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R S Warren

Publications and source records attributed to R S Warren.

At least 37 records · Page 2Linked to original sources
PubMed1996

Intra-abdominal desmoplastic small round-cell tumor: expansion of the pathologic profile.

This report describes an intra-abdominal desmoplastic small round-cell tumor in a 29-year-old man that significantly differed from the classically described appearances of this unique tumor. It showed extensive papillary areas, no necrosis, and very little desmoplasia. The latter was limited, paucicellular, and present in areas separate from the papillary structures. Also, areas of back-to-back, single-cell infiltration, which mimicked lobular breast carcinoma, were present. These epithelial features suggested the diagnosis of adenocarcinoma or peculiar mesothelioma. But, the immunohistochemical features (tumor cells positive for keratin, desmin, and vimentin) were more consistent with an intra-abdominal desmoplastic small round-cell tumor. The diagnosis became clear after application of reverse transcriptase-polymerase chain reaction techniques to formalin-fixed, paraffin-embedded tissue, which showed the presence of a 100-base pair product containing the fusion junction of Ewing's sarcoma-1 exon 7 to Wilms' tumor-1 exon 8. This feature is considered unique to intra-abdominal desmoplastic small round-cell tumors. This case illustrates the less common histologic findings that can be found in intra-abdominal desmoplastic small round-cell tumor. This deviation from the classic histologic findings may be an expression of an uncommon morphologic variant and/or partially produced by the effects of prior chemotherapy. In either event, only by illustrating the various histologic appearances of intra-abdominal desmoplastic small round-cell tumor are the chances increased for the accurate diagnosis of this aggressive neoplasm with a poor prognosis.

Adult↗
PubMed1996

Regional chemotherapy approaches for primary and metastatic liver tumors.

There are pharmacologic principles that make regional chemotherapy to the liver a logical treatment strategy. Patients with colorectal liver metastases and hepatocellular carcinoma would appear to be the best candidates for such an approach. Although there are many objective responses to such treatment, survival benefit has not been demonstrated, but new regimens and refined techniques appear to be improving results. Ultimately, regional delivery may be best suited for innovative treatments such as biologicals and gene therapies.

Antineoplastic Agents↗
PubMed1995

Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation.

Vascular endothelial cell growth factor (VEGF), an endothelial cell-specific mitogen that plays an important role in angiogenesis, promotes the tyrosine phosphorylation of at least 11 proteins in bovine aortic endothelial cells (BAEC). Proteins immunoprecipitated from lysates of control- and VEGF-stimulated BAEC with antisera to phospholipase C-gamma (PLC-gamma) were fractionated by SDS-polyacrylamide gel electrophoresis and transferred to Immobilon-P. Evaluation of the Western blots with antisera to phosphotyrosine demonstrated that PLC-gamma and two proteins (100 and 85 kDa) that associate with PLC-gamma were phosphorylated in response to VEGF. By using antisera specific to other mediators of signal transduction that contain SH2 domains for immunoprecipitation, it was demonstrated that VEGF promotes phosphorylation of phosphatidylinositol 3-kinase, Ras GTPase activating protein (GAP), and the oncogenic adaptor protein NcK. Proteins of M(r) consistent with the VEGF receptors Flt-1 and Flk-1/KDR were also tyrosine phosphorylated in stimulated cells. Tyrosine-phosphorylated Nck, PLC-gamma, and two GAP-associated proteins, p190 and p62, were in GAP immunoprecipitates of VEGF-stimulated BAEC, and tyrosine-phosphorylated NcK was in phosphatidylinositol 3-kinase immunoprecipitates. These observations suggest that VEGF promotes formation of multimeric aggregates of VEGF receptors with proteins that contain SH2 domains and activate various signaling pathways. VEGF-promoted proliferation of endothelial cells and tyrosine phosphorylation of SH2 domain containing signaling molecules were inhibited by the tyrosine kinase inhibitor genistein.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis.

To investigate the relationship between angiogenesis and hepatic tumorigenesis, we examined the expression of vascular endothelial growth factor (VEGF) in 8 human colon carcinoma cell lines and in 30 human colorectal cancer liver metastases. Abundant message for VEGF was found in all tumors, localized to the malignant cells within each neoplasm. Two receptors for VEGF, KDR and flt1, were also demonstrated in most of the tumors examined. KDR and flt1 mRNA were limited to tumor endothelial cells and were more strongly expressed in the hepatic metastases than in the sinusoidal endothelium of the surrounding liver parenchyma. VEGF monoclonal antibody administration in tumor-bearing athymic mice led to a dose- and time-dependent inhibition of growth of subcutaneous xenografts and to a marked reduction in the number and size of experimental liver metastases. In hepatic metastases of VEGF antibody-treated mice, neither blood vessels nor expression of the mouse KDR homologue flk-1 could be demonstrated. These data indicate that VEGF is a commonly expressed angiogenic factor in human colorectal cancer metastases, that VEGF receptors are up-regulated as a concomitant of hepatic tumorigenesis, and that modulation of VEGF gene expression or activity may represent a potentially effective antineoplastic therapy in colorectal cancer.

Animals↗
PubMed1991

Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer.

Hepatic intra-arterial (HIA) infusion of floxuridine (FUDR) via an implanted pump has shown promise in the treatment of colorectal cancer metastasized to the liver. However, the potential benefit of this therapy may be offset by the high incidence of treatment-limiting biliary toxicity. Although weekly HIA bolus of fluorouracil (5-FU) is effective against metastatic colorectal cancer to the liver with no biliary toxicity, it is limited by systemic side effects. In December 1986, we began a phase II trial of alternating HIA FUDR and 5-FU via the implanted pump in an attempt to extend the duration of treatment by obviating the limiting biliary (FUDR) and systemic (5-FU) drug toxic effects. Patients received continuous HIA FUDR at 0.1 mg/kg of body weight per day on days 1 through 8 followed by an HIA bolus of 5-FU at 15 mg/kg given via the pump sideport on days 15, 22, and 29, with the cycle repeated every 35 days. Sixty-eight patients were enrolled in this trial, and 64 were fully evaluable. Of the 64 patients, 30 (47%) previously had received chemotherapy. Major response (complete response plus partial response) was observed in 32 (50%) of 64 patients, and the median survival from pump implantation in all patients was 22.4 months. In contrast to the experience with the single-agent HIA FUDR regimen, no patient had treatment terminated because of drug toxicity. Alternating HIA FUDR and 5-FU has efficacy similar to that of HIA FUDR given alone, but when closely monitored and adjusted appropriately, is not associated with toxic effects requiring treatment termination.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

A model of reversible obstructive jaundice in the rat.

A model of reversible, extrahepatic biliary obstruction is described. Vessel loop blockade of the biliary tree results in obstructive jaundice while removal of the exteriorized vessel loop provides internal biliary drainage without subsequent laparotomy. This technique combined with a system for chronic venous infusion and arterial blood sampling in the unrestrained rat is ideal for long-term metabolic studies of obstructive jaundice. Male Fisher 344 rats (275-350 g) underwent either the combined procedure of total biliary tract blockade and vascular access or sham operation. Mean serum bilirubin was significantly elevated (12.7 +/- 8.9 mg/dl) in the experimental group and following relief of biliary obstruction significantly dropped below 1 mg/dl in all animals except one. Concomitant changes in alkaline phosphatase, glutamate oxaloacetate transaminase, and glutamate pyruvate transaminase were seen. Experimental and control rats initially lost weight following laparotomy; however, mean body weight stabilized by the 5th postoperative day and was similar in both groups on the 10th postoperative day. This combined procedure is a simple, effective and reproducible method of obstructive jaundice.

Alanine Transaminase↗
PubMed1990

The transport of heavy metals within a small urban catchment.

A small urban catchment has been monitored for levels of Pb, Zn, Cd and Cu in the atmosphere, deposition, surface dust and stormwater runoff. The contribution of local emissions to total deposition is considered and found to be significant only for Zn. In rainfall, the metals are mainly particulate associated. Wet deposition is more important than dry deposition for Pb and Zn but the processes are comparable for Cd and Cu. The percentage of the dissolved metal level in rainfall which was observed in the storm runoff varied from 92% for Cu to 13% for Pb. A predictive model for metal concentration in runoff is presented and the results obtained for three monitored storms are assessed.

Cadmium↗
PubMed1988

Hormonal and metabolic response to recombinant human tumor necrosis factor in rat: in vitro and in vivo.

Tumor necrosis factor (TNF; cachectin) has been implicated as a mediator of the toxic manifestations of overwhelming bacterial infection as well as the chronic catabolic state of cancer cachexia. We have examined the acute metabolic and hormonal response after administration of recombinant human TNF in the rat. TNF given by intraperitoneal injection produced dose- and time-related increases in hepatic amino acid uptake, decreases in serum trace metal concentrations, and a pattern of endocrine hormone alterations characteristic of the acute phase response to tissue injury. In vitro zinc transport studies by rat hepatocytes cultured in the presence of TNF alone, or in combination with recombinant human interleukin 1, another mediator of the acute phase response, demonstrated that neither monokine was capable of directly stimulating zinc transport into cells. These findings suggest that TNF may function as an endogenous mediator of the early metabolic response to sepsis and that the trace metal changes induced by TNF in vivo may occur through a secondary mechanism.

Amino Acids↗
PubMed1988

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.

Acute-Phase Reaction↗
PubMed1987

The acute metabolic effects of tumor necrosis factor administration in humans.

It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4 +/- 1.2 mg/dL vs 11.6 +/- 1.8 mg/dL) and a reduction in the serum zinc level (12.9 +/- 0.8 mumol/L vs 7.3 +/- 0.8 mumol/L [79 +/- 5 mg/dL vs 48 +/- 5 mg/dL]) (values are the mean +/- SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia.

Adult↗
PubMed1987

Comparison of hepatic protein synthesis in vivo versus in vitro in the tumor-bearing rat.

We have used the model of the freshly isolated hepatocyte to study liver metabolism in a rat tumor model and have reported elevations in the rates of protein synthesis, gluconeogenesis, alanine transport, and oxygen utilization by the tumor-influenced hepatocyte. While the metabolic activity of the isolated hepatocyte has been taken to reflect metabolism in the in vivo state, this assumption has not been validated. In the present study, we measure hepatic protein synthesis in vivo using a flooding dose of tracer amino acid, and in vitro in hepatocytes freshly isolated from tumor-bearing (TB) and pair-fed control rats. Increased protein synthesis was observed for the TB rats using both methods of analysis. However, the degree of stimulation seen in the TB animals was much greater in the in vitro assay than in the in vivo approach, suggesting that absolute protein synthetic rates in vitro must be interpreted with caution when extrapolating to the in vivo state.

Amino Acids↗
PubMed1987

Altered peripheral amino acid uptake in obstructive jaundice.

To characterize amino acid metabolism in obstructive jaundice, the amino acid uptake in tissues of bile duct-ligated (BDL) rats was determined. Fischer 344 rats underwent either bile duct ligation or sham laparotomy and were pair fed for 72 hr. Amino acid uptake was determined in peripheral skeletal muscle (quadriceps femoris, soleus, and rectus abdominis), liver, blood, and other tissues by accumulation of alpha-[14C]-aminoisobutyric acid following intracardiac injection. Although total hepatic amino acid uptake was unaltered in the BDL animals compared with the sham-operated controls, amino acid uptake in peripheral skeletal muscle was significantly decreased in all muscle groups studied in the BDL rats. The relative concentration (percentage dose per gram normalized to the animal mass) for quadriceps femoris was 0.16 +/- 0.02 for BDL and 0.32 +/- 0.04 for sham-operated rats, P less than 0.005. Muscle protein was lower in BDL animals when compared with sham-operated rats (P less than 0.05). Total trunk blood amino acid levels were not significantly different in the two groups; however, there was a decreased serum level of branched-chain amino acids in the BDL group, P less than 0.05. No differences in plasma glucose or serum insulin were found in the two groups; lactate levels were lower in the BDL group, and plasma triglyceride levels were three times higher in the BDL animals. These data suggest that obstructive jaundice in the rat is associated with organ-specific metabolic abnormalities consistent with impaired peripheral amino acid uptake.

Amino Acids↗
PubMed1987

Modulation of endogenous hormone action by recombinant human tumor necrosis factor.

Tumor necrosis factor (TNF) has been implicated in the toxic manifestations of overwhelming bacterial infection and in the tissue wasting that often accompanies prolonged infections and malignancy. We have examined a possible role of TNF in the early metabolic alterations following acute tissue injury or sepsis. Recombinant human TNF stimulated rat liver amino acid uptake up to 5-fold in vivo and there was a concomitant increase in plasma glucagon. In vitro TNF had no direct effect on hepatocyte amino acid uptake, but it markedly enhanced the stimulation of amino acid transport by glucagon, without an alteration in binding of glucagon to hepatocytes. This permissive effect of TNF on glucagon action represents an interrelationship between the immune and endocrine systems, and it may help to explain the mechanism of hormonal regulation of both the anabolic and catabolic responses to acute injury.

Amino Acids↗
PubMed1987

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.

Adult↗
PubMed1987

Clinical pharmacology of recombinant human tumor necrosis factor in patients with advanced cancer.

Twenty-six patients with advanced cancer refractory to standard therapy were treated with recombinant human tumor necrosis factor (rTNF) in a study aimed at determining the toxicity and tolerance of rTNF and at seeking evidence of antitumor activity. The study design involved two treatments per week for 4 weeks with alternating subcutaneous and intravenous (IV) administration, and weekly dose escalation through four levels in each patient. The dose range was 1 to 200 micrograms/m2 for IV bolus injection, and 5 to 250 micrograms/m2 for subcutaneous injection. Thirteen patients completed the full course. Early discontinuation of treatment was related to rTNF toxicity in seven cases. The major side effects were rigors, fever, headache, fatigue, and hypotension. Acute changes in granulocyte, lymphocyte, and monocyte counts, changes in serum zinc levels and plasma cortisol levels consistent with an acute phase response, and inflammation at the site of subcutaneous injection were also seen. At doses of 125 to 250 micrograms/m2, inflammation at the subcutaneous injection site was unacceptably severe. Minor changes were seen in hemostatic parameters. Hypotension was corrected by fluid administration and did not require treatment with vasopressors. Initial serum concentrations of rTNF were measured at five minutes after IV administration and were found to range from 2.5 ng/mL after a dose of 35 micrograms/m2 to 80 ng/mL after a dose of 200 micrograms/m2. The half-life of rTNF in the blood was 20 minutes. A decrease in lymph node size was observed in a patient with B cell lymphoma.

Adult↗
PubMed1986

Impaired metabolic response to endotoxin in obstructive jaundice.

Surgical management of extrahepatic cholestasis is frequently complicated by sepsis, which can be explained in part by diminished function of the reticuloendothelial system. We have explored the possibility that the metabolic response to infection may also be abnormal. Fischer 344 rats underwent either bile duct ligation (BDL) or sham operation and were studied 3 days after operation. Hepatic amino acid uptake measured in vivo by the accumulation of 14C-alpha-aminoisobutyric acid or in vitro by the rate of transport of 14C-alanine by isolated hepatocytes was unaltered in the BDL animals, while gluconeogenesis from alanine by viable hepatocytes from BDL rats was actually enhanced. However, the expected increase in hepatic amino acid uptake in response to endotoxin was diminished in the BDL animals. In addition, we observed impaired responses of the jaundiced animals to glucagon and interleukin-1, two mediators of the hepatic acute phase response to endotoxin. These data suggest that while hepatic amino acid transport is normal in the basal state, the rat with extrahepatic biliary obstruction does not respond appropriately to stress and that this defect cannot be explained solely on the basis of altered handling of endotoxin by the reticuloendothelial system.

Alanine↗
PubMed1985

Protein synthesis in the tumor-influenced hepatocyte.

Total body protein turnover is elevated in the Fischer 344 rat bearing a subcutaneous transplantable methylcholanthrene-induced sarcoma. To assess the contribution of the liver, we have measured protein synthesis by hepatocytes freshly isolated from tumor-bearing animals over a range of tumor burdens and from sham-inoculated nontumor bearers. Synthetic rates of total hepatocyte protein were more than twofold greater in hepatocytes from tumor-bearing animals (P less than 0.005) and the increase was proportional to the tumor burden in individual animals (n = 19; r = 0.68; p less than 0.005). When compared with pair-fed nontumor bearers, the differences in rates of total hepatocyte protein synthesis reached statistical significance only when the tumor burden exceeded 5% of total body weight. The stimulation in synthetic rates applied equally to secretory and nonsecretory hepatocyte protein. Furthermore, a lack of net protein accrual in the livers of tumor-bearing animals suggests a concomitant increase in the rate of hepatic protein degradation.

Animals↗