Conference of the International Clinical Hyperthermia Society 2012View this Special Issue
Modulation Effect in Oncothermia
Conventional hyperthermia is based on the local or systemic heating, which is measured by the realized temperature in the process. Oncothermia applies nanoheating, which means high energy absorption in the nanoscopic range of the malignant cell membrane selectively. This high temperature and its consequent stress create special effects: it evolves the possibility for chaperone proteins to be expressed on the outer membrane by softening the membrane and starts various excitations for programmed cell death of the targeted malignant cell. The process needs special delivery of the energy which selects as desired. A strict 13.56 MHz sinusoidal carrier frequency is amplitude modulated by time-fractal signals. The modulation is far from any sinus or other periodic patterns; it is a 1/f spectrum having definite templates for its construction. In some personalized cases, a definite template is used for the fractal pattern, which is copied from the actual character of the tumor pathology or any other specialty of the target.
To understand the principle of modulation, let us start with a simple everyday task: to listen to our favorite radiobroadcasts, like 107.1 MHz Cologne, 91.8 MHz Frankfurt, Radio Energy (Munich) 93.3 MHz, and so forth. We should choose the frequency (tune the radio to select it), and we can enjoy the broadcast. The carrier frequency which was the basis of the tuning never meets the ear; it is too high to sense, and anyway it would be a too monotonic sound as it is only a single frequency. Instead of monotony, we hear the music or other information carried by this chosen frequency. The carrier frequency delivers the real information coded in its modulation (see Figure 1).
The carrier frequency carries two important information characters: (i)its modulation finds the target on cellular level; (ii)its energy heats up the selected cells from the outside by its neighboring extracellular matrix.
The modulation method is similar to the process when light goes through the window’s glass. When the glass is transparent to a 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, and so forth, those irregularities will absorb a bigger part of the energy, their transparency will be locally low, their energy absorption will be high, and they will be heated up locally. It is a self-selection depending on the material and the frequency (color) which we apply in the given example. The carrier frequency delivers the information (modulation frequencies), for which the cancer cells are much less “transparent” than their healthy counterpart is. Malignant cells are heated up by the selectively absorbed energy.
The applied signal has synergy with the heating of the extracellular matrix, constructing zero-mode noise component which surpasses the thermal noise . The “demodulation” of the noise  uses the ratchet mechanism  and the stochastic resonance phenomena  combined with the membrane rectification  and nonlinearity .
The applied time-fractal modulation is one of the specialties, which only oncothermia has in hyperthermia applications in oncology. Recently, the research of amplitude-modulated RF in human medicine is intensified . Clinical trials show its progress [8, 9]. Research had shown how an AC electric field inhibits the metastatic spread of a solid lung tumor . The time-fractal modulation follows the natural (healthy) dynamic fluctuations of the tissue, adding a selection facility to distinguish it from the malignant counterpart. The cell junctions and other cellular connections ensure that the proper communications between the cells are dominantly broken , making isolation of the malignant cells from each other [11, 12].
The living material is not an ordered solid. Contrary to the crystals, it is hard to introduce the cooperativity. The living matter is in an aqueous solution, which is mostly well ordered  in the living state. This relative order formed the “dilute salted water” into the system having entirely different mechanical, chemical, physical, and other behaviors from the normal aqueous solutions. Indeed, the important role of the living systems of the so-called ordered water was pointed out in the middle of the sixties, and later, it was proven . At first, the ordered water was suggested to be as much as 50% of the total amount of the water in the living bodies . The systematic investigations showed more ordered water [16, 17] than it was expected before. Probably, the ordered water bound to the membrane is oriented (ordered) by the membrane potential, which probably decreases the order of the connected water, so it increases the electric permeability of the water  and so decreases the cell-cell adhesion and could be the cause of the cell division even for the proliferation .
According to Warburg’s effect, the metabolism gradually favors the fermentation in malignancy . The end products of both the metabolic processes are ions in the aqua-based electrolyte. The oxidative cycle products dissociate like 6CO2 + 6H2O ↔ 12H+ + , while the lactate produced by fermentation dissociates: 2CH3CHOHCOOH ↔ 2CH3CHOHCOO− + 2H+. Assuming the equal proton production (by more intensive fermentation energy flux), the main difference is in the negative ions. The complex lactateion concentration grows rapidly and increases its osmotic pressure. To keep the pressure normal, the dissolvent (the monomer water) has to be increased as well, seeking to solvent by nonordered water. Indeed, it is measured in various malignancies that the water changes to be disordered [20–22], so in these cases, the ordered water concentration in cancerous cells is smaller than in their healthy counterpart. Consequently, the hydrogen ionic transmitter becomes weak, and the removal of the hydrogen ions becomes less active. This decreases the intracellular pH and the proton gradient in mitochondria, which directly worsens the efficacy of ATP production. To compensate the lowered proton gradient, the membrane potential of mitochondria grows. This lowers the permeability of the membrane and decreases the mitochondrial permeability transition, which have crucial roles in apoptosis [23, 24]. The high mitochondrial membrane potential and low K-channel expression were observed in cancerous processes . These processes lead to apoptosis resistance, and for the cell energizing the ATP production of the host cell (fermentation) becomes supported. The free-ion concentration increases in the cytoplasm, and so the HSP chaperone stress proteins start to be produced. This process needs more ATP, and it is an antiapoptotic agent, so the process could lead to the complete block of apoptosis. Rearranging (disordering) the water structure needs energy . It is similar to the way the ice is melted with latent heat from zero centigrade solid to liquid with unchanged temperature conditions. This drastic change (phase transition) modifies the physical properties (like the dielectric constant) of the material without changing the composition (only the microscopic ordering) of the medium itself.
The decisional role of the two metabolic pathways (the oxidative and the fermentative) was studied by Szent-Györgyi , having an etiology approach and using additional formulation. His interpretation describes the cellular states by two different stages. The alpha state of the cell is the fermentative status.
What makes the difference in the absorption? It is the missing collective order in malignancy. The healthy cells live collectively. They have special “social” signals  commonly regulating and controlling their life. They are specialized for work division in the organism, and their life cycle is determined by the collective “decisions.” The cancerous cells behave noncollectively; 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, and the cellular communications disappear .
The problem of the autonomy of the malignant cells makes the treatment very much complicated, because cancer has its own fractal structure . The analysis of the fractal structures of malignancies could even indicate the stage of the disease . Careful fractal analysis can make predictive information for the prognosis as well .
The effect of modulation was measured on immunodeficient nude mice xenograft model made by HT29 human colorectal carcinoma cell line, like what was described elsewhere . The single shot oncothermia was used for 30 min keeping 42°C in the tumor. A day after oncothermia, a definite difference could be detected between the modulated and unmodulated effects, which became very emphasized after two days (see Figure 2 ). This is one of the reasons why we propose the treatment frequency in the protocols of oncothermia every other day.
The multiple fractal physiological proofs are extended by the oncothermia specialized experimental results too. We used the same xenograft model on a high number of nude mice (30 tumors were examined, 5-5 mice having double tumors in two arms, modulated (active) arm, and nonmodulated arm (passive arm)). The single shot experiment was also for 30 min, but the tumors were treated only on 40°C. We know from other experiments that this temperature is generally not enough to make a hyperthermia effect in a classical heating approach. The animals were sacrificed after 48 h, and the results (see Figure 3) show the modulation effect well: the treated arm in modulated cases had 45.8% higher cell-distortion than that of the nontreated part, while the effect in the nonmodulated mice was only 3.9%.
Oncothermia modulation is one of the three specialties of this treatment. Its efficacy and its role in the personalization process have introduced an effective tool for the apoptotic cancer cell destruction.
The authors acknowledge the experimental work and fruitful discussions of Professor Andras Szasz.
L. Gammaitoni, P. Hänggi, P. Jung, and F. Marchesoni, “Stochastic resonance,” Reviews of Modern Physics, vol. 70, no. 1, pp. 223–287, 1998.View at: Google Scholar
R. D. Astumian, J. C. Weaver, and R. K. Adair, “Rectification and signal averaging of weak electric fields by biological cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 9, pp. 3740–3743, 1995.View at: Google Scholar
A. Beuter, L. Glass, M. C. Mackey et al., Eds., Nonlinear Dynamics in Physiology and Medicine, vol. 25 of Interdisciplinary Applied Mathematics, Spinger, New York, NY, USA, 2003.
A. Barbault, F. P. Costa, B. Bottger et al., “Amplitude-modulated electromagnetic fields for the treatment of cancer: discovery of tumor-specific frequencies and assessment of a novel therapeutic approach,” Journal of Experimental and Clinical Cancer Research, vol. 28, no. 1, article 51, 2009.View at: Publisher Site | Google Scholar
E. D. Kirson, V. Dbal, C. Rochlitz et al., “Treatment of locally advanced solid tumors using alternating electric fields (TTFields)—a translational study. Clinical research 17: phase II and III adult clinical trials 1,” Proceedings of American Association Cancer Research, vol. 47, abstract #5259, 2006.View at: Google Scholar
National Institutes of Health US, Low Levels of Electromagnetic Fields to Treat Advanced Cancer (ADLG3), http://clinicaltrials.gov/ct2/show/NCT00805337.
W. R. Loewenstein and Y. Kanno, “Intercellular communication and tissue growth. I. Cancerous growth,” Journal of Cell Biology, vol. 33, no. 2, pp. 225–234, 1967.View at: Google Scholar
W. R. Loewenstein, The Touchstone of Life, Molecular Information, Cell Communication and the Foundations of the Life, Oxford University Press, Oxford, UK, 1999.
F. W. Cope, “Nuclear magnetic resonance evidence using D2O for structured water in muscle and brain,” Biophysical Journal, vol. 9, no. 3, pp. 303–319, 1969.View at: Google Scholar
R. Damadian, “Tumor detection by nuclear magnetic resonance,” Science, vol. 171, no. 3976, pp. 1151–1153, 1971.View at: Google Scholar
C. F. Hazelwood, D. C. Chang, D. Medina, G. Cleveland, and B. L. Nichols, “Distinction between the preneoplastic and neoplastic state of murine mammary glands,” Proceedings of the National Academy of Sciences of the United States of America, vol. 69, no. 6, pp. 1478–1480, 1972.View at: Google Scholar
A. Szent-Györgyi, “The living state and cancer,” Physiological Chemistry and Physics, vol. 12, no. 2, pp. 99–110, 1980.View at: Google Scholar
O. Warburg, Oxygen, the Creator of Differentiation, Biochemical Energetics, Academic Press, New York, NY, USA, 1966.
P. T. Beall, B. B. Asch, D. C. Chang, D. Medina, and C. F. Hazlewood, “Water-relaxation times of normal, preneoplastic, and malignant primary cell cultures of mouse mammary gland,” in Proceedings of the 23rd Annual Meeting of the Biophysical Society, Atlanta, Ga, USA, February 1979.View at: Google Scholar
G. Fiskum, “Mitochondrial participation in ischemic and traumatic neural cell death,” Journal of Neurotrauma, vol. 17, no. 10, pp. 843–855, 2000.View at: Google Scholar
R. Chidambaram and M. Ramanadham, “Hydrogen bonding in biological molecules-an update,” Physica B, vol. 174, no. 1–4, pp. 300–305, 1991.View at: Google Scholar
L. Ballerini Franzen, “Fractal analysis of microscopic images of breast tissue,” 2012, http://www.wseas.us/e-library/conferences/digest2003/papers/466-198.pdf.View at: Google Scholar
A. Delides, I. Panayiotides, A. Alegakis et al., “Fractal dimension as a prognostic factor for laryngeal carcinoma,” Anticancer Research, vol. 25, no. 3 B, pp. 2141–2144, 2005.View at: Google Scholar
G. Andocs, “Unpublished experiments for oncothermia know-how,” 2008-2009.View at: Google Scholar
A. Szasz, N. Szasz, and O. Szasz, Oncothermia—Principles and Practices, Springer, Heidelberg, Germany, 2010.
A. Szasz, N. Szasz, and O. Szasz, “Radiofrequency hyperthermia device with target feedback signal modulation,” European Patent Application No. EP, 08075820.4, 2009.View at: Google Scholar
A. Szasz, N. Szasz, and O. Szasz, “Device and procedure for measuring and examining the signal of systems releasing measurable signals during operation or in response to external excitation,” European Patent Application No. EP, 05798498.1, 2011.View at: Google Scholar
A. Szasz, N. Szasz, and O. Szasz, “Fractal templates and fractal feedback in homeostatic control,” European Patent Application, 2012.View at: Google Scholar