Association of positive transection margins with gastric cancer survival and local recurrence.

PURPOSE: To examine the association between positive resection margins and survival and local recurrence in patients with gastric cancer undergoing resection with curative intent. METHODS: Patients who underwent curative intent resection for gastric carcinoma from 1985 to 2010 were identified from a prospectively maintained database. Positive margins were defined as disease present at the line of luminal transection. Clinicopathological features and outcome of patients undergoing gastrectomy with negative and positive margins were compared. RESULTS: Among 2384 patients undergoing curative intent resection, 108 (4.5 %) had positive margins. Positive margins were associated with higher American Joint Committee on Cancer (AJCC) stage, T stage, N stage, median number of positive nodes, diffuse Lauren type, and poorly differentiated tumors. Treatment of positive margins consisted of: observation (39 %), chemoradiotherapy (26 %), chemotherapy (20 %), repeat resection (10 %), radiotherapy (4 %), and unknown (1 %). Multivariate analysis of the entire cohort demonstrated margin status, T stage, N stage, grade, and perineural invasion to be independent predictors of survival. Margin status was an independent predictor of survival in patients with ≤3 positive nodes or T1-2 disease but was not in patients with >3 positive nodes or T3-4 disease. Local recurrence occurred in 16 % of patients with a positive margin. We identified no factors predictive of local recurrence in patients with positive margins. CONCLUSIONS: Positive resection margin is associated with advanced AJCC stage and aggressive tumor biology but remains an independent predictor of worse survival. The significance of a positive margin in gastric cancer is confined to patients with nontransmural disease and/or limited nodal involvement.

Malignant progression in IPMN: a cohort analysis of patients initially selected for resection or observation.

BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) may represent a field defect of pancreatic ductal instability. The relative risk of carcinoma in regions remote from the radiographically identified cyst remains poorly defined. This study describes the natural history of IPMN in patients initially selected for resection or surveillance. METHODS: Patients with IPMN submitted to resection or radiographic surveillance were identified from a prospectively maintained database. Comparisons were made between these two groups. RESULTS: From 1995 to 2010, a total of 356 of 1,425 patients evaluated for pancreatic cysts fulfilled inclusion criteria. Median follow-up for the entire cohort was 36 months. Initial resection was selected for 186 patients (52 %); 114 had noninvasive lesions and 72 had invasive disease. A total of 170 patients underwent initial nonoperative management. Median follow-up for this surveillance group was 40 months. Ninety-seven patients (57 % of those under surveillance) ultimately underwent resection, with noninvasive disease in 79 patients and invasive disease in 18. Five of the 18 (28 %) invasive lesions developed in a region remote from the monitored lesion. Ninety invasive carcinomas were identified in the entire population (25 %), ten of which developed the invasive lesion separate from the index cyst, representing 11 % with invasive disease. CONCLUSIONS: Invasive disease was identified in 39 % of patients with IPMN selected for initial resection and 11 % of patients selected for initial surveillance. Ten patients developed carcinoma in a region separate from the radiographically identified IPMN, representing 2.8 % of the study population. Diagnostic, operative, and surveillance strategies for IPMN should consider risk not only to the index cyst but also to the entire gland.

Downstaging in pancreatic cancer: a matched analysis of patients resected following systemic treatment of initially locally unresectable disease.

BACKGROUND: Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10-14 months. The objective of this study was to evaluate outcome of initially unresectable patients who respond to multimodality therapy and undergo resection. METHODS: Using a prospectively collected database, patients were identified who were initially unresectable because of vascular invasion and had sufficient response to nonoperative treatment to undergo resection. Overall survival (OS) was compared with a matched group of patients who were initially resectable. Case matching was performed using a previously validated pancreatic cancer nomogram. RESULTS: A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with either systemic therapy or chemoradiation. Initial unresectability was determined by operative exploration (n = 15, 42%) or by cross-sectional imaging (n = 21, 58%). Resection consisted of pancreaticoduodenectomy (n = 31, 86%), distal pancreatectomy (n = 4, 11%), and total pancreatectomy (n = 1, 3%). Pathology revealed T3 lesions in 26 patients (73%), node positivity in 6 patients (16%), and a negative margin in 30 patients (83%). The median OS in this series was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and those who presented with resectable disease (P = .35). CONCLUSIONS: In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced survival similar to those who were initially resectable. Resection is indicated in this highly select group of patients.

Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma.

BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.

The prognostic impact of isolated tumor cells in lymph nodes of T2N0 gastric cancer: comparison of American and Japanese gastric cancer patients.

BACKGROUND: The clinical significance of immunohistochemically detected isolated tumor cells (ITC) in lymph nodes of gastric cancer patients is controversial. This study examined the prognostic impact of ITC on patients with early-stage gastric cancer in two large volume centers in the United States and Japan. METHODS: Fifty-seven patients with T2N0M0 gastric carcinoma who underwent gastric resection between January 1987 and January 1997 at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York and 107 patients resected at National Cancer Center Hospital (NCCH) in Tokyo between January 1984 and December 1990 were studied. The sections were newly prepared from each lymph node for immunohistochemical staining for cytokeratin. Lymph nodes and original specimens from MSKCC were examined by pathologists in NCCH. The prognostic significance of the presence of ITC in lymph nodes was investigated in patients of both institutions. RESULTS: ITC were identified in 30 of 57 patients (52.6%) at MSKCC and in 38 of 107 patients (35.5%) at NCCH. In both institutions, there was no significant difference in the prognosis of the studied patients with or without ITC (P= .22, .86 respectively). CONCLUSIONS: The presence of ITC detected by immunohistochemistry in the regional lymph nodes did not affect the prognosis of American and Japanese patients with T2N0M0 gastric carcinoma who underwent gastrectomy with D2 lymph node dissection.

Current management of cystic neoplasms of the pancreas.

Over the last decade there has been a dramatic increase in the number of patients identified with pancreatic cysts. This increase has been largely attributed to advances in imaging. The majority of these cysts represent benign neoplasms; however, a significant fraction of these are pre-malignant or malignant. Because the majority of these neoplasms are benign, many reports have advocated a selective approach to surgical resection. Here we review the literature that has contributed to the development of our approach to the management of these cystic neoplasms. We provide an overview of the key features in diagnosis and in predicting malignancy. Particular attention is given to the natural history and management of intraductal papillary mucinous neoplasms (IPMN).

Protein synthesis in hepatocytes isolated from patients with gastrointestinal malignancy.

To investigate the effect of remote and proximate cancer on hepatic protein metabolism, we determined rates of total protein synthesis by hepatocytes (HPS) isolated from 31 patients undergoing liver wedge biopsy: 7 patients with benign disease, 14 with gastric cancer, and 10 with colorectal cancer (5 of whom had liver metastases). Patients with malignant disease without weight loss had a threefold higher rate of total HPS (4,980 +/- 814 pmol/h per 10(5) viable cells) than patients with benign disease without weight loss (1,278 +/- 318 pmol/h per 10(5) viable cells, P less than 0.001). Among the patients with gastric cancer, eight with preoperative weight loss had lower rates of HPS (380 +/- 90 pmol/h per 10(5) viable cells) than those without weight loss (4,061 +/- 401 pmol/h per 10(5) viable cells, P less than 0.002). The highest rates of HPS were seen in patients with colorectal cancer with liver metastases (8,005 +/- 1,975 pmol/h per 10(5) viable cells) vs. colorectal cancer patients without liver metastases (3,060 +/- 575 pmol/h per 10(5) viable cells, P less than 0.03). These data indicate that modulation of hepatic protein synthesis occurs in malignancy in man. However, the stimulatory influence of the tumor-bearing state may be overridden by the inhibitory effects of cachexia.

Leucine meal increases glutamine and total nitrogen release from forearm muscle.

To assess the consequences of elevated branched chain amino acid levels on alanine, glutamine, and ammonia metabolism in muscle, L-leucine meals (14.7 g) were consumed by six normal postabsorptive individuals. Bilateral forearm studies were performed, and the dominant arm was subjected to 15 min of light exercise, using a calibrated dynamometer, beginning 45 min after the ingestion of the meal. Large uptakes of leucine were seen across both forearm muscle beds within 30 min of the meal. After exercise, blood flow in the dominant arm increased from 3.1 +/- 0.4 to 5.2 +/- 0.9 ml/100 ml forearm per minute (mean +/- SEM, P less than 0.005). Glutamine flux out of the dominant forearm increased threefold after the ingestion of the leucine meal and increased eightfold over base line after exercise. Less marked changes (significant only at 90 min) in the nonexercised, nondominant arm were also seen. Alanine flux out of the dominant forearm muscle bed increased modestly at 75 and 90 min. No significant change in ammonia flux across either forearm muscle bed was noted. Unexpectedly, large and significant net nitrogen loss from both forearm muscle beds was documented. Thus, following the ingestion of a leucine meal and light exercise, the primary means by which excess nitrogen is routed out of muscle is via glutamine formation and release with alanine and ammonia pathways playing relatively minor roles. More importantly, the ingestion of significant amounts of leucine by normal subjects, presumably in optimal nitrogen balance, results in a net loss of nitrogen from muscle.

Tumor necrosis factor and the acute metabolic response to tissue injury in man.

Tumor necrosis factor (cachectin), a protein produced by monocytes and macrophages, has been implicated as an important mediator of the lethal effects of endotoxic shock and the cachexia of chronic infection. Recombinant human tumor necrosis factor alpha (rTNF) was given intravenously to patients as part of an antineoplastic trial. Fever, tachycardia, and at higher doses, hypotension occurred after a single injection of rTNF. Metabolic effects after rTNF administration were dose related and included enhanced energy expenditure with elevated CO2 production, increased whole body protein metabolism and peripheral amino acid efflux from the forearm, and decreased total arterial amino acid levels associated with a significant increase in plasma cortisol. Elevated serum triglycerides, as well as increased glycerol and free fatty acid turnover were seen, suggesting increased whole body lipolysis and fat utilization after rTNF. These findings indicate that administration of TNF in man reproduces many of the acute physiologic and metabolic responses to tissue injury, including energy substrate mobilization.

Effect of insulin on muscle glutamate uptake. Whole blood versus plasma glutamate analysis.

For decades, investigators concerned with protein metabolism in man have performed detailed amino acid analyses of human plasma obtained under a wide range of experimental situations. A large body of information has been used to calculated rates of protein synthesis and proteolysis. During the course of an investigation of the effect of intrabrachial artery infusion of insulin (70 muU/min per kg body weight) on glutamate uptake by human forearm muscle, it was discovered that plasma arterio-deep venous glutamate difference analysis failed to document any increase in the uptake of this amino acid, suggesting that insulin had little influence on glutamate uptake by muscle. However, whole blood glutamate analyses, performed on the same blood samples, revealed that (a) the resting muscle uptake of glutamate is smaller than previously reported and (b) insulin is capable of markedly increasing glutamate uptake by muscle from whole blood. Since the hematocrit was obtained on all samples, detailed analyses of the various compartments in which glutamate could be found were performed. It was determined that circulating blood cells have a dynamic role in glutamate transport. These data underscore the need for both whole blood and plasma amino acid analysis in investigations concerned with protein synthesis and/or amino acid flux, for analysis of plasma samples alone could be misleading as illustrated in the present study.

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.

Glucose disposal and gluconeogenesis from alanine in tumor-bearing Fischer 344 rats.

For the study of glucose carbon recycling and incorporation of carbon atoms from plasma glucose, [3-3H]glucose and [U-14C]alanine were injected into inbred non-tumor-bearing (NTB) and tumor-bearing (TB) male F344 rats. The glucose and alanine kinetics were determined in relation to antecedent food intake and carcass weight loss. Whereas fed NTB and TB rats appropriately experienced reduced glucose disposal with decreased food intake (0.99 vs. 0.29 mg/min -100 g(-1) compared wtih observations in starved NTB rats), starved TB rats exhibited increased glucose utilization. Both fully fed and cachectic TB groups exhibited increased isotopic carbon recycling compared to the carbon recycling of NTB control groups, whereas starved TB rats did not demonstrate increased recycling compared to the carbon recycling (27% of C-atoms recycled). These findings suggest that alterations of glucose turnover, carbon recycling, and gluconeogenesis in the fed host parallel hypophagia and weight loss, regardless of TB status.

Prognostic implications of p53 nuclear overexpression and high proliferation index of Ki-67 in adult soft-tissue sarcomas.

BACKGROUND: Morphologically similar soft-tissue sarcomas may behave in very different fashions, making it difficult to predict clinical outcomes and to properly design therapeutic interventions. In a preliminary study, we observed that TP53 mutations and nuclear overexpression of p53 protein were frequent events in soft-tissue sarcoma, and we noticed an association between p53-positive phenotype and poor clinical outcome. PURPOSE: We examined the potential clinical relevance of p53 overexpression in adults with soft-tissue sarcomas. We also studied the clinical implications of a high proliferation index. METHODS: A cohort of 174 adults with soft-tissue sarcomas were analyzed using anti-p53 and anti-Ki-67 antibodies and immunohistochemical assays on consecutive fresh frozen tissue samples. RESULTS: We observed a significant association between p53 nuclear overexpression and tumor grade (P = .001) and tumor size (P = .01). Patients displaying a p53-positive phenotype had significantly reduced survival (P = .02). Similarly, a significant difference was observed between high proliferation index and tumor grade (P < .001) and reduced patient survival (P = .03). A high Ki-67 proliferation index was detected in association with p53 nuclear overexpression. CONCLUSIONS: Overexpression of p53 protein and a high proliferation index strongly correlate with poor clinical outcome and reduced survival in patients having soft-tissue sarcomas.

Alterations of INK4A and INK4B genes in adult soft tissue sarcomas: effect on survival.

BACKGROUND: The INK4A and INK4B genes map to chromosome 9p21, with the INK4A gene encoding two protein products, p16 and pl9ARF. Alterations of the INK4A and INK4B genes occur frequently in certain primary malignant neoplasms. This study was undertaken to evaluate the frequency of INK4A and INK4B gene alterations in a cohort of adult soft tissue sarcomas. METHODS: The status of the INK4A and INK4B genes was determined in 46 soft tissue sarcomas by use of the following methods: Southern blotting, polymerase chain reaction (PCR), single-strand conformation polymorphism analysis, comparative multiplex PCR, and a methylation assay focusing on the p16 promoter. Associations between alterations of the INK4A and INK4B genes and clinicopathologic variables, as well as with p53 and pRB (retinoblastoma protein) status, were evaluated by use of the two-tailed Fisher's exact test. Disease-specific survival was evaluated by use of the Kaplan-Meier method and the logrank test. Proportional hazards analysis was used to obtain estimates of relative risks. All P values are two-sided. RESULTS: Homozygous and hemizygous deletions, but no point mutations, were observed in these two genes. The overall frequency of gene alteration (deletion or rearrangement) was approximately 15% for the INK4A and INK4B genes, with changes restricted to high-grade sarcomas. Statistically significant associations were observed between INK4A/INK4B deletions (P = .036) or alterations (P = .005) and poor survival. Alteration of the INK4A and INK4B genes was the only statistically significant predictor for poor survival when controlling for tumor grade and size (P = .03). CONCLUSION/IMPLICATIONS: Coincident homozygous deletion of the INK4A and INK4B genes occurs frequently in adult soft tissue sarcomas. Loss of p16 and pl9ARF function in primary tumors, although not equivalent to alterations in p53 and pRB function, appears to be associated with cancers that have an aggressive biologic behavior.

Uncomplicated starvation versus cancer cachexia.

Host starvation is a common accompaniment to the presence of cancer. Diminished intake is a major contributor to this starvation and does not require that the oropharynx or gastrointestinal tract be the primary site. There is suggestive evidence that the normal adaptive mechanisms of the nontumor-bearing host to starvation that result in body protein conservation are not functioning in the tumor-bearing host. Cancer cachexia has some similarity to the metabolic disturbances of host metabolism that are seen in major injury or sepsis. The growing tumor shows little respect for normal constraints of host tissue growth. With the widespread availability of methods of total parenteral nutrition, the interrelationship of nutrition and host-tumor growth assumes greater importance.

Tumoricidal potential of nutritional manipulations.

Perturbations of specific nutrient availability is the basis of a large number of chemotherapeutic modalities used in cancer treatment. The creation of transient nutrient deprivation states by deficient diets (deficiency), nutrient destruction or displacement (depletion), the presence of antimetabolites or analogs (deficiency state), or combinations of the above has shown significant antitumor effect in several animal and human cancers. Pair-fed isocalonic diets deficient in micronutrients such as carbohydrates (with or without gluconeogenesis inhibition) or micronutrients such as zinc or pyridoxine have demonstrated antitumor potential. Amino acid depletion by enzymes such as L-asparaginase or L-glutaminase has become a popular modality for treatment of human leukemias. Purine and pyrimidine analogs or folate antimetabolites have been used successfully for several decades in the treatment of human tumors. Excess pyridoxine in tissue culture has demonstrated antineoplastic potential. Dietetic supplementation with naturally occurring sugars, sugar derivatives, or analogs has also demonstrated tumorotropic effects.

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.

Growth hormone administration preserves lean body mass in sarcoma-bearing rats treated with doxorubicin.

Cachexia and malnutrition play a significant role in the morbidity associated with antineoplastic chemotherapy regimens. Conventional nutritional support during cancer therapy has shown little benefit in terms of reducing morbidity and mortality. We examined the anabolic properties of growth hormone (GH) that preserve normal body composition in sarcoma-bearing animals treated with doxorubicin. On day 0, 40 male Fischer 344 rats were inoculated with 10(6) methylcholanthrene-induced sarcoma cells s.c. in the left flank. On day 9, animals were randomized into 3 groups: control (CTL, n = 13); doxorubicin (DOX, n = 13); and doxorubicin plus GH (DOX-GH, n = 14). Two CTL animals were excluded due to tumor invasion into the peritoneal cavity. From day 9 to day 23, the DOX-GH group received daily s.c. recombinant rat GH injection (1 mg/kg). On day 13, DOX and DOX-GH groups received 7 mg/kg of DOX i.v. while the CTL group received sham i.v. sterile saline injection. Body weight and tumor dimensions were measured daily. On day 23, all animals were weighed and sacrificed. Tumors were resected and weighed. Body composition analysis was performed. Plasma GH levels were measured by radioimmunoassay and insulin growth factor 1 levels were measured by chondrocyte proliferation bioassay. The DOX-GH group had a significantly higher mean body weight, carcass weight, total fat free body mass, insulin growth factor 1, and GH plasma levels as compared to the DOX group. No difference in total food intake was observed between the DOX and DOX-GH groups. There was no difference in final tumor weight and tumor growth rate between DOX and DOX-GH groups. Exogenous growth hormone can attenuate weight loss and preserve host body composition in tumor-bearing rats treated with doxorubicin without stimulating tumor growth.

Effect of systemic hyperinsulinemia in cancer patients.

Data defining the isolated effect of insulin on whole body protein and glucose metabolism in cancer patients are limited. Ten normal volunteers (controls), age 55 +/- 3 years (mean +/- SEM); 8 cancer patients, age 61 +/- 3 years, weight loss 2 +/- 1% (CANWL); and 8 cancer patients, age 55 +/- 2 years, weight loss 18 +/- 2% (CAWL), were studied in the post-absorptive state. Whole body leucine kinetics were determined during a baseline and then a study period during which insulin was infused at 1.0 milliunits/kg/min to achieve a high physiological level of 71 +/- 6, 83 +/- 5, and 64 +/- 5 microunits/ml in controls, CANWL, and CAWL, respectively. Whole body net balance equals protein synthesis minus protein breakdown. Glucose disposal (mg/kg/min) is the rate of D30 infusion at steady state. Glucose disposal of CANWL and CAWL during the study period was significantly (P less than 0.05, analysis of variance) less than controls (3.91 +/- 0.6 in CANWL, 3.66 +/- 1.0 in CAWL, and 5.87 +/- 0.6 mg/kg/min in controls), suggesting resistance to insulin with respect to carbohydrate metabolism. Hyperinsulinemia, under euglycemic and near basal amino acid conditions, significantly reversed the negative postabsorptive leucine net balance (P less than 0.05, analysis of variance) by decreasing protein breakdown in controls as well as weight-stable and weight-losing cancer patients, suggesting that cancer patients are not resistant to the anti-catabolic effect of insulin with respect to whole body protein metabolism.

Tumor-induced alterations in tissue lipoprotein lipase activity and mRNA levels.

To elucidate the mechanisms of hypertriglyceridemia observed in the tumor-bearing rat, tissue lipoprotein lipase (LPL) activity and LPL mRNA levels were examined in the fed and fasted states at different degrees of tumor burden and after tumor removal. LPL activity in the epididymal fat pad and cardiac muscle in the 24-h-fasted rats was significantly decreased with increasing tumor burden (r = -0.53, P less than 0.05 and r = -0.72, P less than 0.01, respectively). Tumor removal completely reversed these changes. In contrast, no change in LPL activity was detected in the fed state since food intake stimulated LPL activity to the same extent in both tumor-bearing (TBR) and control rats. LPL activity in the diaphragm and skeletal muscle was only marginally altered in TBR, as compared to controls. LPL mRNA from the epididymal fat pad and cardiac muscle migrated to the same site on agarose gel and hybridized to a LPL-specific complementary DNA probe. The decline in LPL activity in epididymal fat pad observed in TBR was associated with a decrease in LPL mRNA levels. In contrast, there was no significant difference in LPL mRNA levels in cardiac muscle between the two groups despite significantly suppressed enzyme activity in tumor bearers. This study provides evidence that hypertriglyceridemia in TBR is due in part to tumor-dependent suppression of adipose and cardiac LPL activity in the fasted state, which is stimulated by the presence of tumor. Unlike cardiac LPL, the tumor-induced changes in adipose LPL activity are regulated at the mRNA level in this tumor model.