Dietary citrulline does not modify rat colon tumor response to chemotherapy, but failed to improve nutritional status.

During cancer therapy many patients experience significant malnutrition, leading to decreased tolerance to chemotherapy and decreased survival. Dietary citrulline supplementation improves nutritional status in situations such as short bowel syndrome and aging, and is of potential interest in oncology. However, a mandatory prerequisite is to test this amino acid for interaction with tumor growth and chemotherapy response. Dietary citrulline (Cit; 2%), or an isonitrogenous mix of non-essential amino acids (control), was given to Ward colon tumor-bearing rats the day before chemotherapy initiation. Chemotherapy included 2 cycles, one week apart, each consisting of one injection of CPT-11 (50 mg/kg) and of 5-fluorouracil (50 mg/kg) the day after. Body weight, food intake and tumor volume were measured daily. The day after the last injection, rats were killed, muscles (EDL, gastrocnemius), intestinal mucosa, tumor, spleen and liver were weighed. Muscle and intestinal mucosa protein content were measured. Phosphorylated 4E-BP1 was measured in muscle and tumor as a surrogate for biosynthetic activation. FRAPS (Ferric Reducing Ability of Plasma) and thiols in plasma, muscle and tumor were evaluated and plasma amino acids and haptoglobin were measured. Numerous parameters did not differ by diet overall: a) response of tumor mass to treatment, b) tumor antioxidants and phosphorylated 4E-BP1 levels, c) relative body weight and relative food intake, d) weight of EDL, gastrocnemius, intestinal mucosa, spleen and liver and e) plasma haptoglobin concentrations. Moreover, plasma citrulline concentration was not correlated to relative body weight, only cumulated food intake and plasma haptoglobin concentrations were correlated to relative body weight. Citrulline does not alter the tumor response to CPT-11/5FU based therapy but, has no effect on nutritional status, which could be due to the anorexia and the low amount of citrulline and protein ingested.

FIT: Functional and imaging testing for patients with metastatic cancer.

BACKGROUND: Selecting study endpoints in prospective cancer cachexia trials remains poorly defined. The aim of this study was to further evaluate associations in changes in weight, body composition, functional outcomes, and patient-reported outcomes (PROs) in patients with metastatic cancer. METHODS: We completed a 2-year (2016-2018) observational study in patients with metastatic solid cancer and ECOG performance status 0 to 2 while receiving chemotherapy and/or immunotherapy. We completed assessments at study enrollment and 3 months from enrollment. We analyzed longitudinal changes in weight and body composition using validated methods. Functional assessments included the 6-Min Walk Test, Timed Up and Go Test, and Short Physical Performance Battery. PROs included the Functional Assessment of Anorexia/Cachexia Therapy and Functional Assessment of Cancer Therapy Fatigue. We analyzed changes in body composition and functional assessment using paired t tests. Additionally, we utilized linear regression models to assess relationships between changes in body composition and function outcomes and PROs, adjusting for age and sex. RESULTS: A total of 57 patients completed baseline assessments, but 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data, the mean age was 61.8 years and 47% were female. Metastatic cancer types included 71% gastrointestinal, 13% lung, and 8% gynecologic. Half received chemotherapy, 16% immunotherapy, and 34% a combination. From enrollment to 3 months, we did not observe a change in weight or skeletal muscle but did find an increase in total adipose tissue (16.9 ± 52.4 cm2, 95% CI - 33.79-0.63; p = 0.059; ~ 1.5 pounds). We did not observe any association with changes in weight with any functional outcomes or PROs. However, greater losses in skeletal muscle were associated with greater declines in physical function (6-Min Walk Test [B = 0.04, p = 0.01], Short Physical Performance Battery [B = 2.44, p < 0.01]). CONCLUSIONS: Patients with metastatic cancer receiving cancer-directed therapy may not experience a change in body weight. However, we found an association between losses in skeletal muscle and greater declines in physical function. Therefore, when selecting study endpoints, prospective cancer cachexia studies may consider selecting changes in body composition over weight.

Proceedings of the Canadian Frailty Network Workshop: Identifying Biomarkers of Frailty to Support Frailty Risk Assessment, Diagnosis and Prognosis. Toronto, January 15, 2018.

The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.

Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials.

Background: Driven by reduced nutritional intakes and metabolic alterations, malnutrition in cancer patients adversely affects quality of life, treatment tolerance and survival. We examined evidence for oral nutritional interventions during chemo(radio)therapy. Design: We carried out a systematic review of randomized controlled trials (RCT) with either dietary counseling (DC), high-energy oral nutritional supplements (ONS) aiming at improving intakes or ONS enriched with protein and n-3 polyunsaturated fatty acids (PUFA) additionally aiming for modulation of cancer-related metabolic alterations. Meta-analyses were carried out on body weight (BW) response to nutritional interventions, with subgroup analyses for DC and/or high-energy ONS or high-protein n-3 PUFA-enriched ONS. Results: Eleven studies were identified. Meta-analysis showed overall benefit of interventions on BW during chemo(radio)therapy (+1.31 kg, 95% CI 0.24-2.38, P = 0.02, heterogeneity Q = 21.1, P = 0.007). Subgroup analysis showed no effect of DC and/or high-energy ONS (+0.80 kg, 95% CI -1.14 to 2.74, P = 0.32; Q = 10.5, P = 0.03), possibly due to limited compliance and intakes falling short of intake goals. A significant effect was observed for high-protein n-3 PUFA-enriched intervention compared with isocaloric controls (+1.89 kg, 95% CI 0.51-3.27, P = 0.02; Q = 3.1 P = 0.37). High-protein, n-3 PUFA-enriched ONS studies showed attenuation of lean body mass loss (N = 2 studies) and improvement of some quality of life domains (N = 3 studies). Overall, studies were limited in number, heterogeneous, and inadequately powered to show effects on treatment toxicity or survival. Conclusion: This systematic review suggests an overall positive effect of nutritional interventions during chemo(radio)therapy on BW. Subgroup analyses showed effects were driven by high-protein n-3 PUFA-enriched ONS, suggesting the benefit of targeting metabolic alterations. DC and/or high-energy ONS were less effective, likely due to cumulative caloric deficits despite interventions. We highlight the need and provide recommendations for well-designed RCT to determine the effect of nutritional interventions on clinical outcomes, with specific focus on reaching nutritional goals and providing the right nutrients, as part of an integral supportive care approach.

Assessment of body composition and sarcopenia in patients with esophageal cancer: a systematic review and meta-analysis.

There has recently been increased interest in the assessment of body composition in patients with esophageal cancer for the purpose of nutritional evaluation and prognostication. This systematic review and meta-analysis intends to summarize and critically evaluate the current literature concerning the assessment of body composition in patients with esophageal cancer and to assess its potential implication upon early and late outcomes. A systematic literature search (up to August, 2017) was conducted for studies describing the assessment of body composition in patients with esophageal and gastroesophageal junctional cancer. Meta-analysis of postoperative outcomes including long-term survival was performed using random effects models. Twenty-nine studies reported the assessment of body composition in 3193 patients. Methods used to assess body composition in patients with esophageal cancer included computerized tomography (n = 18 studies), bioelectrical impedance analysis (n = 10), and dual-energy X-ray absorptiometry (n = 1). Significant variability was observed in regard to study design and the criteria used to define individual parameters of body composition. Sarcopenic patients had a higher incidence of postoperative pulmonary complications (7 studies, OR 2.03, 95% CI 1.32-3.11, P = 0.001) after esophagectomy. Meta-analysis of six studies presenting long-term outcomes after esophagectomy identified significantly worse survival in patients who were sarcopenic (HR 1.70, 95% CI 1.33- 2.17, P < 0.0001). The assessment of body composition has the potential to become a clinically useful tool that could support decision-making in patients with esophageal cancer. Current evidence is however weakened by inconsistencies in methods of assessing and reporting body composition in this patient group.

Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy.

Body composition, defined as the proportions and distribution of lean and fat tissues in the human body, is an emergent theme in clinical oncology. Severe muscle depletion (sarcopenia) is most easily overlooked in obese patients; the advent of secondary analysis of oncologic images provides a precise and specific assessment of sarcopenia. Here, we review the definitions, prevalence and clinical implications of sarcopenic obesity (SO) in medical and surgical oncology. Reported prevalence of SO varies due to the heterogeneity in the definitions and the variability in the cut points used to define low muscle mass and high fat mass. Prevalence of SO in advanced solid tumor patient populations average 9% (range 2.3%-14.6%) overall, and one in four (24.7%, range 5.9%-39.2%) patients with body mass index ≥ 30 kg/m2 are sarcopenic. SO is independently associated with higher mortality and higher rate of complications in systemic and surgical cancer treatment, across multiple cancer sites and treatment plans. These associations remain unexplained, however, it has been hypothesized that patients with sarcopenia are generally unfit and unable to tolerate stress. Another proposed mechanism relates to increased exposure to antineoplastic therapy, i.e. a large fat mass would be expected to inflate drug dose in BSA-based treatments, causing an increased rate of dose-limiting toxicity. Pharmacokinetic data are needed to confirm or refute this hypothesis. Old age, deconditioning, cancer progression, acute or chronic nonmalignant disease and drug side-effects are suggested causes of muscle loss, and it is unknown the degree to which this can be reversed. Sarcopenia can be readily detected before start of cancer treatment, however, clinical management protocols for SO patients require development. Studies of cancer treatment dose-modulation are in progress.

Sarcopenic obesity: hidden muscle wasting and its impact for survival and complications of cancer therapy.

Body composition, defined as the proportions and distribution of lean and fat tissues in the human body, is an emergent theme in clinical oncology. Severe muscle depletion (sarcopenia) is most easily overlooked in obese patients; the advent of secondary analysis of oncologic images provides a precise and specific assessment of sarcopenia. Here, we review the definitions, prevalence and clinical implications of sarcopenic obesity (SO) in medical and surgical oncology. Reported prevalence of SO varies due to the heterogeneity in the definitions and the variability in the cut points used to define low muscle mass and high fat mass. Prevalence of SO in advanced solid tumor patient populations average 9% (range 2.3%-14.6%) overall, and one in four (24.7%, range 5.9%-39.2%) patients with body mass index ≥ 30 kg/m2 are sarcopenic. SO is independently associated with higher mortality and higher rate of complications in systemic and surgical cancer treatment, across multiple cancer sites and treatment plans. These associations remain unexplained, however, it has been hypothesized that patients with sarcopenia are generally unfit and unable to tolerate stress. Another proposed mechanism relates to increased exposure to antineoplastic therapy, i.e. a large fat mass would be expected to inflate drug dose in BSA-based treatments, causing an increased rate of dose-limiting toxicity. Pharmacokinetic data are needed to confirm or refute this hypothesis. Old age, deconditioning, cancer progression, acute or chronic nonmalignant disease and drug side-effects are suggested causes of muscle loss, and it is unknown the degree to which this can be reversed. Sarcopenia can be readily detected before start of cancer treatment, however, clinical management protocols for SO patients require development. Studies of cancer treatment dose-modulation are in progress.

ESPEN expert group recommendations for action against cancer-related malnutrition.

Patients with cancer are at particularly high risk for malnutrition because both the disease and its treatments threaten their nutritional status. Yet cancer-related nutritional risk is sometimes overlooked or under-treated by clinicians, patients, and their families. The European Society for Clinical Nutrition and Metabolism (ESPEN) recently published evidence-based guidelines for nutritional care in patients with cancer. In further support of these guidelines, an ESPEN oncology expert group met for a Cancer and Nutrition Workshop in Berlin on October 24 and 25, 2016. The group examined the causes and consequences of cancer-related malnutrition, reviewed treatment approaches currently available, and built the rationale and impetus for clinicians involved with care of patients with cancer to take actions that facilitate nutrition support in practice. The content of this position paper is based on presentations and discussions at the Berlin meeting. The expert group emphasized 3 key steps to update nutritional care for people with cancer: (1) screen all patients with cancer for nutritional risk early in the course of their care, regardless of body mass index and weight history; (2) expand nutrition-related assessment practices to include measures of anorexia, body composition, inflammatory biomarkers, resting energy expenditure, and physical function; (3) use multimodal nutritional interventions with individualized plans, including care focused on increasing nutritional intake, lessening inflammation and hypermetabolic stress, and increasing physical activity.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Key determinants of energy expenditure in cancer and implications for clinical practice.

Great discrepancies exist in the reported prevalence of altered energy metabolism (hypo- or hypermetabolism) in cancer patients, which is likely due to the vast array of phenomena that can affect energy expenditure in these patients. The purpose of this review was to critically evaluate key determinants of energy expenditure in cancer and the relevance for clinical practice. Resting energy expenditure (REE) is the largest and most commonly measured component of total energy expenditure. In addition to the energetic demand of the tumor itself, REE may be increased due to changes in inflammation, body composition and brown adipose tissue activation. Energy expenditure from physical activity is often lower in cancer compared with healthy populations, and there is evidence to suggest that the thermic effect of food might also be blunted and affected by cancer therapy. Although accurate assessment of energy metabolism is a cornerstone of adequate nutritional therapy, prediction methods often do not capture the true energy expenditure of most cancer patients. In fact, limits of agreement of prediction equations may range from 40% below to 30% above measured REE. Such variability highlights the need for a more comprehensive understanding of energy expenditure in cancer and the value of accurately assessing the energy needs of these patients.

Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia.

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, ß, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1ß had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.

Nutritional assessment in overweight and obese patients with metastatic cancer: does it make sense?

BACKGROUND: Obesity is causally related with tumor development, and thus, many cancer patients are overweight or obese at diagnosis. Whether these patients need regular nutritional assessment is not known. In the present study, we evaluated the utility of Mini Nutritional Assessment (MNA), a nutritional screening/assessment questionnaire, in overweight or obese patients with metastatic tumors. PATIENTS AND METHODS: Overweight or obese patients referred for initiation of systemic therapy in three cancer centers were eligible. Basic demographics and clinical data were recorded. MNA was completed at baseline and patients were divided into three groups: A (well nourished), B (at risk), and C (malnourished). Survival data were subsequently collected. The prevalence of malnutrition and prognostic significance were evaluated. RESULTS: In total, 1469 patients with metastatic primaries were identified. Of them, 594 (41.9%) were overweight or obese and included in the analysis. According to MNA, almost 50% were at risk and around 12% were already malnourished at presentation. A significant difference in overall survival was found between groups [group A 17.8 (15.5-20.1) months, group B 8.2 (7.3-9.3) months, and group C 6.4 (3.2-9.6) months, P < 0.001]. Moreover, MNA was the only independent predictor of survival. CONCLUSIONS: Our findings support that a significant percentage of overweight or obese cancer patients may be at nutritional risk and this is moreover related with adverse prognosis. An MNA score could be used for the identification of this risk.

Functional body composition and related aspects in research on obesity and cachexia: report on the 12th Stock Conference held on 6 and 7 September 2013 in Hamburg, Germany.

The 12th Stock Conference addressed body composition and related functions in two extreme situations, obesity and cancer cachexia. The concept of 'functional body composition' integrates body components into regulatory systems relating the mass of organs and tissues to corresponding in vivo functions and metabolic processes. This concept adds to an understanding of organ/tissue mass and function in the context of metabolic adaptations to weight change and disease. During weight gain and loss, there are associated changes in individual body components while the relationships between organ and tissue mass are fixed. Thus an understanding of body weight regulation involves an examination of the relationships between organs and tissues rather than individual organ and tissue masses only. The between organ/tissue mass relationships are associated with and explained by crosstalks between organs and tissues mediated by cytokines, hormones and metabolites that are coupled with changes in body weight, composition and function as observed in obesity and cancer cachexia. In addition to established roles in intermediary metabolism, cell function and inflammation, organ-tissue crosstalk mediators are determinants of body composition and its change with weight gain and loss. The 12th Stock Conference supported Michael Stocks' concept of gaining new insights by integrating research ideas from obesity and cancer cachexia. The conference presentations provide an in-depth understanding of body composition and metabolism.

Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model--a study based on data from an international multicentre project (EPCRC-CSA).

BACKGROUND: Weight loss limits cancer therapy, quality of life and survival. Common diagnostic criteria and a framework for a classification system for cancer cachexia were recently agreed upon by international consensus. Specific assessment domains (stores, intake, catabolism and function) were proposed. The aim of this study is to validate this diagnostic criteria (two groups: model 1) and examine a four-group (model 2) classification system regarding these domains as well as survival. PATIENTS AND METHODS: Data from an international patient sample with advanced cancer (N = 1070) were analysed. In model 1, the diagnostic criteria for cancer cachexia [weight loss/body mass index (BMI)] were used. Model 2 classified patients into four groups 0-III, according to weight loss/BMI as a framework for cachexia stages. The cachexia domains, survival and sociodemographic/medical variables were compared across models. RESULTS: Eight hundred and sixty-one patients were included. Model 1 consisted of 399 cachectic and 462 non-cachectic patients. Cachectic patients had significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. In model 2, differences were not consistent; appetite loss did not differ between group III and IV, and performance status not between group 0 and I. Survival was shorter in group II and III compared with other groups. By adding other cachexia domains to the model, survival differences were demonstrated. CONCLUSION: The diagnostic criteria based on weight loss and BMI distinguish between cachectic and non-cachectic patients concerning all domains (intake, catabolism and function) and is associated with survival. In order to guide cachexia treatment a four-group classification model needs additional domains to discriminate between cachexia stages.

Measurement of skeletal muscle radiation attenuation and basis of its biological variation.

Skeletal muscle contains intramyocellular lipid droplets within the cytoplasm of myocytes as well as intermuscular adipocytes. These depots exhibit physiological and pathological variation which has been revealed with the advent of diagnostic imaging approaches: magnetic resonance (MR) imaging, MR spectroscopy and computed tomography (CT). CT uses computer-processed X-rays and is now being applied in muscle physiology research. The purpose of this review is to present CT methodologies and summarize factors that influence muscle radiation attenuation, a parameter which is inversely related to muscle fat content. Pre-defined radiation attenuation ranges are used to demarcate intermuscular adipose tissue [from -190 to -30 Hounsfield units (HU)] and muscle (-29 HU to +150 HU). Within the latter range, the mean muscle radiation attenuation [muscle (radio) density] is reported. Inconsistent criteria for the upper and lower HU cut-offs used to characterize muscle attenuation limit comparisons between investigations. This area of research would benefit from standardized criteria for reporting muscle attenuation. Available evidence suggests that muscle attenuation is plastic with physiological variation induced by the process of ageing, as well as by aerobic training, which probably reflects accumulation of lipids to fuel aerobic work. Pathological variation in muscle attenuation reflects excess fat deposition in the tissue and is observed in people with obesity, diabetes type II, myositis, osteoarthritis, spinal stenosis and cancer. A poor prognosis and different types of morbidity are predicted by the presence of reduced mean muscle attenuation values in patients with these conditions; however, the biological features of muscle with these characteristics require further investigation.

Low skeletal muscle is associated with toxicity in patients included in phase I trials.

BACKGROUND: Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials. PATIENTS AND METHODS: Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm(2)/m(2)). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1(st) cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity. RESULTS: 93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8 ± 4.6 vs. 48.1 ± 9.6 cm(2)/m(2) (p = 0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4 ± 5.8 vs. 48.4 ± 9.7 cm(2)/m(2) (p = 0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p = 0.02). CONCLUSION: Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies.

Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies.

Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia.