Influence of body composition profile on outcomes following colorectal cancer surgery.

BACKGROUND: Muscle depletion is characterized by reduced muscle mass (myopenia), and increased infiltration by intermuscular and intramuscular fat (myosteatosis). This study examined the role of particular body composition profiles as prognostic markers for patients with colorectal cancer undergoing curative resection. METHODS: Patients with colorectal cancer undergoing elective surgical resection between 2006 and 2011 were included. Lumbar skeletal muscle index (LSMI), visceral adipose tissue (VAT) surface area and mean muscle attenuation (MA) were calculated by analysis of CT images. Reduced LSMI (myopenia), increased VAT (visceral obesity) and low MA (myosteatosis) were identified using predefined sex-specific skeletal muscle index values. Univariable and multivariable Cox regression models were used to determine the role of different body composition profiles on outcomes. RESULTS: Some 805 patients were identified, with a median follow-up of 47 (i.q.r. 24·9-65·6) months. Multivariable analysis identified myopenia as an independent prognostic factor for disease-free survival (hazard ratio (HR) 1·53, 95 per cent c.i. 1·06 to 2·39; P = 0·041) and overall survival (HR 1·70, 1·25 to 2·31; P < 0·001). The presence of myosteatosis was associated with prolonged primary hospital stay (P = 0·034), and myopenic obesity was related to higher 30-day morbidity (P = 0·019) and mortality (P < 0·001) rates. CONCLUSION: Myopenia may have an independent prognostic effect on cancer survival for patients with colorectal cancer. Muscle depletion may represent a modifiable risk factor in patients with colorectal cancer and needs to be targeted as a relevant endpoint of health recommendations.

Enhanced Recovery After Surgery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthesia practice.

BACKGROUND: The present interdisciplinary consensus review proposes clinical considerations and recommendations for anaesthetic practice in patients undergoing gastrointestinal surgery with an Enhanced Recovery after Surgery (ERAS) programme. METHODS: Studies were selected with particular attention being paid to meta-analyses, randomized controlled trials and large prospective cohort studies. For each item of the perioperative treatment pathway, available English-language literature was examined and reviewed. The group reached a consensus recommendation after critical appraisal of the literature. RESULTS: This consensus statement demonstrates that anaesthesiologists control several preoperative, intraoperative and postoperative ERAS elements. Further research is needed to verify the strength of these recommendations. CONCLUSIONS: Based on the evidence available for each element of perioperative care pathways, the Enhanced Recovery After Surgery (ERAS®) Society presents a comprehensive consensus review, clinical considerations and recommendations for anaesthesia care in patients undergoing gastrointestinal surgery within an ERAS programme. This unified protocol facilitates involvement of anaesthesiologists in the implementation of the ERAS programmes and allows for comparison between centres and it eventually might facilitate the design of multi-institutional prospective and adequately powered randomized trials.

Enhanced Recovery After Surgery (ERAS) for gastrointestinal surgery, part 1: pathophysiological considerations.

BACKGROUND: The present article has been written to convey concepts of anaesthetic care within the context of an Enhanced Recovery After Surgery (ERAS) programme, thus aligning the practice of anaesthesia with the care delivered by the surgical team before, during and after surgery. METHODS: The physiological principles supporting the implementation of the ERAS programmes in patients undergoing major abdominal procedures are reviewed using an updated literature search and discussed by a multidisciplinary group composed of anaesthesiologists and surgeons with the aim to improve perioperative care. RESULTS: The pathophysiology of some key perioperative elements disturbing the homoeostatic mechanisms such as insulin resistance, ileus and pain is here discussed. CONCLUSIONS: Evidence-based strategies aimed at controlling the disruption of homoeostasis need to be evaluated in the context of ERAS programmes. Anaesthesiologists could, therefore, play a crucial role in facilitating the recovery process.

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy.

PURPOSE: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic ß2-agonist and an appetite stimulant in patients with cancer cachexia. METHODS: Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 µg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥ 4 % or function ≥ 10 %. RESULTS: Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p=0.012; right 1.02 vs. 1.06 L, p=0.004). There was a trend towards an increase in quadriceps and handgrip strength (p>0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p=0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). CONCLUSIONS: In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

A novel oral tracer procedure for measurement of habitual myofibrillar protein synthesis.

RATIONALE: Conventionally, myofibrillar protein synthesis is measured over time periods of hours. In clinical studies, interventions occur over weeks. Functional measures over such periods may be more representative. We aimed to develop a novel method to determine myofibrillar protein fractional synthetic rate (FSR) to estimate habitual rates, while avoiding intravenous tracer infusions. METHODS: Four healthy males were given 100 g water enriched to 70 Atom % with (2)H2O as a single oral bolus. Vastus-lateralis needle biopsies were performed and plasma samples collected, 3-13 days post-dose. (2)H enrichment in body water was measured in plasma using continuous flow isotope ratio mass spectrometry (IRMS). Myofibrillar protein was isolated from muscle biopsies and acid hydrolysed. (2)H enrichment of protein-bound and plasma-free alanine was measured by gas chromatography (GC)/pyrolysis/IRMS. Myofibrillar protein FSR was calculated (% day(-1)). RESULTS: The tracer bolus raised the initial enrichment of body water to 1514 ppm (2)H excess. Water elimination followed a simple exponential. The average elimination half-time was 8.3 days. Plasma alanine, labelled during de novo synthesis, followed the same elimination kinetics as water. The weighted average myofibrillar protein FSR from the four subjects was 1.38 % day(-1) (range, 1.0-1.9 % day(-1) ). CONCLUSIONS: Myofibrillar protein FSR was measured in free-living healthy individuals over 3-13 days. Using a single oral (2)H2O bolus, endogenous labelling of alanine occurred in a predictable manner giving estimates of synthesis comparable with published values. Furthermore, the protocol does not compromise the ability to measure other important metabolic processes such as total energy expenditure.

mRNA profiling of the cancer degradome in oesophago-gastric adenocarcinoma.

BACKGROUND: Degradation of the extracellular matrix is fundamental to tumour development, invasion and metastasis. Several protease families have been implicated in the development of a broad range of tumour types, including oesophago-gastric (OG) adenocarcinoma. The aim of this study was to analyse the expression levels of all core members of the cancer degradome in OG adenocarcinoma and to investigate the relationship between expression levels and tumour/patient variables associated with poor prognosis. METHODS: Comprehensive expression profiling of the protease families (matrix metalloproteinases (MMPs), members of the ADAM metalloproteinase-disintegrin family (ADAMs)), their inhibitors (tissue inhibitors of metalloproteinase), and molecules involved in the c-Met signalling pathway, was performed using quantitative real-time reverse transcription polymerase chain reaction in a cohort of matched malignant and benign peri-tumoural OG tissue (n=25 patients). Data were analysed with respect to clinico-pathological variables (tumour stage and grade, age, sex and pre-operative plasma C-reactive protein level). RESULTS: Gene expression of MMP1, 3, 7, 9, 10, 11, 12, 16 and 24 was upregulated by factors >4-fold in OG adenocarcinoma samples compared with matched benign tissue (P<0.01). Expression of ADAM8 and ADAM15 correlated significantly with tumour stage (P=0.048 and P=0.044), and ADAM12 expression correlated with tumour grade (P=0.011). CONCLUSION: This study represents the first comprehensive quantitative analysis of the expression of proteases and their inhibitors in human OG adenocarcinoma. These findings implicate elevated ADAM8, 12 and 15 mRNA expression as potential prognostic molecular markers.

Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients.

BACKGROUND: Profound loss of adipose tissue is a hallmark of cancer cachexia. Zinc-α2-glycoprotein (ZAG), a recently identified adipokine, is suggested as a candidate in lipid catabolism. METHODS: In the first study, eight weight-stable and 17 cachectic cancer patients (weight loss 5% in previous 6 months) were recruited. Zinc-α2-glycoprotein mRNA and protein expression were assessed in subcutaneous adipose tissue (SAT), subcutaneous adipose tissue morphology was examined and serum ZAG concentrations were quantified. In the second cohort, ZAG release by SAT was determined in 18 weight-stable and 15 cachectic cancer patients. The effect of ZAG on lipolysis was evaluated in vitro. RESULTS: Subcutaneous adipose tissue remodelling in cancer cachexia was evident through shrunken adipocytes with increased fibrosis. In cachectic cancer patients, ZAG mRNA was upregulated (2.7-fold, P=0.028) while leptin mRNA decreased (2.2-fold, P=0.018); serum ZAG levels were found to be unaffected. Zinc-α2-glycoprotein mRNA correlated positively with weight loss (r=0.51, P=0.01) and serum glycerol levels (r=0.57, P=0.003). Zinc-α2-glycoprotein release by SAT was also elevated in cachectic patients (1.5-fold, P=0.024) and correlated with weight loss (r=0.50, P=0.003). Recombinant ZAG stimulated lipolysis in human adipocytes. CONCLUSIONS: Zinc-α2-glycoprotein expression and secretion by adipose tissue is enhanced in cachectic cancer patients. Given its lipid-mobilising effect, ZAG may contribute to adipose atrophy associated with cancer cachexia in human beings.

Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer.

BACKGROUND: Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC). METHODS: Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of > or =10 mg l(-1) or modified Glasgow prognostic score (mGPS) of > or =1), and nutritional status were assessed in newly diagnosed OGC patients (n=293). Healthy volunteers (n=35) served as controls. RESULTS: MIC-1 was elevated in patients (median=1371 pg ml(-1); range 141-39 053) when compared with controls (median=377 pg ml(-1); range 141-3786; P<0.001). Patients with gastric tumours (median=1592 pg ml(-1); range 141-12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml(-1); range 383-39 053) and oesophageal tumours (median=1180 pg ml(-1); range 258-31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0-33.4%), and 42% of patients had an mGPS of > or =1 or plasma CRP of > or =10 mg l(-1) (median=9 mg l(-1); range 1-200). MIC-1 correlated positively with disease stage (r(2)=0.217; P<0.001), age (r(2)=0.332; P<0.001), CRP (r(2)=0.314; P<0.001), and mGPS (r(2)=0.336; P<0.001), and negatively with Karnofsky Performance Score (r(2)=-0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r(2)=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157-251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259-373; P=0.036), but MIC-1 was not an independent prognostic indicator. CONCLUSIONS: There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.

Randomized clinical trial of laxatives and oral nutritional supplements within an enhanced recovery after surgery protocol following liver resection.

BACKGROUND: Routine laxatives may expedite gastrointestinal recovery and early tolerance of food within an enhanced recovery after surgery (ERAS) programme. Combined with carbohydrate loading and oral nutritional supplements (ONS), it may further enhance recovery of gastrointestinal function and promote earlier overall recovery. METHODS: Seventy-four patients undergoing liver resection were randomized in a two-by-two factorial design to receive either postoperative magnesium hydroxide as a laxative, preoperative carbohydrate loading and postoperative ONS, their combination or a control group. Patients were managed within an ERAS programme of care. The primary outcome measure was time to first passage of stool. Secondary outcome measures were gastric emptying, postoperative oral calorie intake, time to functional recovery and length of hospital stay. RESULTS: Sixty-eight patients completed the trial. The laxative group had a significantly reduced time to passage of stool: median (interquartile range) 4 (3-5) versus 5 (4-6) days (P = 0.034). The ONS group showed a trend towards a shorter time to passage of stool (P = 0.076) but there was no evidence of interaction in patients randomized to the combination regimen. Median length of hospital stay was 6 (4-7) days. There were no differences in secondary outcomes between groups. CONCLUSION: Within an ERAS protocol for patients undergoing liver resection, routine postoperative laxatives result in an earlier first passage of stool but the overall rate of recovery is unaltered.

The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer.

Although weight loss is often a dominant symptom in patients with upper gastrointestinal malignancy, there is a lack of objective evidence describing changes in nutritional status and potential associations between weight loss, food intake, markers of systemic inflammation and stage of disease in such patients. Two hundred and twenty patients diagnosed with gastric/oesophageal cancer were studied. Patients underwent nutritional assessment consisting of calculation of body mass index, measurement of weight loss, dysphagia scoring and estimation of dietary intake. Serum acute-phase protein concentrations were determined by enzyme-linked immunosorbent assay. In all, 182 (83%) patients had lost weight at diagnosis (median loss, 7% body weight). Weight loss was associated with poor performance status, advanced disease stage, dysphagia, reduced dietary intake and elevated serum C-reactive protein (CRP) concentrations. Multiple regression identified dietary intake (estimate of effect, 38%), serum CRP concentrations (estimate of effect, 34%) and stage of disease (estimate of effect, 28%) as independent variables in determining degree of weight loss. Mechanisms other than reduced dietary intake or mechanical obstruction by the tumour appear to be involved in the nutritional decline in patients with gastro-oesophageal malignancy. Recognition that systemic inflammation plays a role in nutritional depletion may inform the development of appropriate therapeutic strategies to ameliorate weight loss, making patients more tolerant of cancer-modifying treatments such as chemotherapy.

Determinants of outcome after colorectal resection within an enhanced recovery programme.

BACKGROUND: Postoperative outcomes were studied in relation to adverse nutritional risk (body mass index (BMI) below 20 kg/m(2)), advanced age (80 years or more) and co-morbidity (American Society of Anesthesiologists (ASA) grade III-IV) in patients undergoing colorectal resection within an enhanced recovery after surgery programme. METHODS: Outcomes were audited prospectively in 1035 patients. Morbidity and mortality were compared with those predicted using the Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity, and a multivariable model was used to determine independent predictors of outcome. RESULTS: Postoperative morbidity was lower than predicted (observed to expected 0.68; P < 0.001). Independent predictors of delayed mobilization were ASA III-IV (P < 0.001) and advanced age (P = 0.025). Prolonged hospital stay was related to advanced age (P = 0.002), ASA III-IV (P < 0.001), male sex (P = 0.037) and rectal surgery (P < 0.001). Morbidity was related to ASA III-IV (P = 0.004), male sex (P = 0.023) and rectal surgery (P = 0.002). None of the factors predicted 30-day mortality. CONCLUSION: Age and nutritional status were not independent determinants of morbidity or mortality. Pre-existing co-morbidity was an independent predictor of several outcomes.

Cross sectional imaging of truncal and quadriceps muscles relates to different functional outcomes in cancer.

INTRODUCTION: Following the consensus definition of cancer cachexia, more studies are using CT scan analysis of truncal muscles as a marker of muscle wasting. However, how CT-derived body composition relates to function, strength and power in patients with cancer is largely unknown. AIMS: We aimed to describe the relationship between CT truncal (L3) skeletal muscle index (SMI) and MRI quadriceps cross sectional area with lower limb strength, power and measures of complex function. METHODS: Patients undergoing assessment for potentially curative surgery for oesophagogastric or pancreatic cancer were recruited from the regional upper gastrointestinal (UGI) or hepatopancreaticobiliary (HPB) multi-disciplinary team meetings. Maximum Isometric Knee Extensor Strength (IKES) and Maximum Leg Extensor Power (Nottingham Power Rig) (LEP) were used as measures of lower limb performance. Both Sit to Stand (STS) and Timed Up and Go (TUG) were used as measures of global complex muscle function. Muscle SMI was measured from routine CT scans at the level of the third lumbar vertebrae (L3) and MRI scan was used for the assessment of quadriceps muscles. Linear regression analysis was performed for CT SMI or MRI quadriceps as a predictor of each measure of performance. RESULTS: Forty-four patients underwent assessment. Height and weight were significantly related to function in terms of quadriceps power, while only weight was associated with strength (P < 0.001). CT SMI was not related to measures of quadriceps strength or power but had significant association with more complex functional measures (P = 0.006, R2 = 0.234 and 0.0019, R2 = 0.175 for STS and TUG respectively). In comparison, both gross and fat-subtracted measures of quadriceps muscle mass from MRI were significantly correlated with quadriceps strength and power (P < 0.001), but did not show any significant association with complex functional measures. CONCLUSION: CT SMI and MRI quadriceps have been shown to reflect different aspects of functional ability with CT SMI being a marker of global muscle function and MRI quadriceps being specific to quadriceps power and strength. This should therefore be considered when choosing outcome measures for trials or definitions of muscle mass and function.

Variation in dermcidin expression in a range of primary human tumours and in hypoxic/oxidatively stressed human cell lines.

Dermcidin acts as a survival factor in a variety of cancer cell lines under hypoxia or oxidative stress. The aim of this study was to evaluate dermcidin expression in cell lines following simulation of tumour microenvironmental conditions and in a range of primary tumours. Tumour tissues were collected from patients with oesophageal (28 samples), gastric (20), pancreatic (five), bile duct (one) and prostatic (52) carcinomas as well as 30 benign tissue samples, for assessment of dermcidin mRNA levels using real-time PCR. Dermcidin expression was assessed in prostatic and pancreatic cancer cell lines, with and without induction of hypoxia or oxidative stress. Dermcidin mRNA expression was very low or absent in both unstressed and stressed prostate cell lines. None of the primary prostate tissue, benign or malignant, expressed dermcidin mRNA. Only two (4%) of the gastro-oesophageal cancer samples expressed moderate quantities of dermcidin mRNA. However, three (60%) of the pancreatic cancer samples and the single cholangiocarcinoma specimen had moderate/high levels of dermcidin expression. Of the two pancreatic cancer cell lines, one expressed dermcidin moderately but neither showed a response to hypoxia or oxidative stress. Expression of dermcidin in human primary tumours appears highly variable and is not induced substantially by hypoxia/oxidative stress in cell line model systems. The relationship of these findings to dermcidin protein levels and cell survival remains to be determined.

Cancer cachexia: developing multimodal therapy for a multidimensional problem.

Cancer cachexia is a multi-factorial syndrome that encompasses a spectrum from early weight loss (pre-cachexia) to a state of severe incapacity incompatible with life. The molecular basis of the syndrome in animal models (based on host-tumour cell interaction, the neuro-hormonal control of appetite and the hypertrophy/atrophy pathways that govern muscle-wasting) has provided a new raft of biomarkers and therapeutic targets. Key defining features of cachexia in humans (weight loss, reduced food intake and systemic inflammation) now provide not only a framework for classification but also a rationale for targets for therapeutic intervention. The role of age and immobility in muscle-wasting also provides a rationale for the nature of nutritional support in cachexia. There is now a substantive evidence that multimodal approaches that address these key issues can stabilise and even improve the nutritional status, function and quality of life of at least a proportion of advanced cancer patients. Novel biomarkers for patient stratification and more specific techniques for the estimation of muscle mass and physical activity level herald a new era in trial design. The current evidence-base justifies new enthusiasm for the design of complex intervention studies in the management of cancer cachexia.

Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection.

BACKGROUND: Accelerated recovery from surgery has been achieved when patients are managed within a multimodal Enhanced Recovery After Surgery (ERAS) protocol. This study evaluated the benefit of an ERAS programme for patients undergoing liver resection. METHODS: The ERAS protocol of epidural analgesia, early oral intake and early mobilization was studied prospectively in a consecutive series of 61 patients. Outcomes were compared with those in a consecutive series of 100 patients who underwent liver resection before the start of the study. Endpoints were postoperative length of hospital stay, postoperative resumption of oral intake, readmissions, morbidity and mortality. RESULTS: Fifty-six patients (92 per cent) in the ERAS group tolerated fluids within 4 h of surgery and a normal diet on day 1 after surgery. Median hospital stay, including readmissions, was 6.0 days compared with 8.0 days in the control group (P < 0.001). There were no significant differences in rates of readmission (13 and 10.0 per cent respectively), morbidity (41 and 31.0 per cent) and mortality (0 and 2.0 per cent) between ERAS and control groups. CONCLUSION: The ERAS fast-track protocol is safe and effective for patients undergoing liver resection. It allows early oral intake, promotes faster postoperative recovery and reduces hospital stay.

Preoperative conditioning with oral carbohydrate loading and oral nutritional supplements can be combined with mechanical bowel preparation prior to elective colorectal resection.

OBJECTIVE: Preoperative conditioning with oral fluid and carbohydrate (CHO) loading allows the patient to undergo surgery in the fed state and is associated with reduced postoperative insulin resistance. Further benefit may accrue from oral nutritional supplements (ONS) to counteract the fasting associated with mechanical bowel preparation (MBP). In this study we assess the ability to prescribe, dispense and have patients comply with a protocol combining preoperative ONS and CHO/fluid loading during MBP. METHOD: One hundred and forty-seven patients undergoing elective left colonic or rectal resection were recruited to an Enhanced Recovery after Surgery (ERAS) programme. All patients were prescribed MBP (2 sachets Picolax). On the daytime prior to surgery, eligible patients were prescribed 2 x 200 ml of ONS (Fortijuice, Nutricia) and in the evening 800 ml oral CHO/fluid loading (Preop(R), Nutricia,). Patients were prescribed a further 400 ml of oral/CHO/fluid on the morning of surgery 2 h prior to induction of anaesthesia. Protocol compliance was audited prospectively. RESULTS: One hundred and forty-seven patients received MBP. Twenty-three patients were ineligible for oral CHO/fluid loading [diabetes (n = 22), allergy to lemon flavoured drinks (n = 1)]. Fourteen patients did not receive the preoperative CHO drinks due to failure to prescribe (n = 8) or dispense (n = 6). One hundred and ten patients were dispensed the combined ONS and CHO/fluid loading regimen, compliance rates were 83% with ONS, 80% with CHO/fluid loading and 74% with both. CONCLUSION: Approximately 74% of patients undergoing MBP can comply with preoperative conditioning with ONS and CHO/fluid loading. Prescription and dispensing requires close attention to detail.

Clinical prognostic scoring system to aid decision-making in gastro-oesophageal cancer.

BACKGROUND: Accurate prediction of prognosis in gastro-oesophageal cancer remains challenging. The aim of this study was to develop a robust model for outcome prediction. METHODS: The study included 220 patients with gastric or oesophageal cancer newly diagnosed over a 2-year period. Patients were staged and underwent treatment following discussion at a multidisciplinary team (MDT) meeting. Clinical and investigative variables were collected, including performance and nutritional status, and serum C-reactive protein (CRP) level. Primary endpoints were death within 12 and 24 months. RESULTS: Overall median survival was 13 months. Advanced clinical stage (P < 0.001), reduced performance score (P < 0.001), weight loss exceeding 2.75 per cent per month (P = 0.026) and serum CRP concentration above 5 mg/l (P = 0.031) were identified as independent prognostic indicators in multivariable analysis. A prognostic score was constructed using these four variables to estimate a probability of death. Applying the model gave an area under the receiver-operator characteristic curve of 0.84 and 0.85 for prediction of death at 12 and 24 months respectively (both P < 0.001). CONCLUSION: This model accurately estimated the probability of death within 12 and 24 months. This may aid the MDT decision-making process.

Prediction of 90 Day and Overall Survival after Chemoradiotherapy for Lung Cancer: Role of Performance Status and Body Composition.

AIMS: If appropriate patients are to be selected for lung cancer treatment, an understanding of who is most at risk of adverse outcomes after treatment is needed. The aim of the present study was to identify predictive factors for 30 and 90 day mortality after chemoradiotherapy (CRT), and factors that were prognostic for overall survival. MATERIALS AND METHODS: A retrospective cohort study of 194 patients with lung cancer who had undergone CRT in South East Scotland from 2008 to 2010 was undertaken. Gender, age, cancer characteristics, weight loss, body mass index (BMI), performance status (Eastern Cooperative Oncology Group; ECOG) and computed tomography-derived body composition variables were examined for prognostic significance using Cox's proportional hazards model and logistic regression. RESULTS: The median overall survival was 19 months (95% confidence interval 16.3, 21.7). Four of 194 patients died within 30 days of treatment completion, for which there were no independent predictive variables; 22/194 (11%) died within 90 days of treatment completion. BMI < 20 and ECOG performance status ≥2 were independent predictors of death within 90 days of treatment completion (P = 0.001 and P = 0.004, respectively). Patients with either BMI < 20 or ECOG performance status ≥ 2 had an odds ratio of death within 90 days of 5.97 (95% confidence interval 2.20, 16.19), rising to an odds ratio of 13.27 (1.70, 103.47) for patients with both BMI < 20 and ECOG performance status ≥ 2. Patients with low muscle attenuation had significantly reduced overall survival (P = 0.004); individuals with low muscle attenuation had a median survival of 15.2 months (95% confidence interval 12.7, 17.7) compared with 23.0 months (95% confidence interval 18.3, 27.8) for those with high muscle attenuation, equating to a hazard ratio of death of 1.62 (95% confidence interval 1.17, 2.23, P = 0.003). CONCLUSION: Poor performance status, low BMI and low muscle attenuation identify patients at increased risk of premature death after CRT. Risk factors for adverse outcomes should inform personalised discussions with patients about the potential harms as well as the intended benefits of treatment.

The molecular mechanisms of skeletal muscle wasting: implications for therapy.

Skeletal muscle wasting is an important systemic manifestation of a wide range of diseases, including trauma, sepsis and cancer. The clinical consequences of muscle wasting undoubtedly include significant patient morbidity and worsened survival. Recently, there has been important progress in our understanding of the molecular mechanisms behind muscle wasting. In this review, the common systemic mediators, intracellular signalling pathways and effector mechanisms of skeletal muscle wasting are discussed with particular reference to different models of wasting and the development of novel therapeutic strategies.