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Background: Breast magnetic resonance imaging (MRI) is a developing technique for the evaluation of patients with primary breast carcinoma. The authors assessed the impact of preoperative breast MRI on surgical management., Methods: The current study was a retrospective review of 267 patients with primary breast tumors who had MRI studies prior to undergoing definitive surgery., Results: Two hundred sixty-seven patients with invasive breast carcinoma who had preoperative breast MRI studies and had complete clinical, radiologic, and pathologic data available were identified and formed the basis of this analysis. The overall sensitivity of MRI for detecting primary, intact breast tumors was 95%. Planned surgical management was altered in 69 of 267 patients (26%); and, in 49 of those patients (71%), there was pathologic verification of malignancy in the surgical specimen that confirmed the need for wider or separate excision or mastectomy. Forty-four of 267 patients (16.5%) had conversion of planned breast conservation to mastectomy. In a univariate analysis, change in management was associated significantly with histology; management was altered in 11 of 24 lobular tumors (46%) compared with 58 of 243 ductal tumors (24%; P = 0.02)., Conclusions: Breast MRI was very sensitive for the detection of primary, intact, invasive breast carcinoma and improved local staging in almost 20% of patients. Preoperative breast MRI studies may be particularly useful in surgical planning for and management of patients with lobular carcinoma., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11490)

Background: Choline has recently been recognized as an essential nutrient, in part based on deficiency data in long-term home total parenteral nutrition (TPN) patients. Choline, a methyl donor in the metabolism of homocysteine, is intricately related to folate status, but little is known about choline and vitamin B12 status. Long-term TPN patients are also subject to vitamin B12 deficiency., Objective: The objective of the study was to evaluate any interaction between choline, vitamin B12, and folate in patients with severe malabsorption syndromes, requiring long-term TPN., Design: Plasma free choline, serum and red blood cell (RBC) folate, serum vitamin B12 methylmalonic acid, B6, and plasma total homocysteine concentrations were assayed by standard methods. Low choline was defined as values that fall 1 to < or =3 and marked low choline concentration as >3 SD below the control mean., Results: Both low choline concentrations (52% were marked low, 33% low, 14% normal) and elevated methylmalonic acid concentrations (47%) were prevalent. Choline concentration was significantly lower and RBC folate higher in patients with elevated methylmalonic acid. Total homocysteine elevations were rare (3 of 21) and mild., Conclusions: These data suggest a strong interaction between vitamin B12 and choline deficiencies and folate status in this population, which may be due in part to variations in vitamin and choline delivery by TPN. Folate adequacy may increase B12 use for homocysteine metabolism, thus limiting B12 availability for methylmaIonic acid metabolism. Choline use may also increase, and choline deficiency may worsen if choline substitutes when the vitamin B12 side of the homocysteine metabolic pathway cannot be used.

This article reviews nutritional considerations that arise in the care of patients with Crohn's disease. The causes and presentation of malnutrition in these patients are discussed, and a rational method is presented for comprehensive nutritional assessment. The indications for nutritional intervention, either as supportive or primary therapy for Crohn's disease, are reviewed.

Background: Hyperhomocysteinemia is associated with venous thrombosis and vitamin deficiency. Patients with short bowel syndrome have increased risk of venous thrombosis due to central catheters, and of vitamin deficiency due to malabsorption. The current investigation was designed to evaluate the relationship between history of venous thrombosis and current hyperhomocystinemia and vitamin deficiency in patients with short bowel syndrome., Methods: Plasma total homocysteine (tHcy), serum vitamin B12, folate, B6, and methylmalonic acid (MMA) were measured. Venous thrombosis was documented by venogram or ultrasound., Results: Ten of 17 patients had venous thromboses, including 17 of 38 observed superior and 12 of 26 inferior veins. Total homocysteine was correlated with number of thromboses. The relative risk of multiple thromboses in the highest tHcy tertile was 3.6-fold that of the lowest tertile. Vitamin B12 and folate levels were within normal limits, but B12 deficiency by MMA or tHcy level was apparent in 7 patients. Vitamin-deficient patients had higher tHcy and MMA than those without deficiency., Conclusions: Venous thrombosis in patients with short bowel syndrome is related to hyperhomocystinemia, which is also related to vitamin B12 deficiency, not detected by serum vitamin B12 concentration. Whether treatment of vitamin deficiencies and associated reduction in tHcy will reduce recurrent venous thrombosis in these patients is not known.

The purpose of this study was to determine the efficacy, engraftment kinetics, effect of bone marrow tumor contamination, and safety of high-dose therapy and granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) support for patients with responding metastatic breast cancer. Forty two patients underwent G-CSF (10 microg/kg) stimulated PBPC harvest. PBPC and bone marrow aspirates were analyzed by histologic and immunocytochemical methods for tumor contamination. Thirty-seven patients received high-dose therapy consisting of cyclophosphamide 6 g/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) given as an infusion over 4 d followed by PBPC reinfusion and G-CSF (5 microg/kg) support. No transplant related deaths or grade 4 toxicity was recorded. CD34+ cells/kg infused was predictive of neutrophil and platelet recovery. With a median follow-up of 38 months, three year survival was 44% with relapse-free survival of 19%. Histological bone marrow involvement, found in 10 patients, was a negative prognostic factor and was associated with a median relapse-free survival of 3.5 months. Tumor contamination of PBPC by immunohistochemical staining was present in 22.5% of patients and found not to be correlated with decreased survival. G-CSF stimulated PBPC collection followed by a single course of high dose chemotherapy and stem cell infusion with G-CSF stimulated marrow recovery leads to rapid, reliable engraftment with low toxicity and promising outcome in women with responding metastatic breast cancer.

Background: High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy., Patients and Methods: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients., Results: Overall and disease-free survival rates at 18 months were 83% (+/- 4%) and 77% (+/- 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation., Conclusion: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

We have described numerous alternatives for establishing central venous access in challenging patients. Using these techniques has proven successful in our experience in essentially all patients, although occasionally initial efforts fail and repeated attempts by alternate routes are required. The keys to eventual success appear to be good basic surgical skills, a strong working relationship between surgeon and interventional radiologist, and perhaps most important, perseverance in the face of frustration.

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.

An economic analysis accompanied a multicenter Department of Veterans Affairs randomized, controlled trial of perioperative total parenteral nutrition (TPN). The cost of providing TPN for an average of 16.15 days before and after surgery was $2405, more than half of which ($1025) included costs of purchasing, preparing, and delivering the TPN solution itself; lipid solutions accounted for another $181, additional nursing care for $843, and miscellaneous costs for $356. Prolonged hospital stay added another $764 per patient to the $2405 cost of providing TPN, bringing the total to $3169. The incremental costs attributed to perioperative TPN were highest ($3921) for the patients least likely to benefit, that is, those who were less malnourished and at low risk of nutrition-related complications. Incremental costs were lowest ($3071) for high-risk patients. On the basis of the hospital-based method of administering TPN that was used in the clinical trial, perioperative TPN did not result in decreased costs for any subgroup of patients.

The past decade has seen a maturation of the art and science of perioperative nutritional support. We now have sufficient data to make informed and reasonable judgments regarding when we should and should not provide perioperative TPN. These judgments can be considered medically sound and fiscally responsible. The following guidelines are proposed: (1) Postoperative TPN should be considered when oral or enteral feeding is not anticipated within 7 to 10 days in previously well-nourished patients or within 5 to 7 days in previously malnourished or critically ill patients. (2) Preoperative TPN should be considered in patients who cannot or should not eat or receive enteral feedings if the operation must be delayed for more than 3 to 5 days. (3) Preoperative TPN should be considered in the most severely malnourished surgical candidates if an operative delay is not contraindicated. In patients with only mild to moderate degrees of malnutrition preoperative TPN is not indicated.

To evaluate the efficacy of nonglucose energy substrates in promoting nitrogen retention and survival in stressed states, two series of studies were done. In study 1, 50 rats underwent cecal ligation/perforation and subsequent infusion for 24 hr with one of four isocaloric (220 kcal/kg/day), isonitrogenous (1.4 g/N/kg/day), isovolemic regimens which differed in caloric source: Glucose (GLU) + long-chain triglycerides (LCT) (50%:50%), GLU + LCT + medium-chain triglycerides (MCT) (50%:32%:18%), GLU + LCT/Carnitine (10 mg/dl) or GLU + LCT + Xylitol (XYL) (33%:33%:33%). The nitrogen-sparing effect of GLU + LCT was not enhanced by the addition of carnitine to facilitate LCT mitochondrial uptake or by MCT to bypass carnitine-dependent transport. In contrast, relative to GLU + LCT GLU + LCT + XYL decreased urinary 3-methylhistidine (3MH) excretion (p less than 0.01), and enhanced nitrogen retention (p less than 0.01 vs GLU + LCT). For study 2, 24 male rats were anesthetized, cannulated for TPN, and given a 25% burn. They were then randomized into three dietary groups. The diets were isocaloric (103 kcal/kg/day) and isonitrogenous (2.0 g N/kg/day) but differed in nonprotein calorie source: GLU + LCT (51%:49%), GLU + Glycerol (51%:49%) and XYL + LCT (51%:49%). As in the septic animals, N balance was best with the xylitol regimen (p less than 0.01). The polyol, xylitol, appears to have a significant nitrogen sparing effect in stressed animals.

Pharmacologic therapy designed to block adrenergic activity or alter hormonal milieu may modulate energy and protein metabolism in stress. The metabolic effects of propranolol (beta adrenergic receptor blocker) in sepsis was investigated in 22 well-nourished rats that underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 0.7 mg/day of propranolol combined with parenteral nutrition (n = 11) or parenteral nutrition alone (n = 11). Both groups received isocaloric, isonitrogenous, isovolemic, parenteral nutrition post-operatively for 24 hr. Nitrogen balance was better for the propranolol group than for the control group (+743 +/- 84 mg/kg/day versus +300 +/- 63 mg/kg/day, respectively, P less than 0.05). A significant difference between the pharmacologic therapy and control groups was noted for urinary 3-methylhistidine excretion versus control (0.99 +/- 0.08 micrograms/kg/day versus 7.5 +/- 0.37 micrograms/kg/day, respectively, P less than 0.01). Measured energy expenditure was similar for both pharmacologic therapy and control groups (149 +/- 20 kcal/kg/day versus 134 +/- 11 kcal/kg/day, respectively, P = N.S.). No statistically significant difference was demonstrated for 24-hr survival between propranolol and control groups (73 and 64%, respectively). Continuous, low-dose propranolol promotes nitrogen retention and decreases 3-methylhistidine excretion without altering energy expenditure in parenterally fed septic rats.

We studied the effect of parenteral nutrition with amino acids and hypertonic glucose on protein synthesis and liver fat metabolism. Patients with operable gastrointestinal tract malignancies were divided into two groups. Group I ate the hospital diet ad libitum for the 7-10 days preceding surgery. Group II were given adjuvant parenteral nutrition (APN) for 7-10 days prior to the surgical removal of the tumor. Daily nutrient intake and nitrogen balance were determined. [15N[glycine (1-2 g) was infused at a constant rate for 12-18 prior to surgery. During surgery, blood, liver, and muscle specimens were taken for 15N analysis. Fractional protein synthesis rates were estimated by the method of Garlick et al. (Biochem. J. 136: 935-945, 1973). The fat content and distribution pattern in the liver was determined by gas chromatography-mass spectrometry. The following results were found. 1) APN increaed the albumin synthesis rate. 2) The fraction of linoleate in the total liver fatty acids were reduced by 75% in the APN patients. 3) Some of the APN patients developed fatty livers during the study. When the APN patients were subdivided on the basis of whether they had fatty livers, it was found that only those patients who did not accumulate fat showed an improvement in their plasma albumin concentration during the period of parenteral nutrition.

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.

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.

Protein and energy metabolism were investigated in acutely septic rats. Rats were made septic by cecal puncture and ligation. For the next 24 h they were given one of five parenteral formulations differing only in the nonprotein calorie source. The five calorie sources were 1) glucose, 2) long-chain triglycerides (LCT), 3) a 27:73 mixture of medium- and long-chain triglycerides (M/LCT), 4) a 50:50 mixture of glucose plus LCT, and 5) a 50:50 mixture of glucose plus the M/LCT mixture. The formulations also contained amino acids at a calorie:ratio of 165:1. The results were that N retention was greater with the glucose plus LCT mixture than with glucose alone. With this mixture, N retention increased as calorie intake increased, whereas with glucose, N retention plateaued. In spite of the high glucose load given to the glucose-only groups, there was a significant reduction in endogenous fat in peripheral depots. Lipid loss was least with the glucose plus LCT combination. The M/LCT mixture given alone or with glucose resulted in significantly lower survival rates.

To establish the subhuman primate as an effective laboratory animal in parenteral nutrition research, 18 male macaque monkeys were adapted to chronic chair restraint and maintained on intravenous nutrition for 1- and 2-week periods. The animals remained in the restraint chairs for 11.6 +/- (2.3) weeks and the inferior vena cava catheters remained for 53 +/- (7.8) days. Catheter and metabolic complications during intravenous nutrition infusion were few and morbidity was low. The animals maintained weight, serum albumin, and serum transferrin levels as well as a positive nitrogen balance during the study period. The macaque is a highly suitable model for nutritional studies requiring a controlled environment during long-term studies.

Exogenous nutrient administration has been shown to significantly stimulate tumor growth in numerous animal models. The present study was performed to determine if substrate-induced alterations in tumor metabolism could be exploited to potentiate tumor response to cycle-specific chemotherapy. Following subcutaneous mammary tumor (AC-33) implantation, 55 female Lewis/Wistar rats were randomly assigned to one of three nutritional regimens for 48 hr: (1) protein-depleted chow (0.03% protein) ad lib per os, (2) standard rat chow (22.0% protein) ad lib per os, or (3) total parenteral nutrition (TPN; 18.6% dextrose/2.8% amino acids). One-half of the animals in each group received a single dose of methotrexate (5 mg/kg im) while the remaining animals received placebo (saline) injections. At sacrifice, methotrexate-treated animals receiving TPN demonstrated a significantly smaller tumor volume (0.47 +/- 0.44 cm3) compared to animals given either protein depleted chow (1.30 +/- 0.76 cm3) or standard rat chow (1.34 +/- 0.83 cm3) (P less than 0.01). In this animal model, adjuvant TPN was found to significantly potentiate tumor response to cycle-specific chemotherapy with no detectable exacerbation of host toxicity.

Protein and fat metabolism were studied in fed and protein-depleted rats. The rats were given one of three isocaloric, isonitrogenous nutrient mixes parenterally. The nutritional regimens differed in the source of nonprotein calories: i) glucose, ii) an emulsion containing long-chain fatty acid triglyceride esters (LCT), and iii) an emulsion containing both LCTs and medium-chain fatty acid triglycerides (MCT). Nitrogen balance, protein synthesis and breakdown, fat deposition in the liver, and the periuterine fat pads were measured using [15N]glycine as the tracer for the protein metabolism and deuterium for the lipid studies. Results are as follows. i) Nitrogen retention and protein synthesis were greater in the fed rats treated with glucose than with LCT. ii) Nitrogen fluxes were lower with LCT than with glucose. iii) Extensive lipogenesis in the liver was only found with the glucose-treated rats. iv) None of the caloric regimens promoted lipogenesis in the periuterine fat pads. v) With the two lipid-containing regimens there was a relative depletion of the depot fat in the periuterine fat pads relative to their glucose-treated counterparts. v) Although the MCT-containing emulsion did not cause hepatomegaly, its apparent caloric effectiveness was lower than that of either glucose or LCT. vi) Chain elongation is not a major pathway for MCT metabolism in parenterally nourished rats.

A consensus definition of malnutrition does not exist. We define "clinically relevant malnutrition" as the state of altered nutritional status that adversely affects clinical outcome. Over four years we have attempted to delineate a clinically applicable and validated nutritional assessment approach. This was accomplished through multiple clinical studies on a large number of surgical patients many of whom were seriously ill. Although an initial prospective study in 64 patients confirmed the relationship between certain nutritional markers and outcome, we found that 97% of patients had at least one abnormality, while 35% had three or more abnormalities, clearly documenting the imprecision in unselected battery testing. In a subsequent retrospective analysis of 161 patients, serum albumin (Alb), serum transferrin (TFN), triceps skinfold (TSF), and skin test reactivity (DH) proved to be the best markers of clinically relevant malnutrition and their relative quantitative importance is embodied in our Prognostic Nutritional Index (PNI), where PNI (% risk) = 158 - 16.6 (Alb) - 0.78 (TSF) - 0.20 (TFN) - 5.8 (DH). In numerous prospective studies of different patient groups, a large percentage of which were critically ill, the PNI has been shown to be a reliable nutritional assessment tool for diagnosing clinically relevant malnutrition. Furthermore, we have shown that seriously malnourished patients classified by the PNI will clinically benefit from preoperative nutritional support. The relevance of baseline and serial nutritional assessment to the nutritional care of the critically ill patient is discussed.

"Nonrestraining" superior vena cava (SVC) cannulae are commonly used in rat metabolic studies. The objective of this study was to evaluate the level of stress and metabolic alterations associated with surgical placement and subsequent maintenance and use of an indwelling intravenous cannula as measured by resting energy expenditure (REE), respiratory quotient (RQ), urinary nitrogen excretion, and substrate utilization pattern. Nine rats underwent SVC cannulation and six rats underwent sham operation. Postoperatively, animals were starved for 48 hr and then refed either parenterally or orally for 48 hr. Sham-operated animals adapted appropriately to starvation within 24 hr by decreasing REE 14% and increasing utilization of fat (RQ:0.89----0.78). Hypometabolic adaptation to starvation was delayed in cannulated animals until the second postoperative day, but appropriate alterations in energy substrate utilization were not affected by the presence of cannulae. Cannulae did not affect the metabolic response to oral refeeding with similar increases in REE and similar patterns of substrate utilization in sham-operated and cannulated animals. Animals refed parenterally demonstrated higher REE and apparent fat deposition (RQ greater than 1) consistent with continuous hypercaloric glucose administration. Urinary nitrogen excretion was not affected by the presence of cannulae. Cannula-associated metabolic alterations are minimal and transient and do not preclude detection and quantification of alterations associated with composition or utilization of exogenous substrates.

Pentobarbital therapy has been associated with decreased urinary nitrogen excretion and resting energy expenditure in stressed patients. The metabolic effects of pentobarbital in sepsis were investigated in 29 well-nourished rats who underwent superior vena caval cannulation, cecal ligation, and puncture. Animals were randomly assigned to receive either a continuous infusion of 20 mg/kg/day of pentobarbital combined with parenteral nutrition (n = 13) or parenteral nutrition alone (n = 16). Both groups received isocaloric, isonitrogenous parenteral nutrition postoperatively for 24 hr. Mean nitrogen balance (+/- SEM) was better in the pentobarbital group (+169 +/- 76 mg/kg/day vs -190 +/- 66 mg/kg/day, p less than 0.01). No significant differences between the pentobarbital and control groups were noted for urinary 3-methylhistidine excretion (9 +/- 0.7 micrograms/kg/day vs 11 +/- 0.6 micrograms/kg/day, respectively) or 24 hr survival (77% vs 69%, respectively). Pentobarbital improves nitrogen retention without decreasing urinary 3-methylhistidine excretion in septic rats.

The administration of chemotherapy in clinical situations is limited frequently because of the associated toxicity to normal bone marrow cells, gastrointestinal epithelium, and other host tissues. Although nutritional support has been advocated to reduce chemotherapy-related toxicity in cancer patients, few studies substantiate this clinical impression. The current study was performed to determine the role of nutritional status and enteral nutrient intake as determinants of methotrexate (MTX) toxicity in a well-controlled, tumor-bearing animal model. After subcutaneous mammary tumor (AC-33) inoculation, 56 female Lewis/Wistar rats were assigned randomly to one of the following two nutritional regimens for 14 days: (1) protein-depleted chow (PC) (0.03% protein; 4.27 kcal/g) or (2) standard chow (RC) (22.0% protein; 3.50 kcal/g). After 7 days of dietary control, all animals received one of three weight-adjusted doses of MTX (5, 10, or 20 mg/kg intramuscularly [IM] ) or placebo. All animals received leucovorin rescue (0.6 mg IM) at 6 and 24 hours after MTX injection. Improved nutritional status was associated with a significant reduction in objective measures of MTX-related morbidity and mortality. At low doses of MTX (5 and 10 mg/kg), the mean duration of clinical signs of toxicity (i.e., hair loss, lethargy, and diarrhea) and severity of leukopenia were greater in protein-depleted (PD) animals. With high-dose MTX (20 mg/kg), mortality was increased significantly in PD animals (100%) compared with well-nourished animals (0%). Equivalent tumor response was observed in PD and well-nourished animals. Thus, improved nutritional status by enteral nutrition reduced the morbidity and mortality associated with MTX significantly in this tumor-bearing animal model.

A previously developed and validated predictive nutritional assessment model (Prognostic Nutritional Index) was applied to a heterogenous surgical population. Without knowledge of the then undeveloped PNI, adequate preoperative nutritional repletion (TPN) was provided on clinical indications alone to 50 of 145 patients with the remaining 95 patients receiving no preoperative total parenteral nutrition. Analysis of the two groups found no baseline differences in nutritional status, type and severity of disease and/or operative therapy, and other potentially important variables. In the high-risk stratified group as defined by admission nutritional assessment and calculated PNI (greater than or equal to 50%), adequate preoperative TPN reduced postoperative complications 2.5-fold (p < 0.01), postoperative major sepsis six-fold (p < 0.005) and mortality five-fold (p < 0.01). Clinical "eyeball" evaluation of nutritional status cannot identify high-risk individuals. This nutritional assessment predictive model (PNI) identifies the subset of operative candidates in whom adequate preoperative nutritional support significantly reduces operative morbidity and/or mortality.

Plasma transferrin (TFN) levels are valid as markers of protein-calorie malnutrition (PCM). Current methods for determining TFN, specifically, radial immunodiffusion (RID) plates or derivation from total iron-binding capacity (TIBC), are relatively expensive, time consuming (20-50 hr) and technically demanding, limiting the use of TFN levels in the routine screening for PCM. A rapid (60-90 min), accurate and precise TFN assay, easily performed with common laboratory equipment, was developed for use in a study of hospitalized patients. This assay requires 15 microliter of plasma and is based on an antigen-antibody reaction using commercially available TFN antibody. After a 30-min incubation, turbidity is measured at 413 nm on a spectrophotometer with a 1-cm path length. Values by this method are linear over the range of 50-760 mg/dl. Plasma samples (n = 72) were assayed for TFN by this turbidimetric (TURB) technique and the standard RID technique. Correlation between the two assays was r = 0.942 over the range of TFN = 81-403 mg/dl (TFNRID = 30.7 + (0.931) TFNTURB). Coefficient of variation (CV) for TFNTURB was 4.0%. RID kit insert reports a CV = 2.9% at a value of 380 mg/dl. This assay overcomes many of the difficulties associated with TFN determination by RID or derived from TIBC and may allow more widespread application of plasma TFN levels as a clinically relevant PCM screening tool.

Malnutrition is common in cancer patients and may be an important determinant of operative morbidity and mortality. To determine whether preoperative nutritional assessment can be used to identify a group of high-risk patients, and whether preoperative TPN decreases morbidity and mortality in this group, retrospective, nonrandomized review of 159 patients who were subjected to major cancer surgery was performed. All patients underwent preoperative multiparameter assessment. A previously developed and validated nutritional assessment model (Prognostic Nutritional Index) was used to evaluate the probability of operative complications. Based on predicted outcome (PNI), patients were assigned to either a high-risk or low-risk group for statistical comparison with actual outcome. The effect of preoperative TPN was then analyzed in both risk groups for determination of efficacy of preoperative nutritional support. Substantial malnutrition was found to exist among patients undergoing major cancer surgery and was closely correlated with subsequent morbidity and mortality. This predictive nutritional assessment model accurately identifies a subset of cancer surgery patients at increased risk of operative morbidity and mortality. In this high risk group (PNI greater than or equal to 40%), preoperative nutritional support significantly reduces operative morbidity.

Based on assessment of 161 nonemergency general surgical patients, a multiparameter index of nutritional status was defined relating the risk of postoperative complications to baseline nutritional status. When applied prospectively to 100 gastrointestinal surgical patients, this index provided an accurate, quantitative estimate of operative risk, permitting rational selection of patients to receive preoperative nutritional support.

Unlabelled: We investigated the effect of non-protein calorie source on the repletion by total parenteral nutrition (TPN) of protein-depleted rats. Rats were depleted by feeding them a protein free diet for 4 weeks. Control (non-depleted) and depleted rats were given one of three isocaloric, isonitrogenous TPN regimens for 6 days. They differed in the proportion of non-protein calories given as glucose and fat: diet 1, 100% glucose; diet 2, 75% glucose, 25% fat; and diet 3, 100% fat. The liver, skeletal muscle and whole body protein synthesis and break-down rates were measured by using [15N]glycine as a tracer. The fatty acid distribution in the liver was measured by gas chromatography-mass spectrometry., Results: (a) Omission of fat leads to a decrease in the fraction of linoleate in the liver. (b) Giving all the non-protein calories as a fat emulsion causes fatty acid accumulation in the liver and a significant increase in the liver protein fractional synthesis rate in the control rats and killed about half the depleted rats. (c) For TPN regimens 1 and 2 both the muscle and whole body synthesis rates were increased during repletion. (d) Of the three TPN regimens, the second one which contained both fat and glucose was superior to the other two.

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.

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.

Adequate parenteral nutritional support improves nutritional status in cancer patients, but its effect on tumor growth remains controversial. Using a transplantable mammary adenocarcinoma in a rat-TPN model, the relative effect of different exogenous intravenous nutrients on tumor growth and host maintenance was studied. Relative to chow controls, starvation increased host depletion without reducing tumor growth. Adequate carbohydrate calories alone neither improved host maintenance nor stimulated tumor growth, yet adequate amino acids alone did improve host maintenance but also stimulated tumor growth. Adequate amino acids and carbohydrates given simultaneously maximized both host maintenance and tumor growth. In contrast, an isocaloric, isonitrogenous, intravenous diet providing non-nitrogenous calories as fat promoted host maintenance equivalent to carbohydrate-based TPN with no tumor stimulation. This apparent differential utilization of fat calories by normal and malignant cells may permit manipulation of the relative benefit of parenteral nutrition to host or to tumor, permitting host repletion without tumor stimulation or alternatively tumor stimulation at appropriate times to increase sensitivity to phase-specific antineoplastic therapy.

Cancer cachexia, a common finding in patients with gastrointestinal (GI) malignancy, is frequently attributed to tumor-induced aberrations in host energy expenditure. To characterize the frequency and severity of aberrations in energy expenditure in GI cancer patients, and to identify the potential influence of tumor characteristics in this group, the authors measured resting energy expenditure (REE) by indirect calorimetry in 173 patients and compared REE to predicted-energy expenditure (PEE) from the Harris-Benedict formulae based on current body weight. Fifty-eight percent of patients had abnormal REE (normal REE = +/- 10% PEE); 36% (62 of 173) were hypometabolic (REE less than 90% PEE), and 22% (39 of 173) were hypermetabolic (REE greater than 110% PEE). Host and tumor factors were compared between metabolic groups to identify potential determinants of abnormal energy expenditure. Differences between groups cannot be explained by differences in patient age, sex, body size, nutritional status, tumor burden, or duration of disease. Resting energy expenditure does not correlate with percent of weight loss, serum albumin, or duration of disease. Analysis by tumor site reveals patients with pancreatic or hepatobiliary tumors to be predominantly hypometabolic; gastric cancer patients tend to be hypermetabolic, whereas patients with colorectal or esophageal neoplasms are more evenly distributed across metabolic groups, the largest portion being normometabolic (X2 = 20.7, P less than 0.02). The majority of GI cancer patients have abnormal REE which is unpredictable and not uniformly hypermetabolic. The determinants of these abnormalities do not appear to be age, sex, body size, nutritional status or tumor burden. Primary tumor site is a major determinant of energy expenditure in GI cancer patients.