Cachectic effects of recombinant human tumor necrosis factor in rats.

Treatment of rats with either intermittent bolus i.v. injections or continuous i.v. infusions of the same sublethal daily dose of tumor necrosis factor (TNF) results in decreased food intake and decreased nitrogen balance compared to saline-treated control rats. After 4 days of treatment, rats treated with intermittent bolus doses of TNF develop tolerance to the nutritional effects and consume normal amounts of food and have nitrogen balance similar to those of saline treated rats. Rats receiving the continuous infusion of TNF do not. Rats treated with both routes of TNF lose more weight than pair fed rats who eat the same mean amount as the continuous TNF treated group. In addition, 56% of rats receiving continuous infusion TNF die during the 8-day experimental period while rats receiving either intermittent bolus TNF or similar food intake (pair fed) do not. Body composition studies of rats that completed the 8 days of treatment indicate that rats receiving either continuous infusion or intermittent bolus TNF have increased percentages of body water and reduced percentages of body solid compared to saline treated control rats. Rats pair fed to the food intake of continuous TNF treated rats also had increased percentages of body water and reduced percentages of body solid, but changes were significantly less than those observed in continuous TNF infused rats. Continuous TNF infusion reduced total body nitrogen and potassium while pair feeding did not reduce potassium and reduced nitrogen to a lesser degree. Pair feeding and continuous TNF infusion reduced total body fat to a similar extent. Twice a day administration of TNF resulted in lesser changes in carcass water, solid, nitrogen, lipid, and potassium than continuous infusion of the same dose of TNF. The results indicate that continuous infusion of TNF can produce anorexia, weight loss, edema, loss of body protein, lipid and cell mass, and lethality which is markedly ameliorated with bolus doses of TNF. The findings are consistent with the hypothesis that slow continuous secretion of sublethal amounts of TNF may mediate cancer cachexia.

Tumor necrosis factor: immune endocrine interaction.

Tumor necrosis factor (TNF), a peptide produced by macrophages in response to endotoxin, has been implicated as a mediator of septic shock. This study examined the effects of injections of recombinant (r) human TNF on circulating levels of metabolic substrates and hormones in conscious, unrestrained rats and the effects of TNF on cortisol secretion from human adrenocortical cells in vitro. Sublethal doses of rTNF--doses that did not produce hemodynamic changes in previous work--produced rapid (1 hour), significant increases in blood levels of glucose, lactate, and triglycerides and decreases in plasma levels of branched chain amino acids. Plasma levels of glucagon, corticosterone, ACTH, norepinephrine, and dihydroxyphenylglycol were also increased significantly. Incubation of adrenocortical cells with either 0.15 or 1.5 micrograms of rTNF increased cortisol secretion to the same extent as did 10(-10) mol/L ACTH. Administration of TNF produces a variety of metabolic and neuroendocrine effects including stimulation of anterior pituitary, adrenal cortical, and pancreatic secretion, and sympathoneural activation. These changes, and the in vitro results, are consistent with the view that immune cells can interact with endocrine cells through release of TNF.

Body composition changes in rats with experimental cancer cachexia: improvement with exogenous insulin.

Exogenous insulin treatment has been shown to improve food intake and host weight of cachectic tumor-bearing (TB) rats, but the composition of the host weight gain has not been quantitated. Sixty-six Fischer 344 rats were randomized to seven groups: early nontumor-bearing (NTB) (n = 10) who underwent compositional analysis (CA) on the day the methylcholanthrene sarcoma was implanted in TB rats; pretreatment-NTB (n = 10) and pretreatment-TB (n = 10) who underwent CA 25 days later when rats began treatment with saline or insulin; and finally saline-treated NTB (n = 9), saline-treated TB (n = 9), insulin-treated NTB (n = 9), and insulin-treated TB (n = 9), who underwent CA following 5 days of treatment with daily saline or neutral protamine hagedorn insulin 2 units/100 g. Body weight and food intake were measured daily. For compositional analysis, the tumor was separated from the host in TB rats and the entire rat in NTB animals was homogenized, lyophilized and analyzed for fat, water, protein, potassium, chloride, and sodium. The tumor was processed in a similar fashion. In response to insulin, NTB rats ate significantly more food, and had an increase in body weight gain. Compositional analysis of insulin-treated NTB rats indicated a slight, but insignificant, increase in body fat and a similar insignificant decrease in body protein. TB rats ate significantly less than NTB rats during the 5-day experimental period, and insulin treatment significantly increased food intake to levels similar to NTB animals. Compositional analysis indicated that the tumor-bearing state resulted in a significant decrease in total host water, protein, fat, potassium, sodium, and chloride. Insulin administration resulted in preservation of host nitrogen, fat, potassium, sodium, and chloride in cachectic tumor-bearing rats. Insulin treatment did not affect tumor dry weight or composition. The results suggest that exogenous insulin, can preserve normal host composition of TB rats during cachectic decline.

Gluconeogenesis in the tumor-influenced rat hepatocyte: importance of tumor burden, lactate, insulin, and glucagon.

In an attempt to define the relationship between tumor burden (cachexia) and host hepatocyte gluconeogenesis, the following experiments were performed with the use of an F344 male rat bearing a transplantable sarcoma. Food intake of tumor-bearing (TB) rats was constant until day 24 following implant and a tumor burden of 18 +/- 5.2% (mean +/- SD), at which time food intake progressively declined daily. Tumor burden was arbitrarily divided at 12.8% to determine if any measured changes occurred prior to or following the approximate time when a significant decline in food intake occurred. Plasma glucose levels decreased with tumor burden. Whole-blood lactate levels increased with tumor burden. Fasting plasma alanine levels decreased with tumor burden. Plasma 3-methylhistidine levels increased with tumor burden. Plasma glucagon levels increased with tumor burden, whereas plasma insulin levels decreased. Hormone changes were noted at small tumor burdens prior to a decline in food intake. Viable hepatocytes were isolated from 4 groups: non-tumor-bearing (NTB), small tumor burden [(STB) 3.5% total body weight (TBW)], moderate tumor burden [(MTB) 14% TBW], and large tumor burden [(LTB) 23% TBW]. As expected in NTB rats, hepatocytes produced significantly more glucose with 20 mM lactate than 20 mM alanine or than Hanks' balanced salt solution (HBSS) alone. Hepatocytes from STB rats demonstrated the same basic relationship for lactate, alanine, and HBSS, but they produced significantly more glucose from lactate and HBSS alone than NTB hepatocytes. With alanine as substrate, the rates of glucose production by hepatocytes were not affected by the presence or size of tumor. However, with lactate as substrate, hepatocytes from MTB and LTB rats produced progressively less glucose as tumor burden increased (r = -0.85, p less than .001), which may partly explain the reduction in blood glucose and elevation in blood lactate levels observed. Elevated gluconeogenesis in TB rats occurred early prior to a decline in food intake. The key precursor appeared to be lactate. The balance between glucagon and insulin appeared to promote the abnormal host carbohydrate metabolism observed.

Altered leucine metabolism in noncachectic sarcoma patients.

Leucine and whole body protein metabolism were quantitated in 26 human subjects (6 sarcoma patients, 20 age-matched normal controls) using a primed, continuous infusion of [13C]leucine. Plasma samples were analyzed every 15 min for enrichment of [13C]leucine. Plateau enrichment levels were then used to calculate whole-body protein turnover, synthesis, and breakdown rates. Exhaled gas samples were analyzed every 15 min for enrichment of 13CO2, and plateau enrichment levels (as well as CO2 production rates) were used to calculate leucine oxidation rates. Fasting plasma amino acid levels, serum albumin, and total protein levels were also determined. The 6 patients were otherwise healthy but had a large, localized high-grade sarcoma which had not been previously treated. No patient had weight loss. Amino acid, albumin, and total protein levels were equivalent in patients and controls. Whole-body protein turnover rates were significantly greater in sarcoma patients than age-matched controls (15%). Increased protein turnover rates resulted in increased whole-body protein synthesis and breakdown rates in sarcoma patients compared to controls. Leucine oxidation rates were not different in the 2 groups. The results suggest that in humans with high-grade sarcomas leucine metabolic abnormalities are specific to tumor growth and not malnutrition because abnormalities of turnover, synthesis, and breakdown occur prior to any weight loss or measurable change in blood amino acid or protein level.

Impact of insulin on doxorubicin-induced rat host toxicity and tumor regression.

To test whether the anorexia and host depletion following doxorubicin chemotherapy can be improved by concomitant insulin therapy, 70 F344 rats were divided equally between tumor-bearing (TB) and non-tumor-bearing (NTB) groups and studied for food intake, host weight, and tumor size changes. Sarcoma fragments were implanted s.c. in TB rats and 18 days later all rats received an i.v. dose of doxorubicin (8 mg/kg). The following day TB and NTB rats were randomized to receive neutral protaminehagedorn insulin (2 units/100 g/24 h) or normal saline until food intake returned to normal. Following doxorubicin administration food intake and host weight declined in an identical pattern in both NTB and TB rats treated with saline. However, beginning on day 6 insulin-treated TB and NTB rats ate significantly more than saline-treated controls. Insulin-treated animals returned to normal food intake levels in 50% less time than controls. This improved food intake resulted in an improved host mass beginning also on day 6 for both TB and NTB rats. In addition, it appeared that insulin treatment significantly improved the tumor shrinkage initiated by doxorubicin. Following doxorubicin, insulin-treated TB rats had a greater reduction of tumor size (10.6 +/- 1.2 cm3) compared to saline-treated rats (6.6 +/- 0.8 cm3, P less than 0.01). To further characterize the effect of insulin and/or doxorubicin on tumor growth, the experiment was repeated in the same manner except for two additional TB groups: saline- and insulin-treated tumor bearers with treatment beginning 19 days after tumor implant. Rats treated with doxorubicin had a significant reduction in tumor size compared to rats not treated with doxorubicin (P less than 0.001). Insulin alone did not affect tumor growth, but insulin plus doxorubicin significantly decreased tumor size compared to doxorubicin alone (P less than 0.01). In a second experiment using 80 rats insulin treatment had no apparent effect on reduction of peripheral blood counts including white blood cells, neutrophils, lymphocytes, platelets, and hematocrit induced by doxorubicin in either NTB or TB rats. Insulin given 24 h previously had minimal effect on plasma glucose. The marked improvement in food intake and host weight, as well as additional tumor reduction with exogenous insulin following doxorubicin, suggests that insulin may have a role in reversal of doxorubicin host nutritional toxicity and perhaps improvement of antitumor efficacy.

Wound healing in sarcoma-bearing rats: tumor effects on cutaneous and deep wounds.

Many surgeons think that cancer causes a higher incidence of wound complications. Wound healing was examined in a cutaneous and deep model in control and sarcoma-bearing rats to evaluate this concept. In a dorsal incisional wound, a significant decrease in wound breaking strength was observed from 19 days after tumor implantation onward. The amount of the breaking strength deficit increased with the size of tumor and the day post-tumor implant. In a deeper wound chamber, hydroxyproline levels, 3H-thymidine incorporation into DNA, histology, and collagen types were examined, and tumor produced no significant change in any parameter. The presence of tumor appeared to inhibit wound healing in cutaneous wounds but had no apparent effect on deeper wounds. This difference in healing in the two wound models is important to surgical oncologists. Because there is no demonstrable tumor-induced healing deficit in deep wounds, cancer-bearing organisms probably still heal these wounds normally.

The reversal of an Adriamycin induced healing impairment with chemoattractants and growth factors.

Rats treated with 8 mg/kg Adriamycin intravenously 4 days prior to chamber implantation develop impaired wound healing in a wound chamber model. In this study, the effects on healing of supplemental platelet derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), epidermal growth factor (EGF), and insulin were evaluated in chambers extracted from Adriamycin-treated rats 10 and 20 days after implantation. The effects of individual factors, combinations of factors, and different concentrations of TGF-beta were evaluated. The parameters evaluated included collagen content, protein content, cellular proliferation rate, chamber histology, and collagen types. Supplemental TGF-beta alone reversed much of the healing deficit noted. A minimum concentration of 100 ng/ml TGF-beta was required to significantly reverse this deficit. PDGF and EGF alone had no effect. Addition of PDGF and TGF-beta in combination stimulated a significantly higher level of collagen deposit than TGF-beta alone. Addition of EGF in combination with PDGF and TGF-beta restored collagen deposition to 86% of normal. No synergism was seen between TGF-beta and EGF unless PDGF was also present. These data suggest that growth factors contained in platelets may play key roles in initiating the wound healing response and may have clinical utility in healing deficit states.

Doxorubicin-induced impairment of wound healing in rats.

The mortality rate induced by 3 doses of iv doxorubicin was evaluated in F344 rats, and a dose of 8 mg doxorubicin/kg body weight was the maximum dose tolerated with an acceptable mortality rate. Rats treated with 8 mg doxorubicin/kg prior to or on the day of wounding demonstrated decreased wound breaking strength in incisional wounds at all intervals after wounding. Decreased amounts of collagen and DNA and less cellularity were noted in wound chambers from rats treated in the same manner. In both the incisional wound and wound chamber models, rats treated with doxorubicin 7 days after wounding showed a less dramatic healing impairment. No difference in collagen types was noted between chambers from the doxorubicin-treated and untreated rats. Doxorubicin also produced a significant reduction in platelet and white blood cell counts 1 week after it was administered. The data indicate that doxorubicin impedes healing by decreasing wound cellularity and collagen synthesis.

Basal amino acid concentrations and the response to incremental glucose infusion in tumor bearing rats.

Plasma amino acid concentrations were measured in fasting nontumor bearing (NTB) and tumor bearing (TB; methylcholanthrene induced sarcoma) male Fischer F344 rats during infusion of 0.9% NaCl solution or glucose at 3.72 or 13.05 mumol/100 g total body weight (TBW)/min. The animals were studied when the tumor comprised only 8% of the TBW at a time when decreased food intake and weight loss were not manifest. During 0.9% NaCl infusion there were no significant differences between NTB or TB animals in the concentration of alanine (NTB: 152.6 +/- 20.1; TB: 150.3 +/- 19.0 microM; mean +/- SD), branched chain amino acids (BCAA) (NTB: 343.3 +/- 48.7; TB: 344.2 +/- 20.5 microM), essential amino acids, aromatic amino acids, or total amino acids. During infusion of glucose at 3.72 mumol/100 g TBW/min the alanine levels rose (NTB: 283.6 +/- 33.4; TB: 286.7 +/- 43.3 microM), and the BCAA levels fell (NTB: 215.9 +/- 19.4; TB: 228.7 +/- 43.4 microM) to similar concentrations in both NTB and TB animals. Glucose infusion at 13.05 mumol/100 g TBW/min resulted in an additional increase in the alanine concentration (NTB: 344.5 +/- 28.7; TB: 382.8 +/- 116.6 microM), and a further decrease in the BCAA concentration (NTB: 166.4 +/- 30.8; TB: 160.7 +/- 30.5 microM) without significant differences between NTB and TB animals. Paired analysis for each animal prior to and during glucose infusion demonstrated a similar absolute micromolar change in alanine and BCAA concentration during both glucose infusion rates in both NTB and TB animals. The levels of aromatic amino acids and total amino acids were unchanged and the essential amino acid concentrations were decreased only at the higher glucose infusion rate in both NTB and TB groups. Basal amino acid metabolism appears similar in the NTB and TB animals, prior to the onset of anorexia and weight loss. During exogenous glucose infusion the reciprocal changes in the plasma alanine and BCAA concentrations support the concept of a glucose-alanine-BCAA cycle at the whole body level that appears to respond to a similar extent in NTB and TB animals.

Fasting plasma amino acid levels in cancer patients.

The concentration in plasma of 15 fasting amino acids were measured in 14 control volunteers and 55 cancer patients. In addition, 16 patients (7 with, 9 without total parenteral nutrition [TPN] ) with metastatic sarcoma had sequential amino acid profiles measured during 6 weeks of ablative chemotherapy. In four cancer patient groups (lymphoma, sarcoma, osteosarcoma and metastatic sarcoma) with no or minimal weight loss, most plasma amino acid levels were similar to controls. Proline levels were significantly reduced in the lymphoma and sarcoma patients. Esophageal cancer patients with 20% body weight loss had a marked reduction in total and individual amino acid levels (except branched chain amino acids) compared to controls and all others. The metastatic sarcoma patients who received parenteral nutrition had higher levels of plasma lysine and tyrosine during chemotherapy than controls; however, TPN failed to change the majority of amino acid levels. It appears that plasma amino acid levels except proline were well maintained in cancer patients without weight loss. Esophageal cancer patients with weight loss demonstrated marked reduction in all circulating amino acids except branched chain. Parenteral nutrition did not significantly alter the amino acid profile of cancer patients undergoing chemotherapy.

Liposome uptake by melanoma: in vitro comparison with hepatocytes.

Liposomes are artificially generated vesicles entrapping aqueous solutions within lipid bilayer membranes. A major potential use of liposomes is for the delivery of antineoplastic agents to malignant tissue. However, liposome-cell interactions with both normal and neoplastic cells must be characterized in vitro to identify neoplastic tissues for which this approach may be most applicable in vivo. In this study, mouse melanoma-liposome interactions were examined in vitro. Small, unilamellar vesicle liposomes of three different phospholipid-cholesterol compositions were synthesized incorporating an aqueous phase fluorescent marker. Mouse melanoma had a significantly greater affinity for phosphotidylcholine-cholesterol liposomes than did mouse hepatocytes, as determined by comparing quantities of free intracellular 6-carboxyfluorescein in cells after a 15-min incubation with each of the three different liposome preparations (P less than 0.001). In addition, the efficiency of liposome internalization, calculated as the percentage of total cell-associated 6-carboxyfluorescein present as free, intracellular 6-carboxyfluorescein, was significantly greater for melanoma than for hepatocytes with all three liposome preparations (P less than 0.05). Therefore, in vitro liposome uptake by melanoma depends on lipid characteristics of the liposome preparation. Because melanoma uptake of liposomes appears to be a very efficient process in vitro, liposomes may be a useful vesicle for delivery of antineoplastic agents to melanoma in vivo.

Peripheral tissue metabolism in cancer-bearing man.

Whole-body tracer studies have documented abnormal glucose and amino acid kinetics in cancer-bearing man. Whether these abnormalities are related to systemic or local tumor effects is questioned. Forearm metabolism was examined in six patients with localized squamous cell carcinoma of the distal esophagus and six healthy normal male volunteers. Substrate arterio-venous differences and blood flow across forearm tissues were determined and substrate flux calculated. The mean forearm blood flow (ml min-1 100 ml forearm-1) was not significantly different between cancer patients (3.67 +/- 0.12) and normal subjects (2.80 +/- 0.40). The uptake of glucose (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (1.99 +/- 0.45) compared to control subjects without weight loss (0.47 +/- 0.18). Lactic acid release (mumol min-1 100 ml forearm-1) was significantly higher in cancer patients (-1.15 +/- 0.35) compared to control subjects (-0.26 +/- 0.14). There was no significant difference in the flux of individual amino acids between the groups, although the mean total nitrogen released from forearms of cancer-bearing patients was greater than that from normal controls. The arterial serum insulin level was significantly lower and the arterial plasma glucagon level significantly higher in cancer patients compared to control subjects. These data cannot be explained by weight loss alone and suggest a peripheral defect in metabolism in this group of cancer-bearing patients.

Limiting ischemic liver injury by interfering with lysosomal autophagy.

Two regimens designed to ameliorate hepatic injury from complete liver dearterialization (LD) by interfering with lysosome-mediated proteolysis were studied in 200-g Buffalo rats. Five rats received a lysosome membrane-stabilizing flavenoid, catechin, 200 mg/kg/day for 5 days pre-LD. Five others were infused with lysosome protease inhibitors (LPI), leupeptin and pepstatin, delivered in 0.22-micron multilamellar liposomes at 500 micrograms each per hour for 2 hr, beginning 20 min before LD. Control groups (n = 4 or 5) were untreated LD, and treated and untreated sham LD rats. Blood from an arterial catheter pre-LD and 2 hr (peak enzyme release), 2 days, and 4 days post-LD yielded beta-glucuronidase (BG), aspartate transaminase (AST), and alkaline phosphatase values for each rat. Liver histology was not different between groups at 4 days post-LD. Untreated controls and the catechin LD group had similar enzyme levels at all points. LPI treatment values were statistically similar to sham LD values and had peak values significantly lower (P less than 0.05) than untreated LD controls at 2 hr. BG, 75 +/- 10 (SD) units per liter versus 185 +/- 32 units per liter; AST, 134 +/- 47 units per liter versus 459 +/- 175 units per liter. The BG lowering persisted to day 2 (55 +/- 25 units per liter versus 93 +/- 40 units per liter). Other values remained normal or normalized by Day 2. Hepatic damage as measured by enzyme release was not diminished by the membrane stabilizer catechin but was diminished after ischemic injury by specific targeted lysosomal protease inhibitors.

Glucose metabolism and the percentage of glucose derived from alanine: response to exogenous glucose infusion in tumor-bearing and non-tumor-bearing rats.

Glucose and alanine metabolism were investigated in non-tumor-bearing (NTB) and tumor-bearing (TB) male F344 rats after a 24-hr fast and during the infusion of either 0.9% NaCl solution or glucose at 0.67 or 2.35 mg per 100 g total body weight per min. During 0.9% NaCl solution infusion, the plasma glucose level was higher (98.2 +/- 4.0 versus 85.8 +/- 8.1 mg per di; p less than 0.05), the whole-blood lactate level was lower (5.8 +/- 0.8 versus 8.3 +/- 1.6 mg per di; p less than 0.05), the glucose turnover rate was lower (0.72 +/- 0.04 versus 0.88 +/- 0.13 mg per 100 g total body weight per min; p less than 0.05), alanine turnover rate and the percentage of glucose derived from alanine was measured by [14C]alanine in the NTB and compared to the TB animals. In response to glucose infusions, the whole-blood lactate level rose in both groups but remained lower (7.1 +/- 0.9 versus 10.5 +/- 2.4 mg per dl at 0.67 mg per 100 g total body weight per min, p less than 0.05; 9.1 +/- 1.1 versus 19.3 +/- 5.5 mg per dl at 2.35 mg per 100 g total body weight per min, p less than 0.05; NTB versus TB) in the NTB than in the TB animals. The endogenous production rate of glucose as measured by [3H]glucose displayed a similar response to exogenous substrate in the NTB and TB animals but required a higher plasma glucose concentration to effect a similar degree of suppression in the TB group. The alanine turnover rate rose to a similar level, and the percentage of glucose derived from alanine was similarly depressed in the NTB and TB animals at each glucose infusion rate.

A controlled, prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient.

In order to evaluate the metabolic effects of enteral versus parenteral nutritional support in the cancer patient, patients with localized, squamous cell carcinoma of the distal esophagus were randomized to one of three nutritional regimens: oral feeding, jejunal feeding, or total parenteral nutrition (TPN). Patients were initially studied in the postabsorptive state and again two weeks after beginning, and while receiving, enteral or parenteral feedings. Radioisotopic tracer methods were utilized to evaluate parameters of glucose and alanine kinetics, and arterial substrate and hormone levels were measured. Arterial plasma glucose and blood lactate levels increased and plasma free fatty acid, serum triglyceride, and serum cholesterol levels decreased to comparable levels in patients receiving jejunal feedings or TPN. Changes in serum insulin, plasma glucagon, serum cortisol, serum growth hormone, and serum thyroxine were similar in patients receiving enteral and parenteral nutrition. Enteral and parenteral nutrition also had comparable effects on both alanine and glucose kinetics. In particular, both jejunal feedings and TPN were equally efficacious in markedly suppressing gluconeogenesis in the cancer patient. Our data would support the conclusion that there are few, if any, differences in the measured metabolic effects of enteral venous parenteral nutritional support in the group of cancer patients studied.

Metabolic alterations in a noncachectic animal tumor system.

The increased energy expended by the host to synthesize substrate, which is utilized by the tumor, is a potential cause of cancer cachexia. In vivo glucose and alanine kinetics were examined by tracer methodology in a sarcoma-bearing rat model. The effects of 3-mercaptopicolinic acid, a potent inhibitor of gluconeogenesis, was also examined on this model. Both tumor-bearing (TB) and nontumor bearing (NTB) animals were gaining weight prior to study and the tumors were relatively small. The TB animals had significantly lower plasma glucose and higher blood lactic acid levels compared with NTB animals. After inhibition of gluconeogenesis, the plasma glucose decreased and the blood lactate increased significantly more in TB than NTB animals. The glucose turnover rate was significantly greater in TB compared with NTB animals, as was the rate of glucose recycling and the rate of gluconeogenesis (alanine leads to glucose), both energy demanding processes. These results suggest that the tumor-bearing animal, even prior to significant cachexia, has an excess demand for energy, the provision of which may be a significant factor in malignant cachexia.

Glucose turnover and gluconeogenesis during hypocaloric glucose infusion in tumor-bearing F344 male rats.

Glucose turnover ([3(3)H]glucose) and gluconeogenesis from alanine ([U-14C]alanine) were measured in non-tumor bearing (NTB) and tumor-bearing (TB) inbred F344 male rats during starvation and in response to graded levels of glucose infusion. All groups demonstrated a glucose turnover appropriate to the prevailing steady-state plasma glucose level. Whereas NTB animals exhibited maximal suppression of gluconeogenesis from alanine at infusion rates of 0.39 mg/100 g total body weight/minute, TB animals suppressed alanine-to-glucose conversion only at a glucose infusion rate of 0.71 mg/100 g total body weight/minute. Glucose clearance was consistently higher in TB groups but did not change in either NTB or TB groups during infusion. Blood lactate levels increased in response to glucose infusion only in TB animals. These results suggested that starved TB animals obligately utilized more glucose than did NTB controls but were able to adjust turnover appropriately to plasma glucose levels. However, gluconeogenesis was suppressed only at higher glucose infusion rates in TB rats compared to NTB animals.

Amino acid deficiency and the skin rash associated with glucagonoma.

A 47-year-old white man had a malignant glucagonoma and severe necrolytic migratory erythema. His plasma glucagon levels were markedly elevated at 50 ng/mL and plasma amino acids diminished to 45% of normal. To test the hypothesis that the skin rash associated with a glucagonoma is secondary to an amino acid deficiency, we obtained 2 d of fasting baseline laboratory data from the patient while he consumed his usual diet. He was then given 3 L/d of supplemental intravenous amino acids for 3 d. His plasma amino acid levels increased slightly, and there was some improvement in his skin rash. Immediately thereafter, total parenteral nutrition was administered for 3 d without added zinc or fatty acids. During total parenteral nutrition, 14 of 17 plasma amino acids became normal, and the patient's skin rash rapidly disappeared. These findings suggest that the skin rash associated with a glucagonoma is most likely due to an amino acid deficiency and can be reversed by parenteral nutrition.

Antibiotic concentration in human wound fluid after intravenous administration.

Since the wound is the most common focus of infection in the surgical patient, adequate levels of antibiotic within the wound ar essential. This study examines the concentrations of antibiotic achieved in human wounds. Fluid was collected at timed intervals on the first postoperative day from the wounds of 56 patients receiving antibiotics after regional lymph node dissection. Antibiotic concentration was determined by bioassay. Six antibiotics were studied: cephalothin, cefazolin, cephapirin, oxacillin, ampicillin and clindamycin. The cephalosporins and penicillins showed similar patterns of appearance in the wound fluid. The peak level occurred early (1--1 1/2 hours) with subsequent slow decrease. Clindamycin produced nearly constant levels in wound fluid. The concentration of each antibiotic in wound fluid surpassed the serum levels after 2.5 hours. At the dosages studied each antibiotic produced wound fluid concentrations greater than the MIC for most susceptible organisms. Higher doses provided higher wound fluid levels. The rate of appearance and the levels achieved should be considered in the choice of antibiotics in the surgical subject.