‘Relationship between thermal dose and cell death for “rapid” ablative and “slow” hyperthermic heating’

Abstract

Aim: Thermal isoeffective dose (TID) has not been convincingly validated for application to predict biological effects from rapid thermal ablation (e.g., using >55 C). This study compares the classical method of quantifying TID (derived from hyperthermia data) with a temperature-adjusted method based on the Arrhenius model for predicting cell survival in vitro, after either 'rapid' ablative or 'slow' hyperthermic exposures. Methods: MTT assay viability data was obtained from two human colon cancer cell lines, (HCT116, HT29), subjected to a range of TIDs (120-720 CEM 43) using a thermal cycler for hyperthermic (>2 minutes, <50 C) treatments, or a novel pre-heated water bath based technique for ablative exposures (<10 seconds, >55 C). TID was initially estimated using a constant R CEM>43 C ¼0.5, and subsequently using R CEM (T), derived from temperature dependent cell survival (injury rate) Arrhenius analysis. Results: 'Slow' and 'rapid' exposures resulted in cell survival and significant regrowth (both cell lines) 10 days post-treatment for 240 CEM 43 (R CEM>43 C ¼0.5), while 340-550 CEM 43 (R CEM>43 C ¼0.5) delivered using 'rapid' exposures showed 12 ± 6% viability and 'slow' exposures resulted in undetectable viability. Arrhenius analysis of experimental data (activation energy DE ¼ 5.78 ± 0.04 Â 10 5 J mole À1 , frequency factor A ¼ 3.27 ± 11 Â 10 91 sec À1) yielded R CEM ¼0.42 Ã e 0.0041 Ã T which better-predicted cell survival than using R CEM> 43 C ¼0.5. Conclusions: TID calculated using an R CEM (T) informed by Arrhenius kinetic parameters provided a more consistent, heating strategy independent, predictor of cell viability, improving dosimetry of ablative thermal exposures. Cell viability was only undetectable above 305 ± 10 CEM 43 using this revised measure.

Mathematical model for the thermal enhancement of radiation response: thermodynamic approach

“…. The CEM43°C concept is routinely used in the clinical context, although it presents several theoretical and practical problems, particularly when different heating rates are used [73][74][75][76] . Firstly, the Arrhenius approach presumes a constant Gibbs energy for transitions to occur at 43 °C; this is not necessarily true in different cell types and tissues.…”

Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review

“…The use of a suitable thermal damage model depends on both the temperature range to which the target had been exposed to, and the desired expression of the thermal damage outcome. E.g., CEM43 C can provide a reasonable prediction of cell death for the temperature range 40 C-47 C [87]. However, it does not provide the probability of thermal damage as in the Arrhenius equation.…”

Thermochromic Tissue Phantoms for Evaluating Temperature Distribution in Simulated Clinical Applications of Pulsed Electric Field Therapies

“…43 One approach to describe thermal damage is to calculate the cumulative equivalent minutes at 43°C (CEM43°C). 67,68 According to this thermal dosage method, 2-3 s at 57°C resulted in similar survival of multiple cell lines as 270 min at 43°C, indicating that cells are sensitive to instantaneous temperature exposures from 55°C to 60°C. 69 As NK-IRE and PEF treatments typically aim to deliver the intended dose over 1-5 min and given that peak temperatures typically occur late in the treatment (30+ s), a 60°C threshold for the phantom is the most relevant criteria for studying NK-IRE.…”