This paper is one of several in this Special Issue of the International Journal of Hyperthermia that discusses the current state of knowledge about the human health risks of hyperthermia. This special issue emanated from a workshop sponsored by the World Health Organization in the Spring of 2002 on this topic. It is anticipated that these papers will help to establish guidelines for human exposure to conditions leading to hyperthermia. This comprehensive review of the literature makes it clear that much more work needs to be done to clarify what the thresholds for thermal damage are in humans. This review summarizes the basic principles that govern the relationships between thermal exposure (temperature and time of exposure) and thermal damage, with an emphasis on normal tissue effects. Methods for converting one time-temperature combination to a time at a standardized temperature are provided as well as a detailed discussion about the underlying assumptions that go into these calculations. There are few in vivo papers examining the type and extent of damage that occurs in the lower temperature range for hyperthermic exposures (e.g. 39-42 degrees C). Therefore, it is clear that estimation of thermal dose to effect at these thermal exposures is less precise in that temperature range. In addition, there are virtually no data that directly relate to the thermal sensitivity of human tissues. Thus, establishment of guidelines for human exposure based on the data provided must be done with significant caution. There is detailed review and presentation of thermal thresholds for tissue damage (based on what is detectable in vivo). The data are normalized using thermal dosimetric concepts. Tables are included in an Appendix Database which compile published data for thresholds of thermal damage in a variety of tissues and species. This database is available by request (contact MWD or PJH), but not included in this manuscript for brevity. All of the studies reported are for single acute thermal exposures. Except for brain function and physiology (as detailed in this issue by Sharma et al) one notes the critical lack of publications examining effects of chronic thermal exposures as might be encountered in occupational hazards. This review also does not include information on the embryo, which is covered in detail elsewhere in this volume (see article by Edwards et al.) as well as in a recent review on this subject, which focuses on thermal dose.

In this review we have summarized the basic principles that govern the relationships between thermal exposure (Temperature and time of exposure) and thermal damage, with an emphasis on normal tissue effects. We have also attempted to identify specific thermal dose information (for safety and injury) for a variety of tissues in a variety of species. We address the use, accuracy and difficulty of conversion of an individual time and temperature (thermal doses) to a standardized value (eg equivalent minutes at 43 degrees C) for comparison of thermal treatments. Although, the conversion algorithm appears to work well within a range of moderately elevated temperatures (2-15 deg C) above normal physiologic baseline (37-39 deg C) there is concern that conversion accuracy does not hold up for temperatures which are minimally or significantly above baseline. An extensive review of the literature suggests a comprehensive assessment of the "thermal doesto-tissue effect" has not previously been assembled for most individual tissues and never been viewed in a semi-comprehensive (tissues and species) manner.Finally, we have addressed the relationship of thermal does-to-effect vs. baseline temperature. This issues is important since much of the thermal dose-to-effect information has been accrued in animal models with baseline temperatures 1-2 deg higher than that of humans. INTRODUCTIONThe purpose of this review is to present basic concepts relating thermal dose (time at temperature) to cell killing and tissue damage. © 2003 SPIE HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThis review summarizes the basic principles that govern the relationships between thermal exposure (temperature and time of exposure) and thermal damage, with an emphasis on normal tissue effects. Methods for converting one time-temperature combination to a time at a standardized temperature (cumulative minutes at 43° / CEM) are provided as well as some discussion about the underlying assumptions that go into these calculations. There are few in vivo papers, examining the type and extent of damage that occurs in the lower temperature range for hypothermic exposures (e.g. 39-42°C). Although not specifically calculated, the authors believe the CEM analysis for estimating an equivalent thermal does not retain a high degree of accuracy when temperatures above 55°C or so. Therefore it is appears that estimation of thermal dose to effect at low (temperatures a few degree above baseline body temperature) and high temperatures are more difficult to assesses and quantify. It is also apparent from this review that an extremely large variation in the type and the quality of tissue damage endpoint assessment significantly affects the ability to accurately compared study results.The authors have assembled a detailed review of thermal thresholds for tissue damage in the majority of organs (based on what is detectable in vivo). The data are normalized using thermal dosimeter concepts. This database is available by reques...

Purpose: The objective was to test whether tumor pH and 31 P magnetic resonance spectroscopic end points were related to treatment outcome in pet canine patients with spontaneous soft tissue sarcomas treated with thermoradiotherapy. Experimental Design: Forty-two dogs with evaluable 31 P magnetic resonance spectroscopic end points and pH data were included in this study. Tumor variables (grade and volume), extracellular pH (pHe), T 2 relaxation times, intracellular pH, and selected phosphometabolite ratios were examined for correlation with clinical outcome. Results: From 39 dogs, pHe was a predictor of metastasis-free survival (MFS), with hazard ratio (HR, 0.29; P = 0.005) and overall survival (OS) with (HR, 0.36; P = 0.013). Tumor volume (>19 cm 3 ) was related to MFS (HR, 2.14; P = 0.04), time to local failure (HR, 3.4; P = 0.025), and OS (HR, 2.27; P = 0.03). There was no association betweenT 2 or intracellular pH and clinical outcome. Tumor grade (high versus low/intermediate) and phosphodiester/hATP ratio were identified as significant predictors for MFS, with (HR, 2.66; P = 0.009) and (HR, 0.75; P = 0.027), respectively, and as predictors of OS with (HR, 2.66; P = 0.009) and (HR, 0.76; P = 0.03), respectively.The phosphodiester/phosphocreatinine ratio predicted time to local failure (HR, 1.24; P = 0.017). Conclusions: pHe was predictive of metastasis and OS in canine spontaneous sarcomas. To our knowledge, this is the first time that pHe has been shown to be predictive of clinical outcome. The results suggest that additional studies should be considered evaluating the prognostic significance of this variable. Phospholipid resonances, related to membrane metabolism, were related to clinical outcome, confirming recent results reported in human patients with soft tissue sarcomas treated with thermoradiotherapy.Location, histologic grade, and tumor volume are three wellestablished predictors of clinical outcome for soft tissue sarcomas (STS) in humans and dogs (1 -3). These factors, however, do not adequately identify patients who are at the highest risk for development of metastatic disease. Approximately half of the patients diagnosed with high-grade sarcomas will eventually develop metastases (4), but currently, there is no established test to distinguish which patients in this group are at highest risk. In addition, variation among pathologists leads to disagreement up to 25% of the time when staging sarcomas (4). For these reasons, imaging is being used more frequently to stage tumors in the clinic.Magnetic resonance imaging (MRI) is used routinely to assess the characteristics and anatomic extent of tumors. Several groups have reported that contrast-enhanced MRI is of prognostic value for survival (5) and local changes in sarcomas in response to therapy (6). Additionally, T 2 relaxation time and phosphorous magnetic resonance spectroscopy (P-31MRS) variables including intracellular pH (pHi) have been associated with the percentage of necrosis and duration of local tumor control following thermo...