@article{rickard_yoshikawa_palmer_liu_dewhirst_nolan_zhang_2020, title={Cherenkov emissions for studying tumor changes during radiation therapy: An exploratory study in domesticated dogs with naturally-occurring cancer}, volume={15}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0238106}, abstractNote={Purpose Real-time monitoring of physiological changes of tumor tissue during radiation therapy (RT) could improve therapeutic efficacy and predict therapeutic outcomes. Cherenkov radiation is a normal byproduct of radiation deposited in tissue. Previous studies in rat tumors have confirmed a correlation between Cherenkov emission spectra and optical measurements of blood-oxygen saturation based on the tissue absorption coefficients. The purpose of this study is to determine if it is feasible to image Cherenkov emissions during radiation therapy in larger human-sized tumors of pet dogs with cancer. We also wished to validate the prior work in rats, to determine if Cherenkov emissions have the potential to act an indicator of blood-oxygen saturation or water-content changes in the tumor tissue–both of which have been correlated with patient prognosis. Methods A DoseOptics camera, built to image the low-intensity emission of Cherenkov radiation, was used to measure Cherenkov intensities in a cohort of cancer-bearing pet dogs during clinical irradiation. Tumor type and location varied, as did the radiation fractionation scheme and beam arrangement, each planned according to institutional standard-of-care. Unmodulated radiation was delivered using multiple 6 MV X-ray beams from a clinical linear accelerator. Each dog was treated with a minimum of 16 Gy total, in ≥3 fractions. Each fraction was split into at least three subfractions per gantry angle. During each subfraction, Cherenkov emissions were imaged. Results We documented significant intra-subfraction differences between the Cherenkov intensities for normal tissue, whole-tumor tissue, tissue at the edge of the tumor and tissue at the center of the tumor (p<0.05). Additionally, intra-subfraction changes suggest that Cherenkov emissions may have captured fluctuating absorption properties within the tumor. Conclusion Here we demonstrate that it is possible to obtain Cherenkov emissions from canine cancers within a fraction of radiotherapy. The entire optical spectrum was obtained which includes the window for imaging changes in water and hemoglobin saturation. This lends credence to the goal of using this method during radiotherapy in human patients and client-owned pets.}, number={8}, journal={PLOS ONE}, author={Rickard, Ashlyn G. and Yoshikawa, Hiroto and Palmer, Gregory M. and Liu, Harrison Q. and Dewhirst, Mark W. and Nolan, Michael W. and Zhang, Xiaofeng}, year={2020}, month={Aug} }
 @article{chi_thrall_jiang_snyder_fels_landon_mccall_lan_hauck_macfall_et al._2011, title={Comparison of Genomics and Functional Imaging from Canine Sarcomas Treated with Thermoradiotherapy Predicts Therapeutic Response and Identifies Combination Therapeutics}, volume={17}, ISSN={["1557-3265"]}, DOI={10.1158/1078-0432.ccr-10-2583}, abstractNote={Abstract}, number={8}, journal={CLINICAL CANCER RESEARCH}, author={Chi, Jen-Tsan and Thrall, Donald E. and Jiang, Chen and Snyder, Stacey and Fels, Diane and Landon, Chelsea and McCall, Linda and Lan, Lan and Hauck, Marlene and MacFall, James R. and et al.}, year={2011}, month={Apr}, pages={2549–2560} }
 @article{viglianti_lora-michiels_poulson_lan_yu_sanders_craciunescu_vujaskovic_thrall_macfall_et al._2009, title={Dynamic Contrast-enhanced Magnetic Resonance Imaging as a Predictor of Clinical Outcome in Canine Spontaneous Soft Tissue Sarcomas Treated with Thermoradiotherapy}, volume={15}, ISSN={["1557-3265"]}, DOI={10.1158/1078-0432.CCR-08-2222}, abstractNote={Abstract}, number={15}, journal={CLINICAL CANCER RESEARCH}, author={Viglianti, Benjamin L. and Lora-Michiels, Michael and Poulson, Jeanie M. and Lan, Lan and Yu, Dahio and Sanders, Linda and Craciunescu, Oana and Vujaskovic, Zeljko and Thrall, Donald E. and Macfall, James and et al.}, year={2009}, month={Aug}, pages={4993–5001} }
 @article{siddiqui_li_larue_poulson_avery_pruitt_zhang_ullrich_thrall_dewhirst_et al._2007, title={A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas}, volume={6}, ISSN={["1535-7163"]}, DOI={10.1158/1535-7163.MCT-06-0342}, abstractNote={Abstract}, number={1}, journal={MOLECULAR CANCER THERAPEUTICS}, author={Siddiqui, Farzan and Li, Chuan-Yuan and LaRue, Susan M. and Poulson, Jean M. and Avery, Paul R. and Pruitt, Amy F. and Zhang, Xiuwu and Ullrich, Robert L. and Thrall, Donald E. and Dewhirst, Mark W. and et al.}, year={2007}, month={Jan}, pages={380–389} }
 @article{kleiter_yu_mohammadian_niehaus_spasojevic_sanders_viglianti_yarmolenko_hauck_petry_et al._2006, title={A tracer dose of technetium-99m-labeled liposomes can estimate the effect of hyperthermia on intratumoral Doxil extravasation}, volume={12}, ISSN={["1078-0432"]}, DOI={10.1158/1078-0432.CCR-06-0839}, abstractNote={Abstract}, number={22}, journal={CLINICAL CANCER RESEARCH}, author={Kleiter, Miriam M. and Yu, Daohai and Mohammadian, Lenore A. and Niehaus, Nelsen and Spasojevic, Ivan and Sanders, Linda and Viglianti, Benjamin L. and Yarmolenko, Pavel S. and Hauck, Marlene and Petry, Neil A. and et al.}, year={2006}, month={Nov}, pages={6800–6807} }
 @article{thrall_larue_pruitt_case_dewhirst_2006, title={Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas}, volume={22}, ISSN={["0265-6736"]}, DOI={10.1080/02656730600836386}, abstractNote={Tumour oxygenation was measured in seven canine soft tissue sarcomas being treated with a fractionated course of radiation and hyperthermia. Measurements obtained during treatment were compared to pre-treatment measurements. The most important finding was an increase in oxygenation in tumours with low pre-treatment oxygenation that persisted throughout treatment. This is an advantageous hyperthermia effect as it may lead to increased radiation cell killing at each fraction. In other tumours, potentially less advantageous changes in oxygenation may be hyperthermia fractionation related and this deserves further investigation.}, number={5}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={Thrall, D. E. and Larue, S. M. and Pruitt, A. F. and Case, B. and DeWhirst, M. W.}, year={2006}, month={Aug}, pages={365–373} }
 @article{meyer_braun_dewhirst_2001, title={Anesthetic considerations for the study of murine tumor models}, journal={Tumor models in cancer research}, publisher={Totowa, NJ: Humana Press}, author={Meyer, R. E. and Braun, R. D. and Dewhirst, M. W.}, year={2001}, pages={407–431} }
 @article{poulson_dewhirst_gaskin_vujaskovic_samulski_prescott_meyer_page_thrall_2000, title={Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs}, volume={14}, number={6}, journal={In Vivo (Athens, Greece)}, author={Poulson, J. M. and Dewhirst, M. W. and Gaskin, A. A. and Vujaskovic, Z. and Samulski, T. V. and Prescott, D. M. and Meyer, R. E. and Page, R. L. and Thrall, D. E.}, year={2000}, pages={709–714} }
 @article{matteucci_anyarambhatla_rosner_azuma_fisher_dewhirst_needham_thrall_2000, title={Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas}, volume={6}, number={9}, journal={Clinical Cancer Research}, author={Matteucci, M. L. and Anyarambhatla, G. and Rosner, G. and Azuma, C. and Fisher, P. E. and Dewhirst, M. W. and Needham, D. and Thrall, D. E.}, year={2000}, pages={3748–3755} }
 @article{meyer_braun_rosner_dewhirst_2000, title={Local 42 degrees C hyperthermia improves vascular conductance of the R3230Ac rat mammary adenocarcinoma during sodium nitroprusside infusion}, volume={154}, ISSN={["0033-7587"]}, DOI={10.1667/0033-7587(2000)154[0196:LCHIVC]2.0.CO;2}, abstractNote={Abstract Meyer, R. E., Braun, R. D., Rosner, G. L. and Dewhirst, M. W. Local 42°C Hyperthermia Improves Vascular Conductance of the R3230Ac Rat Mammary Adenocarcinoma during Sodium Nitroprusside Infusion. The effect of sodium nitroprusside-induced hypotension on the perfusion of the R3230 adenocarcinoma during local 42°C hyperthermia was studied using a combination of intravital microscopy and laser Doppler flowmetry. Fischer 344 rats were implanted with dorsal skin flap window chambers containing the R3230Ac tumor and allocated to three treatment groups (34°C with nitroprusside, 42°C with nitroprusside, and 42°C with 0.9% saline). After baseline observation at 34°C, tumors were locally heated to 42°C using a water bath and either 0.9% saline or nitroprusside sufficient to reduce blood pressure 20% below pretreatment baseline was infused. Nitroprusside at 34°C decreased tumor vascular conductance 40% with no effect on the diameter of arterioles entering the tumor. The diameter of arterioles entering 42°C heated tumors increased 35% independent of blood pressure change. Saline at 42°C had no effect on tumor vascular conductance; however, nitroprusside at 42°C increased tumor vascular conductance 55%. Local 42°C tumor heating, combined with a moderate reduction in blood pressure with nitroprusside, overrides the vascular steal effect associated with reduced perfusion pressure alone and results in improved tumor perfusion. Observations of the effect of vasodilator substances on normothermic tumor perfusion cannot be extrapolated to situations where moderate hyperthermia is used.}, number={2}, journal={RADIATION RESEARCH}, author={Meyer, RE and Braun, RD and Rosner, GL and Dewhirst, MW}, year={2000}, month={Aug}, pages={196–201} }
 @article{vujaskovic_poulson_gaskin_thrall_page_charles_macfall_brizel_meyer_prescott_et al._2000, title={Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment}, volume={46}, ISSN={["0360-3016"]}, DOI={10.1016/s0360-3016(99)00362-4}, abstractNote={The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia.Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI).There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values.This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.}, number={1}, journal={INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS}, author={Vujaskovic, Z and Poulson, JM and Gaskin, AA and Thrall, DE and Page, RL and Charles, HC and MacFall, JR and Brizel, DM and Meyer, RE and Prescott, DM and et al.}, year={2000}, month={Jan}, pages={179–185} }
 @article{thrall_rosner_azuma_larue_case_samulski_dewhirst_2000, title={Using units of CEM 43 degrees C T-90, local hyperthermia thermal dose can be delivered as prescribed}, volume={16}, ISSN={["1464-5157"]}, DOI={10.1080/026567300416712}, abstractNote={A randomized study was designed in dogs with spontaneous soft tissue sarcomas to gain information about the relationship between hyperthermia dose and outcome. The study compared two levels of thermal dose applied to dogs with heatable tumours, so it was necessary to deliver either a low (2-5 CEM 43°C T90) or high (20-50 CEM 43°C T90) thermal dose as precisely as possible. It was also desirable to have similar numbers of hyperthermia treatments in each thermal dose group. Identification of heatable tumours and randomization to high or low heat dose group was done during the first hyperthermia treatment. This was readily accomplished using mapping of temperatures in thermometry catheters, manual recording of thermal data, and visual inspection of raw thermal data with subsequent adjustment of the duration of the hyperthermia treatment. An analysis of precision of thermal dose delivery was conducted after approximately 50% of projected accrual had been met in a randomized phase III assessment of thermal dose effect. Fifty-four dogs were eligible for randomization; in 48 dogs the tumour was deemed heatable according to predetermined temperature criteria applied during the first heat treatment. Twenty-four dogs were randomized to the high heat dose group, and 24 to the low heat dose group. Median (range) total thermal dose for dogs in the high dose group was 43.5 CEM 43°C T90 (16.4-66.6) compared to 3.2 CEM 43°C T90 (2.1-4.6) for dogs in the low dose group. There was no overlap of thermal doses between groups. Thus, thermal dose could be delivered accurately, being within the predetermined range in 47 of the 48 dogs. Thermal dose quantified as CEM 43°C T50, however, did overlap between groups and the clinical significance of this finding will not be known until outcome data are analysed. Most dogs in both groups received five hyperthermia treatments. Median (range) treatment duration for dogs in the high dose group was 300min (147-692) compared to 111min (51-381) for dogs in the low dose group. Relatively simple but accurate methods of delivering prescribed thermal dose as described herein will aid the translation of clinical hyperthermia from the research setting into more general practice once the characteristics of the relationship between hyperthermia dose and outcome are understood.}, number={5}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={Thrall, DE and Rosner, GL and Azuma, C and Larue, SM and Case, BC and Samulski, T and Dewhirst, MW}, year={2000}, month={Sep}, pages={415–428} }
 @article{larue_fox_ogilvie_page_getzy_thrall_johnson_dewhirst_gillette_1999, title={Tumour cell kinetics as predictors of response in canine lymphoma treated with chemotherapy alone or combined with whole body hyperthermia}, volume={15}, DOI={10.1080/026567399285477}, abstractNote={Kinetic parameters including potential doubling time (Tpot), duration of S phase (Ts), labelling index (LI), and DNA index (DI) were obtained from 42 dogs with previously untreated lymphoma. Standard flow cytometric techniques using BrdUrd were employed. All dogs were treated with L-asparaginase and remission was induced in 26 dogs, which were then randomized to receive chemotherapy only (doxorubicin [DOX] alone or with lonidamine) or chemotherapy plus whole body hyperthermia (WBH). Dogs were treated every 3 weeks for up to five treatments and evaluated every 3 weeks for evidence of tumour recurrence. Within this subset of animals there was no difference in outcome based on treatment group. Median values for Tpot, Ts and LI were 3.4 days, 7.23 h and 12.49%, respectively. Dogs that had tumours with LI > or = 20% had a shorter time until recurrence than dogs with tumours characterized by LI < 20%. In dogs treated only with chemotherapy, dogs bearing tumours with longer than median Tpot and Ts values and lower than median LI had significantly longer remission duration than dogs with more rapidly proliferating tumours. Dogs treated only with chemotherapy, which had longer than median Tpot and Ts values and lower than median LI, had significantly longer remission duration than all other dogs in the study. The mechanisms in which kinetics are associated with response to chemotherapy are not clear and vary depending on tumour type and treatment regimen. More work is needed to understand factors involved in cell killing during in vivo hyperthermia.}, number={6}, journal={International Journal of Hyperthermia}, author={Larue, S. M. and Fox, M. H. and Ogilvie, G. K. and Page, R. L. and Getzy, D. M. and Thrall, D. E. and Johnson, J. L. and Dewhirst, M. W. and Gillette, E. L.}, year={1999}, pages={475–486} }
 @article{thrall_larue_powers_page_johnson_george_kornegay_mcentee_levesque_smith_et al._1999, title={Use of whole body hyperthermia as a method to heat inaccessible tumours uniformly: a phase III trial in canine brain masses}, volume={15}, number={5}, journal={International Journal of Hyperthermia}, author={Thrall, D. E. and Larue, S. M. and Powers, B. E. and Page, R. L. and Johnson, J. and George, S. L. and Kornegay, J. N. and McEntee, M. C. and Levesque, D. C. and Smith, M. and et al.}, year={1999}, pages={383–398} }
 @article{hauck_coffin_dodge_dewhirst_mitchell_zalutsky_1997, title={A local hyperthermia treatment which enhances antibody uptake in a glioma xenograft model does not affect tumour interstitial fluid pressure}, volume={13}, ISSN={["0265-6736"]}, DOI={10.3109/02656739709023538}, abstractNote={Solid tumours have an elevated interstitial fluid pressure (IFP) due to the lack of normal lymphatics, increased permeability of tumour vasculature and an expanding cell population within a potentially limited space. This elevated IFP has been proposed to be an important barrier to the delivery of drugs and marcromolecules. We have demonstrated that local hyperthermia (4 h, 41.8 degrees C) is capable of significantly enhancing the uptake of radiolabelled monoclonal antibodies (mAbs) in D-54 MG glioma xenografts grown subcutaneously in athymic mice. To determine if this increased uptake was attributable to alterations in the tumour IFP, pressure measurements using the wick-in-needle technique were made in tumours after hyperthermia treatment. These pressure measurements were taken at various time points from 4 to 90 h following the initiation of the hyperthermia and compared with pressures taken concurrently in untreated tumours. In addition, pressures were measured following a 2 h, 41.8 degrees C hyperthermia treatment, a protocol which does not result in elevated uptake of radiolabeled mAbs. No significant differences were seen at any time point in IFP measured in the tumours receiving either hyperthermia treatment when compared with untreated tumours. Thus, we conclude that the mechanism by which this hyperthermia regimen enhances mAb uptake in this human glioma xenograft model is not due to alternations in tumour IFP.}, number={3}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={Hauck, ML and Coffin, DO and Dodge, RK and Dewhirst, MW and Mitchell, JB and Zalutsky, MR}, year={1997}, pages={307–316} }
 @article{hauck_dewhirst_bigner_zaultsky_1997, title={Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model}, volume={3}, journal={Clinical Cancer Research}, author={Hauck, M. L. and Dewhirst, M. W. and Bigner, D. D. and Zaultsky, M. R.}, year={1997}, pages={63–70} }
 @misc{dewhirst_meyer_bonaventura_deangelo_1997, title={Methods for improving therapeutic effectiveness of agents for the treatment of solid tumors and other disorders}, volume={5612310}, publisher={Washington, DC: U.S. Patent and Trademark Office}, author={Dewhirst, M. W. and Meyer, R. E. and Bonaventura, J. and DeAngelo, J.}, year={1997} }
 @article{hahn_braun_dewhirst_shan_snyder_taube_ong_rosner_dodge_bonaventura_et al._1997, title={Stroma-free human hemoglobin a decreases R3230Ac rat mammary adenocarcinoma blood flow and oxygen partial pressure}, volume={147}, ISSN={["0033-7587"]}, DOI={10.2307/3579420}, abstractNote={We examined the effect of a nitric oxide (NO) quencher, stroma-free human hemoglobin A (HbA0; 0.01, 0.05, 0.1, 0.2 g/kg), on the blood flow measured using the Doppler flow technique, tumor oxygen pressure (pO2) and the diameter of the arterioles using R3230Ac mammary adenocarcinoma as the tumor model. In female Fischer 344 rats with 1-cm-diameter tumors implanted in the lateral aspect of the left quadriceps, intravenous infusion of 0.1 and 0.2 g/kg HbA0 decreased both central tumor and peripheral tumor blood flow by 20-30% (P < 0.05). Tumor pO2 decreased 28% with 0.2 g/kg HbA0, from 15 mm Hg (baseline) to 11 mm Hg at 10 min (P = 0.02). Although 0.2 g/kg HbA0 increased blood flow 55% in the left quadriceps muscle proximal to the implanted tumor (P < 0.05), HbA0 had little effect on blood flow in right quadriceps muscle with no tumor implanted, and increased right quadriceps pO2, from 21 mm Hg (baseline) to 23 mm Hg at 10 min (P = 0.03). HbA0 increased mean arterial pressure 5-10% in a manner that was dependent on dose while heart rate concurrently decreased 9-19%. The diameter of the arterioles supplying the tumor was rapidly reduced 10% by 0.2 g/kg HbA0 (P = 0.037) and remained stable through 60 min of observation (P = 0.005). HbA0 selectively reduces tumor blood flow and tumor pO2 through vasoconstriction of the arterioles supplying the tumor. Vascular NO quenching provides an alternative to NO synthase inhibition as a means to achieve the goal of selective tumor hypoxia.}, number={2}, journal={RADIATION RESEARCH}, author={Hahn, JS and Braun, RD and Dewhirst, MW and Shan, SQ and Snyder, SA and Taube, JM and Ong, ET and Rosner, GL and Dodge, RK and Bonaventura, J and et al.}, year={1997}, month={Feb}, pages={185–194} }
 @inbook{meyer_dewhirst_1997, title={The use of blood substitutes in tumor therapy}, booktitle={Red blood cell substitutes: Basic principles and clinical application}, publisher={New York: Marcel Dekker}, author={Meyer, R. E. and Dewhirst, M. W.}, editor={A. S. Rudolph, R. Rabinovici and Feuerstein, G. Z.Editors}, year={1997} }
 @article{hauck_price_ogilvie_johnson_gillette_thrall_dewhirst_page_1996, title={Phase I evaluation of mitoxantrone alone and combined with whole body hyperthermia in dogs with lymphoma}, volume={12}, ISSN={["0265-6736"]}, DOI={10.3109/02656739609022520}, abstractNote={The maximum tolerated dose of mitoxantrone (MX) administered alone or combined with whole body hyperthermia (WBH) was determined in this nonrandomized, prospective study in dogs with lymphoma. MX was administered to 53 dogs every three weeks for a total of six treatments unless progressive disease or persistent, severe toxicity developed. Fifty dogs were evaluable (MX alone n = 30, MX/WBH n = 20). MX was administered as a 1 h infusion at the onset of the plateau phase of WBH in dogs treated with combined therapy. Dogs were evaluated weekly between treatments for the first four treatments with physical examination and complete blood counts to define acute and cumulative toxicity. Dogs were evaluated every three weeks for tumour response until relapse. The maximum tolerated dose (MTD) was defined as that dose in each group that resulted in a 50% incidence of moderate or severe toxicity as estimated from logistic regression analysis of the toxicity data. Myelosuppression was the only toxicity observed. Neutropenia was equal in frequency and severity between treatment groups. Thrombocytopenia was not observed in any dog receiving MX/WBH but occurred in 13% of dogs treated with MX alone. The MTD for MX +/- WBH was 6.1 +/- 0.6 and 6.5 +/- 0.8mg/M2 respectively. A steeper dose response relationship was observed in dogs receiving combined therapy compared to dogs treated with MX alone suggesting WBH may improve the uniformity of patient response to chemotherapy. We concluded that MX may be administered without dose reduction to dogs undergoing WBH and that MX should be evaluated more thoroughly in future thermochemotherapy studies.}, number={3}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={Hauck, ML and Price, GS and Ogilvie, GK and Johnson, J and Gillette, EL and Thrall, DE and Dewhirst, MW and Page, RL}, year={1996}, pages={309–320} }
 @article{hauck_dewhirst_zalutsky_1996, title={The effects of clinically relevant hyperthermic temperatures on the kinetic binding parameters of a monoclonal antibody}, volume={23}, ISSN={["0883-2897"]}, DOI={10.1016/0969-8051(96)00039-x}, abstractNote={Hyperthermia is a therapeutic modality under investigation for its ability to increase absolute levels of tumor uptake of radiolabeled monoclonal antibodies (MAbs). We have investigated whether hyperthermia may affect the binding parameters of MAbs. The effects of clinically relevant levels of hyperthermia on the kinetic binding parameters were investigated for 81C6, an antibody undergoing Phase I/II clinical trials for the treatment of brain tumors and neoplastic meningitis. No obvious effects of temperature in either the association or dissociation rate constants, nor in the equilibrium constants, were apparent between 37 ° and 45 °C. The improved binding stability of the bivalent form of the MAb was apparent when compared with its monovalent Fab fragment.}, number={4}, journal={NUCLEAR MEDICINE AND BIOLOGY}, author={Hauck, ML and Dewhirst, MW and Zalutsky, MR}, year={1996}, month={May}, pages={551–557} }
 @inbook{hauck_dewhirst_zalutsky_1995, title={Enhancement of radiolabeled monoclonal antibody uptake in tumors with local hyperthermia}, booktitle={Handbook of targeted delivery of imaging agents}, author={Hauck, M. L. and Dewhirst, M. W. and Zalutsky, M. R.}, year={1995}, pages={333–359} }
 @article{page_mcentee_williams_george_price_novotney_hauck_riviere_dewhirst_thrall_1994, title={EFFECT OF WHOLE-BODY HYPERTHERMIA ON CARBOPLATIN DISPOSITION AND TOXICITY IN DOGS}, volume={10}, ISSN={["0265-6736"]}, DOI={10.3109/02656739409012373}, abstractNote={Fifty dogs with refractory or disseminated spontaneous tumours were evaluated in two independent phase I studies using either carboplatin (CBDCA) alone or CBDCA plus whole body hyperthermia (WBH). CBDCA was administered as a 30 min infusion at the onset of the plateau phase of WBH in dogs receiving combined treatment. Serum samples were collected and drug disposition was determined in both treatment groups. The dose-effect relationship was mathematically described with a logistic regression model developed from categorical toxicity data accumulated throughout the first two treatment courses in all dogs. The maximum tolerated dose (MTD) was defined as that dose which resulted in a 50% probability of achieving moderate or severe toxicity. The only toxicities observed were neutropenia and thrombocytopenia, which were dose-dependent. The nadir occurred between 7 and 14 days following treatment. A significant decrease in the area under the serum CBDCA versus time curve for dogs undergoing WBH was consistent with increased tissue binding of the drug as well as increased urinary eliminations. Serum AUC values determined following the first course of treatment were predictive of subsequent toxicity in both treatment groups. The MTD (95%CI) for CBDCA and CBDCA/WBH were estimated to be 318(44) and 239(51) mg/M2 respectively (p = 0.08). A randomized phase II evaluation should be initiated to determine if a therapeutic gain can be achieved using combined CBDCA and WBH. Further refinement of the CBDCA dose in such a trial should be based on both pharmacokinetic parameters and normal tissue response.}, number={6}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={PAGE, RL and MCENTEE, MC and WILLIAMS, PL and GEORGE, SL and PRICE, GS and NOVOTNEY, CA and HAUCK, ML and RIVIERE, JE and DEWHIRST, MW and THRALL, DE}, year={1994}, pages={807–816} }
 @article{page_thrall_george_price_heidner_mcentee_novotney_hauck_dewhirst_1992, title={QUANTITATIVE ESTIMATION OF THE THERMAL DOSE-MODIFYING FACTOR FOR CIS-DIAMMINEDICHLOROPLATINUM (CDDP) IN TUMOR-BEARING DOGS}, volume={8}, ISSN={["0265-6736"]}, DOI={10.3109/02656739209005024}, abstractNote={A statistical method for estimating clinical toxicity was used to determine a theoretical isoeffect dose-modifying factor for dogs with disseminated or refractory neoplasia treated with cis-diammine dichloroplatinum (II) plus whole-body hyperthermia or CDDP alone. CDDP was administered every 3 weeks with vigorous saline hydration to 54 dogs (CDDP alone n = 21, CDDP/WBH n = 33) that were eligible for entry into this non-randomized study. CDDP was administered during the plateau phase of WBH in dogs receiving combined therapy. Acute toxicity included myelosuppression (CDDP n = 7; CDDP/WBH n = 5), nephrotoxicity (CDDP n = 1, CDDP/WBH n = 1) and respiratory distress (CDDP/WBH n = 2). Eight dogs experienced chronic renal dysfunction as a result of CDDP (n = 2) or CDDP/WBH (n = 6). A theoretical thermal dose-modifying factor was determined for both acute and cumulative toxicity by comparing the maximum tolerated dose of each treatment group. The maximum tolerated dose (MTD) of CDDP +/- WBH was defined as that dose producing a 50% incidence of moderate acute toxicity or acute plus mild chronic toxicity as estimated from logistic regression analysis of the toxicity data. The MTD (+/- .standard error) of CDDP/WBH for acute toxicity only was 54.6 (4.3) mg/M2 and for CDDP alone the MTD was 73.6 (40) mg/M2. Thus, the isoeffect dose-modifying factor for acute toxicity was 1.35 (0.12). The MTD (SE) of CDDP/WBH for cumulative toxicity (acute plus chronic toxicity) was 46.4 (2.7) mg/M2 and for CDDP alone waas 70.0 (2.9) mg/M2. The isoeffect dose-modifying factor for total cumulative toxicity was 1.5 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)}, number={6}, journal={INTERNATIONAL JOURNAL OF HYPERTHERMIA}, author={PAGE, RL and THRALL, DE and GEORGE, SL and PRICE, GS and HEIDNER, GL and MCENTEE, MC and NOVOTNEY, CA and HAUCK, ML and DEWHIRST, MW}, year={1992}, pages={761–769} }
 @article{zakris_dewhirst_riviere_hoopes_page_oleson_1987, title={PHARMACOKINETICS AND TOXICITY OF INTRAPERITONEAL CISPLATIN COMBINED WITH REGIONAL HYPERTHERMIA}, volume={5}, ISSN={["0732-183X"]}, DOI={10.1200/JCO.1987.5.10.1613}, abstractNote={ Hyperthermia (HT) potentiates in vitro cytotoxicity of cisplatin, providing a rationale for HT enhancement of cisplatin effect in vivo. In this study, regional abdominal HT was combined with intraperitoneal (IP) cisplatin in canines to characterize temperature distributions, as well as pharmacokinetics and toxicity of IP cisplatin with and without HT. Cisplatin (65 mg/m2) in normal saline was administered IP with a two-hour dwell time in ten Beagle dogs. Five of the ten dogs were randomly selected to receive concurrent regional microwave-producing HT at approximately 41.5 degrees C (IP) for a 60-minute period. Systemic temperatures in heated animals ranged from 37 degrees C to 40 degrees C; IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP temperatures ranged from 39 degrees C to 44 degrees C. Initial IP cisplatin concentrations were ten to 22 times greater than serum levels; the IP drug half-lives were 133 +/- 9 minutes and 68 +/- 15 minutes in heated and unheated dogs, respectively (P less than .001). Total concentrations of serum and urine cisplatin did not differ between the heated and unheated controls. The area under the concentration v time curve for free, ultrafilterable cisplatin in serum in units of percent minutes was 40 +/- 8 in heated and 60 +/- 7 in unheated controls (P = .006). Except for transient nausea and vomiting, no evidence of serious toxicity was observed in serum chemistries or histopathologic sections at 21 days post-treatment. Experiments involving in vitro incubation of cisplatin in normal saline were performed as a function of saline temperature; these showed that the amount of reactive cisplatin metabolites formed increased linearly with temperature by approximately 30% from 38 degrees C to 44 degrees C. This study supports the hypothesis that, with IP temperature elevation, there is an increased rate of generation and retention of reactive metabolites of cisplatin in the peritoneal cavity relative to unheated controls. In spite of these differences in pharmacokinetics, no significant toxicity was encountered. This study provides a model for treatment of IP malignancy such as ovarian carcinoma with IP cisplatin and regional HT. }, number={10}, journal={JOURNAL OF CLINICAL ONCOLOGY}, author={ZAKRIS, EL and DEWHIRST, MW and RIVIERE, JE and HOOPES, PJ and PAGE, RL and OLESON, JR}, year={1987}, month={Oct}, pages={1613–1620} }
 @article{riviere_page_dewhirst_tyczkowska_thrall_1986, title={Effect of hyperthermia on cisplatin pharmacokinetics in normal dogs}, volume={2}, DOI={10.3109/02656738609004965}, abstractNote={In vitro and in vivo cisplatin pharmacokinetic studies were conducted at 37 degrees C and 42-43 degrees C in dogs. Cisplatin at 1, 2, 3, 4 and 5 micrograms/ml was incubated with canine serum at 37 degrees and 43 degrees C. Aliquots were processed immediately for atomic absorption spectrophotometry to determine total as well as free, ultrafilterable cisplatin concentrations. Thirteen healthy, average-sized mongrel dogs received 1 mg/kg cisplatin as an intravenous bolus. Four were maintained unanaesthetized at 37 degrees C, two were anaesthetized and maintained at 37 degrees C and seven were anaesthetized and maintained at a rectal temperature of 42 degrees C for 60 min. Serum samples were obtained and processed for free and total cisplatin. There were no detectable concentration effects present in either in vitro group. The rate constant reflecting the decay of free cisplatin at 37 degrees C was 0.0035 +/- 0.0007 min-1 and increased significantly (P less than 0.0001) to 0.0053 +/- 0.001 min-1 at 43 degrees C. In vivo pharmacokinetic analysis consisted of model-independent parameters (total body clearance, volume of distribution, half-life and mean residence time). A significant increase (P less than or equal to 0.05) in all parameters was observed with free-cisplatin at 42 degrees C. This data would indicate that at the elevated temperatures encountered in whole body hyperthermia, the rate of formation of reactive metabolites from parent cisplatin is increased.(ABSTRACT TRUNCATED AT 250 WORDS)}, journal={International Journal of Hyperthermia}, author={Riviere, J. E. and Page, R. L. and Dewhirst, M. W. and Tyczkowska, K. and Thrall, D. E.}, year={1986}, pages={351–358} }