary antiinflammatory and appetite-stimulating effects of CS in inflammatory diseases mitigate this effect. We measured nitrogen balance before, during, and after 3 d of high-dose methylprednisolone therapy in nine patients with flare-ups of rheumatoid arthritis. There was evidence of preexisting somatic protein and fat depletion in seven of nine subjects. Patients were allowed to eat freely on a metabolic ward. Nitrogen balances were -0.89 +/- 1.38 g/d (means +/- SEM) before CS therapy, -5.77 +/- 1.30 g/d during therapy (P less than 0.001), and -3.54 +/- 1.38 g/d after therapy (P less than 0.01) despite increased energy and nitrogen intake and clinical resolution of inflammation during and after the pulse therapy. We conclude that patients with rheumatoid arthritis are often cachectic and high-dose CS cause nitrogen wasting in these patients despite an antiinflammatory and appetite-stimulatory benefit.

Advantage of knee height over height as an index of stature in expression of body composition in adults.

It is not clear how body composition should best be compared between subjects, but it is accepted that simply comparing total mass or percentage fat-free mass (FFM) or fat mass (FM) is not adequate. Indexing body composition to stature seems more appropriate, but the decline in height with age or osteoporosis could confound comparisons of body composition across age or disease groups. Using bioimpedance data from 600 adults in the Framingham Offspring Study, we examined the ability of height and knee height indexes to correctly describe the loss of FFM seen with increasing age between 28 and 75 y. Indexing body composition to height obscured the loss of FFM with age (r = -0.065, P < 0.26 for men; r = -0.050, P < 0.394 for women), whereas indexing body composition to knee height preserved the correct information (r = -0.154, P < 0.007 for men; r = -0.161, P < 0.006 for women). These data suggest that knee height is a reliable surrogate for stature and should be used to adjust body composition measurements when bioimpedance is used to estimate body composition.

Total body potassium and body fat: relevance to aging.

Understanding the mechanisms that govern sarcopenia (depletion of muscle mass with age) may suggest ways to preserve lean tissue and functional capacity, and to maintain quality of life in the elderly. We investigated the body-composition changes in normal aging in a cross-sectional study of 188 healthy volunteers aged 20-89 y, which examines the differences in body cell mass and fat as a function of age. In aging, the assumptions of indirect body-composition-measurement techniques, such as the "constant" hydration coefficient of lean body mass or the "constant" density of fat-free mass, may not hold. Therefore, we selected body-composition-measurement techniques that are not sensitive to assumptions about the composition of lean tissue. Cellular mass, lean body mass, and fat were assessed "directly" by total body potassium (TBK) measurements and neutron inelastic scattering. Our results show that TBK content declines at a rate of 7.20 +/- 1.00 mg K.kg body wt-1.y-1 for females (r = 0.601, P < or = 0.001) and 9.16 +/- 0.96 mg K.kg body wt-1.y-1 for males (r = 0.710, P < or = 0.001). Body fat measurements by neutron inelastic scattering have shown a significant increase of percentage body fat with age for female volunteers between the ages of 20 and 50 y and a continuous increase for male volunteers throughout adult life.

Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women.

BACKGROUND: Alterations in body composition have been reported in HIV-positive adults receiving highly active antiretroviral therapy (HAART), but the magnitude and potential determinants of these changes are unclear. OBJECTIVE: We compared total and regional body composition, as measured by dual-energy X-ray absorptiometry, in 203 HIV-positive men and 62 HIV-positive women according to HAART. DESIGN: This was a cross-sectional analysis of a cohort study of nutrition and HIV infection. RESULTS: After adjustment for age, weight, race, and exercise habits, total weight and fat mass did not differ significantly in men or women by HAART. Trunk fat was greater in men (1.0 kg; P < 0.001) and women (1.4 kg; P = 0.005) and leg fat was lower in men (-1.0 kg; P < 0.001) and women (-1.5 kg, P = 0.005) receiving HAART than in those not. This corresponded to a greater percentage of total fat mass located in the trunk (men: 7.5%, P < 0.001; women: 5.1%, P = 0.02). Lean mass was also greater with longer duration of HAART in men (P < 0.002). In men receiving HAART, total and regional bone mineral content were less than in the men not receiving HAART (P < 0.001). These effects increased with longer duration of HAART. Protease inhibitors were associated with the largest differences in regional fat. CONCLUSIONS: HAART is associated with redistribution of fat mass from the legs to the trunk, despite no significant differences in total fat mass or weight. In men, HAART is also associated with a reduction in bone mineral content, suggesting that HAART increases the risk of central obesity and osteoporosis.

Exercise and the treatment of wasting: aging and human immunodeficiency virus infection.

A common feature of human immunodeficiency virus (HIV) infection and aging is the loss of skeletal muscle mass. Although the causes of this loss of muscle are multifactorial, there may be some shared characteristics to this loss, and therefore common strategies for its prevention or reversal. For example, loss of muscle mass early in life and early in the progression of HIV infection may result from decreased levels of physical activity. The rapid loss of skeletal muscle mass at the end of life (sometimes referred to as failure to thrive syndrome) and in acquired immunodeficiency syndrome (AIDS) patients may also have common cause: cachexia. However, it also must be pointed out that loss of skeletal muscle mass with advancing age also may result from losses of motor units, decreased rate of skeletal muscle protein synthesis, and impaired regulation of appetite. These factors have not been demonstrated to be consequences of HIV infection. The use of exercise to treat the losses of muscle size, strength, and functional capacity holds great promise. Although the losses of muscle with HIV infection may be more rapid and dramatic than those seen with aging, resistance exercise training can attenuate or arrest this loss. In elderly people, resistance exercise has been demonstrated to result in increased nitrogen balance, muscle mass and strength, functional capacity, energy requirements, and when combined with a protein calorie supplement, increased energy intake. The use of resistance exercise in HIV-infected patients may also provide similar results. This review discusses many of the changes in body composition, physiological function, and metabolism associated with aging and HIV infection. The specific effects of exercise in the elderly and in patients infected with HIV on the treatment of muscle wasting, and its consequences are also discussed.

The prognostic effect of increased resting energy expenditure prior to treatment for lung cancer.

OBJECTIVE: Increased resting energy expenditure (REE) is thought to confer a poor prognosis in patients with non-small cell lung cancer (NSCLC). However, no study has validated this hypothesis to date. This study's objective was to examine the prognostic significance of REE in NSCLC. METHODS: Seventeen patients with NSCLC (stages IA-IIIB) underwent measurement of REE with indirect calorimetry before the initiation of cancer treatment. Similar measurements were performed in 17 control subjects, each of whom was matched to a cancer patient by age ( +/-5 years), sex and body mass index ( +/-3 kg/m2). Patients were classified as hypermetabolic or hypometabolic based on a direct comparison of measured REE between cancer patients and their matched controls. After cancer treatment, these 17 patients were followed for evidence of metastatic disease for up to 32 months. RESULTS: Six patients developed metastatic disease. The eight hypometabolic cancer patients had a significantly shorter mean disease-free survival compared to the nine hypermetabolic cancer patients: 19 months (95% confidence interval (CI) 12, 26) versus 29 months (95% CI 24, 34), respectively (P < 0.05 by log-rank test). In contrast, Cox regression showed no relationship between disease-free survival and differences in REE between cancer patients and their matched controls (P = 0.20). CONCLUSIONS: These results suggest that hypermetabolism may predict a longer disease-free survival in NSCLC patients. This finding differs from the prevailing hypothesis that hypometabolic patients with NSCLC survive longer, and deserves further investigation.