Division of Urology, Duke University Medical Center, Durham, NC, USA.
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
Int J Hyperthermia. 2020;37(1):854-860. doi: 10.1080/02656736.2020.1780328.
Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity.
To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS).
Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry.
The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose.
Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.
高热（加热至 43°C）可激活固有免疫系统并提高膀胱癌的化疗敏感性。
使用 Combat 膀胱再循环系统（BRS）评估腔内丝裂霉素 C（MMC）药代动力学联合对流热疗在活体猪膀胱模型中的组织穿透和安全性。
40 头 60kg 雌性猪麻醉并通过三通 16F 导管置管。使用 Combat 设备将膀胱加热至 43°C 的目标温度，并用 40、80 和 120mg 的再循环腔内 MMC 进行治疗。驻留-加热时间为 30-180 分钟。快速尸检并立即对组织、血液和尿液进行冷冻。通过液相色谱串联质谱法测量 MMC 浓度。
Combat BRS 系统能够在 12 分钟内达到目标范围温度（42-44°C），并且只要设备运行，该温度就会保持。有两个因素增加了膀胱中 MMC 的组织穿透：药物浓度和热的存在。在热疗组中，MMC 穿透在 80mg 时达到饱和，这表明随着加热，药物吸收可能达到饱和，不需要更高的剂量即可达到最大的生物学效应。即使在 120mg 剂量下，对流热疗也不会增加肝脏、心脏、肾脏、脾脏、肺和淋巴结组织中的 MMC 浓度。
使用 Combat BRS 设备进行对流性膀胱热疗是安全的，并且温度可以维持在 43°C。热疗可能会增加 MMC 向膀胱壁的渗透，但不会导致其他器官中 MMC 水平增加。
