Objective: Thermal treatment (TT), defined as treatment using supra-physiological body temperatures (39-45 C), somewhat resembles fever in terms of temperature range, one of the first natural barriers for the body to fight exposure to external pathogens. Methods: Whole-body thermal treatment (WBTT) consists of heating up the complete body to a temperature range of 39 to 45 C. Despite the recognized therapeutic potential of hyperthermia, the broad clinical use of WBTT has been limited by safety issues related to medical devices and procedures used to achieve WBTT, in particular adequate control of the body temperature. To circumvent this, a sophisticated medical device was developed, allowing long-term temperature controlled WBTT (41.5 C for up to 8 h). Technical feasibility and tolerability of the WBTT procedure (including complete anesthesia) were tested using female Aachen minipig. Optical fiber temperature sensors inserted in multiple organs were used and demonstrated consistent monitoring and control of different organs temperature over an extended period of time. Results: Clinical evaluation of the animals before, during and after treatment revealed minor clinical parameter changes, but all of them were clinically acceptable. These changes were limited and reversible, and the animals remained healthy throughout the whole procedure and follow-up. In addition, histopathological analysis of selected key organs showed no thermal treatment-related changes. Conclusion: It was concluded that WBTT (41.5 C for up to 8 h) was well tolerated and safe in female Aachen minipigs. Altogether, data supports the safe clinical use of the WBTT medical device and protocol, enabling its implementation into human patients suffering from life-threatening diseases.

Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration (IC50). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an IC50 reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes.

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An eleven-year-old Galgo Espagnol was diagnosed with metastasized anal sac adenocarcinoma. The patient was enrolled into a clinical trial and underwent three “whole-body thermal therapy” (WBTT) sessions combined with four hypofractionated radiotherapy sessions during a ten-weeks’ time period. The medical device and corresponding treatment protocol were designed by ElmediX (ElmediX NV, Belgium). Air was injected at high speed in a treatment chamber and automatically regulated to reach and maintain a body temperature of 41.5°C for eight hours. Thermometry was ensured by temperature sensors placed in and on the patient. During four radiotherapy sessions, an external beam delivered hypofractionated doses of 6Gy on both the primary tumor and the metastatic lymph nodes. Clinical monitoring and assessment of quality of life confirmed that the WBTT sessions were well tolerated. Although burn wounds at pressure points occurred, prolonged severe adverse effects were not observed. Furthermore, the disease progression was deemed slower than the expected progression based on the literature.

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