REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)-Protocol for a prospective characterisation study of patients with incurable cancer.

INTRODUCTION: There is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services. METHODS: Routine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires. DISCUSSION: This study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the 'symptom phenotype' and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition.

Power Comparisons and Clinical Meaning of Outcome Measures in Assessing Treatment Effect in Cancer Cachexia: Secondary Analysis From a Randomized Pilot Multimodal Intervention Trial.

Background: New clinical trials in cancer cachexia are essential, and outcome measures with high responsiveness to detect meaningful changes are crucial. This secondary analysis from a multimodal intervention trial estimates sensitivity to change and between treatment effect sizes (ESs) of outcome measures associated with body composition, physical function, metabolism, and trial intervention. Methods: The study was a multicenter, open-label, randomized pilot study investigating the feasibility of a 6-week multimodal intervention [exercise, non-steroidal anti-inflammatory drugs, and oral nutritional supplements containing polyunsaturated fatty acids (n-3 PUFAs)] vs. standard cancer care in non-operable non-small-cell lung cancer and advanced pancreatic cancer. Body composition measures from computerized tomography scans and circulating biomarkers were analyzed. Results: Forty-six patients were randomized, and the analysis included 22 and 18 patients in the treatment and control groups, respectively. The between-group ESs were high for body weight (ES = 1.2, p < 0.001), small for body composition and physical function [handgrip strength (HGS)] measures (ES < 0.25), moderate to high for n-3 PUFAs and 25-hydroxyvitamin D (25-OH vitamin D) (ES range 0.64-1.37, p < 0.05 for all), and moderate for serum C-reactive protein (ES = 0.53, p = 0.12). Analysis within the multimodal treatment group showed high sensitivity to change for adiponectin (ES = 0.86, p = 0.001) and n-3 PUFAs (ES > 0.8, p < 0.05 for all) and moderate for 25-OH vitamin D (ES = 0.49, p = 0.03). In the control group, a moderate sensitivity to change for body weight (ES = -0.84, p = 0.002) and muscle mass (ES = -0.67, p = 0.016) and a high sensitivity to change for plasma levels of 25-OH vitamin D (ES = -0.88, p = 0.002) were found. Conclusion: Demonstrating high sensitivity to change and between treatment ES and body composition measures, body weight still stands out as a clinical and relevant outcome measure in cancer cachexia. Body composition and physical function measures clearly are important to address but demand large sample sizes to detect treatment group differences. Trial registration: ClinicalTrials.gov identifier: NCT01419145.

Cancer cachexia: rationale for the MENAC (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia) trial.

Cancer cachexia is a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support alone. Cachexia has a high prevalence in cancer and a major impact on patient physical function, morbidity and mortality. Despite the consequences of cachexia, there is no licensed treatment for cachexia and no accepted standard of care. It has been argued that the multifactorial genesis of cachexia lends itself to therapeutic targeting through a multimodal treatment. Following a successful phase II trial, a phase III randomised controlled trial of a multimodal cachexia intervention is under way. Termed the MENAC trial (Multimodal-Exercise, Nutrition and Anti-inflammatory medication for Cachexia), this intervention is based on evidence to date and consists of non-steroidal anti-inflammatory drugs and eicosapentaenoic acid to reduce inflammation, a physical exercise programme using resistance and aerobic training to increase anabolism, as well as dietary counselling and oral nutritional supplements to promote energy and protein balance. Herein we describe the development of this trial. TRIAL REGISTRATION NUMBER: NCT02330926.

An exploration of the hypothesis that testosterone is implicated in the psychological functioning of women with polycystic ovary syndrome (PCOS).

One of the diagnostic features of polycystic ovary syndrome (PCOS) is elevation of the androgen, testosterone. It is known that women with PCOS are more likely to suffer from psychological problems, especially anxiety and depression, than other women. However, little is known of how much of this is due to testosterone, and if so, what the mechanism(s) might be. This study explores the hypothesis that testosterone impacts women with PCOS both directly and indirectly, via testosterone currently in the bloodstream and through prenatal exposure. It is hypothesised that direct effects occur when testosterone acts directly upon receptors; indirect effects occur where the impact of testosterone is mediated via another variable; activational effects are ephemeral and are caused by testosterone in the bloodstream; organizational effects occur prenatally and cause permanent changes. Four pathways are hypothesised in this paper: 1/ a direct and activational pathway which improves mental rotation ability; 2/ an indirect and activational pathway, whereby distress is caused when the physiological symptoms of testosterone are experienced as embarrassing or otherwise disturbing; 3/ an indirect and organizational effect on mood, where elevated prenatal testosterone predisposes women with PCOS to low blood sugar levels and thus low mood; 4/ and finally, it is suggested that the pathway from biology to psychology can be travelled in reverse, with a direct activational effect of relaxation training on the reduction of adrenal androgens. Testing these hypotheses has important implications for our understanding of PCOS, and our ability to treat this condition more effectively.

A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.

BACKGROUND: Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy. METHODS: Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival. RESULTS: Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups. CONCLUSIONS: A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention.

Evidence base for multimodal therapy in cachexia.

PURPOSE OF REVIEW: The lack of success of unimodal treatment studies in cachexia and the growing awareness that multiple components are responsible for the development of cachexia have led to the view that cachexia intervention should include multimodal treatment. The aim of this article is to examine the evidence for multimodal treatment in the management of cancer cachexia. RECENT FINDINGS: There are some studies involving multimodal treatment that indicate significant effects on cachexia outcomes. There are, however, no randomized controlled trials to date that incorporate fully a structured exercise program, nutrition, good symptom treatment as well as drug treatment, to counteract the effects of altered metabolism. SUMMARY: The effectiveness of any drug intervention for cancer cachexia probably will only be maximized if incorporated into multimodal treatment. Further, cachexia treatment trials should also aim to include patients at an early phase in their cachexia trajectory and use validated outcome measures.

The hypoglycaemic and antihyperglycaemic effect of citrullus colocynthis fruit aqueous extract in normal and alloxan diabetic rabbits.

Effects of the aqueous, glycosidic, alkaloidal and saponin extracts of the rind of Citrullus colocynthis on the plasma glucose levels were investigated in normal rabbits, while the effects of saponin extract on the fasting plasma glucose levels were studied in alloxan induced diabetic rabbits. In normal rabbits, oral administration of aqueous extract (300 mg/kg) produced significant reduction in plasma glucose after 1 h and highly significant after 2,3 and 6 h. Phytochemical screening revealed that the rind of C. colocynthis and its aqueous extract contains tertiary and quaternary alkaloids, glycoside and saponin components. The hypoglycaemic effects of these components given orally at a dose (50 mg/kg) were studied in normoglycaemic rabbits. Result showed that the alkaloidal extract did not significantly lower the blood glucose levels from 132 mg/100 ml at 0 h to 120 mg/100 ml after 6 h, while the glycosidic extract significantly lowered the fasting glucose levels after 2 and 3 h and highly significant after 6 h. The effect was more pronounced with saponin extract, the saponin significantly lowered the fasting glucose levels after 1 and 2 h and highly significant (P<0.001) after 3 and 6 h. Graded doses (10, 15 and 20 mg/kg) of saponin extract, when given orally to alloxan diabetic rabbits, produced a significant reduction of plasma glucose concentration. These results suggest that the aqueous extract of the rind of C. colocynthis possesses a hypoglycaemic effect and its hypoglycaemic action could be attributed for more extent to the presence of saponin in addition to the presence of glycosidic components.

Acute intraperitoneal and oral toxicity of the leaf glycosidic extract of Trigonella foenum-graecum in mice.

The present study was carried out to determine the acute toxicity of the leaf glycosidic extract of Trigonealla foenum-graecum by estimation of its medium lethal dose (LD(50)) after oral and intraperitoneal administration to mice and also to identify the target organs for its possible toxic effects. The main target organ affected among the four organs studied (liver, kidney, stomach, small and large intestine) was the liver, where early degeneration with infiltration of mononuclear and mild hepatitis was found in some animals treated with toxic doses of glycosidic extract. It is concluded that the glycosidic extract of T. foenum-graecum leaves is considered to be safe and have minimal adverse effect.

Hypoglycaemic effect of aqueous extract of the leaves of Trigonella foenum-graecum in healthy volunteers.

The safety and efficacy of Trigonella foenum-graecum extract was investigated using 20 male volunteers aged 20-30 years. They were randomly treated with either 40 mg/kg aqueous extract powder in 10 mL distilled water or 10 mL distilled water in which coffee simulated the extract. The extract significantly lowered blood glucose level by 13.4% 4 hours after ingestion. A significant change of 14.1% was observed in potassium levels. No significant alteration in serum cholesterol, total serum protein and blood urea occurred. Approximately one-third experienced feelings of hunger, frequency of micturition or dizziness during the 24 hours after ingestion. The aqueous extract effectively reduced blood glucose in normal subjects safely. Its hypokalaemic effect merits further investigation.

Hypoglycaemic effect of aqueous extract of the leaves of Trigonella foenum-graecum in healthy volunteers

The safety and efficacy of Trigonella foenum-graecum extract was investigated using 20 male volunteers aged 20-30 years. They were randomly treated with either 40 mg/kg aqueous extract powder in 10 mL distilled water or 10 mL distilled water in which coffee simulated the extract. The extract significantly lowered blood glucose level by 13.4% 4 hours after ingestion. A significant change of 14.1% was observed in potassium levels. No significant alteration in serum cholesterol, total serum protein and blood urea occurred. Approximately one-third experienced feelings of hunger, frequency of micturition or dizziness during the 24 hours after ingestion. The aqueous extract effectively reduced blood glucose in normal subjects safely. Its hypokalaemic effect merits further investigation

Hypoglycaemic and antihyperglycaemic effects of Trigonella foenum-graecum leaf in normal and alloxan induced diabetic rats.

The aqueous and alcoholic extracts of Trigonella foenum-graecum leaf were tested for hypoglycaemic activity in normal and alloxan-diabetic rats. Graded amounts (0.06, 0.2, 0.5, 1 g/kg, i.p. and 1, 2, 8 g/kg, p.o.) of the aqueous extract of Trigonella foenum-graecum leaf when given to both normal and alloxan-diabetic rats, a significant reduction of blood glucose concentration was noticed. On the other hand ethanolic extract of Trigonella foenum-graecum leaf produced no reduction in blood glucose concentration in normal rats but intra-peritoneal administration of 0.8 g/kg of the ethanolic leaf extract to diabetic rats produced a significant reduction of blood glucose concentration (p < 0.02) at 2 and 24 h only. Intraperitoneal and oral acute toxicity (LD50) and target organ effects were studied for the aqueous extract of Trigonella leaf in mice. LD50 of i.p. and oral administration were 1.9 and 10 g/kg respectively. The main organ affected after i.p. administration of the aqueous extract was the liver while oral administration of the aqueous extract of Trigonella did not produce any sign of organ damage. These results suggest that the aqueous extract of Trigonella foenum-graecum leaves given both orally and intraperitoneally possesses a hypoglycaemic effect in normoglycaemic and alloxan induced hyperglycaemic rats.

In vivo 31P NMR study of early cellular responses to hyperosmotic shock in cultured glioma cells.

Cell volume regulation in the face of osmotic stress is a fundamental homeostatic activity, and is most critical in brain, which is spatially constrained. Despite the importance of this phenomenon, little is known about volume regulation in the brain, primarily because of the cellular heterogeneity in the tissue. We describe here simultaneous in vivo 31P nuclear magnetic resonance (NMR) measurements of cell volume, intracellular pH and phosphate metabolites during early responses to hyperosmotic stress in C6 glioma cells perfused in NMR-compatible bioreactors. Cell volume was measured using dimethyl methylphosphonate (DMMP) as a probe which has an intracellular NMR resonance shifted upfield from the extracellular resonance. The sensitivity of these measurements allowed 31P NMR spectra to be collected every 30 s. Following an increase in osmolarity from 320 to 480 mOsm by addition of NaCl to the perfusate, C6 glioma cells shrank to 67% of their original volume. We also observed a simultaneous increase of intracellular pH coincident with the decrease in cell volume. The signals from ATP decreased by 10%, but those from phosphocreatine (PCr) increased by 31% after hyperosmotic shock. However, correcting the ATP signals for the decrease in cell volume indicated that its intracellular concentrations increased after treatment. Signals from glycerophosphorylcholine (GPC) and glycerophosphorylethanolamine (GPE) were not changed significantly. This is the first in vivo report of early cellular responses monitored by NMR spectroscopy following hyperosmotic shock in cultured cells.