Effect of nutritional status and 5-fluorouracil on protein synthesis in parenterally alimented LEW/Mai rats.

LEW/Mal rats bearing transplantable adenocarcinomas were maintained parenterally for 4 days on 1) a regimen adequate in amino acids and glucose and 2) severely hypocaloric glucose. Rats from both groups were given 17.5 mg 5-fluorouracil (FUra)/kg/day as a continuous infusion for 3 days. Cumulative nitrogen balance, fractional tissue protein synthesis rates, and liver and muscle distribution of FUra and its metabolites were determined. Results were compared to those found with a series of control rats that were not treated with FUra. No changes attributable to FUra were found in the starved rats (1.25 g glucose/day). In the fed rats (15 g glucose plus 2.5 g amino acids/day), FUra decreased the liver and diaphragm fractional protein synthesis rates and the nitrogen retention.

Alteration in pyruvate metabolism in the liver of tumor-bearing rats.

Weight loss associated with tumor burden has been postulated to be due to an energy imbalance resulting from increased hepatic gluconeogenesis secondary to Cori cycle activity. The mechanisms which control pyruvate metabolism are inherent to the control of gluconeogenesis in the liver. Therefore, the metabolism of pyruvate was evaluated in a transplanted tumor model in rodents which has previously shown an increased rate of hepatic gluconeogenesis. Female Lewis-Wistar rats received a s.c. injection of a suspension of mammary tumor cells in the left flank. Tumor-bearing rats were allowed ad libitum food consumption, and non-tumor-bearing controls were pair-fed to the consumption of their tumor-bearing cohorts. At Days 12, 13, and 14 following inoculation, tumor-bearing and non-tumor-bearing controls were used for in vivo body composition analysis or subjected to isolated liver perfusion. Animals were not fasted prior to sacrifice. Pyruvate use by the livers of tumor-bearing and pair-fed non-tumor-bearing rats was evaluated in the presence of 8 mM glucose and 5 mM lactate. Pyruvate clearance was increased by 270%, and pyruvate intake was increased by 212% compared to pair-fed non-tumor-bearing rats. Oxidation of pyruvate to CO2 was increased 130%, and pyruvate conversion to lactate was increased by 197% above that seen in pair-fed non-tumor-bearing rats. Gluconeogenesis from pyruvate was increased by 184% in tumor-bearing rats. The increased gluconeogenesis in tumor-bearing rats above that of control animals at a 5 mM lactate concentration suggests that some factor, other than substrate supply, may stimulate gluconeogenesis in tumor-bearing rats. Although the use of pyruvate was greater in tumor-bearing rats, the disposal of pyruvate carbon into CO2, lactate, and glucose was proportionally the same in both groups. Therefore, these data suggest that the increased metabolism of pyruvate in tumor-bearing rats is controlled by a mechanism affecting cellular pyruvate transport.

The treatment of anorexia nervosa with total parenteral nutrition.

Treatment outcome of 11 anorectic patients receiving total parenteral nutrition (TPN) is compared with outcome of anorectic patients receiving standard behaviorally oriented inpatient therapy. TPN resulted in significantly more rapid weight gain. Most patients could be successfully weaned from TPN to enteral feeding with continued weight gain. Complications during TPN were common including transaminase elevations and electrolyte imbalance. There was one death in the series. The role of TPN in the management of anorexia nervosa is discussed.

The link between nutritional status and clinical outcome: can nutritional intervention modify it?

Most clinicians subjectively feel that malnutrition in surgical patients is associated with poor clinical outcome. This overview provides a chronologic review of studies relating poor nutritional status to increased surgical morbidity. Techniques for identifying surgical patients with clinically important nutritional deficits are discussed. Retrospective and/or non-randomized clinical studies evaluating the efficacy of perioperative forced feeding are reviewed. These data suggest a possible role for preoperative nutritional support of selected malnourished surgical candidates and provide the rationale for a large-scale nutrition-intervention clinical trial.

Interval nitrogen excretion and maintenance nitrogen requirements for parenteral nutrition in primates.

This paper discusses a regression technique for determining maintenance nitrogen requirements in well-nourished primates (M fascicularis) on total parenteral nutrition. Animals were administered a continuous glucose infusion, and parenteral nitrogen intake was varied at constant time intervals in a random order (from 0 to 1 g nitrogen/kg/day). Interval nitrogen balance (intake minus urinary nitrogen output) was plotted against interval nitrogen intake. The x-intercept was defined as the maintenance nitrogen requirement. First, 24-h intervals were used at a nonprotein caloric intake of 85 kcal/kg/day (approximately 175% of primate resting energy expenditure) and the nutritional adequacy of the estimated requirement evaluated prospectively. Next, 8-h balance intervals were used and the maintenance nitrogen requirements predicted by this abbreviated technique were compared to those obtained using the longer method. Finally, the short-interval technique was repeated at two other levels of continuous glucose infusion (60 kcal/kg/day and 8 kcal/kg/day) and the effect on predicted nitrogen requirement examined. Maintenance parenteral nitrogen requirements for primates may be determined in 48 h using the abbreviated techniques.

The relationship of serum cholesterol and vitamin A in hospitalized patients with and without cancer.

Interrelationships among circulating levels of cholesterol, vitamin A, and selected transport proteins, as well as other nutritional variables were examined in a large population of hospitalized cancer (CA, n = 94) and noncancer (NONCA, n = 432) patients in order to help clarify a relationship between serum cholesterol and vitamin A. Serum cholesterol and vitamin A levels were positively correlated (r = 0.39; p less than 0.001) in both CA and NONCA groups. One hypothesis that might explain such a relationship was investigated. Results suggest that serum-transport protein levels and nutritional status are important factors that lead to a correlation between serum cholesterol and vitamin A by virtue of their mutual associations with both substances. Results suggest also that NONCA patients may have a more complex relationship of variates to serum-vitamin A levels than CA patients and that low levels of both cholesterol and vitamin A in CA patients may be related more to nutritional status than to the presence of cancer.

Effect of parenteral nutrition on protein synthesis in adult cancer patients.

The rate of whole body protein synthesis was measured with 15N glycine in three groups of subjects: 1) normal healthy adult controls, 2) semistarved adult patients with upper gastrointestinal tract malignancies and, 3) a group of patients similar to 2) except they were maintained parenterally on a regimen adequate in amino acids and glucose. By comparing the patient results with data obtained from rat studies with 15N glycine were concluded that the patients were protein rather than energy depleted.

Weight gain and nutritional efficacy in anorexia nervosa.

To evaluate the usefulness of interval weight change in assessing nutritional support efficacy, we studied four anorexia nervosa patients (52% ideal body weight) requiring long-term total parenteral nutrition (TPN) for 63 +/- 18 days. Fluid and electrolyte deficits were corrected before the initiation of nutritional support. Resting energy expenditure was measured before the initiation of TPN and weekly thereafter, using indirect calorimetry. Daily caloric expenditure was estimated at 1.1 X resting energy expenditure, based on previous studies of continuous heart rate monitoring in this patient population. Daily excess calories were calculated as caloric intake minus caloric expenditure. Each patient was weighed daily and linear regression analysis (excess calories versus weight change) was performed for individual patients and the group over intervals of varying length. There was no individual or group correlation between excess calories and weight gain on a daily or weekly interval basis. Cumulative weight changes over the long-term course of TPN correlated significantly with cumulative excess calories for each patient and the whole group (r = +0.82, p less than 0.01). The excess calories required to gain a kilogram body weight ranged from 5569 to 15619 kcal/kg with a mean of 9768. Cumulative long-term weight changes during nutritional repletion in anorexia nervosa are meaningful indicators of caloric balance, but short interval weight changes (daily, weekly) are not. The caloric cost of weight gain is variable in this population.

A randomized clinical trial of total parenteral nutrition in malnourished surgical patients: the rationale and impact of previous clinical trials and pilot study on protocol design.

The rationale for a large-scale clinical trial of preoperative total parenteral nutrition (TPN) is described in the context of previous clinical trials that have attempted to demonstrate reduction of operative morbidity with preoperative TPN. Defects in study design or execution potentially compromising the validity of these studies are analyzed. Results of a single-institution pilot study performed during the planning phase of the multiinstitutional preoperative TPN trial are presented. This literature review and pilot study provided the data necessary to permit appropriate design of many critical elements in the protocol for the clinical trial including sample size, eligibility criteria, duration and intensity of treatment regimens, and end-point criteria. The rationale underlying critical decisions in protocol design are presented in detail to allow more meaningful interpretation of the results of the clinical trial.

Measuring the economic impact of perioperative total parenteral nutrition: principles and design.

Although the use of total parenteral nutrition (TPN) has been increasing in recent years, few studies have been performed on both its costs and its effectiveness or benefits. This paper provides a general review of the methods of cost-effectiveness and cost-benefit analysis, summarizes briefly the existing cost-analysis studies of TPN, and outlines the authors' proposed study design for their economic assessment of TPN.

Study protocol: a randomized clinical trial of total parenteral nutrition in malnourished surgical patients.

CSP #221 is a randomized multiinstitutional clinical trial to assess the efficacy of 10 d of perioperative total parenteral nutrition (TPN) in reducing morbidity and mortality in malnourished patients undergoing intraperitoneal and/or intrathoracic operations. In this paper a detailed protocol for the clinical efficacy trial is presented primarily as a reference document for use in interpretation of the results of the clinical trial. It is also anticipated, however, that review of this protocol may be useful to other investigators planning future clinical nutrition intervention trials.

(Mercaptopropanoyl)indoline-2-carboxylic acids and related compounds as potent angiotensin converting enzyme inhibitors and antihypertensive agents.

1-(3-Mercapto-2-methyl-1-oxopropyl)indoline-2-carboxylic acids (7b) and related compounds were synthesized in order to examine their ability to inhibit angiotensin converting enzyme (ACE) and to reduce the systolic blood pressure of spontaneously hypertensive rats (SHR). All four possible stereoisomers of the precursor 1-[3-(benzoylthio)-2-methyl-1-oxopropyl]indoline-2-carboxylic acid (6b) were characterized with absolute stereochemical assignment. The removal of the benzoyl group of the precursor to give 7b was conveniently carried out by treatment with 2-methoxyethylamine. Three of the four stereoisomers of the benzoyl derivative 6 showed in vitro ACE inhibitory activity in the following order: 6b(S,S) greater than 6b(S,R) greater than 6b(R,S). The stereoisomer having the R,R configuration was essentially inactive. The substitution at the C5 of the indoline nucleus with the Et or OMe group caused only marginal changes in the inhibitory activity. The mercaptan 7b(S,S) was the most active ACE inhibitor synthesized in this study, showing in vitro potency 3 times that of captopril. The augmentation of the potency may be due to the increased hydrophobicity of 7b(S,S) compared with captopril and suggests the presence of a hydrophobic pocket at the active site of ACE. When tested in spontaneously hypertensive rats, 7b(S,S) exhibited oral antihypertensive activity 27 times that of captopril. The corresponding benzoyl derivative 6b(S,S) was 24 times as potent as captopril. The thio lactone 10 obtained by cyclization of 7b(S,S) as a potential prodrug was less potent than the parent compound, 7b(S,S), in the ACE inhibitory and antihypertensive tests.

Comparison of eligible randomized patients with two groups of ineligible patients: can the results of the VA Total Parenteral Nutrition clinical trial be generalized?

The recently reported VA Cooperative Study "A Randomized Clinical Trial of Total Parenteral Nutrition (TPN) in Malnourished Surgical Patients" randomized 395 pre-operative patients to TPN treatment or control. The study concluded that the use of perioperative TPN should be limited to the most severely malnourished patients. The study also followed 233 patients eligible for the study who refused to give informed consent for randomization (Eligible Refusers) as well as 1220 patients who were ineligible because they were not sufficiently malnourished (Index Group). Patients in the Index Group were determined to be significantly healthier than those in the two eligible groups of patients. Those in the Eligible Refuser group were shown to be slightly less malnourished than the Randomized Patients. The 395 patients randomized to the study (Randomized Patients) showed the highest rate of septic complications at 30 days and at 90 days (10% and 13% respectively) with rates for the Eligible Refusers slightly lower (8% and 9%) and Index Group rates still lower (4% and 4%). Nonseptic complication rates showed the same pattern (19% and 22% for the Randomized group, 12% and 12% for Eligible Refusers, and 10% and 10% for the Index Group). Because (a) the beneficial effect of TPN is attained only in severely malnourished patients, (b) there is increased risk of septic complications with TPN use in patients not severely malnourished, (c) Index Group patients, and presumably the population of patients from which they are drawn, are not severely malnourished, it follows that unless specifically indicated, TPN should not be used in nonseverely malnourished patients.

Factors associated with a positive reexcision after excisional biopsy for invasive breast cancer.

BACKGROUND: Breast-conserving therapy followed by adjuvant radiotherapy represents an alternative to mastectomy as a treatment for invasive breast cancer. When excisional biopsy has been performed outside the parent institution, reexcision is often performed, with tumor being identified in 32% to 62% of the subsequent specimens. We analyzed not only the factors associated with a positive reexcision but also those factors associated with final surgical margins that are positive for tumor. METHODS: Between 1978 and 1991, 956 female patients with American Joint Committee on Cancer clinical stage I or II breast cancer were treated with breast-conserving therapy where a total of 420 patients underwent reexcision after an initial excisional biopsy. Several factors were analyzed to determine their association with a positive reexcision, the status of the final surgical margin, and the nature of the disease present within the reexcision specimen. RESULTS: Factors that correlated with a positive reexcision in both univariate and multivariate analysis were clinical tumor size, method of detection, the pathologic status of the axillary lymph nodes, and the histologic appearance. Those factors associated with finding invasive disease at the time of reexcision were clinical tumor size, clinical presentation, and nodal status. The single factor associated with finding residual in situ disease at the time of reexcision was histologic appearance of the primary tumor. A final positive margin was associated with method of tumor detection, age of the patient, and the presence of axillary lymph node metastases. CONCLUSIONS: The most significant factors associated with a positive reexcision are clinical tumor size, method of tumor detection, pathologic nodal status, and histologic appearance. Patients with larger tumors or those that are detected by physical examination, as well as invasive lobular carcinomas, may require a more generous initial resection to achieve negative surgical margins and avoid the likelihood of reexcision.

Protein synthesis dynamics in human gastrointestinal malignancies.

The malnourishing effects of cancer and its treatments haveprovided a strong clinical incentive for the nutritional support of cancer patients with intravenous hyperalimentation (IVH), but potential enhancement of tumor growth by additional substrate provision has generated concern. Twenty-five patients undergoing surgical treatment for gastrointestinal cancer were studied on one of two preoperative dietary regimens: ad libitum oral diet or intravenous hyperalimentation. Using a stable isotope tracer, N-glycine, in vivo tissue fractional protein synthesis rates were determined from operative specimens of tumor and normal gastrointestinal tissue. Despite substantial advantage in caloric and protein intake, and nitrogen retention, tumors in IVH-fed patients were synthesizing protein no faster (14.2%/day) than those in orally fed patients (15.1/day). Tumor fractional protein synthesis rates (PSRs) correlated (r = + 0.708, P less than 0.005) with the PSR of the tissues from which they arose. IVH maintained gut PSR at the level occurring in the orally fed patients. Parenteral nutritional support in cancer patients does not maintain protein synthesis rates at levels greater than those present with regular oral diets. Although not a direct measure of tumor growth, these data provide preliminary evidence that optimal nutritional support of the cancer patient may be possible without undesirable stimulation of tumor growth.

Adjuvant, pulse total parenteral nutrition and tumor response to cycle-specific and cycle-nonspecific chemotherapy.

Previous work has demonstrated that substrate-induced alterations of tumor metabolism can be exploited to enhance tumor response to a cycle-specific chemotherapeutic agent (methotrexate). This study was designed to further investigate the biologic mechanism of this phenomenon by determination of tumor response to additional cycle-specific (Adriamycin) and cycle-nonspecific (Cytoxan) chemotherapeutic agents. Significant potentiation of tumor response during adjuvant total parenteral nutrition (TPN) was observed with methotrexate and Adriamycin but not with Cytoxan. This may imply that tumor sensitization by adjuvant TPN occurs by acceleration of the growth rate of proliferating tumor cells and not by recruitment of dormant tumor cells into the cell cycle.

Implications of malnutrition in the surgical patient.

The substantial prevalence of malnutrition in the hospitalized patient population has only been recently recognized. Preoperative nutritional and immunological assessment was performed prospectively on admission in 64 consecutive surgical patients. Factors measured included weight loss, triceps skinfold, midarm muscle circumference, creatinine-height index, serum albumin level, serum transferrin level, total lymphocyte count, serum complement level, serum immunoelectrophoresis, lymphocyte T rosettes formation, neutrophil migration, and delayed hypersensitivity. Using these criteria for malnutrition, 97% of the patients had at least one abnormal measurement and 35% had at least three abnormal measurements. Patients were monitored for complications during their hospital course. Serum albumin level, serum transferrin level, and delayed hypersensitivity reactions were the only accurate prognostic indicators of postoperative morbidity and mortality. Substantial unrecognized malnutrition exists in the surgical patient population. An isolated indicator of malnutrition should be interpreted with caution. The visceral protein compartment (serum albumin and serum transferrin levels and delayed hypersensitivity) is the most accurate prognostic indicator of postoperative morbidity and mortality. Perioperative nutritional support may reduce operative morbidity and mortality in the malnourished operative candidate.

Changing presentation and management of neutropenic enterocolitis.

OBJECTIVE: To characterize the current clinical presentation and management of neutropenic enterocolitis. DESIGN: Retrospective review of records of oncology unit patients requiring general surgical consultation for abdominal complaints in a 1-year period. SETTING: Oncology unit of a tertiary care, university teaching hospital. PATIENTS AND INTERVENTIONS: Fourteen patients diagnosed as having neutropenic enterocolitis were managed conservatively with operation reserved for failure of conservative therapy. MAIN OUTCOME MEASURES: Clinical data from patients at the time of presentation and during treatment for neutropenic enterocolitis. RESULTS: All 14 patients diagnosed as having neutropenic enterocolitis were receiving chemotherapy for solid tumors or leukemias. Seven patients were undergoing stem cell or autologous bone marrow transplantation. Presenting symptoms and physical examination findings were nonspecific. All patients except one had neutropenia at the time of diagnosis. Computed tomographic scans of the abdomen were the most useful confirmatory study for the diagnosis of neutropenic enterocolitis. All patients except one had resolution of neutropenic enterocolitis with conservative therapy. One patient whose course of conservative management failed had protracted neutropenia and required operation for resection of bowel with full-thickness necrosis. CONCLUSIONS: Neutropenic enterocolitis has evolved from a complication of patients with leukemia to a disease of patients receiving high-dose chemotherapy for many malignancies, solid as well as hematologic. Diagnosis of neutropenic enterocolitis continues to be a challenge, as patients typically present with nonspecific gastrointestinal tract symptoms. Neutropenia and computed tomographic scan findings are useful adjuncts in diagnosing neutropenic enterocolitis. Timely conservative treatment frequently allows resolution of neutropenic enterocolitis without operation.

Energy expenditure in malnourished patients with colorectal cancer.

To evaluate energy expenditure in patients who have colorectal cancer with varying stages of disease and to examine the possible determinants of energy expenditure in a group of patients with cancer who have the same type of tumor, we studied 73 patients with biopsy proven and pathologically staged adenocarcinomas of the colon and rectum. Resting energy expenditure (REE) was measured by indirect calorimetry and compared with predicted energy expenditure (PEE), which was calculated from the Harris-Benedict formulas. Nutritional and tumor characteristics were examined. Forty-nine percent of patients had abnormal REE (normal = PEE +/- 10%). One quarter of the patients were hypometabolic (REE less than 90% PEE). The abnormalities persisted despite normalization of REE to metabolic body size (kg0.75) or predicted values based on weight, height, age, and sex. There were no differences in nutritional status, as judged by the percent of weight loss and visceral protein levels, between those patients in the hypometabolic, normometabolic, or hypermetabolic categories, and there were no significant relationships between energy expenditure and the tumor burden. The mean duration of disease in the normometabolic group was 4.5 months, while the hypometabolic and hypermetabolic groups had mean durations of 9.5 and 14.2 months, respectively. The tumor site and duration of the disease are important variables in studies of energy expenditure in patients with cancer.

Alterations in exogenous substrate metabolism in sepsis.

Metabolic rates and substrate utilization patterns were evaluated by using a rate cecal ligation and perforation model. Animals that survived for 48 hours after the induction of sepsis were hypermetabolic and responded appropriately to varying exogenous substrate infusions. In contrast, animals that did not survive to 48 hours were premorbidly hypometabolic and failed to adjust their oxidation patterns in response to the exogenous substrate supply. These findings suggest the benefit of individually tailoring the supply of exogenous nutrients in critically ill patients with sepsis and of frequent reassessment of metabolic parameters, including the resting energy expenditure and respiratory quotient.