Emergency department use after outpatient thyroidectomy across three states.

BACKGROUND: Although outpatient thyroidectomy has become common, few large-scale studies have examined post-thyroidectomy emergency department use, readmission, and encounters not resulting in readmission, known as "treat-and-release" encounters. We evaluated post-outpatient thyroidectomy emergency department use and readmission and characterized associated factors. METHODS: Using the Healthcare Cost and Utilization Project databases, we identified adult outpatient (same-day or <24-hour discharge) thyroidectomies performed in Florida, Maryland, and New York from 2016 to 2017. We identified the procedures linked with emergency department treat-and-release encounters and readmissions within 30 days postoperatively and the factors associated with post-thyroidectomy emergency department use and readmission. RESULTS: Of the 17,046 patients who underwent outpatient thyroidectomy at 374 facilities, 7.5% had emergency department treat-and-release encounters and 2.3% readmissions. The most common reasons for emergency department treat-and-release encounters (9.9%) and readmissions (22.2%) were hypocalcemia-related diagnoses. Greater odds of treat-and-release were associated with identifying as non-Hispanic Black (adjusted odds ratio: 1.5, 95% confidence interval: 1.3-1.8) or Hispanic race/ethnicity (adjusted odds ratio: 1.4, 95% CI: 1.1-1.6), having Medicaid insurance (adjusted odds ratio: 2.7, 95% CI: 2.3-3.2), and living in non-metropolitan areas (adjusted odds ratio: 1.6, 95% CI: 1.1-2.2). We observed no associations between these factors and the odds of readmission. CONCLUSION: Emergency department use after outpatient thyroidectomy is common. Racial, ethnic, socioeconomic, and geographic disparities are associated with treat-and-release encounters but not readmissions. Standardization of perioperative care pathways, focusing on identifying and addressing specific issues in vulnerable populations, could improve care, reduce disparities, and improve patient experience by avoiding unnecessary emergency department visits after outpatient thyroidectomy.

Association between travel distance and overall survival among patients with adrenocortical carcinoma.

BACKGROUND AND OBJECTIVES: Regionalization of care is associated with improved perioperative outcomes after adrenalectomy. However, the relationship between travel distance and treatment of adrenocortical carcinoma (ACC) is unknown. We investigated the association between travel distance, treatment, and overall survival (OS) among patients with ACC. METHODS: Patients diagnosed with ACC between 2004 and 2017 were identified with the National Cancer Database. Long distance was defined as the highest quintile of travel (≥42.2 miles). The likelihood of surgical management and adjuvant chemotherapy (AC) were determined. The association between travel distance, treatment, and OS was evaluated. RESULTS: Of 3492 patients with ACC included, 2337 (66.9%) received surgery. Rural residents were more likely to travel long distances for surgery than metropolitan residents (65.8% vs. 15.5%, p < 0.001), and surgery was associated with improved OS (HR 0.43, 95% CI 0.34-0.54). Overall, 807 (23.1%) patients received AC with rates decreasing approximately 1% per 4-mile travel distance increase. Also, long distance travel was associated with worse OS among surgically treated patients (HR 1.21, 95% CI 1.05-1.40). CONCLUSIONS: Surgery was associated with improved overall survival for patients with ACC. However, increased travel distance was associated with lower likelihood to receive adjuvant chemotherapy and decreased overall survival.

How to use molecular testing results to guide surgery: a surgeon's perspective.

PURPOSE OF REVIEW: Multiple genetic mutations have been found to be associated with thyroid cancer, and molecular testing of thyroid nodule fine-needle aspiration (FNA) specimens has been proposed as an adjunct to the cytologic diagnosis. The purpose of this review is to examine how molecular testing of FNAs could be used to guide surgical decision-making. RECENT FINDINGS: B-type RAF kinase mutations in papillary thyroid cancer have been found to be associated with extrathyroidal extension, lymph node metastases, and advanced stage in two meta-analyses that are based largely on retrospective data. Testing for a panel of gene mutations has been found to have high specificity and positive predictive value, whereas microarray testing using a commercially available gene-expression classifier has been found to have high sensitivity and negative predictive value for the diagnosis of malignancy in cytologically indeterminate FNAs. Although there is no consensus regarding the use of such tests, they have already started to change clinical practice. SUMMARY: Molecular testing of FNA specimens may help to avoid diagnostic thyroidectomy or may help in deciding the extent of surgery in a patient with an indeterminate FNA biopsy. The use of these tests is currently undergoing review by a task force within the American Thyroid Association.

A multi-institutional international study of risk factors for hematoma after thyroidectomy.

BACKGROUND: Cervical hematoma can be a potentially fatal complication after thyroidectomy, but its risk factors and timing remain poorly understood. METHODS: We conducted a retrospective, case-control study identifying 207 patients from 15 institutions in 3 countries who developed a hematoma requiring return to the operating room (OR) after thyroidectomy. RESULTS: Forty-seven percent of hematoma patients returned to the OR within 6 hours and 79% within 24 hours of their thyroidectomy. On univariate analysis, hematoma patients were older, more likely to be male, smokers, on active antiplatelet/anticoagulation medications, have Graves' disease, a bilateral thyroidectomy, a drain placed, a concurrent parathyroidectomy, and benign pathology. Hematoma patients also had more blood loss, larger thyroids, lower temperatures, and higher blood pressures postoperatively. On multivariate analysis, independent associations with hematoma were use of a drain (odds ratio, 2.79), Graves' disease (odds ratio, 2.43), benign pathology (odds ratio, 2.22), antiplatelet/anticoagulation medications (odds ratio, 2.12), use of a hemostatic agent (odds ratio, 1.97), and increased thyroid mass (odds ratio, 1.01). CONCLUSION: A significant number of patients with a postoperative hematoma present >6 hours after thyroidectomy. Hematoma is associated with patients who have a drain or hemostatic agent, have Graves' disease, are actively using antiplatelet/anticoagulation medications or have large thyroids. Surgeons should consider these factors when individualizing patient disposition after thyroidectomy.

Primary hyperaldosteronism: challenges in subtype classification.

BACKGROUND: Primary hyperaldosteronism (PA) is a serious and potentially debilitating disease. Detailed guidelines have been written to guide endocrinologists in establishing the diagnosis of PA as well as in subtype classification of PA. The objective of this case report is to present a case where subtype classification of PA was challenging and repeated imaging of the adrenal glands helped establish the diagnosis in a patient with initial normal adrenal glands on CT and MRI images. CASE PRESENTATION: We report a case of a 29-year-old woman with an established diagnosis of PA, but unclear subtype, who presented to us for further management. She initially presented for medical evaluation of uncontrolled hypertension and spontaneous hypokalemia 4 years prior. In the investigation of secondary causes of hypertension, plasma aldosterone-to-plasma renin activity ratio was elevated on two separate occasions, and primary hyperaldosteronism was confirmed by saline infusion test. Also during this time, she had adrenal venous sampling done 3 times at multiple institutions yielding confusing results. Initially, imaging by CT and MRI showed normal adrenal glands. To help establish the subtype of PA, we reimaged this patient's adrenal glands one year later revealing a 2 cm left adrenal adenoma. Laparoscopic left adrenalectomy improved her hypertension and was curative of her hypokalemia. CONCLUSION: This case presents an unusual case where reimaging of the adrenal glands led to the discovery of a single adenoma, initially not observed on imaging studies.

Influence of lymph node metastases on survival in pediatric medullary thyroid cancer.

PURPOSE: Lymph node metastases (LNM) from medullary thyroid cancer (MTC) are common in adults and are a poor prognostic factor. Less is known about LNM in children, who often have hereditary forms of MTC. Guidelines recommend prophylactic thyroidectomy in early childhood, but randomized prospective trials are not feasible. We hypothesized that LNM is associated with poor prognosis in children. METHODS: Patients with MTC 21 years or younger from the National Cancer Data Base from 1985 to 2007 were studied. Multivariable logistic regression was used to identify factors associated with lymph node evaluation. Survival was estimated using the Kaplan-Meier method. RESULTS: Of 430 patients, 276 (64.2%) had nodal evaluation with LNM present in 121 (28.1%). Older patients, those with tumors larger than 2 cm, and those with involved margins were more likely to have LNM (all P < .05). Patients undergoing total thyroidectomy, those with involved margins, and older patients were more likely to undergo lymph node evaluation after controlling for patient, tumor, and hospital factors (all P < .05). Over time an increasing number of patients with MTC have undergone total thyroidectomy. Patients 16 to 21 years of age had lower 10-year overall survival compared to patients 0 to 15 years old (88.7% vs 98.1%, P = .005). Lymph node metastases were also associated with decreased 10-year overall survival (84.4% vs 100%, P < .001). CONCLUSIONS: In pediatric MTC, LNM predict poorer overall survival. Adequate lymph node assessment can provide valuable prognostic information for the pediatric MTC patient. Lymph node assessment should be considered for older pediatric patients undergoing surgery for hereditary MTC or biopsy confirmed MTC.

Prior head and neck radiation exposure is not a contraindication to minimally invasive parathyroidectomy.

BACKGROUND: Most patients with primary hyperparathyroidism can have a minimally invasive parathyroidectomy based on localization studies showing single-gland disease. In patients with a history of head and neck irradiation, due to the increased risk of multigland disease and risk of concurrent thyroid cancer, minimally invasive parathyroidectomy is considered by some to be a contraindication. We postulated that previous history of head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy and tested this hypothesis in a prospective cohort of patients undergoing parathyroidectomy for primary hyperparathyroidism. STUDY DESIGN: We performed a retrospective analysis of a prospective database of 491 consecutive parathyroidectomies performed between May 2005 and May 2007 at a tertiary referral medical center. RESULTS: Fifty-two (12.6%) patients had a history of head and neck irradiation and 360 (87.4%) had no exposure to radiation. The 2 groups had no significant difference in terms of gender or ethnicity. The radiation group was older, with an average age of 65.1 years versus 58.1 years (p < 0.0009). There was no significant difference in concurrent benign thyroid neoplasm, thyroid cancer, and type of parathyroid disease (single vs multigland) in the 2 groups. There was no significant difference in the operative approach used between the 2 groups (focused vs unilateral or bilateral). CONCLUSIONS: Head and neck irradiation should not be a contraindication for minimally invasive parathyroidectomy in patients with primary hyperparathyroidism in the setting of preoperative localization studies showing single-gland disease and no concurrent thyroid neoplasm. Furthermore, history of head and neck irradiation is associated with a later age of presentation for parathyroidectomy.

Are additional localization studies and referral indicated for patients with primary hyperparathyroidism who have negative sestamibi scan results?

HYPOTHESIS: Additional imaging studies are useful to select patients who are candidates for minimally invasive parathyroidectomy, and referral is not indicated when results from a preoperative sestamibi scan are negative. DESIGN, SETTING, AND PATIENTS: Prospective analysis of 492 operations for primary hyperparathyroidism from May 2005 to May 2007 at a tertiary care center. MAIN OUTCOME MEASURES: Accuracy of imaging studies, pathologic findings, and biochemical cure. RESULTS: Among the patients, 96% were cured. Of the sestamibi scan results, 91% were positive and 82% were true-positive. Ultrasonography results were positive in 51% of patients with negative sestamibi scan results, and 43% were true-positive. Patients with positive sestamibi scan results compared with those with negative sestamibi scan results had a higher rate of single-gland disease (87% vs 63%, respectively) and lower rates of double adenoma (6% vs 22%, respectively) and asymmetric hyperplasia (7% vs 15%, respectively) (P<.001). In patients with positive sestamibi scan results compared with those with negative sestamibi scan results, there was no significant difference in the rate of ectopic parathyroid glands (18% vs 12%, respectively) but there was a significant difference in cure rate (97% vs 89%, respectively) (P=.008). CONCLUSIONS: Additional imaging with neck ultrasonography is helpful for selecting minimally invasive parathyroidectomy in most patients with primary hyperparathyroidism who have negative sestamibi scan results. Referral for parathyroidectomy may be considered in patients with negative sestamibi scan results because these results are associated with multigland disease and lower cure rates.

Localization of recurrent thyroid cancer using intraoperative ultrasound-guided dye injection.

BACKGROUND: Small, nonpalpable lymph node recurrences are frequently identified in the follow-up of patients with thyroid cancer, and finding and removing these lesions in a reoperative field can be very challenging. The goal of this study was to evaluate the utility of preincision ultrasound-guided injection of blue dye into the abnormal lymph nodes to facilitate their safe and efficient removal. METHODS: We performed a prospective study between January and June 2007 at a single academic institution. Ten patients with isolated, nonpalpable nodal recurrences of papillary thyroid cancer underwent an operation for a neck recurrence (8 central, 2 lateral). A preincision ultrasound was performed in the operating room to localize the lesions, and 0.1 ml of blue dye was injected under ultrasound guidance into each abnormal lymph node. We examined the feasibility of the injection procedure, the accuracy of identifying pathologic lymph nodes, and the complications of injection. RESULTS: The pathologic lymph nodes averaged 11 mm in size (range = 6-16 mm) and were detectable by ultrasound in all cases. Ultrasound-guided blue dye injection was successful in all cases. There were no complications related to dye injection. The blue node was easily identified and removed in all cases. The mean operative time was 80.4 min (range = 37-157 min). CONCLUSIONS: Blue dye injection was feasible and was very useful for the identification of lymph node recurrences, especially in the reoperative neck. There were no complications related to the injection in this series. Further study is needed to determine the widespread safety and efficacy of this technique.

Waiting for change: symptom resolution after adrenalectomy for Cushing's syndrome.

BACKGROUND: The debilitating symptoms and physical changes from Cushing's syndrome may resolve after treatment, but the time course to resolution is not well established. METHODS: Between February 1995 and May 2007, 60 patients underwent adrenalectomy for Cushing's syndrome. Pre-operative and operative variables were collected from a prospective database. Long-term follow-up was obtained via patient survey. RESULTS: Unilateral adrenalectomy was performed in 53% and a bilateral adrenalectomy in 47% of patients. Median time to diagnosis was 24 months (range, 1-384). Three percent had intra-operative complications, and 28% developed post-operative complications. Steroids were required post-operatively for a median of 30 months after unilateral adrenalectomy (range, 0-96). At a median follow-up of 3.7 years (range, 0-13.3), 85% of patients are still alive. The majority of the physical changes resolved after adrenalectomy. The time to symptom resolution varied from a few weeks to up to 4 years. Most of the physical changes resolved by a mean of 7-9 months after surgery. Quality of life improved in 78% of patients, with 68% improving dramatically (P < .001). CONCLUSION: Adrenalectomy can provide excellent palliation of the symptoms of cortisol excess and can dramatically improve patient quality of life, but both patients and physicians must know that these changes may take years.

Tumor size predicts malignant potential in Hürthle cell neoplasms of the thyroid.

BACKGROUND: A fine needle aspiration (FNA) diagnosis of a Hürthle cell neoplasm is associated with a 20% risk of malignancy. We sought to determine if the primary tumor size correlated with the risk of malignancy in patients with a preoperative FNA diagnosis of a Hürthle cell neoplasm. METHODS: Between January 2000 and November 2006, 57 patients underwent a thyroidectomy with a preoperative FNA diagnosis of a Hürthle cell neoplasm. Patient histories, FNA reports, operative notes, and pathology reports were retrospectively reviewed. Statistical analysis was performed. RESULTS: The overall rate of malignancy in patients with Hürthle cell neoplasms was 21%. The average tumor size was 3.2 cm, with malignant tumors being significantly larger than benign tumors (5.0 vs. 2.7 cm, p<0.01). The risk of malignancy directly correlated with tumor size. No malignancies were seen in tumors 2 cm or smaller (0/15). The risk of malignancy was only 13% (6/46) in tumors 4 cm or smaller and increased to 55% (6/11) in tumors larger than 4 cm. All tumors larger than 6 cm were malignant (4/4). CONCLUSIONS: Tumor size correlates directly with malignant potential in patients with Hürthle cell neoplasms of the thyroid. Among our patients, malignancy was not present in any tumors 2 cm or smaller and was present in all tumors larger than 6 cm. Because the risk of malignancy is greater than 50% in patients with a tumor larger than 4 cm, consideration should be given for an initial total thyroidectomy in these patients.

Current status and treatment of primary hyperparathyroidism.

Primary hyperparathyroidism (HPT) is diagnosed in approximately 100,000 patients in the US each year, with a 2-3:1 female-to-male distribution. In most cases, occurrence is sporadic rather than familial, and 80% to 85% of cases of sporadic primary HPT are caused by a solitary parathyroid adenoma. The diagnosis is made by hypercalcemia with an inappropriately elevated parathyroid hormone (PTH) level and a 24-hour urine calcium excretion level that is normal or high. Truly asymptomatic primary HPT is rare, as most patients have symptoms or metabolic complications when carefully evaluated by standardized health questionnaires. The National Institutes of Health (NIH) published guidelines in 2002, recommending parathyroidectomy for all symptomatic patients and for asymptomatic patients less than age 50 years or those who cannot participate in medical surveillance. These criteria have been called into question as being too limited, because multiple studies have demonstrated symptomatic and metabolic benefits of parathyroidectomy in "asymptomatic" patients. Given the studies showing an improvement in quality-of-life measures, future risk for developing renal calculi, bone density, cardiovascular health, and risk of death, we believe that virtually all patients with primary HPT should undergo surgical resection. An improvement in preoperative localization studies as well as the development of a rapid intraoperative PTH assay has changed the approach to parathyroid surgery since the 1980s. Because most sporadic primary HPT is caused by a single gland adenoma, our preferred procedure has now changed from a bilateral neck exploration to a focused or unilateral approach, with similar rates of success in patients with a solitary tumor identified preoperatively.

Does the presence of additional thyroid nodules on ultrasound alter the risk of malignancy in patients with a follicular neoplasm of the thyroid?

BACKGROUND: Follicular neoplasms of the thyroid are associated with an approximately 20% risk of malignancy. We sought to determine whether the presence of additional thyroid nodules on preoperative ultrasound decreased the risk of malignancy in a patient with a follicular neoplasm. METHODS: Between January 2000 and November 2006, 325 patients underwent thyroidectomy with a fine needle aspiration diagnosis of either follicular neoplasm, Hürthle cell neoplasm, or indeterminate (not including suspicious for papillary thyroid cancer). Records were reviewed retrospectively and statistical analysis was performed using SPSS (SPSS Corporation, Chicago, Ill). RESULTS: The rate of malignancy in our patient population was 20% (23% in follicular neoplasm, 19% in Hürthle cell neoplasm, 9% in indeterminate). Overall, 57% of patients had multiple thyroid nodules on preoperative ultrasound. The risk of malignancy was lower in patients with greater than or equal to 1 additional nodule in comparison with those with a solitary nodule (16.6% vs 28.0%, P = .02). The risk of malignancy was lowest in those with 1-3 additional nodules in comparison with those with greater than or equal to 4 nodules (14.5% vs 21.7%, P = .04). CONCLUSIONS: The presence of additional thyroid nodules on preoperative ultrasound is associated with a lower risk of malignancy in a patient with a follicular neoplasm.

Changing management in patients with papillary thyroid cancer.

The incidence of thyroid cancer has been increasing over the past 30 years, and it is now the seventh most common cancer in women. Papillary thyroid cancer is the most common subtype of thyroid cancer, occurring in 80% of cases. Its main pattern of spread is to cervical lymph nodes, with distant metastases occurring uncommonly. Initial treatment of papillary thyroid cancer involves resection of the primary tumor, with resection of regional lymph nodes if involved with metastatic disease. Postoperative adjuvant therapy consists of radioactive iodine ablation for most patients, followed by thyroid-stimulating hormone (TSH) suppression with thyroxine. An ongoing controversy in the surgical treatment of papillary thyroid cancer is that of extent of thyroid gland and nodal resection. Consensus guidelines recommend total or near-total thyroidectomy, rather than thyroid lobectomy, as the initial procedure of choice, given its advantages of treating potential multicentric disease, facilitating maximal uptake of adjuvant radioactive iodine, and facilitating the post-treatment follow-up by monitoring serum thyroglobulin (Tg) levels. In the hands of an experienced endocrine surgeon, complication rates are comparable to those for lobectomy. Major changes in the management of patients with papillary thyroid cancer over the last 10 years include the use of preoperative neck ultrasound, which can detect nonpalpable cervical lymph node metastases and potentially change the initial operation. In addition, neck ultrasound and measurement of serum Tg levels have taken the place of routine whole body radioactive iodine scans in the postoperative follow-up of patients with papillary thyroid cancer. Recurrent locoregional cervical lymph node disease should be treated by compartmental lymph node dissection, followed by another treatment dose of radioactive iodine. Chemotherapy is generally ineffective for the treatment of metastatic disease. For those patients whose tumor has become radioactive iodine resistant, emerging therapies include redifferentiation agents, antiangiogenic agents, and multi-tyrosine kinase inhibitors.

The role of interleukin 1 in growth and metastasis of human cancer xenografts.

BACKGROUND: Interleukin 1 (IL-1) is a pluripotent cytokine that promotes angiogenesis, tumor growth, and metastasis in experimental models; its presence in some human cancers is associated with aggressive tumor biology. The purpose of these studies was to characterize the role of IL-1 in human cancers and determine if inhibition of IL-1 via its receptor antagonist, IL-1Ra, alters tumor growth and metastatic potential. METHODS: IL-1 mRNA or protein levels were determined in clinical tumor samples, cancer cell lines, and xenografts using quantitative reverse transcription-PCR or ELISA. Biological activity of tumor-derived IL-1 protein was shown via induction of permeability across endothelial cell monolayers. The effects of recombinant IL-1Ra on tumor lines in culture (cell proliferation and IL-8 secretion) and in xenograft models (tumor growth, metastatic potential, and intratumoral levels of IL-8 and VEGF) were characterized. The effects of IL-1Ra-mediated regression of xenograft growth on angiogenic proteins (IL-8 and VEGF) were evaluated in an IL-1-producing melanoma (SMEL) xenograft model. RESULTS: IL-1 mRNA was highly expressed in more than half of all tested metastatic human tumor specimens including non-small-cell lung carcinoma, colorectal adenocarcinoma, and melanoma tumor samples. Constitutive IL-1 mRNA expression was identified in several cancer cell lines; tumor supernatant from these cell lines produced a significant increase in endothelial cell monolayer permeability, a hallmark event in early angiogenesis, in an IL-1-dependent manner. Moreover, systemic recombinant IL-1Ra resulted in significant inhibition of xenograft growth and neovessel density of IL-1-producing, but not non-IL-1-producing, tumor cell lines. Subsequent analysis of SMEL, a melanoma cell line with constitutive IL-1 production, showed that neither exogenous IL-1 nor IL-1Ra altered tumor cell proliferation rates in vitro. Gene expression analyses of IL-1Ra-treated SMEL xenografts showed a >3-fold down-regulation of 100 genes compared with control including a marked down-regulation of IL-8 and VEGF. CONCLUSIONS: These data show that the IL-1 gene is frequently expressed in metastases from patients with several types of human cancers. IL-1Ra inhibits xenograft growth in IL-1-producing tumors but has no direct antiproliferative effects in vitro; decreased tumor levels of IL-8 and VEGF may be an early surrogate of IL-1Ra-mediated antitumor activity. IL-1Ra may have a role alone or with other agents in the treatment of human cancers.

A pilot study of antiangiogenic therapy with bevacizumab and thalidomide in patients with metastatic renal cell carcinoma.

The use of antiangiogenic agents represents a promising strategy for the treatment of patients with metastatic renal cell carcinoma. Objective responses to single-agent thalidomide have been described, and a randomized study showed that bevacizumab (a neutralizing antibody against vascular endothelial growth factor) delayed time to progression of metastatic renal cancer. A pilot study combining these two agents was performed. Sequential cohorts of 10 and 12 patients (crossing over from placebo therapy in the aforementioned randomized bevacizuamab trial) were treated with low-dose bevacizumab alone or bevacizumab plus the maximum tolerated dose of thalidomide as determined by intrapatient escalation. Toxicity, objective responses, and time to progression were the endpoints of this study. Patients tolerated thalidomide and bevacizumab well, with more than 50% of patients escalating to at least 500 mg/d thalidomide. Grades 1 and 2 sensory neuropathy limited thalidomide dose escalation in 3 of 12 patients. The incidence of grades 3 and 4 toxicity was not different between patients treated with bevacizumab alone versus bevacizumab plus thalidomide. There were no objective responses and no difference in progression-free survival between the groups (2.4 months for bevacizumab alone, 3.0 months for bevacizumab plus thalidomide). Combination antiangiogenic therapy with bevacizumab plus thalidomide in patients with renal cell carcinoma is associated with similar toxicity and progression-free survival compared with bevacizumab alone. This study illustrates a clinical trial design for rapidly testing the feasibility and safety of combining antiangiogenic agents, an approach that will be necessary for rapidly evaluating the many potential combinations of antiangiogenic agents.

Alterations in tumor necrosis factor-induced endothelial cell procoagulant activity by hyperthermia.

TNF is a cytokine with potent antitumor activity in murine models and when administered clinically via regional perfusion. There is substantial evidence that this antitumor activity depends in large part on TNF's procoagulant effect on tumor neovasculature, which is mediated by induction of endothelial cell tissue factor (TF), a component of the extrinsic clotting cascade. In regional perfusion of a cancer-bearing limb or organ, TNF is always administered under hyperthermic temperatures; however, little is known about the effect of hyperthermia on TNF-mediated procoagulant activity in endothelium. We examined the effects of hyperthermia on TNF-mediated procoagulant activity in human umbilical vein endothelial cells (HUVECs). HUVECs were exposed to TNF at normothermic (37 degrees C) and hyperthermic (41 degrees C) temperatures for 90 min, then assayed for clotting activity, TF protein production and mRNA production of TF and tissue factor pathway inhibitor-2 (TFPI-2), an endogenous inducible inhibitor of TF activity in HUVECs. TNF treatment at 41 degrees C significantly reduced clotting activity, TF protein and mRNA as well as TFPI-2 mRNA compared to treatment at 37 degrees C. These data show that hyperthermia significantly reduces the procoagulant effects of TNF on endothelial tissue compared to normothermia, which may have important clinical implications for the use of TNF in regional perfusion.