**3.3. Selection by order-disorder effect (fractal physiology selection)**

The non-equilibrium phenomena is well formulated in the description of the Avramiequation [217], pioneered by Kolmogorov [218], by Johnson & Mehl [219] and by others, [220], [221]. The description could serve as a mathematical model for different biological processes, [222], [223]. Experimental data which were collected by Cope [224], [225], and by others [226], [227], show a definite universality to describe the real processes.

Local Hyperthermia in Oncology – To Choose or not to Choose? 33

32 Hyperthermia

membrane increasing the glucose permeability and so supports the fermentation way of metabolism together with the changes of the intracellular circulations, [209], [210]. This

At the divisional processes the intracellular flows and all pathway activities are probably higher both at regular and at malignant cell-division. Possibly the order-disorder transition

However, finishing the division, the daughter cells are separated, a higher surface suddenly appears and the separated volumes limit the intracellular flows and change the order of structure as well. It decreases the gradient through the membrane. This regulates the heatflow through the cellular membrane and changes the energy-exchange from convective to the conductive one again **[**207**]**. The conductive heat-exchange does not support the intensive diffusion of the large-molecule glucose, so the oxidative way becomes necessary and regular. The two daughter cells have less than half energy-consumption (each) than it was requested by the mother cell. It is because the mother cell was large (doubled its volume) and was intensively producing various elements to complete the daughter cells. Instead of the division conditions where the high energy-request gained the energy-demand and preferred the high-energy flux fermentative metabolism, the normal homeostatic

The significantly larger permittivity and conductivity in tumor-tissue in vitro is explained on this basis, [212]. Both the conductivity and dielectric differences between the healthy- and tumor-tissues at the applied 13.56 MHz frequency in most cases of the malignancies are over 15% [213], **[**172**]**. It is clinically proven, that the cancerous and healthy tissues of the hepatic tumors are significantly different [214]. Also the VX-2 carcinoma can be measured [215]: rabbit-liver at low frequency in vivo had a conductivity 6-7.5 times higher, permittivity 2-5 times lower than in the healthy parts (impedance difference is about 600%), while for 10 MHz region it is 200%. With impedance tomography we can make a distinction between the living and necrotic malignancy as well, **[**214**]**; both the conductivity and permittivity are higher in the

The dielectric properties are also distinguishable by the water content of the malignant tissue, which is higher than that of their healthy counterpart. The proliferating cells control their cell-volume by their water content, in the malignant growth [216], and this effect

The high dielectric constant allows the additional selection (focusing): the higher dielectric

The non-equilibrium phenomena is well formulated in the description of the Avramiequation [217], pioneered by Kolmogorov [218], by Johnson & Mehl [219] and by others, [220], [221]. The description could serve as a mathematical model for different biological processes, [222], [223]. Experimental data which were collected by Cope [224], [225], and by

increases the conductivity and generally the dielectric properties in the given tissue.

**3.3. Selection by order-disorder effect (fractal physiology selection)** 

others [226], [227], show a definite universality to describe the real processes.

malignant liver, but the frequency dependence of necrotic tissue differs.

constant absorbs more from the RF-energy, (see Figure 27*.).* 

complex change could down-regulate the mitochondrial oxidative metabolism.

of the aqueous solution also has a role in the changes [211].

conditions will dominate again.

**Figure 27.** The disordered state could absorb more form the applied electric field energy than the ordered one

The modern physiology is an essentially interdisciplinary subject, combining the knowledge of various fields, like the electronic structure approach of solid-state physics (e.g. Szent-Gyorgyi, [228], [229]), the superconductivity (e.g. Cope, [230]), the electromagnetism (e.g. Liboff, [231], [232]), the thermodynamics (e.g. Schrodinger, [233], Katchalsky & Curran [234]), etc. Various modern approaches were developed in the last decades based on this complexity, like self-organization ([235], [236],), fractal physiology ([237], [238], [239], [240]), and the bioscaling ([241], [242], [243]).

The healthy cells work collectively, their energy-consumption as well as their life-cycles and the availability of resources are controlled collectively by the various forms of the selforganizing, [244], [245]. The healthy cells are organized this way, their standard cycles, reactions and structures are complexly regulated in both internal and external areas. The healthy cells have special "social" signals [246] commonly regulate and control their life. They are specialized for work-division in the organism and their life-cycle is determined by the collective "decisions".

What makes the difference in the absorption? It is the missing collective order in malignancy. The cancerous cells behave non-collectively; they are autonomic. They are "individual fighters", having no common control over them, only the available nutrients regulate their life. The order, which characterizes the healthy tissue is lost in their malignant version, the cellular communications are missing [247].

The malignancy has a special fractal structure, which can be identified by impedance measurements on Erlich solid tumors [248]. This structure (due to its definite percolative self-similarity) is a better conductor [249] than the non-fractal healthy tissue.

The living matter has a highly self-organized hierarchical structure. It is in non-equilibrium and its processes are non-stationer, [250]. The subsystems of living organisms are multiple, connected with various physical, chemical and physiological processes and the interacting

signals change in a wide range. The simplest biological systems show various processes on different time-scales in vivo, which are connected by bio-scaling [241]. There are no two identical living objects exist, the living matter is variable, changeable and mutable, [240]. It differs from the lifeless [251]. While the thermal and quantum fluctuations in lifeless are negligible by the size of the system; the living object has a high number of homologue phase-states randomly transformed and altered into each other, they mutate by the time, which is unchanged among identical environmental conditions. In contrast, the permanent and immanent change makes the living object possible for adaptation, for mutation and for natural selection. This dynamism appears in the change of the confirmation state of proteins optimizing the enzymatic reactions of life. Due to these fluctuations, the living matter is "noisierand" because of its self-similar [252] and self-organized [244] behavior, its powerspectrum shows pink-noise (1/f noise), [238], [239].

Local Hyperthermia in Oncology – To Choose or not to Choose? 35

**Figure 28.** The malignant absorption selects by the disorder of the cancer, having no transparency for

**Figure 29.** The transparency of the glass. In full transparent case all the energy goes over the glass (a), but when the glass has aggregates, those absorb a part of energy (b), and they will be hotter than their

This is the effect, which is used by oncothermia with some modulation. The carrier frequency delivers the information (modulation frequencies), for which the cancer cells are much less "transparent" than their healthy counterparts are. Malignant cells are heated up

The physiology is an interdisciplinary subject. It uses numerous principles and discoveries. Its electronic structure approach derived from solid state physics (e.g. Szent-Gyorgyi, [228], [229]), the superconductivity approach (e.g. Cope, [258]), the electromagnetic resonances (e.g. Liboff, [259], [232]), the thermodynamics of life (e.g. Schrodinger, [233], Katchalsky & Curran [234]), etc. are all parts of the physiology, and make it really complex like the

The important category of the hyperthermia was generated by electric fields [260], [198],which is even a hot topic in science presently[261], [262]. The electric conductive

the well-chosen modulated RF carrier frequency (It is a patented method and know-how of

oncothermia.)

environment

by the selectively absorbed energy.

phenomena of the life itself is.

**3.4. Effect of electric field on malignancies** 

The highest deficiency of information (highest entropy) is achieved by the noise, which has Gaussian distribution [253] (Gaussian noise). Because the effective power-density of pinknoise is constant in all characteristic scales, the Gaussian pink-noise then has maximal entropy in all the scales. The living system has special fractal dynamism, [254], in consequence of its self-similar stochastic behavior, it fluctuates by the pink-noise, [255]. The maximal entropy of Gaussian pink-noise allows an important conclusion: the noise of the living state has maximal entropy (stable dynamic equilibrium) in all of the characteristic scales.

The cell motility probed by noise analysis of thickness shear mode resonators [256]. The noise analysis of the electric currents has become a new tool in the field, [240]. Absorption and fluctuations of giant liposomes were studied by electrochemical impedance measurements, [257].

Oncothermia uses these new approaches to fit in the best curative performance. This new approach (the fractal physiology) is applied for oncothermia. The carrier electric field delivers the time-fractal structure to the tissues enhancing considerable the selection between the connected healthy cellular community and the individual autonomy of the malignant proliferation.

The disordered structure of malignancy is a good absorbent. To show it again by a simple example: when somebody's hair is in order, the comb slides through the over-combed hair. However, when the same hair is disordered, combing is able even to cut out the hair by their energy-absorption mechanisms. In malignancy the disorder makes the same energyabsorption process, (see Figure 28.).

The order-disorder selection method is similar to the process when the light goes through the windows-glass (see Figure 29.). When the glass is transparent to that specific set of colors (visible light, definite interval of frequencies) its absorption is almost zero, all energy goes through it. However, when it has any bubbles, grains, precipitations etc. those irregularities will absorb more from the energy, their transparency is locally low, their energy absorption is high, they are heated up locally. It is a self-selection depending on the material and the frequency (color) which we apply in the given example.

#### Local Hyperthermia in Oncology – To Choose or not to Choose? 35

**Figure 28.** The malignant absorption selects by the disorder of the cancer, having no transparency for the well-chosen modulated RF carrier frequency (It is a patented method and know-how of oncothermia.)

**Figure 29.** The transparency of the glass. In full transparent case all the energy goes over the glass (a), but when the glass has aggregates, those absorb a part of energy (b), and they will be hotter than their environment

This is the effect, which is used by oncothermia with some modulation. The carrier frequency delivers the information (modulation frequencies), for which the cancer cells are much less "transparent" than their healthy counterparts are. Malignant cells are heated up by the selectively absorbed energy.

### **3.4. Effect of electric field on malignancies**

34 Hyperthermia

scales.

measurements, [257].

malignant proliferation.

absorption process, (see Figure 28.).

frequency (color) which we apply in the given example.

signals change in a wide range. The simplest biological systems show various processes on different time-scales in vivo, which are connected by bio-scaling [241]. There are no two identical living objects exist, the living matter is variable, changeable and mutable, [240]. It differs from the lifeless [251]. While the thermal and quantum fluctuations in lifeless are negligible by the size of the system; the living object has a high number of homologue phase-states randomly transformed and altered into each other, they mutate by the time, which is unchanged among identical environmental conditions. In contrast, the permanent and immanent change makes the living object possible for adaptation, for mutation and for natural selection. This dynamism appears in the change of the confirmation state of proteins optimizing the enzymatic reactions of life. Due to these fluctuations, the living matter is "noisierand" because of its self-similar [252] and self-organized [244] behavior, its power-

The highest deficiency of information (highest entropy) is achieved by the noise, which has Gaussian distribution [253] (Gaussian noise). Because the effective power-density of pinknoise is constant in all characteristic scales, the Gaussian pink-noise then has maximal entropy in all the scales. The living system has special fractal dynamism, [254], in consequence of its self-similar stochastic behavior, it fluctuates by the pink-noise, [255]. The maximal entropy of Gaussian pink-noise allows an important conclusion: the noise of the living state has maximal entropy (stable dynamic equilibrium) in all of the characteristic

The cell motility probed by noise analysis of thickness shear mode resonators [256]. The noise analysis of the electric currents has become a new tool in the field, [240]. Absorption and fluctuations of giant liposomes were studied by electrochemical impedance

Oncothermia uses these new approaches to fit in the best curative performance. This new approach (the fractal physiology) is applied for oncothermia. The carrier electric field delivers the time-fractal structure to the tissues enhancing considerable the selection between the connected healthy cellular community and the individual autonomy of the

The disordered structure of malignancy is a good absorbent. To show it again by a simple example: when somebody's hair is in order, the comb slides through the over-combed hair. However, when the same hair is disordered, combing is able even to cut out the hair by their energy-absorption mechanisms. In malignancy the disorder makes the same energy-

The order-disorder selection method is similar to the process when the light goes through the windows-glass (see Figure 29.). When the glass is transparent to that specific set of colors (visible light, definite interval of frequencies) its absorption is almost zero, all energy goes through it. However, when it has any bubbles, grains, precipitations etc. those irregularities will absorb more from the energy, their transparency is locally low, their energy absorption is high, they are heated up locally. It is a self-selection depending on the material and the

spectrum shows pink-noise (1/f noise), [238], [239].

The physiology is an interdisciplinary subject. It uses numerous principles and discoveries. Its electronic structure approach derived from solid state physics (e.g. Szent-Gyorgyi, [228], [229]), the superconductivity approach (e.g. Cope, [258]), the electromagnetic resonances (e.g. Liboff, [259], [232]), the thermodynamics of life (e.g. Schrodinger, [233], Katchalsky & Curran [234]), etc. are all parts of the physiology, and make it really complex like the phenomena of the life itself is.

The important category of the hyperthermia was generated by electric fields [260], [198],which is even a hot topic in science presently[261], [262]. The electric conductive heating started in the late 19th century is called "galvanocautery" [263]. The method was further developed by D'Arsonval, introducing the impedance (alternating current [*AC*], later higher frequencies, even spark-generated currents) calling it "*Arsonvalization*", [264], and later a more modernized method was the "*fulguration*" [265]. The Arsonvalization method had fantastic popularity at the turn of the 19th-20th centuries, developing three different branches: the interstitial hyperthermia, including the galvanic heat-stimulation (*electrochemical-cancer-treatment*), the ablation techniques and the capacitive coupling. The first capacitive coupled device on conductive basis was the "*Universal Thermoflux*". It was launched on to the market by such a giant of the electric industry in that time as Siemens, which was later further developed, and the new device by the name "*Radiotherm*" was launched on the market in the early 1930s. The first start of the new capacitive-coupling technologies was in 1976 by LeVeen [266] and has been widely applied since then [267], [268], [74]. Many hyperthermia devices use capacitive coupling since its treatment is easy.

Local Hyperthermia in Oncology – To Choose or not to Choose? 37

barrier function (tight-junction permeability changes) can be measured by electric

**Figure 30.** Oncothermia was 3 times more effective than hyperthermia on the identically high (42 oC) temperature. However, cooling down the tumor during the treatment, the death-rate decreased only

The special membrane effect (rectification on membranes, [298]), is also a factor of the cellular selectivity of cancer by RF electric field. The impedance measurement is useful for the control of other treatment modalities. It adequately measures the distortion, made by irradiation [299], and the drug-effect can also be controlled, [300]. Such usual practice, like following the wound healing, is also objectively traceable [301]. Bioimpedance vector pattern can distinguish cancer patients without disease versus locally advanced or

The impedance measures selectively, differentiates between the cancerous and healthy tissue, and is able to distinguish the extra- and intra-cellular electrolyte. Selective impedance measurements are provided clinically as well. Many comparative studies have been provided for malignant tissues, however, the results are not identical; the measurements very much depend on the conditions. (This is a trivial consequence of many factors, which we listed above.) However, all the studies measured lower impedance in the tumor than in their healthy

Hyperthermia increases biochemical reaction rates [303] and therefore the metabolic rate as well. The metabolic heat production of tumor depends on the doubling time of its volume [304]. The high metabolic rate keeps the temperature for tumor tissues higher than its neighborhood, [305]. This works as selection factor for heating of tumor tissue. Therefore, in case of 6 oC increase the amount of growth will be 1.8-times higher [306] than its healthy

counterpart in all of the tissue and staging of the tumor, in vitro and in vivo as well.

slightly, exceeding more than 2 times the classic hyperthermia on high temperature

impedance measurement, [297].

disseminated diseases [302].

counterpart.

An electric field application without an increase in temperature (using less than 5W power) has also been found effective against cancer [269], [270], [271], [272], [273], [274], by using galvanic (DC) current applications. The control of these treatments is the tissue-resistance and the quality parameter is the applied charge load, [275], [276]. Numerous devices were developed and applied widely, but the expected breakthrough result was missing. An entirely new line was started with Professors Rudolf Pekar, [277], [278], [279], Bjorn Nordenstrom [273], [274] and Xin You Ling [280], [281], [282]; and continued by others [283], [284], [285], [286], [287], [288], [289]. Remarkable results were produced by this method; and the biological mechanisms involved in electromagnetic field are intensively investigated [290], [72], and the effect of electric field is studied on various side of its complex behavior, [261], [262]. Recently, the effect of electric field has been used for special therapies in oncology, [291], [292], [293], [294].

A sophisticated study was performed to study the synergy of temperature and modulated electric field [295]. The model was HT-29 human colorectal carcinoma cell-line being xenografted to nude mice (BALB (nu/nu)). For comparison we performed low temperature oncothermia experiment, where the bolus of the upper-electrode was cooled down. The intensive cooling kept the tumor near the physiological temperature (38 oC) while the oncothermia field was identical with the heating conditions of 42 oC. The result is surprisingly interesting (see Figure 30). The effect of electric field made nano-range heating only, the overall temperature had a minor role in the cell-killing mechanism.
