Reduction of the growth rate of the Walker 256 tumor in rats by rhodamine 6G together with hypoglycemia.

Previous attempts to use tumor energy metabolism as a target for antineoplastic therapy have used single agents aimed at inhibiting either glycolysis or oxidative phosphorylation. Since most tumor cells use both pathways for energy production, this approach is unlikely to succeed. The aim of this study was to simultaneously manipulate both sources of intracellular ATP to achieve more selective control of tumor growth. Rhodamine 6G (R6G) is a fluorochrome mitochondrial dye which inhibits oxidative phosphorylation. 3-Mercaptopicolinic acid inhibits gluconeogenesis and is a potent hypoglycemic agent in the fasting state. Dose-response relationships were established for R6G and 3-mercaptopicolinic acid, and a nontoxic dose of the compounds was selected for subsequent experiments. Thereafter, groups of rats (n = 7 per group) underwent s.c. implantation of Walker 256 carcinosarcoma. Following a 24-h fast each group received either saline, R6G (0.8 mg/kg), 3-mercaptopicolinic acid (40 mg/kg), or the combination given i.p. Seven days after tumor implantation animals were sacrificed, and tumors were exercised and weighed. Administration of R6G during a period of hypoglycemia significantly reduced the tumor growth rate when compared to control experiments (3.6 +/- 0.3 g cf. 7.1 +/- 0.7 g, mean +/- SE; P less than 0.05). In contrast, neither R6G nor the period of hypoglycemia alone significantly affected tumor growth. These results suggest that simultaneous manipulation of oxidative phosphorylation and glycolysis may be used to selectively inhibit tumor growth in vivo.

Influence of whole body protein turnover rate on resting energy expenditure in patients with cancer.

Whole body protein turnover and resting energy expenditure are measured simultaneously in weight stable and weight losing patients with lung (n = 22) or colorectal cancer (n = 38). These results were compared with those from weight stable and weight losing non-cancer controls (n = 22). Rates of whole body protein turnover were calculated from the plateau isotopic enrichment of urinary ammonia and urea following a primed, continuous, 24-h infusion of [15N]glycine. Resting energy expenditure was measured by indirect calorimetry. All groups of cancer patients had significantly elevated rates of whole body protein turnover (P less than 0.05) and synthesized, on average, 1.9 g/kg/day more protein compared with weight stable non-cancer controls. In contrast, the resting energy expenditure of cancer patients and controls was similar. Moreover, there was no correlation between individual rates of whole body protein turnover. Thus, although cancer patients had rates of whole body protein turnover which were 50-70% greater than controls, this did not result in a measurable increase in resting energy expenditure. The assumption that elevation of whole body protein turnover or resting energy expenditure causes weight loss in cancer patients must be an oversimplification. An acute phase protein response was observed in the majority of cancer patients. Although the presence of such an inflammatory response did not correlate with the rate of whole body protein turnover, the role of inflammatory mediators in the pathogenesis of disturbed protein metabolism in cancer patients merits further investigation.

The utilisation of peripherally-administered intravenous nutrient solutions.

The utilisation of three peripherally-administered intravenous nutritional regimens has been evaluated in 42 patients on the first four days following surgery for colorectal cancer. A standard dextrose-saline (DS) regimen (n = 16) has been compared with an amino-acid (AA) regimen (n = 12) and a regimen consisting of glucose, amino-acid and fat (GAF) (n = 14). Fat and carbohydrate oxidation was calculated pre- and post-operatively using indirect calorimetry. Patients receiving AA showed a fall in carbohydrate oxidation (p < 0.01) and a rise in fat oxidation (p < 0.05) post-operatively, whereas no significant changes in fat and carbohydrate oxidation occurred in the DS and GAF groups. Cumulative nitrogen balance (NB) for the first four post-operative days was significantly better (p < 0.01) in the AA group (-10.3 +/- 3.8 g; mean +/- s.e.m.) than in the DS group (-25.3 +/- 3.1 g), due to an improved NB in the AA group on the first and second days only. Cumulative NB in the GAF group (+7.7 +/- 2.3 g) was significantly better (p < 0.01) than in the other two groups. Where the provision of peripheral intravenous nutritional support is desired, the use of a combination of glucose, amino-acid and fat is recommended.

Comparison of various predictive formulae for the estimation of resting energy expenditure.

The accuracy of the Harris-Benedict (HB), Kleiber and Robertson-Reid predictive formulae and the Fleisch tables in estimating resting energy expenditure (REE) has been assessed in 114 cancer patients and 54 patients with nonmalignant illness. The effects of weight status and disease on the predictive ability of the formulae were assessed by comparison of the estimated REE value with that measured by indirect calorimetry. Underestimation of measured REE by greater than 10% occurred in 6-62% of patients, depending on the formula used. Weight loss did not affect predictive ability, whereas the presence of cancer resulted in inaccurate prediction of REE in female patients. Using a multiple comparison procedure, the Fleisch tables were the most accurate in all groups, while the HB formula was least accurate in male patients, irrespective of weight status or disease status. The use of predictive formulae and tables are inappropriate for the accurate estimation of REE in individual patients.

Palmitate turnover and its response to glucose infusion in weight-losing cancer patients.

Palmitate turnover in weight-stable control subjects (n = 4) and weight-losing patients with progressive malignant disease (n = 4) has been determined. Measurements were made after an overnight fast and during glucose infusion (3.5 mg/kg/min). Turnover rates were calculated from plateau isotopic enrichment of palmitate in plasma during a continuous infusion of 1-13C palmitate. Palmitate turnover was higher in the cancer group before (180%) and during glucose loading (170%) compared with the control group. Palmitate turnover was reduced during glucose administration by approximately 34% in both groups. Plasma concentration of insulin was decreased and of cortisol was increased in the cancer group compared with the control group before and during glucose infusion. We conclude that cancer patients with weight loss have increased rates of fatty acid turnover indicative of enhanced mobilisation of body fat stores. Altered plasma concentrations of insulin and cortisol may mediate this effect. Nonetheless, even at more advanced stages of cachexia cancer patients have normal control mechanisms for inhibiting fatty acid turnover following administration of carbohydrate.

Effect of megestrol acetate on weight loss, body composition and blood screen of gastrointestinal cancer patients.

Reduced food intake is probably the major cause of continuing weight loss in cancer patients. Therefore, agents which stimulate food intake may be of significant benefit to such patients. To examine this, a randomized double-blind placebo controlled study of megestrol acetate was carried out. 38 gastrointestinal cancer patients with weight loss (8-43% of pre-illness stable weight) were entered into the study. 26 were evaluable at 6 weeks and 21 at 12 weeks. Clinical details, serum biochemistry and haematology were examined at 6 and 12 weeks and total body water, total body potassium at 12 weeks after the baseline assessment. There was no significant weight change in either group over the 6 or 12 weeks. Furthermore, there was no significant difference in total body water, total body potassium, blood biochemistry or haematology between the groups over the study period. It does not appear that megestrol acetate at a dose of 480 mg/day results in weight gain in advanced gastrointestinal cancer patients with weight loss.

Colon and rectal carcinoma in the west of Scotland. Symptoms, histologic characteristics, and outcome.

Multiple clinical and pathologic factors have been analyzed retrospectively for a group of 456 patients with colon and rectal cancer treated in Glasgow over a span of 4 years. Sixty-five percent of these patients underwent curative resection, and another 16 percent had palliative resection. Obstruction and perforation (present in 19 and 5 percent, respectively) were associated with the highest operative mortality (17 percent for both) of any presenting symptom. However, when only patients who survived curative resection were considered, obstruction carried only a slightly lower 5 year survival than did other common symptoms, whereas perforation still led to only a 10 percent 5 year survival. Neither mucin production nor degree of differentiation influenced survival significantly. Adherence of the primary tumor to an adjacent organ was associated with a very poor prognosis (9 percent 5 year survival), but curative resection of the involved organs with the primary tumor increased the 5 year survival to 34 percent. Patterns of recurrence were noted to be markedly different for each primary site and for different stages. Dukes' stage was the most important overall determinant of prognosis.

Protein synthesis in cancer patients with inflammatory response: investigations with [15N]glycine.

It has been proposed that the increase in amino acid flux and derived protein synthesis rates observed in weight-losing cancer patients may contribute to an ongoing negative energy balance. The mediators and tissues responsible for such apparent increased protein synthesis have not been clearly identified. The aim of this study was to examine the relationship between protein synthetic rates in whole-body, skeletal muscle, and circulating cortisol concentrations in healthy subjects (n = 6) and cancer patients with evidence of an inflammatory response (n = 6). Protein synthetic rates were measured with a primed continuous 20-h infusion of [15N]glycine. Skeletal muscle was biopsied at laparotomy. Serum cortisol, resting energy expenditure, plasma proteins, nitrogen metabolites in urine, and skeletal muscle free amino acids were also measured. Derived whole-body and skeletal muscle protein synthetic rates in the cancer group were increased significantly (by 70 and 93%, respectively, p < 0.05). Circulating concentrations of cortisol, fibrinogen, and C-reactive protein were also significantly increased in the cancer group and indicated the presence of an inflammatory response. However, there was no significant increase in resting energy expenditure. Mechanisms by which apparent increases in whole-body and skeletal protein synthesis do not result in an increase in resting energy expenditure are discussed. We conclude that glycine utilization is increased in cancer patients but that rates of protein synthesis derived from [15N]glycine kinetics may not be valid in such patients.

Resting and total energy expenditure in patients with ischemic heart disease.

Total energy expenditure (TEE) was measured by doubly labeled water in 13 preoperative patients undergoing elective coronary artery surgery and compared to resting energy expenditure (REE) measured by indirect calorimetry (IC) calculated from the Harris-Benedict (HB) formula or from formulas based on midarm circumference and arm muscle circumference. Mean REE measured by IC and calculated from the HB, midarm circumference, arm muscle circumference formulas were 62, 75, 62, and 69%, respectively, of TEE measured by doubly labeled water. REE measured by IC correlated significantly with that predicted by the HB (p = 0.006) but not the anthropometric formulas. The relationship between REE derived from anthropometric predictive formulas and REE measured by IC is altered in ischemic heart disease.

The effects of an anabolic steroid and peripherally administered intravenous nutrition in the early postoperative period.

Sixty patients undergoing colorectal surgery for malignancy were randomized to receive the anabolic steroid stanozolol (n = 30) or to a control group (n = 30). Patients were further randomized to receive on the first 4 postoperative days a) a standard dextrose-saline regimen (DS), b) an amino acid regimen (AA), or c) a glucose-amino acid-fat regimen (GAF) via a peripheral vein. Fat and carbohydrate oxidation rates were calculated pre- and postoperatively using indirect calorimetry. Postoperative nitrogen balance (NB) in patients receiving amino acids was significantly improved (p less than 0.02) by the administration of stanozolol. Fat and carbohydrate oxidation rates were not significantly affected by stanozolol. Patients in the stanozolol and control AA groups showed a fall in carbohydrate oxidation (p less than 0.01) and a rise in fat oxidation (p less than 0.05) postoperatively, whereas no significant changes in fat and carbohydrate oxidation occurred in the two DS and two GAF groups. Cumulative NB for the first 4 postoperative days was significantly better (p less than 0.01) in the two AA groups than in the two DS groups, due to an improved NB in the two AA groups on the 1st and 2nd days only. Cumulative NB in the two GAF groups was significantly better (p less than 0.01) than in all the other groups. This study shows that stanozolol improves postoperative NB in patients receiving amino acids alone, whereas the provision of a more complete nutritional regimen containing glucose, amino acids, and fat results in a positive NB unaffected by stanozolol.

Improved vascular access for patients receiving chemotherapy.

Indwelling central venous catheters were used for vascular access in 25 oncology patients. The lines were used for sampling, administration of blood products, chemotherapeutic agents, parenteral nutrients and occasionally plasmapheresis. The complication rate was no higher than in reported series in which the catheters were reserved for parenteral nutrition. We believe that a central venous cannula can be safely used as the sole means of vascular access in those patients with consequent psychological and practical benefits.

Does deprivation affect breast cancer management?

We evaluated whether social deprivation affected decision-making for breast cancer surgery. Of 3419 patients, 53.6% had mastectomy and this was predicted by deprivation, age, tumour size and hospital, all of which retained significance on multivariate analysis, except deprivation. Pathological characteristics and surgical decision-making determined choice of operation not deprivation.

The metabolic and nutritional effects of injury and sepsis.

The existence of a co-ordinated response to stress of a variety of causes has clearly been established. Basically, this consists of an elevation in energy expenditure and an increased breakdown of skeletal muscle protein. In addition, glucose level in the plasma increases as a result of increased synthesis and decreased uptake of glucose into cells. Release of fatty acid into the plasma is also increased, and an elevation in the proportion of energy derived from oxidation of fatty acids is observed. This response is qualitatively very different from that seen in simple starvation, where a progressive reduction in energy expenditure and a reduction in the synthesis of glucose allows fat to become the major energy-producing substrate and also allows sparing of body protein stores. The mechanisms responsible for this altered pattern of metabolism are probably primarily hormonal in nature, with adrenaline, cortisol and glucagon being the major catabolic stimulants. Some evidence exists, however, for alteration in intracellular pathway metabolism. Within the past decade a new class of mediators of the stress response, the cytokines, has been recognized. These substances are protein products of circulating monocytes and the way in which they integrate into the control of the stress response has not been completely elucidated. At present there is evidence that they can stimulate production of catabolic hormones, and also they may well have direct effects in enhancing protein catabolism in muscle. At present the main method for modification of the stress response remains the provision of energy and amino acid, either intravenously or enterally. In the present state of our knowledge, 30-40 kcal kg-1 day-1 would appear to be adequate for most patients, with half provided as fat. Amino acids 3 g kg-1 day-1 will provide adequate nitrogen. It must be said, however, that the most effective method of modifying the stress response is removal of the source of stress by surgery, antibiotics or other primary therapy.

Polyorchidism.

Polyorchidism is an unusual abnormality of the genital tract in which supernumerary testes are present, usually within the scrotum. We report a recently encountered case, discuss the aetiology of the condition and suggest a course of management when encountered at operation.

Regulation of muscle protein turnover: possible implications for modifying the responses to trauma and nutrient intake.

The physiological control of muscle protein balance has been reviewed. In addition to trauma, fasting and reduced activity have been shown to cause muscle protein loss through changes in synthesis and breakdown. Many of the effects of these states are mediated by alterations in the concentrations of insulin, glucagon, steroids and catecholamines. Branched-chain amino acids also appear to have specific effects in improving protein synthesis. Recently, prostaglandins have been identified as having a central role as mediators in the control of protein metabolism by many hormones and pathological states. Identification of factors which control muscle protein synthesis leads to the possibility that the metabolic response to illness and injury and its attendant muscle protein loss could be open to pharmacological manipulation. Inhibition of prostaglandin synthesis by non-steroidal anti-inflammatory drugs can improve muscle protein turnover, but their clinical usefulness may be limited by side-effects. Hormonal manipulation may offer the possibility of abolishing the metabolic response. For example, inhibition of adrenal secretion in surgical patients by spinal anaesthesia appears to modify many of the metabolic effects of injury. A variety of other treatments have been used to minimize the metabolic derangements of injury. Some of these have considerable potential, but as yet clinical benefits from their use have not been positively identified. It is likely that a pharmacological approach to the nutritional disorders of stress and injury will prove to be of major interest in the future.

Effect of naftidrofuryl on the metabolic response to surgery.

In a randomised study of 34 patients undergoing elective operations of moderate severity naftidrofuryl infusion significantly improved postoperative nitrogen balance. The control group excreted 26.2 +/- 2.7 g nitrogen in the first three postoperative days. A group treated with naftidrofuryl excreted 18.0 +/- 1.6 g nitrogen in the same period (p less than 0.0005). The preoperative nutritional state of patients treated with naftidrofuryl did not differ from that of the controls. Though hormonal changes causing an improvement in nitrogen balance could not be excluded by this study, the results show that naftidrofuryl infusion may stimulate postoperative catabolism of endogenous carbohydrate and fat, thus sparing tissue protein.

Metabolic acidosis in the critically ill.

The processes that lead to increased blood lactate concentration in shock and critical illness are complex. Although it is widely believed that lactic acidosis develops because of tissue hypoxia and reduced aerobic metabolism, a number of workers have shown that lactate oxidation rate is actually increased. Lactate production is also increased and this is probably the cause of increased blood lactate concentration. The clinical usefulness of lactate estimation in critical illness is also obscure. Suggestions that whole blood lactate concentration is an accurate predictor of the outcome of an episode of shock are unconvincing. At best this method may differentiate between groups of patients. However, the rate of improvement in lactate concentration with intensive resuscitation probably correlates better with survival, and further investigation of this possibility is suggested.

Semantic integration of verbal information into a visual memory.

A total of 1,242 subjects, in five experiments plus a pilot study, saw a series of slides depicting a single auto-pedestrian accident. The purpose of these experiments was to investigate how information supplied after an event influences a witness's memory for that event. Subjects were exposed to either consistent, misleading, or irrelevant information after the accident event. Misleading information produced less accurate responding on both a yes-no and a two-alternative forced-choice recognition test. Further, misleading information had a larger impact if introduced just prior to a final test rather than immediately after the initial event. The effects of misleading information cannot be accounted for by a simple demand-characteristics explanation. Overall, the results suggest that information to which a witness is exposed after an event, whether that information is consistent or misleading, is integrated into the witness's memory of the event.