Thrall, Donald E., D.V.M., Ph.D.
Professor, College of Veterinary Medicine, Department of Molecular Biomedical Sciences

DVM: Purdue University
MS: Colorado State University
PhD: Colorado State University
Diplomate, American College of Veterinary Radiology (Radiology, Radiation Oncology)

Phone: (919) 5132-6292
Fax: (919) 513-6578
E-mail: don_thrall@ncsu.edu


Research Area:

My primary research focus is the use of spontaneous tumors in pet dogs and cats as a model to study tumor physiology and novel treatments. Information derived from study of these large animal models is relevant to animal and human cancer patients. Data can be used to assess causes of treatment failure, for identifying tumors/patients likely to respond favorably to treatment, to streamline introduction of potentially beneficial new treatments into the human clinic, and to avoid human clinical trials of ineffective or potentially harmful therapies.

Current Research:

My current research is centered around the use of hyperthermia as a cancer treatment modality. Research is funded through a Program of Projects grant at Duke University Medical Center (M. Dewhirst, DVM, PhD, P.I.) Our main focus areas are thermal dosimetry and the effect of hyperthermia on tumor physiology.

The biologic effect of increased temperature is a function of both temperature and time but hyperthermia dosimetry is made even more complex because of the temporal and spatial heterogeneity of temperatures produced in solid tumors from radiative heating methods.

Recently, we tested a system of thermal dosimetry based upon a unit of thermal isoeffective dose in dogs with soft tissue sarcomas. In this trial, dogs were randomly assigned one of two hyperthermia doses (a low dose and a high dose) administered in conjunction with radiation therapy. Local tumor control, metastasis and complications were evaluated. For a trial of this type to be meaningful, the prescribed thermal dose must be administered precisely. We were able to do this quite accurately, with no overlap in thermal doses between dose groups; this overlap has been problematic in other trials of hyperthermia making the true effect of the increased temperature impossible to quantify.

We found a statistically significant effect of thermal dose on the duration of local tumor control when other factors also contributing to local control (tumor volume and tumor histologic grade) were controlled.

Figure 1. Estimated survival distribution functions of time to local failure for a “typical” dog in the low and high thermal dose groups from a Cox proportional hazards model. There is a significant association between thermal dose group and time to local failure after controlling for total duration of heating, tumor volume and tumor grade (hazard ratio of low vs. high=2.28 (95% CI: 1.12-4.64); p-value=0.023). Duration of heating and tumor volume values used in the estimation of survival fuctions were median values for the respective group and overall, respectively. Htmin=total duration of heat treatment; median duration of heating in the thermal dose group was used in the plot. Stumvol=median tumor volume over all dogs in trial.

An unexpected finding in our study was the discovery of a independent association between total duration of heating and duration of local tumor control. This relationship was found within each thermal dose group and interestingly, longer durations of heating were associated with shorter local tumor control; this is opposite of what might be expected intuitively.

Figure 2. Kaplan-Meier survival distribution function estimates of time to local failure for dogs in the high thermal dose group. Total heating duration was divided into thirds for the analysis (n=21 dogs each curve). The longest heating duration is associated with shorter duration of tumor control.

As noted above, this finding of an inverse relationship between overall duration of heating and time to local control was unexpected. Thermal dose group had more influence on duration of local tumor control than did total duration of heating. However, the finding of an effect of total duration of heating independent of thermal dose group (Fig 2) is provocative and suggests that physiologic alterations created by heating, e.g. perfusion, oxygen consumption, interstitial pressure, may be influential in determining tumor response following heat and radiation combinations. Longer heating times may result in some portions of the tumor being exposed to high temperatures over a prolonged period leading to deleterious changes in the tumor microenvironment.

This topic is the basis of a new clinical trial where an identical thermal dose will be delivered in one of two fractionation schemes…a coarsely fractionated scheme with one hyperthermia treatment per week and a finely fractionated scheme with multiple hyperthermia treatments per week. It is hypothesized that longer tumor control will be found in the finely fractionated group due to the lower overall temperatures needed to reach the prescribed thermal dose. Extensive physiologic monitoring of tumors will be undertaken to quantify the differences in microenvironmental response of the tumor to the method of hyperthermia dose fractionation.

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Representative Publications:

Raleigh, J.A., Chou, S-C, Bono, E.L., Thrall, D.E., and Varia, M.A.: Semiquantitative Immunohistochemical Analysis for Hypoxia in Human Tumors. Int J Radiat. Oncol. Biol. Phys. 49:569-574, 2001

Dickerson, M.E., Page, R.L., LaDue, T.A., Hauck, M.L., Thrall, D.E., Stebbins, M.E., and Price, G.S.: Retrospective Analysis of Axial Skeleton Osteosarcoma in 22 Large-Breed Dogs. J. Vet. Int. Med. 15:120-124, 2001.

McEntee, M.C. and Thrall, D.E.: Computed Tomographic Imaging of Infiltrative Lipoma in 22 Dogs. Vet. Radiol. & Ultrasound 42:221-225, 2001.

Raleigh, J.A., Thrall, D.E., Varia, M.A.: Development and clinical application of pimonidazole as a marker for tumor hypoxia. Recent Res. Devel. Cancer 3:189-210, 2001

Chaffin, K., and Thrall, D.E. Results of Radiation Therapy in 19 Dogs with Cutaneous Mast Cell Tumor and Regional Lymph Node Metastasis. Veterinary Radiology & Ultrasound 43:392-395, 2002.

Kobayashi, T., Hauck. M.L., Dodge, R., Page, R.L., Price. S., Williams, L.E., Hardie, E.M., Mathews, K.G., and Thrall, D.E.: Preoperative Radiotherapy for Vaccine Associated Sarcoma in 92 Cats. Vet. Radiol. & Ultrasound 43:473-479, 2002.

Proulx, D.R., Ruslander, D.M., Dodge, R.K., Hauck, M.L., Williams, L.E., Horn, B., Price, G.S., and Thrall, D.E.: A Retrospective Analysis of 140 Dogs with Oral Melanoma Treated with External Beam Radiation. Vet Radiol. & Ultrasound 44:352-359, 2003.

Poulson, J.M., Vujaskovic, Z., Gaskin, A.A., LaRue, S.M., Meyer, R.E., Prescott, D.M., Samulski, T.V., Thrall, D.E., and Dewhirst, M.W.: Effect of Calcitonin Gene Related Peptide vs Sodium Nitroprusside to Increase Temperature in Spontaneous Canine Tumours During Local Hyperthermia. Int. J. Hyperthermia 20:477-489, 2004.

Kleiter, M., Malarkey, D.E., Ruslander, D.E., Thrall, D.E.: Expression Of Cyclooxygenase-2 In Canine Epithelial Nasal Tumors. Vet. Radiol. & Ultrasound, 45:255-260, 2004. [PDF]

Mcentee, M.C., Page. R.L., Theon, A. ,Erb, H.N., and Thrall, D.E.:Malignant Tumor Formation In Dogs Previously Irradiated For Acanthomatous Epulis. Vet. Radiol. & Ultrasound, 45:357–361, 2004. [PDF]

Pruitt, A. F.and Thrall, D.E.: Use Of Photon Fields With Noncoincident Isocenters To Improve Homogeneity Of Dose Distribution. Vet. Radiol. & Ultrasound, 45:471-475. [PDF]

Williams, L.E., Johnson, J.L., Hauck, M.L., Ruslander, D.M., Price, G.S., and Thrall, D.E.: Chemotherapy followed by Half-Body Radiation Therapy for Canine Lymphoma. J. Vet. Int. Med. 18:703-709, 2004.

Thrall, D.E., LaRue, S.M., Yu, D., Samulski, T.V., Sanders, L., Case, B., Rosner, G., Azuma, C., Poulson, J., Pruitt, A.F., Stanley, W., Hauck. M.L., Williams, L., Hess, P., and Dewhirst, M.W.: Thermal Dose is Related to Duration of Local Control in Canine Sarcomas Treated with Thermoradiotherapy. Clin. Cancer Res. 11:5206-5214, 2005. Featured on Journal Cover.

Thrall DE. Magnetic resonance imaging findings in a dog with caudal aortic thromboembolism and ischemic myopathy. Vet Radio Ultrasound. 2006 Jul-Aug; 47(4):334-8.

LaRue SM, Petros WP, Poulson YM, Yu D, Spasojevic I, Pruitt AF, Klein A, Case B, Thrall DE, Needham D, Dewhirst MW. Phase1 trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors. Clin Cancer Res. 2006 Jul1; 12(13): 4004-10.

Thrall DE, Dewhirst MW, Vujaskovic Z. Prospective thermal dosimetry: the key to hyperthermia's future. Int J Hyperthermia. 2006 May;22(3):247-53.

Sullivan S, Olby N, Galano H, Cerda-Gonzalez S, Robertson ID, Gavin P, Thrall D. Value of a single-shot turbo spin-echo pulse sequence for assessing the architecture of the subarachnoid space and the constitutive nature of cerebrospinal fluid. Vet Radiol Ultrasound. 2006 May-Jun;47(3):254-9.

Lyons J, Thrall DE, Pruitt AF. Comparison of isodose distributions in canine brain in heterogeneity-corrected versus uncorrected treatment plans using 6 MV photons.
Vet Radiol Ultrasound. 2007 May-Jun;48(3):292-6.

Siddiqui F, Li CY, Larue SM, Poulson JM, Avery PR, Pruitt AF, Zhang X, Ullrich RL, Thrall DE, Dewhirst MW, Hauck ML. A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. Mol Cancer Ther. 2007 Jan;6(1):380-9.

 

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