Aoife M. Ryan

Enteral Nutrition Enriched With Eicosapentaenoic Acid (EPA) Preserves Lean Body Mass Following Esophageal Cancer Surgery : Results of a Double-Blinded Randomized Controlled Trial

Background:Esophagectomy represents an exemplar of controlled major trauma, with marked metabolic, immunologic, and physiologic changes as well as an associated high incidence of complications. Eicosapentaenoic acid (EPA) enriched enteral nutrition (EN) modulates immune function and limits catabolism in patients with advanced cancer, but its impact in the peri-operative period is unclear. Objectives:To examine the effects of perioperative EPA enriched EN on the metabolic, nutritional, and immuno-inflammatory response to esophagectomy, and on postoperative complications. Methods:In a double-blind design, patients were randomized to a standard EN formula or a formula enriched with 2.2 g EPA/d for 5 days preoperatively (orally) and 21 days postoperatively (jejunostomy). Segmental bioelectrical impedance analysis was performed preoperatively and on POD 21. Postoperative complications were monitored, as well as the acute phase response, coagulation markers, and serum cytokines. Results:Fifty-three patients (28 EPA, 25 standard) completed the study, and both groups were well matched. Serum and peripheral blood mononuclear cell (PBMC) membrane EPA levels were significantly increased in the EPA group. There was no difference in the incidence of major complications. The EPA group maintained all aspects of body composition postoperatively, whereas patients in the standard EN group lost significant amounts of fat-free mass (1.9 kg, P = 0.030) compared with the EPA group [leg (0.3 kg, P = 0.05), arm (0.17 kg, P = 0.01), and trunk (1.44 kg, P = 0.03)]. The EPA group had a significantly (P < 0.05) attenuated stress response for TNFα, IL-10, and IL-8 compared with the standard group. Conclusions:EPA supplemented early EN is associated with preservation of lean body mass post esophagectomy compared with a standard EN. These properties may merit longer-term study to address its impact on recovery of function and quality of life in models of complex surgery or multimodal cancer treatment regimens.

Cancer Cachexia: Mechanisms and Clinical Implications

Cachexia is a multifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be fully elucidated. Cachexia is compounded by anorexia and the relationship between these two entities has not been clarified fully. Inconsistencies in the definition of cachexia have limited the epidemiological characterisation of the condition and there has been slow progress in identifying therapeutic agents and trialling them in the clinical setting. Understanding the complex interplay of tumour and host factors will uncover new therapeutic targets.

Metabolic Syndrome, Central Obesity and Insulin Resistance are Associated with Adverse Pathological Features in Postmenopausal Breast Cancer

AIMS Obesity is associated with both an increased risk of postmenopausal breast cancer and increased mortality rates. The mechanism is unclear, and central (visceral) obesity, insulin resistance, altered sex steroids and altered adipokines are mooted as possible factors. These features may cluster in the so-called metabolic syndrome. The relevance of metabolic syndrome to the biology of breast cancer is unknown, and this was the focus of the present study. MATERIALS AND METHODS All postmenopausal women with newly diagnosed breast cancer (n=105) were recruited. A detailed clinical history was carried out, as well as a body composition analysis, metabolic screen and measurement of adipokines and inflammatory markers. RESULTS The median age was 68 years (40-94 years) and the mean body mass index was 28.3+/-5.2 kg/m2, with 87% of patients centrally obese. Metabolic syndrome was diagnosed in 39% of patients, and was significantly associated with central obesity (P<0.005) and increased inflammation, with C-reactive protein levels doubling in metabolic syndrome patients compared with non-metabolic syndrome patients (10.3 vs 5.8 mg/l; P=0.084). Patients with a later pathological stage (II-IV) were significantly more likely to be obese (P=0.007), centrally obese (P=0.009), hyperglycaemic (P=0.047) and hyperinsulinaemic (P=0.026); 51% had metabolic syndrome compared with 12% for early stage disease. Patients with node-positive disease were significantly more likely to be hyperinsulaemic (P=0.030) and have metabolic syndrome (P=0.028) than patients with node-negative disease. DISCUSSION The data suggest that metabolic syndrome and central obesity are common in postmenopausal breast cancer patients, and that metabolic syndrome may be associated with a more aggressive tumour biology.

Obesity, metabolic syndrome and esophageal adenocarcinoma: epidemiology, etiology and new targets.

BACKGROUND Rates of distal and junctional adenocarcinomas are increasing in Western countries. METHODS Systematic review of epidemiological evidence linking obesity to esophageal adenocarcinoma (EA) was performed for studies published from 2005 to 2010. The current understanding of obesitys role in the etiology and potential dysplastic progression of Barretts esophagus (BE) to EA is reviewed. RESULTS Accumulating epidemiological studies provide evidence of obesitys role as a driving force behind the increasing rates of EA. The simplest construct is that obesity promotes reflux, causing chronic inflammation and BE, predisposing to adenocarcinoma. However, as obesity is positively associated with the prevalence of many cancers, other mechanisms are important. A link may exist between fat distribution patterns and the risk of BE and EA. Altered metabolic profiles in the metabolic syndrome (MetS) may be a key factor in cell cycle/genetic abnormalities that mark the progression of BE towards cancer. Research highlighting a unique role of MetS in the length of BE, and its association with systemic inflammation and insulin resistance is discussed, as well as adipokine receptor expression in both BE and esophageal epithelium, and how MetS and the systemic response impacts on key regulators of inflammation and tumorigenesis. CONCLUSIONS/IMPACT: Obesity is positively associated with EA. The systemic inflammatory state consequent on the altered metabolism of obese patients, and the associated impact of adipocytokines and pro-coagulant factors released by adipocytes in central fat, may underlie obesitys relationship to this cancer. Novel therapeutic agents that may antagonize adipo-cytokines and potentially offer a promising role in cancer therapy are discussed.

Barrett esophagus: prevalence of central adiposity, metabolic syndrome, and a proinflammatory state.

Background:Obesity is a risk factor for esophageal adenocarcinoma, with a pathway through inflammation and metaplasia secondary to reflux the dominant hypothesis. The proinflammatory impact of adipocytokines associated with the metabolic syndrome of central adiposity may also be relevant. The objective of this study was to explore this profile in Barrett esophagus. Methods:Patients with specialized intestinal metaplasia were invited to attend the metabolic syndrome screening where they underwent anthropometry, segmental bioelectrical impedance analysis, and blood pressure measurement, and had blood taken for quantification of fasting lipids, insulin, glucose, C-reactive protein, and adipocytokines. Results:One hundred two patients were studied. Forty-six percent of Barrett patients had metabolic syndrome and 78% were centrally obese. Patients with metabolic syndrome were significantly more obese by body mass index, had a 9.4 cm greater waistline, were more hypertensive, and were insulin resistant with 25% having fasting hyperinsulinemia compared with Barrett patients without metabolic syndrome. Metabolic syndrome was associated with elevated C-reactive protein, leptin, and a trend toward decreased adiponectin levels. Sixty percent of patients with long-segment Barrett had metabolic syndrome, and 92% were centrally obese compared with 23.8% and 62%, respectively (P = 0.007 and 0.005) in short-segment Barrett. Long-segment Barrett was associated with hyperinsulinemia and significantly increased levels of interleukin-6 compared with short-segment Barrett. Conclusions:The prevalence of metabolic syndrome in Barrett far exceeds population norms, and the syndrome was significantly associated with the length of specialized intestinal metaplasia. The data do suggest that the metabolic syndrome may be relevant to the continuum of metaplasia within the Barrett cohort.

Cancer-associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later.

An awareness of the importance of nutritional status in hospital settings began more than 40 years ago. Much has been learned since and has altered care. For the past 40 years several large studies have shown that cancer patients are amongst the most malnourished of all patient groups. Recently, the use of gold-standard methods of body composition assessment, including computed tomography, has facilitated the understanding of the true prevalence of cancer cachexia (CC). CC remains a devastating syndrome affecting 50-80 % of cancer patients and it is responsible for the death of at least 20 %. The aetiology is multifactorial and complex; driven by pro-inflammatory cytokines and specific tumour-derived factors, which initiate an energy-intensive acute phase protein response and drive the loss of skeletal muscle even in the presence of adequate food intake and insulin. The most clinically relevant phenotypic feature of CC is muscle loss (sarcopenia), as this relates to asthenia, fatigue, impaired physical function, reduced tolerance to treatments, impaired quality of life and reduced survival. Sarcopenia is present in 20-70 % depending on the tumour type. There is mounting evidence that sarcopenia increases the risk of toxicity to many chemotherapy drugs. However, identification of patients with muscle loss has become increasingly difficult as 40-60 % of cancer patients are overweight or obese, even in the setting of metastatic disease. Further challenges exist in trying to reverse CC and sarcopenia. Future clinical trials investigating dose reductions in sarcopenic patients and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.

Sarcopenia and cachexia in the era of obesity: clinical and nutritional impact

Our understanding of body composition (BC) variability in contemporary populations has significantly increased with the use of imaging techniques. Abnormal BC such as sarcopenia (low muscle mass) and obesity (excess adipose tissue) are predictors of poorer prognosis in a variety of conditions or clinical situations. As a catabolic illness, a defining feature of cancer is muscle loss. Although the conceptual model of wasting in cancer is typically conceived as involuntary weight loss leading to low body weight, recent studies have shown that both sarcopenia and cachexia can be present with obesity. The combination of low muscle and high adipose tissue (sarcopenic obesity) is an emerging abnormal BC phenotype prevalent across the body weight, and hence BMI spectra. Sarcopenia and sarcopenic obesity in cancer are in most instances occult conditions, which have been independently associated with higher incidence of chemotherapy toxicity, shorter time to tumour progression, poorer outcomes of surgery, physical impairment and shorter survival. Although the mechanisms are yet to be fully understood, the associations with poorer clinical outcomes emphasise the value of nutritional assessment as well as the need to develop appropriate interventions to countermeasure abnormal BC. Sarcopenia and sarcopenic obesity create diverse nutritional requirements, highlighting the compelling need for a more comprehensive and differentiated understanding of energy and protein requirements in this heterogeneous population.

Body Composition by Computed Tomography as a Predictor of Toxicity in Patients With Renal Cell Carcinoma Treated With Sunitinib.

Background: Sunitinib is a standard first-line option for metastatic renal cell carcinoma (mRCC). Body composition is a prognostic factor in cancer patients and patients with loss of skeletal muscle mass and fat-free mass (FFM) are prone to dose-limiting toxicity (DLT) during targeted drug therapy. We investigated whether body composition by computed tomography predicted DLT from sunitinib in mRCC. Methods: Patients with clear cell mRCC receiving sunitinib (50 mg) were included. Skeletal muscle cross-sectional area at L3 was measured by computed tomography. Sarcopenia was defined using published cutoffs. Toxicity was assessed after 4 cycles of the drug. Results: Fifty-five patients (43 male), mean age 64 years were included. Overall, 33% (N=18) of all patients were sarcopenic and of these 12.7% (N=7) were sarcopenic and overweight or obese. DLT occurred in <6 months in 53% of patients (44% male vs. 83% female) and those who experienced DLT were older (68 vs. 60 y), had a lower skeletal muscle index (51.7 vs. 59.4 cm2/m2), a lower FFM (51.4 vs. 57.7 kg), and received a higher drug dose in mg/kg FFM (0.9 vs. 0.8). Patients with the lowest compared with the highest measurements of skeletal muscle mass experienced more DLT, respectively, 92% versus 57% and experienced on average 5 toxicities versus 2. Conclusions: Sarcopenia is prevalent in patients with mRCC, is an occult condition in patients with normal/high body mass index, and is a significant predictor of DLT in patients receiving sunitinib. Our results highlight the potential use of baseline body composition to predict toxicity.

Health-related quality of life assessment at presentation may predict complications and early relapse in patients with localized cancer of the esophagus

SUMMARY Health-related quality of life (HR-QOL) assessment in esophageal cancer is increasingly performed. However, the association of baseline HR-QOL in predicting outcome is unclear. This study aimed to assess the impact of HR-QOL scores at diagnosis with major morbidity, mortality, failure to progress to surgery, recurrence within 1 year, and survival in patients with localized esophageal cancer. The European Organization for Research and Treatment of Cancers quality of life questionnaire was completed at diagnosis. Univariate and multivariate logistic regression were used to investigate the relationship between baseline HR-QOL and outcomes adjusting for confounding variables. A total of 185 patients with localized esophageal cancer were included, 89 undergoing multimodal therapy and 96 surgery alone. Global QOL scores were significantly associated with in-hospital mortality (P = 0.020) but not with major morbidity (P = 0.709) or 1-year survival (P = 0.247). Symptoms of fatigue and dyspnea at baseline were significantly (P < 0.05) associated with major morbidity, in-hospital mortality, and survival in univariate analysis. After adjusting for known confounding variables in multivariate analysis, only worse dyspnea score remained predictive of in-hospital mortality and a worse fatigue score remained predictive of 1-year survival. HR-QOL was of no benefit in predicting survival in multivariate analysis that identified pathological nodal status as the most significant factor. HR-QOL questionnaires may be helpful in preoperative assessment of risk. It is possible that patients with unrecognized micrometastatic disease at the time of surgery may report worse systemic symptoms at diagnosis, in particular fatigue and dyspnea, and these and global QOL scores may also identify poorer reserves that may increase in-hospital morbidity and mortality postoperatively.

Genetic Polymorphisms and the Risk of Infection Following Esophagectomy. Positive Association with TNF-α Gene −308 Genotype

Objective:To examine the association of single nucleotide polymorphisms (SNPs) in inflammation-related genes in the development of infections following esophagectomy. Summary Background Data:Genetic polymorphisms for immunoregulatory cytokines may explain individual variation in response to trauma. Esophagectomy is associated with a high risk of postoperative infection and sepsis, and this study explored a number of SNPs in cytokine genes and their relationship to postoperative infection. Methods:In a prospective analysis of 197 patients with esophageal cancer undergoing resection, 55 developed postoperative infections. DNA was extracted and genotyping was performed for polymorphisms in genes encoding TNF-α, IL-1β, IL-1 receptor antagonist, IL-10, and Toll-like receptor 4 (TLR-4) using Taqman chemistry and PCR/RFLP. In a blinded analysis, the cohort with infections was compared with the no complication cohort (n = 114) and a cohort that had noninfective complications (n = 28). Results:No differences in polymorphisms for IL-1β, IL-1 RN, IL-10, and TLR-4 genes were observed across groups. The frequency of TNF-α −308 GG homozygotes was significantly (P = 0.021) higher in the postoperative infection group. The G allele was significantly higher in the postoperative infection group compared with the no complication group (P = 0.017) and other complication group (P = 0.013). By multivariate analysis, this polymorphism as well as age and body mass index were predictors of infection. Conclusion:The TNF-α −308A allele has been shown to be associated with higher circulating levels of TNF-α and the −308 G allele is a comparative low secretor allele. We propose that the polymorphism in the promotor region of TNF-α gene may lead to altered expression and a possible suboptimal activity of TNF-α in persons with GG genotypes, and these data suggest a link with infection following major surgery.