Does prehabilitation modify muscle mass in patients with rectal cancer undergoing neoadjuvant therapy? A subanalysis from the REx randomised controlled trial.

BACKGROUND: Patients with rectal cancer who present with sarcopenia (low muscle mass) are at significantly greater risk of postoperative complications and reduction in disease-free survival. We performed a subanalysis of a randomised controlled study [the REx trial; www.isrctn.com ; 62859294] to assess the potential of prehabilitation to modify muscle mass in patients having neoadjuvant chemoradiotherapy (NACRT). METHODS: Patients scheduled for NACRT, then potentially curative surgery (August 2014-March 2016) had baseline physical assessment and psoas muscle mass measurement (total psoas index using computed tomography-based measurements). Participants were randomised to either the intervention (13-17-week telephone-guided graduated walking programme) or control group (standard care). Follow-up testing was performed 1-2 weeks before surgery. RESULTS: The 44 patients had a mean age of 66.8 years (SD 9.6) and were male (64%); white (98%); American Society of Anesthesiologists class 2 (66%); co-morbid (58%); overweight (72%) (body mass index ≥ 25 kg/m2). At baseline, 14% were sarcopenic. At follow-up, 13 (65%) of patients in the prehabilitation group had increased muscle mass versus 7 (35%) that experienced a decrease. Conversely, 16 (67%) controls experienced a decrease in muscle mass and 8 (33%) showed an increase. An adjusted linear regression model estimated a mean treatment difference in Total Psoas Index of 40.2mm2/m2 (95% CI - 3.4 to 83.7) between groups in change from baseline (p = 0.07). CONCLUSIONS: Prehabilitation improved muscle mass in patients with rectal cancer who had NACRT. These results need to be explored in a larger trial to determine if the poorer short- and long-term patient outcomes associated with low muscle mass can be minimised by prehabilitation.

Comparison of the paper-based and electronic versions of the Dermatology Life Quality Index: evidence of equivalence.

BACKGROUND: The use of patient-reported outcome measures in electronic format has been increasing. However, these formats are usually not validated or compared with the original paper-based formats, so there is no evidence that they are completed in the same way. OBJECTIVES: To compare the conventional paper version with a web-based application (iPad® ) version of the Dermatology Life Quality Index (DLQI) to assess equivalence of scores. METHODS: The study employed a randomized crossover design using a within-subjects comparison of the two formats of the questionnaire. International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines were followed. Participants aged over 18 years with any confirmed skin condition were recruited from a teaching hospital dermatology outpatient clinic. Expected intraclass correlation coefficient (ICC) was 0·9 (α = 0·05). RESULTS: A total of 104 patients were recruited, median age 53·5 years (interquartile range 37·3-67·8; 43% male). The ICC showed high concordance between the total DLQI scores from paper and iPad versions (ICC 0·98; 95% confidence interval 0·97-0·99). Patients took a median of 78 s to complete the electronic version and 73 s for paper (P = 0·008): 76% preferred the electronic version and perceived completion to take a shorter time. CONCLUSIONS: There is high concordance and thus equivalence between the iPad and paper versions of the DLQI, with an ICC of 0·98, and a clear patient preference for the iPad version.

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.

Risk factors, complications and survival after upper abdominal surgery: a prospective cohort study.

BACKGROUND: Preoperative weight loss and abnormal serum-albumin have traditionally been associated with reduced survival. More recently, a correlation between postoperative complications and reduced long-term survival has been reported and the significance of the relative proportion of skeletal muscle, visceral and subcutaneous adipose tissue has been examined with conflicting results. We investigated how preoperative body composition and major non-fatal complications related to overall survival and compared this to established predictors in a large cohort undergoing upper abdominal surgery. METHODS: From 2001 to 2006, 447 patients were included in a Norwegian multicenter randomized controlled trial in major upper abdominal surgery. Patients were now, six years later, analyzed as a single prospective cohort and overall survival was retrieved from the National Population Registry. Body composition indices were calculated from CT images taken within three months preoperatively. RESULTS: Preoperative serum-albumin <35 g/l (HR = 1.52, p = 0 .014) and weight loss >5 % (HR = 1.38, p = 0.023) were independently associated with reduced survival. There was no association between any of the preoperative body composition indices and reduced survival. Major postoperative complications were independently associated with reduced survival but only as long as patients who died within 90 days were included in the analysis. CONCLUSIONS: Our study has confirmed the robust significance of the traditional indicators, preoperative serum-albumin and weight loss. The body composition indices did not prove beneficial as global indicators of poor prognosis in upper abdominal surgery. We found no association between non-fatal postoperative complications and long-term survival.

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.

Systematic review and meta-analysis of continuous local anaesthetic wound infiltration versus epidural analgesia for postoperative pain following abdominal surgery.

BACKGROUND: Local anaesthetic wound infiltration techniques reduce opiate requirements and pain scores. Wound catheters have been introduced to increase the duration of action of local anaesthetic by continuous infusion. The aim was to compare these infiltration techniques with the current standard of epidural analgesia. METHODS: A meta-analysis of randomized clinical trials (RCTs) evaluating wound infiltration versus epidural analgesia in abdominal surgery was performed. The primary outcome was pain score at rest after 24 h on a numerical rating scale. Secondary outcomes were pain scores at rest at 48 h, and on movement at 24 and 48 h, with subgroup analysis according to incision type and administration regimen(continuous versus bolus), opiate requirements, nausea and vomiting, urinary retention, catheter-related complications and treatment failure. RESULTS: Nine RCTs with a total of 505 patients were included. No differences in pain scores at rest 24 h after surgery were detected between epidural and wound infiltration. There were no significant differences in pain score at rest after 48 h, or on movement at 24 or 48 h after surgery. Epidural analgesia demonstrated a non-significant a trend towards reduced pain scores on movement and reduced opiate requirements. There was a reduced incidence of urinary retention in the wound catheter group. CONCLUSION: Within a heterogeneous group of RCTs, use of local anaesthetic wound infiltration was associated with pain scores comparable to those obtained with epidural analgesia. Further procedure-specific RCTs including broader measures of recovery are recommended to compare the overall efficacy of epidural and wound infiltration analgesic techniques.

Long-term renal outcomes of consecutive patients undergoing open type IV thoracoabdominal aneurysm repair.

OBJECTIVE: To evaluate long-term renal outcomes after open type IV thoracoabdominal aneurysm (TAAA) repair. DESIGN: Retrospective analysis of a prospectively collected database of consecutive operated non-ruptured type IV TAAAs (2007-2011). METHODS: Renal function was analysed by serum creatinine concentration, estimated glomerular filtration rate (eGFR) and Kidney Disease Outcomes Quality Initiative (KDOQI) stage. The primary outcome was the change in creatinine concentration from before surgery to defined time points after surgery: peak postoperative; discharge; at follow-up (>1 year postoperatively). Secondary outcomes were change in eGFR, change in KDOQI stage, dialysis requirement, and 30-day mortality. RESULTS: Between 2007 and 2011, 53 open type IV TAAA repairs were performed. Median creatinine levels significantly increased in the immediate postoperative period, but returned to baseline by discharge. Thirteen patients (28.2%) had an improvement in follow-up eGFR of at least 20% compared with pre-operative eGFR or improved by one KDOQI stage. Twelve patients (26.1%) had a decline in eGFR of at least 20% or one KDOQI stage at follow-up. Three patients (7.5%) required temporary dialysis and one patient (1.9%) required permanent dialysis. The 30-day mortality was 1.9%. CONCLUSIONS: This study demonstrates acceptable renal outcomes following open type IV TAAA repair. Open type IV repair remains the standard against which newer techniques should be compared.

Mediating effects of inequitable gender norms on intimate partner violence and contraceptive use in a cluster randomized control trial in Niger: A causal inference mediation analysis.

Background: Gender inequity, a deeply-rooted driver of poor health globally, is expressed in society through gender norms, the unspoken rules that govern gender-related roles and behavior. The development of public health interventions focused on promoting equitable gender norms are gaining momentum internationally, but there remain critical gaps in the evidence about how these interventions are working to change behavioral outcomes. Methods: A four-arm cluster randomized control trial (cRCT) was conducted to evaluate the effects of the Reaching Married Adolescents in Niger (RMA) intervention on modern contraceptive use and intimate partner violence (IPV) among married adolescent girls and their husbands in Dosso, Niger (T1: 1042 dyads; 24 mos. follow-up: 737 dyads, 2016-2019). This study seeks to understand if changes in perceived inequitable gender norms among husbands are the mechanism behind effects on modern contraceptive use and IPV. We estimated natural direct and indirect effects via these gender norms using inverse odds ratio weighting. An intention-to-treat approach and a difference-in-differences estimator in a hierarchical linear probability model was used to estimate prevalence differences, along with bootstrapping to estimate confidence intervals. Results: The total effects of the RMA small group intervention (Arm 2) is estimated to be an 8% reduction in prevalence of IPV [95% CI: -0.18, 0.01]. For this arm, the natural indirect effect through gender inequitable social norms is associated with a 2% decrease (95% CI: -0.07, 0.12), accounting for 22.3% of this total effect, and the natural direct effect with a 6% decrease (95% CI: -0.20, -0.02) in IPV. Of the total effect of the RMA household visit intervention (Arm 1) on contraceptive use (20% increase), indirect effects via inequitable gender norms were associated with an 11% decrease (95% CI: -0.18, -0.01) and direct effects with a 32% increase (95% CI: 0.13, 0.44) in contraceptive use. For the combination arm, of the total effects on contraceptive use (19% increase), indirect effects were associated with a 9% decrease (95% CI: -0.20, 0.02) and direct effects with a 28% increase (95% CI: 0.12, 0.46). Conclusion: The present study contributes experimental evidence that the small group RMA intervention reduced IPV partially via reductions in perceived inequitable gender norms among husbands. Evidence also suggests that increases in perceived inequitable gender norms resulted in decreased contraceptive use among those receiving the household visit intervention component. Not only do these results open the "black box" around how the RMA small group intervention may create behavior change to help inform its future use, they provide evidence supporting behavior change theories and frameworks that postulate the importance of changing underlying social norms in order to reduce IPV and increase modern contraceptive use.

Clinical effectiveness of transversus abdominis plane (TAP) block in abdominal surgery: a systematic review and meta-analysis.

AIM: Reduced opioid use in the immediate postoperative period is associated with decreased complications. This study aimed to determine the effect of transversus abdominis plane (TAP) block on morphine requirements 24 h after abdominal surgery. Secondary outcomes included the effect of TAP block on morphine use 48 h after surgery, incidence of postoperative nausea and vomiting (PONV) and impact on reported pain scores (visual analogue scale). METHOD: A systematic review of the literature was conducted for randomised controlled trials (RCTs) evaluating the effects of TAP block in adults undergoing abdominal surgery. For continuous data, weighted mean differences (WMD) were formulated; for dichotomous data, odds ratios (OR) were calculated. Results were produced with a random effects model with 95% confidence intervals (CI). RESULTS: Nine studies, including published and unpublished data, containing a total of 413 patients were included. Of these 205 received a TAP block and 208 a placebo. Cumulative morphine utilization was statistically significantly reduced at 24 h. [WMD=23.71mg (38.66-8.76); P=0.002] and 48h [WMD=38.08mg (18.97-57.19); P<0.0001] in patients who received a TAP block and the incidence of PONV was significantly reduced [OR=0.41(0.22-0.74); P=0.003]. There was a nonsignificant reduction in the visual analogue scales of postoperative pain [WMD=0.73cm (1.84-0.38), P=0.2]. There were no reported adverse events following TAP block. CONCLUSION: Transversus abdominis plane block is safe, reduces postoperative morphine requirements, nausea and vomiting and possibly the severity of pain after abdominal surgery. It should be considered as part of a multimodal approach to anaesthesia and enhanced recovery in patients undergoing abdominal surgery.

Autologous breast reconstruction using the immediately lipofilled extended latissimus dorsi flap.

BACKGROUND: The latissimus dorsi flap is a popular choice for autologous breast reconstruction. To dramatically improve volume, we report our experience of using the immediately lipofilled extended latissimus dorsi (ELD) flap and show it as a valid option for autologous breast reconstruction. METHODS: Patients undergoing the procedure between December 2013 and June 2016 were included. Demographic, clinical and operative factors were analysed, together with in-hospital morbidity and duration of postoperative hospital stay. RESULTS: A total of 71 ELD flaps with immediate lipofilling were performed. Forty-five reconstructions were immediate and the remaining 26 delayed. Median (range) volume of autologous fat injected immediately was 171 ml (40-630 ml). Contralateral reductions were performed in 25 patients with the median reduction volume 185 g (89-683 g). Median duration of admission was 6.5 (3-18) days and patients were followed up for 12 months (1-37). Three total flap failures occurred and had to be excised (4%). One haematoma occurred requiring drainage (1%). Signs of infection requiring intravenous antibiotics occurred in five patients (7%). In 5 patients wound dehiscence occurred, and only two of these required resuturing (3%). In total, 7 patients developed a seroma requiring repeated drainage (10%). Three reconstructions experienced mild mastectomy flap necrosis with no needing reoperation (4%). CONCLUSIONS: Our experience represents the largest series to date and shows that in carefully selected patients the technique is safe, can avoid the requirement for implants, and has the potential to streamline the reconstructive journey.

Health-Related Quality of Life, Cachexia and Overall Survival After Major Upper Abdominal Surgery: A Prospective Cohort Study.

BACKGROUND AND AIMS: Major upper abdominal surgery is often associated with reduced health-related quality of life and reduced survival. Patients with upper abdominal malignancies often suffer from cachexia, represented by preoperative weight loss and sarcopenia (low skeletal muscle mass) and this might affect both health-related quality of life and survival. We aimed to investigate how health-related quality of life is affected by cachexia and how health-related quality of life relates to long-term survival after major upper abdominal surgery. MATERIALS AND METHODS: From 2001 to 2006, 447 patients were included in a Norwegian multicenter randomized controlled trial in major upper abdominal surgery. In this study, six years later, these patients were analyzed as a single prospective cohort and survival data were retrieved from the National Population Registry. Cachexia was derived from patient-reported preoperative weight loss and sarcopenia as assessed from computed tomography images taken within three months preoperatively. In the original trial, self-reported health-related quality of life was assessed preoperatively at trial enrollment and eight weeks postoperatively with the health-related quality of life questionnaire Short Form 36. RESULTS: A majority of the patients experienced improved mental health-related quality of life and, to a lesser extent, deteriorated physical health-related quality of life following surgery. There was a significant association between preoperative weight loss and reduced physical health-related quality of life. No association between sarcopenia and health-related quality of life was observed. Overall survival was significantly associated with physical health-related quality of life both pre- and postoperatively, and with postoperative mental health-related quality of life. The association between health-related quality of life and survival was particularly strong for postoperative physical health-related quality of life. CONCLUSION: Postoperative physical health-related quality of life strongly correlates with overall survival after major upper abdominal surgery.

Should patients with early breast cancer still be offered the choice of breast conserving surgery or mastectomy?

Breast conserving therapy (BCT) for breast cancer aims to achieve long-term local disease control with reduced local morbidity. BCT has similar long-term survival outcomes to mastectomy in patients with early breast cancer and recent studies have reported similar rates of recurrence compared with mastectomy. An increasing number of studies have shown improved overall survival among women treated with BCT regardless of cancer phenotype compared with mastectomy. Despite BCT being at least equivalent in outcome to mastectomy many women with small breast cancers continue to be treated by mastectomy and several studies in the last decade have shown a trend of increasing numbers of unilateral and bilateral mastectomies. The advent of increasingly effective neoadjuvant treatment has allowed even more women to have breast conservation. Not only has neoadjuvant therapy been shown to increase the rates of BCT, it does so without increasing in breast recurrence rates. Patients who are suitable for BCT should be advised that BCT is the best treatment option for them. They should be informed that not only does it confer at least equivalent survival and local recurrence rates but that compared with mastectomy it has the advantages of less complications, better quality of life and many less operations if reconstructive surgery is performed. It may no longer be appropriate to offer women suitable for BCT the choice of mastectomy or BCT.

Melatonin potentiates cisplatin-induced apoptosis and cell cycle arrest in human lung adenocarcinoma cells.

OBJECTIVES: Melatonin produces anti-cancer effects via several mechanisms, including by induction of apoptosis. In this way, it has been shown to be of use, in combination with chemotherapeutic drugs, for cancer treatment. The study described here has evaluated effects of melatonin on cytotoxicity, apoptosis and cell cycle arrest induced with the chemotherapeutic agent cisplatin, in human lung adenocarcinoma cisplatin-sensitive cell line (SK-LU-1), which previously had only limit data. MATERIALS AND METHODS: Cells of the SK-LU-1 line were treated with melatonin alone at 1-5 mM concentration or cisplatin alone 10-200 µM, for 48 h in culture. Cytotoxicity was measured by MTT reduction assay. Apoptosis induction was detected by annexin V/PI staining using flow cytometric analysis and DAPI nuclear staining. Change in mitochondrial membrane potential (ΔΨm) was quantified using DiOC6(3) reagent and activities of caspases-3/7 were also investigated. DNA fractions were measured using propidium iodide (PI) staining. RESULTS: Melatonin or cisplatin alone had 50% (IC50 ) cytotoxicity at 5 mM or 34 µM concentrations respectively. Combination of 1 or 2 mM melatonin and cisplatin significantly augmented cytotoxicity of cisplatin by reducing its IC50 to 11 and 4 µM, respectively. Consistently, combined treatment increased population of apoptotic cells by elevating mitochondrial membrane depolarization, activating caspases-3/7 and inducing cell cycle arrest in the S phase, compared to treatment with cisplatin alone. CONCLUSION: These data demonstrate that melatonin enhanced cisplatin-induced cytotoxicity and apoptosis in SK-LU-1 lung cancer cells. SK-LU-1 cell population growth inhibition was mediated by cell cycle arrest in the S phase. These findings suggest that melatonin has the potential to be used for NSCLC treatment in combination with a chemotherapeutic agent such as cisplatin.

The role of body composition evaluation by computerized tomography in determining colorectal cancer treatment outcomes: a systematic review.

BACKGROUND: Strong evidence indicates that excessive adipose tissue distribution or reduced muscle influence short-, mid-, and long-term colorectal cancer outcomes. Computerized tomography-based body composition (CTBC) analysis quantifies this in a reproducible parameter. We reviewed the evidence linking computerized tomography (CT) based quantification of BC with short and long-term outcomes in colorectal cancer (CRC). METHODS: A systematic review was performed according to PRISMA guidelines. A literature search was performed by two independent reviewers on all studies that included CTBC analysis in patients undergoing treatment for CRC using Medline, EMBASE, Google Scholar, and Cochrane databases. Outcomes of interest included short-term recovery, oncological outcomes, and survival. RESULTS: Seventy-five studies were identified; sixteen met the inclusion criteria. None were randomized controlled trials and all were cohort studies of small sample size. Several types of CTBC image analysis software were identified, reporting subcutaneous, visceral and skeletal muscle tissues. Visceral obesity and reduced muscle mass were categorical parameters quantified by CTBC analysis. Due to marked study heterogeneity, quantitative data synthesis was not possible. High visceral adipose tissue and reduced skeletal muscle resulted in poorer short-term recovery (eleven studies), poorer oncological outcomes (six studies), and poorer survival (six studies). CONCLUSIONS: CTBC techniques may be linked to outcomes in colorectal cancer patients, however larger studies are required. CTBC based assessment may allow early identification of high-risk patients, allowing early optimisation of patients undergoing cancer treatments.

Glutamatergic projections from the rostral hypothalamus to the periaqueductal grey.

Retrograde transport of fluorescent latex microspheres was combined with immunocytochemistry for glutamate to determine the organization of the projections from glutamate-containing neurones in the rostral hypothalamus to the different subdivisions of the periaqueductal grey (PAG). Double-labelled neurones, i.e. neurones immunoreactive for glutamate and projecting to the PAG, were found throughout the rostral hypothalamus. There were no apparent differences, however, in the origins of presumed glutamatergic projections from the rostral hypothalamus to the different subdivisions of the PAG.

Disseminating medical knowledge: the PROforma approach.

Medical knowledge is traditionally disseminated via the publication of documents and through participation in clinical practice. Information technology offers to extend both modes of dissemination, via electronic publishing and virtual reality training, for example. AI promises even more radical changes through the possibility of publishing clinical expertise in the form of expert systems, which assist patient care through active decision support and workflow management. PROforma is a knowledge representation language that is designed to support this new mode of dissemination. It is based on an intuitive model of the processes of care and well-understood logical semantics. This paper provides a description of the language and associated software tools, and discusses its potential roles in, and implications for, medical knowledge publishing.

PROforma: a general technology for clinical decision support systems.

The need for flexible and well understood knowledge representations which are capable of capturing clinical guidelines and protocols for decision support systems is widely recognised. The PROforma method for specifying clinical guidelines and protocols comprises a graphical notation for their design, and a formal knowledge representation language to enable them to be executed by a computer to support the management of medical procedures and clinical decision making. PROforma technology consists of a graphical knowledge editor for the creation of guidelines, and an enactment engine for testing and executing them. This paper provides an overview of the motivation and structure of PROforma, and illustrates its use in the development of clinical applications.

Immunomodulatory effect of melatonin in SK-LU-1 human lung adenocarcinoma cells co-cultured with peripheral blood mononuclear cells.

OBJECTIVES: The anti-cancer potential of melatonin has been examined using a variety of experimental approaches. Melatonin immunomodulatory action was evaluated against the lung cancer cell line SK-LU-1, in co-culture with human peripheral blood mononuclear cells (PBMC). MATERIALS AND METHODS: Melatonin was tested on the cell line only after 24 h incubation (direct effect), and on the co-culture system of SK-LU-1 and PBMC to investigate any indirect effect. Apoptotic induction of the cancer cells was assessed using annexin V/PI staining with flow cytometric analysis for membrane alteration. Intracellular superoxide anion (O2 (•-) ) and hydrogen peroxide (H2 O2 ) for intracellular oxidative stress and glutathione (GSH) for intracellular anti-oxidation were measured with specific fluorescence probes. DNA fractions were measured employing propidium iodide (PI) fluorescence staining. RESULTS: High doses of melatonin were directly toxic to SK-LU-1 cells, while PBMC-mediated indirect effect occurred after moderate doses (1 µm). Under co-culture conditions, increases in apoptotic cell death, increase in oxidative stress by reduction of GSH and cell cycle arrest in G0 /G1 in SK-LU-1 cells, were observed as the immunomodulatory effect of melatonin. CONCLUSION: Melatonin had indirect effects on lung cancer cells by enhancement of immunomodulatory effects, but further studies of mechanism(s) involved are needed.

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.

Muscle wasting in cancer.

Skeletal muscle loss appears to be the most significant clinical event in cancer cachexia and is associated with a poor outcome. With regard to such muscle loss, despite extensive study in a range of models, there is ongoing debate as to whether a reduction in protein synthesis, an increase in degradation or a combination of both is the more relevant. Each model differs in terms of key mediators and the pathways activated in skeletal muscle. Certain models do suggest that decreased synthesis accompanied by enhanced protein degradation via the ubiquitin proteasome pathway (UPP) is important. Murine models tend to involve rapid development of cachexia and may represent more acute muscle atrophy rather than the chronic wasting observed in humans. There is a paucity of human data both at a basic descriptive level and at a molecular/mechanism level. Progress in treating the human form of cancer cachexia can only move forwards through carefully designed large randomised controlled clinical trials of specific therapies with validated biomarkers of relevance to underlying mechanisms. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.