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Biomedical subjects

S K Libutti

Publications and source records attributed to S K Libutti.

At least 19 recordsLinked to original sources
PubMed2002

Improved antitumor response to isolated limb perfusion with tumor necrosis factor after upregulation of endothelial monocyte-activating polypeptide II in soft tissue sarcoma.

BACKGROUND: Experiments with tumor necrosis factor alpha (TNF) in rodents have shown that a high dose can lead to hemorrhagic necrosis in tumors. Endothelial monocyte-activating polypeptide II (EMAP-II) is a novel tumor-derived cytokine, and its expression increases the TNF-1 receptor on tumor endothelium, enhances the induction of tissue factor on tumor endothelial cells, and has an antiangiogenic effect. It has recently been shown that in vivo sensitivity of tumor vasculature to TNF is determined by tumor production of EMAP-II. METHODS: We measured the level of EMAP-II in a TNF-resistant soft tissue sarcoma. We subsequently stabile-transfected this cell line with a retroviral construct containing the EMAP gene. In an extremity perfusion model in tumor-bearing rats, we measured response rates to TNF therapy. RESULTS: Functional EMAP-II production was increased after this transfection. Immunostaining of paraffin-embedded tumor tissue sections in rats showed an overexpression of human EMAP-II. Results of the TNF perfusions in rats suggest that this tumor is more sensitive to TNF therapy. CONCLUSIONS: EMAP-II is produced in various levels. One can increase the sensitivity of tumor for TNF therapy in vivo by upregulating the EMAP-II production. This result leaves an opportunity for enhanced TNF response of tumors in future settings.

Animals↗
PubMed2002

Microarray gene expression profiling of angiogenesis inhibitors using the rat aortic ring assay.

The rat aortic ring assay has been previously described as a useful ex vivo model for analyzing the biological activity of various inhibitors of angiogenesis. Rat aortic rings are exposed to antiangiogenic agents for a five-day incubation period. Then, the degree of microvessel outgrowth from the rings is analyzed and quantified. In contrast to most in vitro angiogenesis assays, the rat aortic ring model provides a unique microenvironment to evaluate the interaction of various cell types and biological factors for their influence on angiogenesis. Microarray analysis is an accepted method for the evaluation of gene expression profiles and can be used to better understand changes in gene expression that occur when rat aortic rings are exposed to a particular biological agent. Here we describe a method of using microarray technology to evaluate the modulation of gene expression in angiogenesis using the rat aortic ring assay.

Angiogenesis Inhibitors↗
PubMed2002

Advantages of mRNA amplification for microarray analysis.

Expanding applications of cDNA microarrays such as fine needle aspiration biopsy and laser capture microdissection necessitate the ability to perform arrays with minute starting amounts of RNA. While methods for amplifying RNA have been advocated, the fidelity of array results using amplified material has not been fully validated. Here we demonstrate preserved fidelity in arrays using one or two rounds of mRNA amplification, validated by downstream real-time quantitative PCR. In addition, the quality of the array data was superior to that obtained using total RNA. Based on these results, we recommend routine mRNA amplification for all cDNA microarray-based analysis of gene expression.

Animals↗
PubMed2002

Noninvasive fluorescent imaging reliably estimates biomass in vivo.

Whole-body optical imaging of small animals has emerged as a powerful, user friendly, and high-throughput tool for assaying molecular and cellular processes as they occur in vivo. As with any imaging method, the utility of such technology relies on its ability to provide quantitative, biologically meaningful information about the physiologic or pathologic process of interest. Here we used an animal tumor model to evaluate the extent of correlation between noninvasively measured fluorescence and more traditional measurements of biomass (tumor volume and tumor weight). C57/BL6 mice were injected subcutaneously with murine colon adenocarcinoma cells that were engineered to express GFP. Serial measurements of fluorescence intensities were performed with a macroscopic in vivo fluorescence system. The progressive increases in intensity correlated strongly with growth in tumor volume, as determined by caliper measurements (R2 = 0.99). A more stringent correlation was found between fluorescence intensity and tumor weight (R2 = 0.97) than between volume and weight (R2 = 0.89). In a treatment experiment using tumor necrosis factor-alpha, fluorescence intensity (but not tumor volume) was able to differentiate between treated and control groups on day 1 post-treatment. These results validate the ability of noninvasive fluorescent imaging to quantify the number of viable, fluorescent cells in vivo.

Adenocarcinoma↗
PubMed2001

Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes.

We have demonstrated previously the oncolytic effects of a systemically delivered, replicating vaccinia virus. To enhance the tumor specificity of this vector, we have developed a combined thymidine kinase-deleted (TK-) and vaccinia growth factor-deleted (VGF-) vaccinia virus and investigated its properties in vitro and in vivo. The gene for enhanced green fluorescent protein (EGFP) was inserted into the TK locus of a VGF- vaccinia virus by homologous recombination creating a double-deleted mutant vaccinia virus (vvDD-GFP). Infection of resting and dividing NIH3T3 cells with vvDD-GFP yielded reduced viral recovery compared with wild-type (WT), TK-, or VGF- viruses from resting cultures but equivalent virus recovery from dividing cultures. Eight days after nude mice were injected i.p. with 10(7) plaque-forming units (pfu) of WT, TK-, VGF-, or vvDD-GFP vaccinia virus, tissues and tumor were harvested for viral titer determination. No virus was recovered from the brains of mice injected with vvDD-GFP compared with the other viruses, which ranged from 130 to 28,000 pfu/mg protein; however, equivalent amounts were recovered from tumor. There was no toxicity from vvDD-GFP because nude mice receiving 10(8) pfu of IP vvDD-GFP lived >100 days, whereas mice receiving WT, VGF-, or TK- virus had median survivals of only 6, 17, and 29 days, respectively. Similar results were seen when 10(9) pfu of vvDD-GFP were given. Nude mice bearing s.c. murine colon adenocarcinoma (MC38) had significant tumor regression after treatment with 10(9) pfu of systemic (i.p.) vvDD-GFP compared with control (mean tumor size, 180.71 +/- 35.26 mm(3) versus 2796.79 +/- 573.20 mm(3) 12 days after injection of virus). Our data demonstrate that a TK- and VGF- mutant vaccinia virus is significantly attenuated in resting cells in vitro and demonstrates tumor-specific replication in vivo. It is a promising vector for use in tumor-directed gene therapy, given its enhanced safety profile, tumor selectivity, and the oncolytic effects after systemic delivery.

3T3 Cells↗
PubMed2001

Effect of retroviral endostatin gene transfer on subcutaneous and intraperitoneal growth of murine tumors.

BACKGROUND: Inhibiting tumor angiogenesis is a promising new strategy for treating cancer. Difficulties with the stability, manufacture, and long-term administration of recombinant antiangiogenic proteins have prompted investigators to use gene therapy to generate these proteins in vivo. We investigated whether transfer of the gene encoding the angiogenesis inhibitor endostatin into the murine liver cell line NMuLi could inhibit tumor growth in vivo. METHODS: NMuLi cells were transduced with retroviral vectors containing the murine endostatin gene. The presence and function of endostatin in transduced cell supernatants were confirmed by competitive enzyme immunoassay and endothelial cell proliferation assays. Nude mice were given a subcutaneous or intraperitoneal injection with NMuLi cells, control transduced cells (NEF-null), or endostatin-transduced clones (NEF-Endo1 to 4) and were monitored for tumor growth. All statistical tests were two-sided. RESULTS: Supernatants from the clone secreting the lowest amount of endostatin (NEF-Endo4, 28 ng/mL) inhibited endothelial cell proliferation by 6% (95% confidence interval [CI] = 0% to 12%), and those from the clone secreting the highest amount (NEF-Endo1, 223 ng/mL) inhibited endothelial cell proliferation by 20% (95% CI = 13% to 27%). Increased levels of endostatin were detected in tumor lysates, but not serum, of mice given a subcutaneous injection of NEF-Endo1 cells. After 63 days, mice given a subcutaneous injection of parental NMuLi or NEF-null cells had tumor volumes of 2400 mm(3) (95% CI = 1478 mm(3) to 3300 mm(3)) and 2700 mm(3) (95% CI = 2241 mm(3) to 3144 mm(3)), respectively, compared with mean tumor volumes of less than 30 mm(3) in mice given an injection of NEF-Endo clones, a statistically significant difference (P<.001). After 123 days, all 16 mice given an intraperitoneal injection of parental NMuLi or NEF-null cells had died, compared with only three (9%) of 32 mice given an injection of NEF-Endo clones. CONCLUSIONS: Retroviral endostatin gene transfer leads to secretion of functional endostatin that is sufficiently active to inhibit tumor growth. Further studies of retroviral endostatin gene transfer for the treatment of cancer are warranted.

Angiogenesis Inhibitors↗
PubMed2001

Prognostic value of initial fasting serum gastrin levels in patients with Zollinger-Ellison syndrome.

PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

Adolescent↗
PubMed2001

Serum endostatin levels are elevated in patients with soft tissue sarcoma.

BACKGROUND: Solid tumors are angiogenesis dependent, and elevated levels of proangiogenic cytokines have been reported in a variety of histologies. Endostatin is an antiangiogenic fragment of the basement membrane protein, collagen XVIII. Because antiangiogenic protein fragments may be generated by tumor-derived proteases, the authors sought to determine whether circulating levels of endostatin were elevated in patients with localized soft tissue sarcoma. METHODS: The authors analyzed preoperative serum levels of endostatin, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) in 25 patients (14 males and 11 females; mean age, 44 years) with soft tissue sarcoma. For each serum sample, two aliquots were assayed in duplicate using a competitive enzyme immunoassay. Serum levels were compared with levels from 34 age-matched and gender-matched volunteer blood donors. RESULTS: Endostatin levels were significantly higher in sera from sarcoma patients than in sera from healthy controls (43.0 ng/mL vs. 25.8 ng/mL, respectively; P = 0.0002; Mann-Whitney U test). Significant elevations also were noted in VEGF and bFGF levels (P = 0.0002 and P = 0.0001, respectively). Furthermore, endostatin levels > 2 standard deviations above the control mean (55 ng/mL) were associated with an increased risk of tumor recurrence after resection (P = 0.047; log-rank test). CONCLUSIONS: Serum endostatin, VEGF, and bFGF levels are elevated in patients with soft tissue sarcoma. Elevated endostatin levels appear to be associated with tumor aggressiveness. The role of these cytokines in sarcoma angiogenesis and as potential targets for therapy warrants further study.

Adult↗
PubMed2001

A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer syndrome, characterized primarily by multiple tumors in the parathyroid glands, endocrine pancreas, and anterior pituitary. Other tumors, including gastrinoma, carcinoid, adrenal cortical tumors, angiofibroma, collagenoma, and lipoma, also occur in some patients. Individuals with MEN1 almost always have loss-of-function mutations in the MEN1 gene on chromosome 11, and endocrine tumors arising in these patients usually show somatic loss of the remaining wild-type allele. To examine the role of MEN1 in tumor formation, a mouse model was generated through homologous recombination of the mouse homolog Men1. Homozygous mice die in utero at embryonic days 11.5-12.5, whereas heterozygous mice develop features remarkably similar to those of the human disorder. As early as 9 months, pancreatic islets show a range of lesions from hyperplasia to insulin-producing islet cell tumors, and parathyroid adenomas are also frequently observed. Larger, more numerous tumors involving pancreatic islets, parathyroids, thyroid, adrenal cortex, and pituitary are seen by 16 months. All of the tumors tested to date show loss of the wild-type Men1 allele, further supporting its role as a tumor suppressor gene.

Adenoma↗
PubMed2001

A prospective analysis of plasma endostatin levels in colorectal cancer patients with liver metastases.

BACKGROUND: Circulating inhibitors of angiogenesis have been suggested to affect the growth of distant micrometastatic disease in patients with cancer. This study was designed to evaluate circulating endostatin levels in colorectal cancer patients with liver metastases. METHODS: Plasma samples from 30 colorectal cancer patients with liver metastases were analyzed for endostatin and vascular endothelial growth factor (VEGF) by using competitive enzyme immunoassays. Samples were compared with plasma from age- and sex-matched healthy controls; values >2 SD above the control mean were considered elevated. RESULTS: Plasma endostatin levels were significantly higher in the 30 cancer patients than controls (P < .0001) and correlated with preoperative VEGF levels (P = .0008). Eighteen patients underwent surgical treatment (liver resection, n = 10; or isolated hepatic perfusion with melphalan, n = 8). Seventeen treated patients were available for follow-up. Eight of 11 patients who progressed had elevated plasma endostatin levels at the time of progression. None of six patients who remained progression free had elevated endostatin levels at last follow-up (P = .02). CONCLUSIONS: Plasma endostatin levels are elevated in colorectal cancer patients with liver metastases and correlate with VEGF levels. Elevated endostatin levels during follow-up are associated with disease progression. Understanding the role of endogenous endostatin in cancer patients may lead to novel strategies to inhibit tumor angiogenesis.

Adult↗
PubMed2001

Factors affecting survival after complete response to isolated limb perfusion in patients with in-transit melanoma.

BACKGROUND: Isolated limb perfusion (ILP) results in complete response (CR) rates of 60% to 90% in patients with regionally advanced melanoma. Survival after a CR may be influenced by various factors, particularly out-of-field disease in iliac lymph nodes (ILN) identified during lower-extremity ILP. We examined clinical and pathological parameters, including ILN status and outcome, for patients with in-transit melanoma who had a CR to ILP. METHODS: From May 1992 to July 1997, 50 patients (16 men and 34 women; median age, 57 years) with stage IIIA or IIIAB melanoma had a CR to a 90-minute hyperthermic iliac ILP with melphalan (10 mg/L limb volume, n = 20) or melphalan and tumor necrosis factor (4-6 mg+/-200 microg interferon; n = 30). Clinical and pathological parameters were analyzed by univariate and Cox proportional hazards models to determine which were associated with survival or in-field recurrence. RESULTS: The median in-field recurrence-free survival in the cohort of 50 patients after a CR to ILP was 1.4 years, and the actuarial 5-year in-field recurrence-free survival was 30%. By univariate analysis, there was a trend for improved outcome with female sex and stage IIIA (vs. IIIAB) at initial diagnosis was associated with improved survival after a CR to ILP (P = .056 and .012, respectively). Eleven (22%) of 50 patients had positive ILNs identified and resected at ILP. The probability of overall in-field recurrence was 70% after 4 years, and there was no difference between those with or without positive ILNs; median time to in-field recurrence was 13 and 19 months, respectively (P = .62). Similarly, overall survival was not influenced by positive ILN status (median [months]: +ILN, 69 vs. -ILN, 58; P = .68). Of note, Cox models identified that the risk of death was significantly greater in those with a history of prior systemic therapy (hazard ratio: 2.67 [95% confidence interval, 1.17-6.11]; P = .02) and those with an in-transit lesion size > or =1.4 cm2 (hazard ratio, 3.12 [95% confidence interval, 1.30-7.5]; P = .011). When these two variables were combined, there was a highly significant association with shortened survival (P = .002 by log-rank test). CONCLUSIONS: These data indicate that for patients undergoing ILP and in whom positive ILNs are found and resected, ILP is justified. In addition, patients who have a CR after ILP and have a history of prior treatment or larger lesions should be considered for adjuvant systemic therapy.

Adult↗
PubMed2001

A prospective study of 2-[18F] fluoro-2-deoxy-D-glucose/positron emission tomography scan, 99mTc-labeled arcitumomab (CEA-scan), and blind second-look laparotomy for detecting colon cancer recurrence in patients with increasing carcinoembryonic antigen levels.

BACKGROUND: An increasing carcinoembryonic antigen (CEA) level in the absence of disease on imaging studies can present a diagnostic challenge. We evaluated 2-[18F] fluoro-2-deoxy-D-glucose and positron emission tomography (FDG-PET) scan and CEA scan before second-look laparotomy as a means of localizing recurrent colorectal cancer. METHODS: Patients underwent computed tomography scan, bone scan, colonoscopy, and magnetic resonance imaging, and those without evidence of disease or resectable disease in the abdomen had FDG-PET and CEA scans. At second-look laparotomy, a surgeon blinded to the results of the FDG-PET and CEA scans performed an exploration and mapped findings. A second surgeon, with knowledge of the FDG-PET and CEA scans, then explored the patient; all lesions were biopsied or resected for pathology. RESULTS: In 28 patients explored, disease was found at operation in 26 (94%). Ten had unresectable disease. FDG-PET scans predicted unresectable disease in 90% of patients. CEA scans failed to predict unresectable disease in any patient. In 16 patients found to have resectable disease or disease that could be treated with regional therapy, FDG-PET scan predicted this in 81% and CEA scan in 13%. CONCLUSIONS: FDG-PET scan can predict those patients who would likely benefit from a laparotomy. If the FDG-PET scan indicates resectable disease, laparotomy can be considered. However, if the findings predict unresectable disease or the absence of disease, the patient should pursue systemic therapy or continued observation.

Adult↗
PubMed2001

Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer.

BACKGROUND: Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases. METHODS: Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival. RESULTS: There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater. CONCLUSIONS: IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.

Adult↗
PubMed2001

Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1.

BACKGROUND: Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex. METHODS: From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews. RESULTS: Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%). CONCLUSIONS: Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.

Adult↗
PubMed2001

Noninvasive estimation of the aorta input function for measurement of tumor blood flow with.

Quantitative measurement of tumor blood flow with [15O]water can be used to evaluate the effects of tumor treatment over time. Since quantitative flow measurements require an input function, we developed the profile fitting method (PFM) to measure the input function from positron emission tomography images of the aorta. First, a [11C]CO scan was acquired and the aorta region was analyzed. The aorta diameter was determined by fitting the image data with a model that includes scanner resolution, the measured venous blood radioactivity concentration, and the spillover of counts from the background. The diameter was used in subsequent fitting of [15O]water dynamic images to estimate the aorta and background radioactivity concentrations. Phantom experiments were performed to test the model. Image quantification biases (up to 15%) were found for small objects, particularly for those in a large elliptical phantom. However, the bias in the PFM concentration estimates was much smaller (2%-6%). A simulation study showed that PFM had less bias and/or variability in flow parameter estimates than an ROI method. PFM was applied to human [11C]CO and [15O]water dynamic studies with left ventricle input functions used as the gold standard. PFM parameter estimates had higher variability than found in the simulation but with minimal bias. These studies suggest that PFM is a promising technique for the noninvasive measurement of the aorta [15O]water input function.

Aorta↗
PubMed2001

General aspects of anti-angiogenesis and cancer therapy.

Angiogenesis is the outgrowth of new vessels from pre-existing ones. Tumour growth and metastasis is dependent on angiogenesis and many stimulatory and inhibitory factors have been described which play an active role in this process. Inhibition of tumour neovasculature may be one strategy to inhibit tumour growth. Naturally occurring inhibitors of angiogenesis have been discovered and synthetic agents have been designed. Many of these inhibitors are currently being evaluated in clinical trials for the treatment of cancer. This review discusses the mechanism of action of these anti-angiogenics as well as a description of the clinical trials in which they are being evaluated.

Angiogenesis Inhibitors↗
PubMed2001

Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion.

PURPOSE: Isolated limb or liver perfusion with tumor necrosis factor (TNF) and melphalan results in regression of advanced cancers in the majority of treated patients. However, the contribution of TNF to the efficacy of isolation perfusion with melphalan has not been demonstrated conclusively in random assignment trials. Furthermore, TNF is an inflammatory cytokine and may be associated with significant systemic and regional toxicity. This study was conducted to characterize the toxicity and secondary cytokine production attributable to TNF by comparing these parameters in patients undergoing isolated hepatic perfusion (IHP) using melphalan with or without TNF. EXPERIMENTAL DESIGN: Thirty-two patients with unresectable colorectal cancer confined to the liver underwent a 60-min hyperthermic IHP using 1.5 mg/kg melphalan alone (n = 17) or with 1.0 mg of TNF (n = 15) with inflow via the gastroduodenal artery and outflow via an isolated segment of inferior vena cava. Complete vascular isolation was confirmed using the I-131 radiolabeled albumin-monitoring technique. Post-IHP parameters of hepatic and systemic toxicity and cytokine levels [TNF, interleukin (IL)-6 and IL-8] in perfusate and serum were measured. RESULTS: Levels of IL-6 and IL-8 in perfusate at the end of the 60-min IHP were significantly higher in TNF-treated patients (P < or = 0.001). Peak systemic IL-6 and IL-8 levels post-IHP were also significantly higher in TNF-treated compared with non-TNF-treated patients (P < 0.0001) by 28- and 268-fold, respectively. The peak levels of these cytokines were associated with significantly lower systolic blood pressure and higher heart rate and mean pulmonary artery blood pressure in TNF-treated patients during the first 48 h post-IHP (P < or = 0.03). Serum bilirubin levels were significantly higher (P = 0.017) and platelets lower (P = 0.03) in TNF-treated compared with non-TNF-treated patients. However, elevations in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase were not significantly different between groups and returned toward baseline within 1 week after IHP. CONCLUSIONS: Addition of TNF to melphalan during IHP results in significant differences in post-IHP production of IL-6 and IL-8 with associated changes in mean arterial blood pressure and greater regional toxicity, as reflected in higher levels of serum bilirubin. However, these measurable differences were transient and did not appear to be of major clinical consequence. Prior to its routine use, the benefit of TNF in isolation perfusion should be demonstrated in random assignment trials.

Adult↗