Leucine kinetics in patients with benign disease, non-weight-losing cancer, and cancer cachexia: studies at the whole-body and tissue level and the response to nutritional support.

We have performed intraoperative isotopic infusions of carbon 14-labeled leucine in 65 patients to define the abnormalities in protein metabolism at both the whole-body and tissue level in patients with weight-losing and non-weight-losing cancer. Eighteen patients had benign disease, 26 had non-weight-losing cancer, and 21 had cancer cachexia. Samples of plasma and expired breath were taken to determine rates of whole-body protein synthesis (WBPS), whole-body protein catabolism (WBPC), net protein catabolism, and albumin fractional synthetic rates. Tissue samples were taken to determine the fractional synthetic rates (FSR) of protein in muscle, liver, cancer, and the tissue in which the cancer arose. In addition, in 14 patients the effect of nutritional support on protein metabolism was assessed. In all parameters examined we were unable to detect any significant differences between patients with no cancer and the patients with non-weight-losing cancer. In contrast, patients with cancer cachexia had a significant elevation (p less than 0.005) in WBPC compared with the other two groups. WBPS was also elevated (to a lesser extent) in the patients with cancer cachexia, and the rate of net protein catabolism was increased significantly (p less than 0.05). Patients with cancer cachexia also had significantly higher values of FSR of protein in muscle (p less than 0.05), liver (p less than 0.05), and albumin (p less than 0.01) compared with the other two groups. In addition, the protein FSR in the cancer rose progressively when the values for the primary cancer were compared with those for nodal and systemic metastases. Further, although nutritional support resulted in an increase in host muscle protein synthesis (p less than 0.04), there was no promotion of FSR of protein in cancer. We conclude that patients with cancer cachexia are actively losing protein as a result of an increase in WBPC that is only partially compensated for by an increase in WBPS. There are compensatory increases in protein synthesis in muscle and liver, but these increases in host protein synthesis are insufficient to keep pace with the combined effect of the accelerated rate of protein synthesis in the cancer per se and the accelerated rate of net protein catabolism at the whole-body level. In response to nutritional support, there is a significant increase in the muscle protein synthesis, but we could not demonstrate any increase in cancer protein synthesis.

Metabolic intervention in surgical patients: the effect of alpha- or beta-blockade on glucose and protein metabolism in surgical patients receiving total parenteral nutrition.

We performed a series of isotopic studies on the role of alpha- or beta-adrenergic activity in the regulation of glucose and protein metabolism in a group of surgical patients receiving total parenteral nutrition. We quantitated rates of glucose turnover and net protein breakdown by the primed constant infusion of 3H-glucose and 14C-urea, respectively. Basal measurements were first performed, and then the effect of either alpha- or beta-adrenergic blockade was assessed by means of the constant infusion of either phentolamine or propranolol. In addition, we assessed the effect of beta-stimulation by infusing the beta-agonist, salbutamol. The institution of alpha-adrenergic blockade did not significantly alter either the plasma glucose level or the rate of glucose production. However, the rate of net protein catabolism decreased significantly after alpha-adrenergic blockade. Before alpha-blockade the value for NPC was 0.88 +/- 0.27 gm/kg/day, and after alpha-blockade the corresponding value was 0.73 +/- 0.24 gm/kg/day (p less than 0.01). beta-Adrenergic blockade resulted in a decrease in the rate of glucose appearance from 38.2 +/- 6.1 mumol/kg/min to 35.1 +/- 5.7 mumol/kg/min, and the plasma glucose clearance increased from 5.0 +/- 0.8 ml/kg/min to 5.4 +/- 0.8 ml/kg/min. As a result of these changes the plasma glucose concentration decreased significantly (p less than 0.01) from 7.4 +/- 0.3 mumol/ml to 6.5 +/- 0.5 mumol/ml. beta-Adrenergic blockade did not significantly decrease the rate of net protein catabolism. beta-Stimulation with salbutamol resulted in a significant increase (p less than 0.05) in the rate of glucose production from 31.3 +/- 4.2 mumol/kg/min to 38.0 +/- 6.5 mumol/kg/min, and as a result the plasma glucose level increased significantly from 6.7 +/- 0.6 mumol/ml to 7.4 +/- 0.6 mumol/ml (p less than 0.04). We conclude from these studies that the role of the adrenergic nervous system in the promotion of endogenous glucose turnover in surgical patients receiving total parenteral nutrition is primarily a beta-adrenergic effect, whereas the promotion of protein catabolism is mainly an alpha-adrenergic effect.

Relative importance of amino acid infusion as a means of sparing protein in surgical patients.

We performed isotopic infusions in 51 surgical patients to investigate the effectiveness of different substrates to conserve protein. All patients were initially studied in the basal state and then the effects of glucose infusion (GL, N = 13), lipid infusion (LIP, N = 11), or amino acid infusion (AA, N = 17) were determined. Ten patients receiving total parenteral nutrition (TPN) were also studied. The basal value for net protein catabolism (NPC) in GL patients was 1.53 +/- 0.4 (SEM) g/kg/day decreasing to 1.39 +/- 0.4 g/kg/day during glucose infusion (p less than 0.01). The basal NPC in the LIP group was 2.04 +/- 0.4 g/kg/day decreasing to 1.72 +/- 0.3 g/kg/day during lipid infusion (p less than 0.01). In the TPN patients the NPC was 0.79 +/- 0.46 g/kg/day whereas in the AA patients the basal value for NPC was 1.37 +/- 0.14 g/kg/day decreasing to -0.77 +/- 0.11 g/kg/day during amino acid infusion (p less than 0.0005). From our study we conclude that: (1) All substrates commonly used in intravenous feeding have the capacity to spare protein. (2) Protein sparing was more pronounced when a balanced amino acid infusion was used than with either glucose or lipid infusion alone. (3) This effect is not solely due to insulin secretion as larger insulin responses were seen with both GL and TPN patients. (4) These results may have implications for peripheral vein feeding with amino acid solutions where there is a contraindication for full TPN or the lack of resources for administering it.

Soft tissue sarcomas in Auckland 1974-1984: a review of 105 cases.

We have reviewed the records of 105 patients with the diagnosis of soft tissue sarcoma seen in the Auckland region between January 1974 and December 1984. The mean age at diagnosis was 54 years and the average duration of symptoms prior to specialist assessment was 8 months. By the time of presentation 27% of patients had metastatic disease. Forty-six patients underwent biopsy-type procedures and of these only one patient was alive and apparently disease free at one year. Three were alive with disease at an average of 2.2 years, 29 of the 46 had died of their sarcoma at one year and five of the 46 died of other causes. Fifty nine patients had definitive reactions performed and 26 of were alive with disease at an average of 2.2 years, 29 of the 46 had died of their sarcoma at one year and five of the 46 died of these were alive and disease free at two years. Six were alive with recurrent disease and 15 had died of sarcoma 1.9 years after presentation. In terms of site of the primary, patients with limb sarcomas fared better than those with retroperitoneal lesions, whereas sarcomas in other locations had survival figures in between these two groups. Soft tissue sarcomas consitute an aggressive and unforgiving type of cancer, and to entertain any realistic chance of cure complete resection of the lesion must be achieved. However, the patients presented to specialist attention at a relatively late stage of their disease, and the chances of survival are dependent both on the site of the primary lesion and on whether or not definitive surgery and adjuvant therapy is employed.

Parotid cancer in Auckland 1970-1986--too little, too late.

We have reviewed the records of 98 parotid cancer patients seen in Auckland over the seventeen year period January 1970 to December 1986. The average duration of symptoms prior to receiving surgical attention was fifteen months and 58% of patients had stage III disease on presentation. The histological profile of our group of patients was different from that reported in other series with increased numbers of patients having bad outlook tumours. There were seven histological types of parotid cancer and these could be divided into two distinct prognostic groups with mucoepidermoid, malignant mixed, adenoid cystic and acinic cell comprising the more indolent tumours and squamous cell, undifferentiated and adenocarcinoma following a more agressive course. The overall five year cure rate was 35%: 65% of patients were either dead or had developed recurrent disease within this period. Radiotherapy appeared to be beneficial for stage I and II lesions, but in advanced cases it had no obvious impact on survival. The initial surgery for parotid cancer should comprise at least a superficial parotidectomy plus a suprahyoid neck dissection if possible. In addition, patients with positive nodes or more aggressive histology should undergo radical neck dissection. All patients with parotid cancer should have adjuvant radiotherapy.

Metabolism in hematologic malignancy.

The authors used isotopic infusions of 6-3H-glucose, U-14C-glucose, and 14C-urea and calorimetry to investigate energy expenditure and metabolic profiles in 19 patients with hematologic malignancy. The average age of these patients was 62 years. Eleven patients had either leukemia or myeloproliferative disorders (LEMP). The rest had lymphoma (LYMPH). The Resting Energy Expenditure (REE) in the LYMPH patients was 1015 +/- 115 kcal/24 hr. This value in the LEMP group was significantly elevated at 2083 +/- 270 kcal/24 hr (P less than 0.025) despite similar weights and ages between the two groups. Net Protein Catabolism (NPC) in the LYMPH group was 82 +/- 29 mg/kg.hr. In contrast the value in the LEMP group was more than doubled at 174 +/- 30 mg/kg.hr (P less than 0.05). Glucose production in the LYMPH group was 14.1 +/- 2.7 mumol/kg.min, and the percent of glucose uptake oxidized in the LYMPH group was 37% +/- 9%. In contrast, glucose production in the LEMP group was significantly elevated (P less than 0.025) at 41.0 +/- 8.1 mumol/kg.min, and the percent of glucose uptake oxidized was significantly depressed (P less than 0.05) at 20% +/- 4% compared with the value in the LYMPH group. Glucose recycling in the LYMPH group was 9.0% +/- 6%. In the LEMP group the rate of recycling was significantly elevated at 60.3% +/- 4.8% (P less than 0.005). The percent suppression of endogenous glucose turnover during glucose infusion in the LYMPH group was 96% +/- 4%. The value for the LEMP patients was significantly less at 30.2% +/- 5% (P less than 0.0005). The serum cortisol concentration in the LYMPH patients was 285 +/- 74 nmol/l. The value in the LEMP patients was significantly higher (P less than 0.005) at 579 +/- 22 nmol/l. The authors concluded that hematologic malignancy is not a homogeneous group when evaluated metabolically. Lymphoma patients are similar metabolically to normal volunteers, but LEMP patients form a distinct group with major abnormalities in both glucose and protein kinetics and energy expenditure.

Isotopic studies during surgical convalescence.

We have performed paired isotopic studies in four patients undergoing resection of early colorectal cancer and four having removal of parathyroid adenomas. Kinetic measurements of protein and glucose metabolism were made before resection and at home 10 weeks after surgery. During convalescence there were major changes in both groups in glucose metabolism and the hormonal milieu despite no alterations in protein kinetics or metabolic rate. In particular, the rate of glucose production doubled from (mean +/- s.e.m.) 14.8 +/- 1.3 to 28.1 +/- 2.5 mumol kg-1 min-1 (P less than 0.01), the percentage of available glucose undergoing oxidation decreased from 35.5 +/- 3.9 to 21.5 +/- 2.9 per cent (P less than 0.05) and the percentage of glucose undergoing recycling to lactate increased from 20.1 +/- 10.0 to 52.9 +/- 2.3 per cent (P less than 0.05). During convalescence the basal plasma insulin concentration was significantly higher (P less than 0.05) and there was a proportionately smaller response to glucose infusion. The convalescent state was also associated with an elevation in serum cortisol from 291 +/- 54 to 496 +/- 75 nmol litre-1 (P less than 0.05). The values for resting energy expenditure were not significantly different from the predicted energy expenditure in either the preoperative or the convalescent groups. We conclude that (a) there is a marked increase in both glucose production and glucose recycling to lactate in convalescence from clean uncomplicated surgery, and this is associated with a decrease in the percentage of glucose uptake oxidised; (b) a relative hyperinsulinaemia is seen in convalescent patients and is associated with decreased responsiveness to a glucose load; (c) the plasma cortisol level is significantly elevated after 10 weeks of convalescence; and (d) convalescent patients do not have elevated rates of protein catabolism or energy expenditure.

Weight loss in patients with head and neck cancer: malnutrition or tumour effect?

Isotopic infusions, hormone assays and calorimetry have been used to test the hypothesis that weight loss in head and neck cancer (HNC) patients is not due to pure malnutrition, but that a large component of the weight loss in these patients is a consequence of the metabolic effects induced by the tumour on the host. Twelve patients with advanced HNC were compared with eight depleted patients (DEP) who did not have cancer. Both groups had lost more than 10% of well body weight. Neither patient group had an elevated rate of energy expenditure as determined by calorimetry. Both glucose production and plasma glucose clearance were not significantly different between the two groups. The percentage of glucose production undergoing recycling to lactate was elevated in the HNC patients compared with the DEP patients. In addition, the percentage of glucose undergoing oxidation to CO2 was significantly lower in the HNC patients compared with the corresponding DEP value. The HNC patients were significantly more catabolic than the DEP patients and their serum cortisol concentration was also significantly elevated. Although the basal plasma insulin concentrations were similar in the two groups, the response to glucose infusion was markedly less in the HNC patients. It is concluded that patients with advanced HNC are metabolically different from starving patients, although both may lose a similar amount of weight. In particular, the adaptive response of protein conservation seen in simple starvation does not occur in the HNC patient.

Metabolic effects of recombinant human growth hormone: isotopic studies in the postabsorptive state and during total parenteral nutrition.

We have performed a series of isotopic studies in 25 adult patients with sepsis and/or trauma in order to determine the metabolic effects of recombinant human growth hormone (rHGH) administration. Twelve of the patients were receiving total parenteral nutrition, and 13 were eating a normal ward diet and were studied postabsorption. Energy and protein kinetics were quantified isotopically before rHGH administration and following a 3-day course of rHGH (20 units subcutaneously daily). In the total parenteral nutrition group the rate of net loss of protein decreased from 0.82(0.17) g kg-1 day-1 to 0.43(0.20) g kg-1 day-1 (P less than 0.02) following the administration of rHGH. The rate of appearance of leucine was not altered, suggesting that the improvement in nitrogen balance following rHGH was because of an increased rate of protein synthesis rather than reduced catabolism. In the postabsorptive group, rHGH treatment significantly increased the rate of appearance of free fatty acids (from 7.4(2.2) mumol kg-1 min-1 to 11.1(2.6) mumol kg-1 min-1, P less than 0.03) and free fatty oxidation (from 1.3(0.4) mumol kg-1 min-1 to 1.7(0.4) mumol kg-1 min-1, P less than 0.06), while the rate of leucine oxidation was reduced (from 0.44(0.05) mumol kg-1 min-1 to 0.26(0.03) mumol kg-1 min-1, P less than 0.005). Glucose appearance and oxidation remained unchanged. These results suggest that fat was being oxidized in preference to protein, which resulted in a reduction in the net rate of loss of protein of 0.3 g kg-1 day-1 (P less than 0.05). We conclude that rHGH administration is capable of significantly reducing net protein loss in septic or injured surgical patients. Recombinant HGH may be clinically useful in supporting critically ill surgical patients who require intensive nutritional support.