Life is based on energetically open systems, where environmental conditions determine their equilibrium. The general system’s theory [1] was one of the early efforts to show the complexity of open living systems focusing on the deep embedment of its processes in the environmental interactions. Due to the environmental actions, the physical laws work well to explain the evolutionary processes [2]. The energetically open living system intensively interacts with its environment, exchanging molecules and various thermodynamic and electromagnetic parameters. Simply speaking: our focus differs from living motility to the energy-transfer. A. Szent-Gyorgyi described the life-energy relationship using the analogy that it is not important that the monkey goes through the jungle, what is important is how the jungle goes through the monkey, in the form of nutrition, water, and oxygen, keeping the monkey alive using the environmental energy-sources [3]. The living system is complexly controlled, to maintain homeostasis. Diseases, especially cancers, break the relative equilibrium and risk the system’s relative instability. The human body tries to re-establish homeostasis in many ways by enhancing the negative feedback controls. Multiple actions of human physiology try to compensate and correct the damage caused by cancer.

Healthy homeostasis struggles to control the malignancy. The first few attempts block the proliferation and start intracellularly controlling the DNA replication. It fails for various reasons, including genetic aberration [4], mitochondrial dysfunction [5], or other intracellular [6], and additionally extracellular [7] hallmarks of malignancy.

The malignancy in this general meaning is a distortion of the healthy cellular network, the rules of a multicellular organization being broken. The breaking of cellular networks is a general behavior of all tumors independent of their locations within the body. In this sense, cancer is an organizing (networking) disease, where the cells unleashed from their networks abandon the living advantages of collectivism, and individualism prevails [8]. Cancerous and bacterial proliferations have a lot in common [9]. The tumor itself has atavism qualities [10], in the sense that the malignant cells act like self-ruled unicellular organisms. The atavism-like process is general, not only with the loss of cellular connections but also with the altered intracellular genetic structures. The unicellular individualism develops the great potential for adaptability to environmental changes, making these cells more vigorous than those in the multicellular network. The modified genetic activity at the active boundary between unicellular and multicellular areas, causes disorganization of the multicellular structure, promoting primitive transcriptional programs [11]. However, the similarity with atavism is only formal. The atavistic development is supported by the environment which is rich in energy-resources needed for the proliferation. Still, the active use decreases the valuable matter around the bacteria, and only some physical processes (like diffusion, flows in aqueous solution, etc.) may passively replace the missing materials. In cancer conditions, the proliferating cell actively changes its environment, forcing the healthy host to supply the needed materials [12]. The cancer is afforded a friendly environment by the host, which tries to “heal” the abnormality by strengthening angiogenesis, injury current, and numerous other supportive mechanisms. There are telling arguments for the likening of the cancerous process to wound repair [13]. The bio-system falsely recognizes the tumor—as a wound and stimulates its environment to heal the irregularity (meaning to produce cells to heal) [14].

We are in a war against this disease [15]. The end of this war seems to be far away [16]. This war’s strategic decision may be borrowed from the military: attack the enemy’s weakest point, and avert to direct fight with its strongest forces. The most vital force of the malignancy is its uncontrolled proliferation, while the weakest side is the autonomy of the proliferated cells, and their isolation from the regular cellular network. The cooperation of the healthy cells regulates, controls, and supplies the members of the network. The malignant cells are “individual fighters” competing against all healthy and malignant cells for the energy sources to proliferate. This “loneliness” behavior makes the malignant cells vulnerable. They miss the complex support from the network. The missing network otherwise helps the proliferative development due to the easy motility and forming micro and macro metastases. Following this strategy, the final aim of cancer treatments is to eliminate the cancer cells throughout the body.

To follow the strategic goal to attack the malignant cells’ individualism, we have multiple “tactical” possibilities to choose from. The lack of coherence and support it in the network modifies the cells and their microenvironment. This modification could be used to select and kill the cells. The most characteristic changes are a result of the cells’ autonomy:

● The individual cells are more vulnerable than the cells connected via the network. Healthy cells may share their extra absorbed energy with the neighbors, while the autonomous cells are at risk of being overloaded by the absorbed energy can be overloaded.

● The autonomy means that the cell’s microenvironment is like an ocean around it, only with a few, if any, connections. The molecular “bridges” that made the bonds in the network are broken, and numerous transmembrane proteins remain unconnected and free to move along the membrane and form clusters.

● A large part of the homeostatic control is missing due to the autonomy, and the cells live unregulated. This allows the use of metabolic mechanisms which are rare in networked systems. The mitochondrial symbiosis with the cell has less importance and becomes mostly dysfunctional.

● The autonomy promotes cellular motility that uses the transport systems (lymph and blood), and once separated from the group, these cells more vulnerable.

● Consequently, the energy-demand massively increases in malignant cells as the cells require the extra energy to produce the daughter cells and to support the entire division process.

● The basic chemical reactions are out of systemic harmony. The long-range, and broadly scaled fluctuation and constant multiscale entropy is broken by autonomy, producing easily distinguishable fluctuations (noises) in measurable electromagnetic signals.

The above points are interconnected, and the “tactical actions” could affect many of them simultaneously. Some of the popularly applied treatments are as follows:

➢ Change the conditions by special, strict diets (like Gerson’s diet), constraining the body back to the previously working equilibrium. However, in many cases, it works against the natural homeostasis; the constrained action induces new negative feedbacks from the living object. The living organism starts to fight against our constraints together with the fight against the disease itself, which unnecessarily overloads the controlling system and could lead to its collapse, causing serious side effects.

➢ An interesting tactic is to put out the fire with fire. This method increases the already significant metabolic rate of the malignant cells without allowing an increased delivery of the supplies. This was the original idea of hyperthermia: to locally heat the malignant tissue, and force the cells’ metabolism, without allowing the replacement of the energy. This method is against the general physiological control, which is governed the blood-flow. The higher local temperature increases the blood-flow to cool-down the targeted volume. The extra blood delivers nutrients, and oxygen, so the method could easily turn in the opposite direction.

➢ Some proposed treatments favor fasting or supplying the body with only one kind of nutrient, like blocking carbohydrates’ consumption and expecting that the limited supply will starve the malignant cells.

The above treatments do not work, mainly because the living complexity does not isolate one of the other’s dynamic characters, so the action easily turns to the opposite. The general problem with these is proposed methods is that the complexity is not accounted for in the applied principles, the principles involve oversimplified mechanisms, due to the lack of complex knowledge. This problem is well formulated by a playwriter Berthold Brecht: “The aim is not to open the door to the infinite wisdom, but to circumscribe the infinite fallacy… The main reason for the poverty in science is the conceited property.” [17]. The physicist Stephan Hawking formulated the same: “The greatest enemy of knowledge is not ignorance, it is an illusion of knowledge”.

The dark-side of the tactical elements is the multiple quackeries distributed by social media. This approach uses the “formal knowledge” of the complexity, declaring their method as a special secret, which drives the complex processes. This could be characterized by the statement of Frederici Di Trocchio “Swindle was used to art. Nowadays, it became a science too…” [18].

Hyperthermia in oncology appeared in ancient medicine. Today heating processes for medical purposes have become a vital “home remedy”, from the sun-bathing to the hot-bathes, including the Japanese high-temperature bath and Finish sauna. Hippocrates first described the application of heat in oncology in European medicine. The use of heat therapy to cure cancer has since emerged in various settings in the medical field. The appearance of electromagnetism in medicine renewed the heating efforts, and extended the applications for various cancers. Two main categories divide the electromagnetic-based heating applications: the local deep heating which results in local-regional hyperthermia (LRHT), and the whole-body hyperthermia (WBH). Just as the categories of chemotherapy and radiotherapy include many different modes of treatments, “hyperthermia” is also a large category with different technical aspects. Figure 1 maps the main differences between the technical solutions.

The relatively simple physical-physiological heating concepts do not mean a simple application in humans. The complexity of human physiology, and the non-linear feedbacks of the homeostatic regulation, limits the heating possibilities. Despite the proven in vitro benefits of heating in cancer treatment, the clinical results have strongly demonstrated how the control of treatment is often influenced more by the human body than by the treatment intention. This complication made the development of oncologic hyperthermia non-monotonic, having both great successes and failures [19]. It was clear from the beginning of oncological applications that the real, local cell-distortion must have a high temperature, higher than the physiological limit of 42˚C. However, this limit restricts the high temperature application of WBH which has moved towards mild temperature range, promoting the reactivation of the immune system. Contrary to WBH, LRHT does not limit by the temperature in the tumor. When the high temperature targets the healthy host tissues around the tumor, it could produce unintended necrotic burns with serious damage to the treated organ’s function.

Consequently, the energy absorption during the heating process significantly depends on the technique applied. No unified protocol for the various technologically determined targets of the heat has currently been described.

The category “hyperthermia” includes various energy-absorption methods, and each individual solution requires its own protocol. It is very similar in this regard to the chemo-variants of oncological therapies. Chemotherapy, depending on the targets of the drug, has different protocols. Mixing these could cause serious adverse effects and even fatal events such as poisoning. Homogeneous targeting in most of these therapies requires very different protocols to the local or cell-sensitive selection. For example, chemotherapy is administered intravenously (i.v.), at different doses to the doses administered with chemoembolization or other types of local administration. Isodose homogeneity, as in radiotherapy, is also not used in most brachytherapies, radiation seed, or nanoparticle administration. We are sure that the hyperthermia variants also have specific differences in their dose and protocol, sharply depending on their technical solution and targeting method. Defining a general dose and protocol for all hyperthermia methods is a misleading request. The methods are not equal. Their effects are different, so the dose and protocol have to fit the specific situation.

The heating techniques determine the result of the clinical treatment. Just as the categories of chemotherapy or radiotherapy, which include many different treatments, “hyperthermia” is also a large category with different technical aspects. We have seen that exposing the tumor to 42˚C in whole-body hyperthermia has entirely different results than the same temperature in any local treatment. Characterization of the temperature alone is not enough to categorize the technical solutions.

A water bath is used in many experimental models to achieve hyperthermia, and this models homogeneous heating solutions. The various electromagnetic heating technologies also have their specialties. The bioelectromagnetic action of the technology determines the actions. Evaluating the applied technique, we consider the kind of energy delivery, the method of heat absorption, and handling the target tumor’s physiological reactions, together with their inhomogeneities. The target’s absorbed energy, and its temperature distribution are not the same [20], and these characteristics are largely determined by the blood-flow. The technical solutions must handle how the provided energy I transformed into the desired temperature.

Variants of energy-transfer realize the absorption in the target. Various “antennas” (sources) couple the energy to the target (Figure 2 ). The homogeneity of the absorption defines the main character of the actual coupling. The inductive arrangements have two heating forms. One is the Eddy-current (induced current loop in the body) and the other uses magnetic materials for heating. In living objects, both the Eddy-current and magnetic approaches are applied. Life does not have natural inherent magnetic properties. Artificial magnetic materials (like nanoparticles, seeds, rods, etc.) orient the energy for heating. Internal Eddy-current induction needs an extra high magnetic field, and the induced current has no specified orientation but is sensitive for inhomogeneities inside the body. Consequently, both induction methods heat in a heterogenic way. The conventional relative antenna solution radiates the electromagnetic energy, which is absorbed by the target. It is less sensitive to heterogenic structures, so is usually applied for homogeneous heating to use the dosing of isothermal volumes. The capacitive coupling has two major kinds of energy transfers: 1) the plane-wave antenna process, which aims to achieve similar isothermal absorption of the electromagnetic waves as the radiative applications; 2) the impedance coupling process, which uses the precise impedance-matching of the target. The isothermal kind of capacitive coupling requires high energy transferred via the plane-wave, while the impedance matching (mimics the galvanic match), uses less energy provided the heterogenic absorption processes are exploited and dominate. The galvanic coupling firmly touches the actual target. In non-living applications, this is the simple discrete resistor situation. The galvanic coupling in the case of living items applies tightly connected electrodes invasively with direct solid contact with the body’s surface.

Applications using capacitive and radiative (microwave) solutions are the most popular methods used in the technical realization of the treatments; however, due to the sharp decrease of penetration depth with the increase of frequency, microwave solutions are mainly applied for surface lesions (see later). Capacitive coupling of energy delivery has become the most frequently applied technique, and the frequency of choice for the technique is the so-called “free-frequency” of 13.56 MHz, approved for industrial, scientific, and medical use (ISM frequency) [21]. Different effects in the human applications are observed, based on the coupling effects of the applied technique, Figure 3 .

The conventional solution involves plane-wave matching, in which the antenna’s plane-parallel plates are tuned as per the standard antenna-tuning method. This solution does not consider the energy losses by various electric circuit elements and their interactions with the environment. In this case, the increased power (P) compensates for the lost energy. Due to the relatively high complex impedance, the voltage (V) is high, while the current (I) is low. The product of voltage and current defines the useful power, P r e a l = V ⋅ I ⋅ cos ( φ ) , while the reactance (the power refused by the load) is P r e a c t = V ⋅ I ⋅ sin ( φ ) . The possible timing delay of the complex fit of the voltage with current is characterized by the cosine of the phase angle (cos(φ)) of the complex values. In case of dielectric losses and/or radiations 0 < φ < 90 ˚ . Due to the losses, the impedance of the system (Z_sys) from the radiofrequency (RF) source to the target is large. The capacitance (C) describes the dielectric (isolating) resistivity, and the conductive part (defined by the real resistivity (R) defines the reaction time of the system (time-constant, τ = R ⋅ C ). The circuit for the hyperthermia plane-wave system has many various capacitances and resistivities additional to the target in the human body, and then we have to calculate the time-constant in a more complicated way (open-circuit time constant method [22] ).

The time constant, in the case of plane wave solution, is relatively high, limiting the tuning’s reaction time. This delay could cause a challenge when the physiological changes (breathing, heart-rate, etc.) are quicker than the reaction time. The plane wave method applies conventional antenna tuning where the antenna is fixed, so the reaction time has no relevance.

The plane-wave matching radiates RF-waves for energy-absorption, and direct heating, and necrotic cell-death (CEM 43˚C T_x dose) is expected. This matching technology aims to reach at least 43˚C temperature in the T_x effective percentages of the temperature measurement in the tumor.

The wave matching induces extensive radiation, due to the wave-transmission adding a significant factor to the energy-loss, and this could produce safety issues for operating staff. An important phenomenon of this coupling is that it could tune on the air without a patient in the active radiation zone.

The impedance matching of capacitive coupling does not use the wave concept. The system construction approaches the galvanic touch of the electrodes. The normal resistor has the maximal power in the galvanic coupling: P max = U ⋅ I , where U is the galvanic potential (voltage), and I is the current (Amps). In the case of a patient’s complex impedance (Z_pat) the imaginary part limits the effective power. When Z_pat coupled galvanically, it modifies the maximal efficient power to: P P a t = U ⋅ I ⋅ cos ( φ ) . A resonance solution of the components approaches the minimal imaginary part of the Z_pat impedance [23], and maximizes the power on the patient. The resonance uses a near-zero phase angle φ ≅ 0 consequently cos ( φ ) ≅ 1 [24]. The low imaginary part decreases the voltage

and increases on the same ratio the RF-current, [25] [26]; because I P a t 2 = P P a t Z p a t , and U P a t 2 = P P a t ⋅ Z p a t .

Approaching the proper impedance matching, the solution has negligible reflected power (order of 1 W), mimicking the skin’s galvanic contact as much as possible. When the electrodes directly touch the targeted volume’s surface, the galvanic situation, without any isolating materials, offers the most amount of available current. The impedance matching aims to mimic the galvanic situation as much as possible. This solution minimizes the reactive part and maximizes the real power on the load.

The main principle of impedance matching is to approach the “galvanic-like-touching” that would be the best available non-invasive electromagnetic energy-delivery. The invasive method (when electrodes are inserted into the body) is also “galvanic”, but its invasivity has multiple medical complications, such as bleeding, a high risk of infections, ulcer formation, and inflammation. One of the invasive “galvanic” methods is ablation technology, which has remarkable successes in local, small tumors [27]. With minimal energy loss, impedance matching allows the concentration of the energy on the malignant volume [28]. Due to the selection, this solution has better efficacy and offers a safer treatment because the voltage could be less than in higher resistivity isolation cases, at the same power application, while the current is increased.

The full arrangement of impedance matching minimizes the losses in the circuit ( Z l o s s = Z s y s − Z p a t ⇒ m i n . ). The minimal loss allows optimization of the reaction time with a low time-constant. The small delay of the reaction to the physiological changes allows prompt adaptation to alterations during the treatment; even small animals in preclinical experiments have a significantly higher heartbeat and breathing frequency than humans [29].

The impedance matching needs a conductive media between the electrodes, and the RF-current flows through it. Consequently, the system cannot tune on the situation when a patient does not present in the active radiation zone. The technique therefore induces minimal radiation to the environment, and it is safe.

Due to the forced RF-current, the patient becomes an electric component of the real-time adaptive tuned electric circuit, representing active electrical impedance. In this matching, the patient is not simply an “energy absorbent” but an active electric element of the serial circuit.

In general, all capacitive couplings are equal based on the formal capacitive arrangement level, however their technical details differentiate them. The variation could be so significant that it produces—either homogeneous or heterogeneous heating in the target.

Comparing the variants of capacitive couplings requires a detailed study of the electronic, structural, and material design differences of the circuits. All capacitive couplings involve a capacitor used for energy transmission to the target, emphasizing the electromagnetic interactions’ electric field component, using electrodes with the target volume placed between them.

The plane wave capacitive coupling transmits the radiofrequency by the plane antenna, and some of the radiofrequency is even transmitted through the air, Figure 4 . A popular hyperthermia technique applies a typical radiative plane-wave solution [30], but the high voltage for radiation necessitates enormous power (600 W for a mouse with tumors weighing 2 g) [31] [32]. However, the plane-wave solution could work with a lower power when the distance (space in the air) between the electrode and the body surface is small, or negligible, or the matching parameters allow high voltage and low current for the applied power.

Importantly, impedance matching of capacitive coupling does not work when isolated (i.e. when there is a space or air between the electrode and body surface), Figure 5 .

All capacitive couplings have an engineering control point to optimize and maximize the provided power from the RF source and, using the power-supply safely, to avoid its overheating. The measuring points fit the circuit’s impedance to the source’s internal resistivity, using the conventional standard 50 Ω. However, this engineering control does not take into account the medical control. The medical control or reference point refers to the point at which there is minimal loss of energy to the environment and maximal absorption in the patient while ensuring the safety of the patient and minimizing unwanted hot spots.

The optimal engineering settings do not necessarily align with the optimal requirements for the patient safety and treatment, Figure 6 .

There are decisional differences between the realization of capacitive coupling methods at the level of simple measuring observations. The two major categories are the plane-wave and impedance matching techniques Figure 7 , and other solutions combine these two categories.

The observed differences could be technically detected by measuring the engineering reference point (optimal engineering set-up), and the medical reference-request point. The inequality between the reference points is due to the losses in the circuit, including the matching tuner, cables, radiation processes, used materials, and structures, as well as the capacitive coupling with the environmental objects (like walls, other types of equipment nearby, or the operating personnel). At this point, the engineering control and the medical control could significantly differ from each other, Figure 8 .

The tuner electronically compensates for the overall losses, and the power- supply increases the power to replace the missing, lost energy. This type of matching procedure favors plane-waves on the patient, which uses wave-absorption, with a particular exponential decrease from the surface incident energy in the body, and is intended to create homogeneous heating in an actual depth.

The compensation of the general losses by the circuit components and environmental interactions do not optimize the patient-power from a medical point of view. After the medical point (which begins at the electrode), the initial RF-current enters the “coupling complex,” including the patient’s targeted volume. After this point, new unwanted losses challenge the optimization of the treatment. These include the electrode structure, electrode material, the bolus system, the patient’s surface adipose tissue, the healthy impedance, etc. This extra impedance is the vital target: the impedance of the tumor. Hence the optimization of the treatment point is crucial in order to successfully heat the tumor. How this is optimised defines the type of capacitive coupling (Figure 9 ).

The impedance matching focuses on the medical control-point, minimizing the impedance of components that derail the primary target’s energy, the tumor. Without taking into account the medical point, the RF-current flows through two different impedance categories: the objects’ impedance, which fits the current transfer to the body, and the body impedance.

The various components of object impedance challenge the conductive approach (Figure 10 ).

The best solution would be the galvanic contact of electrodes (Figure 11 ), which may be approached by the electrode design accompanied with the resonant compensation.

The body impedance contains a very heterogenic structure. Each of which represents a resistor and a serial capacitor (the inductive parts are missing) (Figure 12 ).

The compensation procedure in impedance matching minimizes the capacitive (imaginary reactance) factor, and the resistive part remains in focus. A particular category of impedance matching is the modulated electro-hyperthermia (mEHT) which selects the malignant cells in this heterogeneity, and the tumor-cells concentrate the primary energy absorption (see later text below). Consequently, the dominant resistivity part is the set of the tumor-cells in the targeted volume. On this basis, we approximate the effect of the different resistivities and the resistivity of the healthy tissues is negligible in the first attempt (Figure 13 ).

All of these considerations involve a resonant matching method. AC/RF circuits imply a certain frequency determined by the values of the resistance, capacitance, and inductance of the serial circuit (Figure 14 ).

The dielectric permittivity and the conductivity affect the RF-current differently, and the result is called impedance. Mathematics using complex numbers describe the two independent effects showing the conduction on the real conductor while the dielectric permittivity defines the isolators, where the conduction of the RF-current is imaginary. The patient’s impedance represents the real part (R_pat), and the reactive part (Y_pat), and Z p a t = R p a t + i Y p a t , where i = − 1 denotes the imaginary part. In geometrical representation, it shows a vector (Figure 15 ).

The impedance minimum characterizes the serial resonance. The impedance

from the imaginary parts of capacity (C), and inductivity (L) are Y C = 1 ω C , and Y L = ω L , respectively, and the impedance is Z = R 2 + ( Y L − Y C ) 2 . Hence, when ω 0 = 1 L ⋅ C then Y L = Y C , and the resulting minimal impedance is Z = R

with zero phases. The selectivity of a circuit depends on the circuit’s serial resistance.

The Y_pat depends on the applied frequency (f), while the real conductor does not depend on f. The living matter has a negligible inductive (coil-like) component in Y_pat. Mostly the membranes, and the other isolation layers form Y_pat,

which act as a C capacitor, Y p a t = 1 2 π   f C = 1 ω C Where ω = 2 π   f . Applying the

vector representation of the impedances (Figure 15), the variation of the major layers in the target volume of a human body gives a resultant impedance

R p a t = ∑ i = 1 N R i , and Y p a t = 1 ω ∑ i = 1 N 1 C i . Using the resonance frequency ω 0 = 1 L ⋅ C , an additional inductive factor would compensate the Y_pat to minimize the impedance of the target. The necessary inductivity for resonance is L = ω 0 2 C = ω 0 2 ∑ i = 1 N 1 C i (Figure 16).

The compensation transforms the impedance near a real resistance value as shown in vectorial representation (Figure 17 ). The vectors show the complex impedances of some critical layers in the body during the RF-current flow. The horizontal axis is the real part (the real conduction), while the perpendicular one is the imaginary part, representing the isolation. All tissues have isolation also due to the various membranes. The electrode isolations are neglected, so the resulting impedance vector shows a decline, which a single inductive resonance could easily compensate for.

The original current was I o r i g = V Z = V R 2 + ( ω L − 1 ω C ) 2 , the new current in resonance is higher I o r i g < I r e s = V R , and in resonance depends only on the real

resistivity. The current changes by resonance. The RF-current flowing through the target depends on the values of the components of the circuit. The well-selected situation filters a relatively small part of the targeted volume, the malignant cells, so their resistivity is small compared to the complete targeted volume. The small resistivity increases the peak of the current in resonance, Figure 18 .

Since this power depends on the square of the current the resonant curves appear steeper and narrower in the presence of lower resistivity. The quality

factor Q is defined by Q = ω 0 Δ ω where ∆ω is the width of the resonant power curve at half maximum (Figure 19 ).

Since that width turns out to be Δ ω = R L , the value of Q can also be expressed as Q = ω 0 L R . The Q is a commonly used parameter in electronics, with

values are usually in the range of Q = 10 to Q = 100 for circuit applications. The smaller the resistance, the higher the “Q” for given values of L and C. The power, of course, depends on the product of actual current and voltage. When the current increases due to the resonance, the voltage decreases, while maintaining the same power.

The resonant approach uses the minimizing of the reactance (imaginary part) of impedance. Physiological regulation also has a vital role in the process. One of the reasons for using the plane-wave capacitive coupling is the surface adipose tissue challenge, forming an isolator-like layer at the skin. In a plane-wave situation, the voltage is increased to surmount the gap by the isolator of the adipose layer. However, this way, the energy-absorption in this layer is extremely large, so the risk of burn increases. In order to avoid this risk, the plane-wave method uses intensive cooling of the skin by using the bolus system, Figure 20 .

However, this cooling has unexpected positive feedback reactions from the physiological control of the body homeostasis: the cooled skin lowers the blood- flow in the subcutis, which increases the layer’s isolation towards RF-current. This induces a higher voltage request, which increases the risk of burn, so a further increase of the cooling is necessary. It further increases the isolation, and so

on, the situation would be hard to control. Furthermore, the intensive cooling absorbs a large part of unmeasured energy, which makes the therapy dosing with incident energy impossible, as is similar in the case of ionizing radiation. Consequently, the impedance matching takes attention to the cooling process and keeps the homeostatic control stable in the subcutis layer under the electrodes.

In summary, the strategy of impedance matching concentrates on increasing the current as much as possible. The major factors to maximize the current are:

● the resonance approach,

● the design, structure, materials of the electrode system,

● the grounding optimization to lower the radiation, and coupling to environmental objects,

● the regulation of the homeostatic status of the skin blood-flow (which regulates the imaginary part of the skin-structure of the patient),

● eliminating the losses in an electric circuit as much as possible,

● the high current value (in the unchanged power conditions) makes a more effective selection,

● the high current accompanied with low voltage at the constant power, increasing the safety of the treatment.

The classical heating concept applies a mass-heating of the entire tumor. The mass heating tries to be homogeneous in temperature (isotherm), and uses the temperature as the only control parameter.

The control of homogeneous (conventional) heating is problematic because

1) the local blood-flow is enhanced, which increases the risk of dissemination and metastases,

2) colossal power is necessary to ensure quasi homogeneity, which again involves many safety issues,

3) due to the heterogeneity of the target, the control of homogeneity is very complicated, in most cases it could not be achieved,

4) the homogeneous hyperthermia thermally kills the cells and occasionally triggers immunogenic effects in the area,

5) the challenge of measuring temperatures at has not been solved; MRI thermometry is promising but still has challenges,

6) the only homogenous (and large CEM43T100) solution is the whole body treatment (WBH), which does not show the expected success.

The invasive measurement of the tumor’s temperature has multiple problems, as a result the temperature is typically measured in the nearby lumina or cavities of the body. So the mass heating must be regional, having comparable temperature in the nearby lumen (like oesophagus, bronchus, colon, vagina). The same isotherm heating appears in the plane-wave concept of capacitive coupling. The modulated electro-hyperthermia (mEHT) method uses impedance matching of capacitive coupling with some unique features, which have been developed over the past 32 years, and documented and patented. The mEHT method harnesses the impedance matching shown above with additional elements, improving its efficacy.

The present technical challenges are:

1) The energy selection ensures the local place of energy absorption. It has major complications due to the normal physiological movements caused by breathing; and the technical solution has limitations when attempting to heat deep-seated tumors without considerable heating of other tissues.

2) The dose determination, which controls the medical application, is a mandatory parameter, but the heating techniques determine the clinical results. We have seen that exposing the tumor isothermally to 42˚C in whole-body hyperthermia, has entirely different results than the same temperature in any local treatment. The technical solutions based on the temperature alone do not characterize the applied method.

3) The role and measurement of temperature in the treatment efficacy are challenging. The value of the temperature in the target supposes an isothermal mass-heating, which never happens in LRHT. The temperature measurement approximates the tumor’s value, checking the temperature in the nearby lumen (like esophagus, bronchus, colon, vagina). This method assumes that the heating does not focus on the tumor-mass, but equally heats its healthy environment.

Due to the above challenges, temperature measurement is mandatory to approximate the absorbed energy, which differs from the technically provided value. The high energy losses (like various electric losses, losses from cooling water, etc.), and the need to control safety (avoid burns) are fundamental reasons to measure the temperature.

The mEHT chooses a new paradigm, it heats the cancer-cells selectively in the tumor, using the malignant cells’ unique thermal and electromagnetic characteristics. The structural change of the local heat-capacities, heat-conduction differences, heat transfer by blood, and lymph electrolytes cause the thermal heterogeneity. Significant differences in the electric behavior of micro-states of living matter determine the electromagnetic heterogeneity. The variation of electric conductivity and dielectric permittivity by the living processes and the differences of lipid-protein structures in the cell-membranes and the cells’ cooperative differences appear to be the most influential factors for electric heterogeneity. Further differences between the malignant cells and their healthy counterparts develop as a result of the heat-resistance, motility of the cells, and cellular and extracellular mechanical properties.

Some other significant differences are present at a molecular level, but these are less effective in distinguishing the malignant cells from their healthy counterparts. Using heterogeneity offers a valuable tool to select the malignant cells in the heterogenic tissue. The RF-current presents a possible tool for clear recognizing of the heterogeneities. The current-flow changes based on the electric heterogeneities and its heating effects connect the current to the thermal properties. An essential component of tissue heterogeneity involves molecular reactions, which differ depending on the tissue and cells. For example, the apoptotic control, a well-known regulation in healthy tissues, is almost entirely missing in malignant tissue, as described in the hallmarks of apoptosis could happen through multiple molecular mechanisms, which do not work in cancer.

From the beginning of human medicine, physicians recognized the equilibrium of the living organisms, which defines the healthy state, and has multiple dynamic components which are finely balanced. This was the first recognition of homeostasis, which has definite lower and upper limits of the interactions and conditions. The body homeostasis is stable within a certain interval of the parameters; the level of any interactions is determined and measured by the harm caused at the extreme limits. However, the harm is a relative notion: the safety and the harmless categories are not identical. The “no action” treatment can be safe but harmful because the uncontrolled disease harms, which we can stop by action. The acceptable changes in medical actions attempt to reestablish the normal, healthy homeostasis; or if it is not possible anymore, then it attempts to approach it as close as possible. The Hippocrates-phrase, “Nil nocere” also has to be understood in this way. Otherwise, the meaning is “Do nothing”.

The internal transports, like the blood-stream, have a central role in keeping homeostasis. The blood circulation regulates multiple vital processes, including the heat exchange, to ensure the body’s proper functional conditions. The blood-stream tries to compensate for the overheating by intensive perfusion and regulation of the vessels’ flow-capacity. However, the regulation process of the blood-stream is non-linear. The quantitative analysis [33] shows the non-linear changes of the blood-flow in characteristic tissues varying by the temperature. The deviation (selection) of the tumor blood-flow starts just above 38˚C, Figure 21 .

Due to the variation of the blood-flow, the necessary energy in a mass unit (specific absorption rate; SAR [W/kg]) non-linearly changes in the range between 39˚C - 42.5˚C [34] by the actual temperature, Figure 22 .

The non-linear regulation is general, using physiologic control by negative feedbacks. The promoter-suppressor action realizes the contraction of the feedbacks, which has a broad response-time for intervention.

The high energy absorption excites the rafts to trigger a signal transmission [78] [79]. The extrinsic signal transfer ignites apoptosis [101] [119] [120], Figure 37 .

The difference between the molecular effect of the two matching methods of capacitive coupling techniques has been effectively demonstrated in vitro [71]. The plane-wave capacitive hyperthermia (PWCHT) gives the same results as the naturally homogeneous water-bath hyperthermia (WBHT), as seen by the apoptotic processes including the reactive oxygen species (ROS) and calreticulin (Figure 38 ) [121].

It is important to note that the purely homogeneous heating resulting from the water-bath hyperthermia (WBHT) produces comparable results to the plane-wave matching, indicating that plane-wave matching techniques also favour homogeneous heating, while mEHT differs significantly in the effects and outcomes. The apoptotic process involves a change in the potential of the mitochondria’s membrane and the Ca²⁺ influx into the cell, Figure 39 [122].

The caspase developments’ variants during the apoptosis require the extrinsic and intrinsic pathways (involving Caspases 8 and 9 Figure 40 ), and the caspase-independent signal routs [101]. Additionally, Septin4 blocks the XIAP, which makes free the extrinsic pathway from this suppressor [123]. All of these factors combined ensure apoptosis is the final result.

The homogeneous heating results in energy-absorption in the tumor-mass, in an attempt to realize an isothermal situation. However, mEHT focuses the energy absorption on membrane rafts (nanoscopic size). The excess energy makes the extrinsic excitation of the apoptotic pathways (TRAIL-FAS-FADD complex), and makes the gradients through the cell-membrane, producing various thermal effects [79]. It increases the extracellular and the raft temperature to a level much higher than their environment. In consequence the calibration curves by measuring the apoptotic intensity significantly differ, Figure 41 [35] [79]. It is clear that mEHT produces the same 25% relative cell-death as homogeneous heating in ≈3˚C lower temperature, which is an approximate difference between the local nano-temperature (at the membrane rafts) and the tumor-average temperature.

In another experiment, a rough calibration comparison between mEHT and water-bath homogeneous heating shows even higher differences between the nano-scale and macro-average temperature, Figure 42 .

A direct temperature measurement of membrane rafts also shows a significant difference in a pilot experiment, Figure 43 [124].

The heating certainly causes stress, producing chaperone proteins. The most characteristic protein family of chaperons is the heat shock protein 70 (HSP70). This protein has a double edge sword reaction: intracellularly it tries to avoid the cell’s apoptosis, extracellularly it acts oppositely: it promotes the cellular apoptosis. Any kind of hyperthermia results in the expression of HSP70, but at different levels. Due to the large electromagnetic load that accompanies the heating processes, mEHT trigger the expression of more HSP70 than homogeneous heating, Figure 44 . This difference is most significant 48 hours after treatment.

However, the location of the measured HSP70 is different. After 48 hours the concentration of the intracellular HSP70 returns to the level it was before the heating, but the extracellular levels increase, Figure 45 [125].

A detailed review of cancer models describes the molecular mechanisms of mEHT [126].

A review of the clinical pieces of evidence of mEHT summarized essential clinical evidence [143]. The clinical trials are summarized in Table 1.