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Biomedical subjects

H Richard Alexander

Publications and source records attributed to H Richard Alexander.

At least 19 recordsLinked to original sources
PubMed2006

Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment.

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFalpha, and TGFbeta. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.

Journal Article↗
PubMed2006

Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020.

PURPOSE: To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. PATIENTS AND METHODS: Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. RESULTS: The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). CONCLUSION: In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate.

Adult↗
PubMed2006

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.

Animals↗
PubMed2006

Interferon gamma-inducible protein 10 selectively inhibits proliferation and induces apoptosis in endothelial cells.

BACKGROUND: Interferon gamma-inducible protein 10 (IP-10) has antitumor effects in various murine models. The IP-10 receptor has two distinct splice variants, CXCR3A and CXCR3B, that have paradoxical effects after ligand-receptor interaction. METHODS: To characterize the putative antiangiogenic effects of IP-10, we measured proliferation rates and apoptosis in human umbilical vein endothelial cells (HUVECs), fibroblasts, and A375 melanoma or WIDR adenocarcinoma cell lines after exposure to the recombinant protein. CXCR3A (activating) and CXCR3B (inhibitory/proapoptotic) messenger RNA (mRNA) expression levels in fibroblasts, 2 human tumor cell lines, T lymphocytes, and HUVECs of varying cell densities were characterized. RESULTS: IP-10 resulted in dose-dependent and selective inhibition of proliferation and countered the proliferative effects of vascular endothelial growth factor in HUVECs but did not affect fibroblasts or 2 human tumor cell lines. In addition, IP-10 resulted in potent and selective induction of apoptosis in HUVECS but had no effect on fibroblasts or A375 melanoma. Confluent HUVECs had a predominance of mRNA for the CXCR3B splice variant by reverse transcriptase-polymerase chain reaction, and the ratio of CXCR3B to CXCR3A mRNA was >40 in HUVECs, compared with </=10 in the other cell types. Moreover, CXCR3B mRNA levels were significantly higher in proliferating compared with confluent HUVECs. In vivo, systemic IP-10 administration resulted in slower A375 xenograft growth rates compared with control-treated animals, and immunohistochemical staining showed decreased microvessel density in xenografts of IP-10-treated mice. CONCLUSIONS: IP-10 has antiangiogenic properties and selective effects on endothelial tissue that may be secondary to higher levels of the CXCR3B inhibitory/proapoptotic receptor in that cell type, particularly in its actively proliferating state.

Adenocarcinoma↗
PubMed2006

Gastrinoma: sporadic and familial disease.

The physiologic sequelae of a gastrinoma can be well controlled with medical therapy. The role of surgery has shifted from managing acid hyper-secretion and ulcer complications to preventing metastatic disease and managing symptomatic metastases. With improved methods of imaging for the detection of occult gastrinomas, the prospective evaluation of the role for surgery in altering the natural history of these tumors is now possible.

Algorithms↗
PubMed2006

Intravenous and isolated limb perfusion delivery of wild type and a tumor-selective replicating mutant vaccinia virus in nonhuman primates.

In this study we examine the safety, feasibility, and biodistribution of a tumor-selective mutant vaccinia (vvDD) and wild-type WR (vF13) vaccinia after delivery via intradermal or intravenous infection or isolated limb perfusion (ILP) in rhesus macaques. By intradermal inoculation, 10(6) PFU of vvDD caused a minimal skin reaction whereas vF13 caused marked erythema and necrosis with a peak indurated area of 108 cm2. By intravenous delivery, vvDD caused no clinical symptoms of viremia and no viral recovery from tissues, serum, saliva, urine, or feces. In contrast, vF13 caused symptoms of lethargy, anorexia, fever, and signs of viremia. Delivery of vF13 via ILP resulted in numerous cutaneous pox lesions localized solely to the perfused limb with high viral recovery in the perfused skin and muscle. ILP with vvDD resulted in no visible pox lesions and no clinical signs or symptoms of viremia. No long-term toxicity was identified after ILP with 10(9) PFU of vvDD, and no virus was recovered from any tissue, serum, saliva, urine, or fecal sample. These results suggest that vvDD appears to be safe in primates, and thus vvDD should be further investigated for clinical trial in human cancer patients.

Animals↗
PubMed2005

Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity.

IL-1beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

Journal Article↗
PubMed2005

Malignant insulinoma: spectrum of unusual clinical features.

BACKGROUND: Malignant insulinoma occurs in a few patients with insulinoma. Due to the small sample of patients, there are little data regarding their clinical manifestation as well as the preferred treatment modalities. The aims of the current study were to summarize the National Institutes of Health experience during the last two decades and to conduct a critical review of the current literature. METHODS: The authors identified 10 patients with metastatic insulinoma. RESULTS: The patients presented with four patterns of clinical behavior. First, four patients presented with lymph node metastasis and, after surgical excision, maintained a prolonged tumor-free survival. Second, four patients presented with metastatic disease to the liver, which appeared years after the initial diagnosis and presumed curative surgery. Third, one patient presented with a large alpha-fetoprotein-secreting liver mass. Finally, 9 of the 10 patients had a prolonged survival. Various treatment modalities were used to control hypoglycemia. Short-term benefits were most often achieved with embolization and diazoxide. Less successful modalities included radiofrequency ablation, radical debulking surgery, verapamil therapy, octreotide therapy, and chemotherapy. CONCLUSIONS: The current study, as well as others, suggested that metastatic insulinoma may have a variable natural history. After the initial surgical resection, the biology of the tumor, rather than any treatment modality, was most likely the major determinant of long-term survival.

Adult↗
PubMed2005

Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.

PURPOSE: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Adult↗
PubMed2005

Endothelial monocyte activating polypeptide-II induced gene expression changes in endothelial cells.

In the current study we used microarray (MA) analysis to examine gene expression changes in human umbilical vein endothelial cells (HUVEC) exposed to the tumor-derived cytokine, endothelial monocyte-activating polypeptide-II (EMAP-II). HUVEC treated with EMAP-II for 0.5, 1, 2, 4 and 8 h, were analyzed using 10K cDNA arrays. Our results demonstrated that changes in gene expression of <0.5 and >2 fold were seen for 69 genes and the majority of gene changes occurred early. Validation of MA analysis for 10 genes by real time RT-PCR, demonstrated the gene changes to be consistent and specific to HUVEC when compared to human fibroblasts treated with EMAP-II. Among these genes, downregulated in ovarian cancer 1 (DOC1) gene was studied further because of its possible role in EMAP-II induced cytoskeletal remodeling. DOC1 expression was silenced using small interfering RNA. SiRNA to DOC1 completely abolished EMAP-II stimulated gene expression of DOC1. Silencing of DOC1 gene expression reversed the modulatory effect of EMAP-II on 4 other genes, suggesting that DOC1 might play a role in mediating some of the effects of EMAP-II on endothelial cells.

Cell Proliferation↗
PubMed2005

Gland size is associated with changes in gene expression profiles in sporadic parathyroid adenomas.

BACKGROUND: Sporadic parathyroid adenomas (SPAs) are benign neoplasms responsible for most cases of primary hyperparathyroidism (pHPT). The molecular pathways responsible for the variations in clinical severity of pHPT are unknown. We studied gene expression profiles in patients with SPAs and pHPT to determine associations between these changes and clinical parameters. METHODS: We selected 10 patients with solitary SPAs and nonfamilial, non-MEN1 pHPT treated with surgery from 2001 to 2003. Pathologic and clinical data were reviewed. At operation, tissues from SPAs were frozen in liquid nitrogen; total RNA was obtained from sections, and the diagnosis was confirmed with hematoxylin and eosin staining. Control normal parathyroid RNA was age- and sex-matched. RNA was amplified, labeled, and hybridized to a microarray of 22,272 human oligonucleotides. Cluster analysis of gene expression, analysis of expression ratios, and comparison of clinical parameters were performed. RESULTS: All patients were cured; all specimens were consistent with SPAs. K means clustering divided the 10 patients into 2 distinct 5-patient gene expression groups by using uncentered correlation based on gene subgrouping. Of the clinical parameters, only the mean gland volume was significantly different between group 1 (390 +/- 160 mm(3)) and group 2 (1080 +/- 615 mm(3); P = .032 by Mann-Whitney test). Seventy-five genes were significantly upregulated or downregulated (with a ratio of <.33 or >3) compared with controls. These genes included the v-fos viral oncogene homolog and six calcium ion-binding signaling proteins. CONCLUSIONS: Differential expression of a few critical genes may contribute to differences in gland volume in SPAs. A better understanding of these pathways may help to define the pathophysiology of pHPT.

Adenoma↗
PubMed2005

Isolated hepatic perfusion for the treatment of patients with colorectal cancer liver metastases after irinotecan-based therapy.

BACKGROUND: Irinotecan given with 5-fluorouracil and leucovorin is currently used as first-line therapy for patients with metastatic colorectal cancer (CRC). However, the response duration is <1 year, and second-line systemic chemotherapy has limited efficacy. We analyzed the efficacy of isolated hepatic perfusion (IHP) for patients with progressive CRC liver metastases after irinotecan. METHODS: Between March 1993 and February 2003, 124 patients with CRC liver metastases underwent IHP on institutional review board-approved protocols. The overall treatment mortality was 4% (5 of 124). Twenty-five patients (10 women and 15 men; mean age, 53 years) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irinotecan. A 1-hour hyperthermic IHP (mean hepatic temperature, 40.0 degrees C) with melphalan 1.5 mg/kg (mean total dose, 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in an isolated segment of the inferior vena cava. During IHP, portal and inferior vena caval flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival. RESULTS: The mean number of prior irinotecan cycles in 25 patients was 6 (range, 2-14), and it was given primarily as second-line therapy. The median number of liver metastases before IHP was 10 (range, 1-50), and the median percentage of hepatic replacement by tumor was 25%. The mean operative time was 9 hours (range, 6-12 hours), and the median hospital stay was 11 days (range, 8-76 days). There was 1 complete response and there were 14 partial responses in 25 patients (60%), with a median duration of 12 months (range, 5-35 months). Disease progressed systemically in 13 of 25 patients at a median of 5 months (range, 3-16 months). The median overall survival was 12 months (range, 1-47 months), and the 2-year survival was 28%. CONCLUSIONS: For patients with progressive CRC liver metastases after irinotecan, IHP has good efficacy in terms of response rate and duration. Continued evaluation of IHP with melphalan as second-line therapy in this clinical setting is justified.

Adult↗
PubMed2005

Limited survival in patients with carcinomatosis from foregut malignancies after cytoreduction and continuous hyperthermic peritoneal perfusion.

Peritoneal carcinomatosis is a frequent mode of metastasis in patients with gastric, duodenal, or pancreatic cancer. Survival in this setting is short and therapeutic options are limited. This analysis examines the outcomes of 18 patients treated with operative cytoreduction and continuous hyperthermic peritoneal perfusion. Eighteen patients (6 males and 12 females) with gastric (n = 9), pancreatic (n = 7), or duodenal (n = 2) cancer were treated on protocol. Patients underwent optimal cytoreduction (complete gross resection, 11; minimal residual disease, 7) and a 90-minute perfusion with cisplatin. Clinical parameters and tumor and treatment characteristics were analyzed. Survival curves were estimated using the Kaplan-Meier method. Procedures included gastrectomy (n = 8), pancreaticoduodenectomy (n = 3), and hemicolectomy (n = 2). After cytoreduction, patients had no evidence of residual disease (n = 11), fewer than 100 implants less than 5 mm (n = 1), more than 100 implants between 5-10 mm (n = 3), or multiple implants with greater than 1 cm (n = 3). Five patients received a postoperative intraperitoneal dwell with 5-fluorouracil and paclitaxel. There was one perioperative mortality, and complications occurred in 10 patients. The median progression-free survival was 8 months (mean, 10 months; range, 1-47 months) with a median overall survival of 8 months (mean, 18 months; range, 1-74 months). In this cohort, peritoneal perfusion with cisplatin used to treat foregut malignancies has a high incidence of complications and does not significantly alter the natural history of the disease. Investigation of novel therapeutic approaches should be considered.

Adenocarcinoma↗
PubMed2005

A six-gene model for differentiating benign from malignant thyroid tumors on the basis of gene expression.

BACKGROUND: Thyroid nodules are common; fine-needle aspirations commonly are read as indeterminate, necessitating surgery to exclude carcinoma. We developed a 6-gene array-based predictor model to diagnose benign versus malignant thyroid lesions. In this study, we verified whether quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using this model reliably can differentiate benign from malignant thyroid nodules. METHODS: Molecular profiles of benign (follicular adenomas, hyperplastic nodules) and malignant tumors (papillary thyroid carcinomas, follicular variants of papillary thyroid carcinomas) were analyzed using qRT-PCR from our 6-gene model (kit, Hs.296031, Hs.24183, LSM7, SYNGR2, C21orf4). The gold standard was standard pathologic criteria. A diagnosis-predictor model was built by using the training samples and was then used to predict the class of 10 additional samples analyzed as unknowns. RESULTS: Our predictor model using 47 training samples correctly predicted 9/10 unknowns. One sample diagnosed as benign by standard histologic criteria was diagnosed as malignant by our model (sensitivity 75%; specificity, 100%; positive predictive value, 100%; negative predictive value, 85.7%). CONCLUSIONS: Molecular diagnosis with our 6-gene model can differentiate between benign and malignant thyroid tumors with high sensitivity and specificity. In combination, these genetic markers may be a reliable test to preoperatively diagnose the malignant potential of thyroid nodules.

Adenoma↗
PubMed2005

A prospective evaluation of laparoscopic exploration with intraoperative ultrasound as a technique for localizing sporadic insulinomas.

BACKGROUND: Preoperative imaging studies localize insulinomas in less than 50% of patients. Arteriography with calcium stimulation and venous sampling (ASVS) regionalizes greater than 90% of insulinomas but requires specialized expertise and an invasive procedure. This prospective study evaluated laparoscopic exploration with IOUS compared with the other localization procedures in patients with a sporadic insulinoma. METHODS: Between March 2001 and October 2004, 14 patients (7 women and 7 men; mean age, 53) with an insulinoma were enrolled in an IRB-approved protocol. Computed tomography, magnetic resonance imaging, ultrasound scan, and arteriography with calcium stimulation and venous sampling were performed preoperatively. A surgeon, blinded to the results of the localizing studies, performed a laparoscopic exploration with intraoperative ultrasound (IOUS). At the completion of the exploration, the success of laparoscopy for localization was scored, and the tumor was resected. RESULTS: Twelve of 14 tumors were localized successfully before laparoscopy (noninvasive, 7 of 14; invasive, 11 of 14). Laparoscopic IOUS localized successfully 12 of 14 tumors. All lesions were resected, and all patients were cured (median follow-up, 36 months). CONCLUSION: Laparoscopic IOUS identified 86% of tumors. The authors consider laparoscopic IOUS to be equivalent to ASVS in localizing insulinomas. Further study is therefore warranted to determine the role of laparoscopy with IOUS in the localization and treatment algorithm for patients with sporadic insulinoma.

Adult↗
PubMed2005

Targeting vaccinia to solid tumors with local hyperthermia.

We have previously demonstrated that mutant vaccinia viruses target tumors in vivo after systemic delivery, and they have potential as vectors for tumor-directed gene therapy. We hypothesized that hyperthermia may augment vaccinia delivery to tumors after systemic injection, as hyperthermia increases the permeability of the endothelial vasculature to nanoparticles. In our in vitro experiments, we have shown that hyperthermia does not alter tumor cells' susceptibility to the intrinsic cytopathogenicity of the vaccinia virus compared with normothermic controls. Hyperthermia also does not change the viral infectivity or the level of viral marker gene expression when compared with normothermia. In an in vitro model of endothelial cell monolayer permeability, we have demonstrated that hyperthermia increases the permeability of the monolayer to vaccinia virus and that this phenomenon is completely reversible. In vivo we have demonstrated that the tumors that were treated with systemic vaccinia under conditions of hyperthermia (41.5 degrees C for 30 min) had significantly higher levels of vaccinia marker gene activity (>100-fold) than those treated under normothermic conditions (p < 0.05) and that this effect was specific to tumor. We also demonstrated that mice with 1 cm subcutaneous tumors treated with a systemically delivered, conditionally replicating vaccinia under conditions of hyperthermia had complete tumor regression in 50% and significantly improved antitumor response, compared with normothermic viral-treated controls (mean tumor volume of 110 mm(3) vs 3169 mm(3), 13 days after treatment) and compared with hyperthermic, nonvirally treated control animals (p < 0.0001). Regional hyperthermia improves vaccinia targeting to tumors, and thereby enhances the antitumor response.

Animals↗