17 Within the bladder there is blood circulating at a temperature of 37°. This blood will through a process known as convection carry heat away from the bladder wall. Therefore, the warmed solution within the bladder must be maintained at the optimum temperature to keep the supercial layer at the required temperature. There are broadly speaking two solutions to keep the contents of the bladder at the magical 43 to 44 °C. Firstly one can insert a warming device into the bladder. This was the basis of the rst system developed in the 1980’s. Warming the uid within the bladder makes modelling of thermal gradients a lot more complicated. Urine contains salts and the urine moving around in the bladder has varying solute concentrations. This urine obviously mixes with the chemotherapeutic agent. The RF transmitters, using frequencies in the microwave range, built into the catheter will warm the urine differently depending on the salt concentration at a particular point in the bladder. The RF energy also penetrates the bladder wall as radiant energy and warms the tissues directly so that heat transfer is not reliant solely on conduction. This can have a positive effect in maintaining temperature in deeper tissues to improve the chemothermal therapeutic effect. It can also result in unplanned and random hot spots which can damage the bladder and surrounding tissues. Another negative point is that cold spots can also occur reducing the effectiveness. The second solution is to instil into the bladder already warmed uid which is constantly replaced so that cooling does not occur. This is the basis of two other solutions to be discussed a little later. This means the uid bathing the walls of the bladder is at a constant temperature and modelling becomes easier. This method relies on conduction only to heat the tissues. Using a rapid circulation counteracts the turbulent ow across the surface of the bladder and leads to a uniform temperature over the entire urothelium. There is a feeling that this method has a disadvantage in that the bladder wall is not warmed as well from radiant energy supplied by a microwave source built into the bladder. On the other hand, the uniform warming means no dangerous temperature spikes in the bladder wall. The input temperature of the uid can be relied on as the maximum thermal temperature of the bladder tissue. A thermal difference of only 6 to 7 °C is considered by some researchers to be a suboptimal for heating the bladder wall. Yet the temperature change occurs over a short distance, so the gradient is steep. This gradient permits heat penetration of 2 to 3 mm into the bladder wall which should be ample for NIMBC. The safety of this system has led to a rapid acceptance amongst the urological community. The heat transfer that occurs to the bladder wall is not instantaneously in the optimum range when a system is switched on. Modelling has shown that there is a period of changing thermal milieu until a steady state is reached which can be up to fteen minutes. Also important is the requirement to prevent an accumulation of heat. This is important in systems that heat the bladder contents in situ. The bladder contents need to be recycled and passed through a cooling device otherwise runaway temperatures inside the bladder could occur. Systems that heat the uid containing the drug outside the body are less complex at holding the temperature at the required level. I have merely scratched the surface of the complex physics and engineering involved in this treatment modality, but I hope I have given the reader some understanding. Turning to the actual drugs used as the partner in chemo thermotherapy. I will use Mitomycin C (MMC) as the drug example as it has been studied extensively. The key takeaway aspect from the drug point of view is that there is greater uptake of the drug into the tissues, so you get more bang for your buck. In the pre thermotherapy situation Mitomycin proved to be inferior to BCG. It was found that the Mitomycin plasma levels were highest shortly after the TURBT when there was a denuded surface in the bladder. Even these levels where ten times lower than the level that causes myelosuppression. As the bladder healed the plasma levels of Mitomycin declined after each weekly instillation of MMC. Two weeks after the TURBT the plasma levels were already two to fourfold lower. The depth of penetration followed a logarithmic curve. Roughly for each 500 microns the MMC concentration fell by 50%. The urothelium however constitutes the major barrier and the tissue concentrations are thirty times lower just under the mucosa than that in the bladder uid. There are various chemical and physical methods to increase the permeability of the urothelium. In this article I will address only the physical thermal effect. The impermeability of the bladder mucosa is due to the tight cell junctions of the Umbrella cells and enhanced by the negatively charged GAG layer. The GAG layer prevents diffusion of substances. The Umbrella cells will only allow active transport of certain molecules. Heat supplies greater energy to the chemotherapeutic molecules assisting the drug to penetrate the tissues more readily. Mitomycin C crosses cell membranes by active transport. UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
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