Review Thermal Med,29(1):1-23,2013.

Challenges and Solutions in Oncological Hyperthermia

ANDRAS SZASZ

Department of Biotechnics,St.Istvan University,Pater Karoly u.1,Godollo,Hungary 2103,Hungary

Abstract:Oncological hyperthermia is an ancient method that has been around for thousands of years.

Despite this,oncological hyperthermia is still in the early stages of development.Like many such

therapies,it lacks adequate treatment experience and long-range,comprehensive statistics that can help

us optimize its use for all indications.The reason for this is simply explained by the reason that the

overall heating of the locally targeted volume has no adequate harmony between physiology,

thermodynamics and technical solutions.Selectively focused heating needs to be applied to the sensitive

points of malignant cells in order to liberate energy in the nano-scale cellular region.The present article

discusses the mechanisms of heating and the effects of hyperthermia in oncology,and provides a solution

by Oncothermia(Nanothermia)which shows efficacy in a wide range of malignancies.

Key Words:oncology,hyperthermia,nano-scale heating,nanothermia,oncothermia

Introduction

Heating was an established therapy in ancient medicine,and it has been one of the most often

applied “home-medicines” in almost all cultures of the world.Hyperthermia reduces pains

significantlyand this is its main therapeutic value.At the same time hyperthermia was the very first

oncological treatment,having its roots in ancient medical practices.Numerous books deal with the

topic ,although suspicions and doubts are also commonly published in the literature .One of

the earliest doubts concerns the readiness of radiotherapists:Is the community radiation oncologist

ready for clinical hyperthermia? The main point of the argument can be summarized as follows:

“Clinical hyperthermia today is a time-consuming procedure,done with relatively crude tools,and is an

inexact treatment method that has many inherent technical problems.Certainly,excellent research work

can be working in the community.If the individual is willing to commit the time and effort required

to participate in clinical studies in this interesting,challenging,exasperating,not-too scientific field;

then he or she should be encouraged to do so.The field is not without its risks and disappointments,

but many cancer patients with recurrent or advanced cancers that are refractory to standard methods of

medical care can unquestionably be helped by hyperthermia.It is not,as some have suggested,the fourth

major method of treating cancer after surgery,radiation and chemotherapy.It may be innovative,but

it still is an experimental form of therapy about which we have much to learn”.

Challenges and solutions in hyperthermia・A.Szasz

― ―1

Received 22 October,2012.Accepted 16 January,2013.Corresponding author;Tel,＋36-30-942-1811;Fax,＋36-23-555-515;e-mail,Szasz.Andras＠gek.szie.hu

doi:10.3191/thermalmed.29.1©2013 Japanese Society for Thermal Medicine

Dr.Storm,a recognized specialist of hyperthermia expressed a very negative opinion on

hyperthermia in his paper:What happened to hyperthermia and what is its current status in cancer

treatment? He writes:“The mistakes made by the hyperthermia community may serve as lessons,not

to be repeated by investigators in other novel fields of cancer treatment”.Two editorials have raised

questions regarding the efficacy of hyperthermia in oncology recently.One is in the European Journal

of Cancer:A future for hyperthermia in cancer treatment? It states:“The role of hyperthermia in

oncology cannot be defined at this moment.Obviously it will be limited to specific scenarios”.

Another editorial is in the Annals of Surgical Oncology(titled:Hyperthermia:Has its Time Come?)

It states:“The results of adjuvant intra-pleural chemotherapy for mesothelioma with or without

hyperthermia have been less than hoped for”.However,it needs to be noted that both editorials also

state that the results of clinical studies employing new and more effective hyperthermia technologies

should be awaited.

The time for paradigm change of hyperthermia in oncology has come.One of the flagships of

clinical studies concerning hyperthermia in oncology was published on cervical cancer.Its results were

also very promising ,but a control study was rather disappointing .The explanation for the

contradictory results is simple:a reference point was missing .

Oncothermia has formulated a new paradigm of hyperthermia in oncology ,and has made clear

what obstructs acceptance of hyperthermia .The basic problem of traditional hyperthermia lies in its

misleading aim of treatment goal:setting temperature as a dosing and ignoring physiological reaction of

patients.The oncothermia solution gives clear answers to doubts on hyperthermia,and introduces the

fourth column of the gold-standard oncological methods,additional to the surgery,radio-and

chemo-therapies.

Questions always arise from unsatisfactory results.Some of the clinical results of hyperthermia are

very promising and show sufficient healing power,however there are also disappointing clinical trials

which pose real challenge,and raise many further questions and doubts.One such example is the

cervical cancer study mentioned above,where the results were very promising ,while a control study ,

was disappointing.

The main question is still open:why hyperthermia with its long history and with detailed

investigations has no wide acceptance in contemporary oncological practices? Upon answering this

question,many researchers share the opinion of the editorial of European Journal of Cancer in 2001

which insists that the biological effects are impressive,but a technical barrier blocks its application;

“The biology is with us,the physics are against us” .However,when technical problems are largely

solved,then complex physiological reaction is blamed:“The biology and the physics are with us,but

the physiology is against us”.

In the present article the way out of this going around trap is shown for local hyperthermia in

oncology.

Challenges of hyperthermia

Local hyperthermia applications in oncology are based on a simple physiological idea:the locally

heated tumor has accelerated metabolism which is not supported by the normal blood-flow in the

Thermal Med,29〔1〕:1-23,2013.

― ―2

neighboring tissues.The“starving”tumor is self-destroyed by acidosis.This approach has good proofs

in modern investigations,showing impoverishment of ATP and enrichment of lactate in the heat-treated

tumors.Furthermore,increased temperatures suppress replication of DNA ,and also stimulate

immune reactions .

Moreover,local hyperthermia synergistically supports the modern“gold-standard”therapies:

increases biochemical reaction rates which is essential for chemotherapies,and at the same time

increases local blood-perfusion enriching drug-concentration in the heated volume.Hyperthermia also

can be applied in low-dose metronomic chemo-regulation ,and can support radiotherapy by higher

oxygenation .Numerous review articles are published discussing positive effects .Furthermore,

the great advantage of hyperthermia is well known for its pain-reducing effect,which increases the life

quality of cancer patients.

In spite of these advantages,why this“miracle”method is not utilized widely? The answer lies in

the adverse effects of heating.Locally or systemically increased blood-flow has definite negative effects:

it delivers more nutrients(glucose)for the surviving tumor and also increases the risk of the dissemination

of malignant cells,which finally enhances the risk of metastases and drastically limits prognostic chances

of patients.In other words,as soon as the hyperthermia treatment is started,a local heating brings about

a contradictory competition between a cell-killing potential and a cancer-supporting potential of higher

temperature realized in the targeted volume.

The well focused deep heating in itself is a huge technical challenge.Even if it is cleverly solved,

a further challenge still remains:heat energy naturally spreads with time and raises the temperature of

the environment of the tumor.On the other hand,blood is an excellent heat exchanger,supported by

the physiological feedback corrections,which cools down the heated volume to homeostatic equilibrium.

All this process works definitely against our efforts to increase local temperature.This direct

physiological reaction shows a general natural law:the level of temperature cannot be focused for long

time.It can be focused only for a short period of time,which is comparable with a few tens of the time

intervals between two R-peaks in ECG signal.The technical focusing should be that of a local

energy-concentration,which can be created very precisely.The precise energy-focusing develops heat

and increases temperature in the volume,but temperature smears with time irrespective of precise focusing

of energy delivery.

In temperature development local metabolic activity also has a role in increasing local temperature

by excess heat and in realizing a naturally higher temperature in the tumor.In consequence,tumors

typically show higher temperatures than the surrounding healthy baseline temperature .

There is another physiological challenge too:energy which is delivered into a definite volume of

body produces heat,however this heat develops very variable temperature in the given volume.The

variation of temperature development comes from high variation of blood-flow and its control in the

various parts and organs of the body.Even if we can measure and focus energy precisely,it does not

mean that we know the temperature pattern created by the development of heat energy.

Further complication is caused by thermal physiology and arteries.One of the main active

controllers of thermal homeostatic adjustment in the body is arterial blood-flow.This controller works

in the musculature of arteries to enlarge or narrow lumen of vessel fitting blood-flow to the actual

Challenges and solutions in hyperthermia・A.Szasz

― ―3

control-aim.The neo-angiogenetic arteries have no musculature in the vessel-wall,therefore cannot be

regulated like normal arteries.This makes certain difference in reaction to heating of the healthy and

malignant tissues.Due to the physiological feedback an effective vascular response to heating could be

observed ,to compensate local temperature increase by cooling blood-flow.

The reaction of malignant tissue and that of healthy tissue deviate in an opposite way when

temperature exceeds a tumor-specific threshold.Over this specific value(starting from about 38℃)

arteries shrink and no muscle in the vessel-wall regulates the blood-flow.Over the threshold an opposite

thermal development can be observed between malignant-tumor and normal/benign tissues in suppressed

and increased blood perfusion respectively.This effect is functions as a heat-trap for tumor,and

helps its local heating by increasing temperature rapidly in the tumor volume compared to the

non-tumorous neighborhood.Although it is the effect that the usual method of local heating targets,it

crucially shows us the existence of a focusing problem above the threshold.In other words,temperature

increase in itself does not help curative processes,because when the arteries shrinkage suppresses the

blood-flow(causing less cooling,more heating,higher temperature),it blocks the delivery of drugs at the

same time and also the oxygenation for complementary radiotherapy.Therefore,even if higher

temperature helps direct heating in the tumor,it blocks complementary applications of chemo-and

radiotherapy.

Temperature increase by local heating over the blood-flow threshold has even more dangerous

disadvantages,because tumor periphery has a large difference of blood-flow between the inside and the

outside of the tumor.This temperature gradient is created at the volumes where the most vivid

proliferation occurs(tumor grows like balloon development),and the consequent risk of malignant

dissemination increases.The risk increases proportionally to the temperature gradient(gradient of the

blood-flow)in the peripheral region.It is this effect that might explain contradictions in direct clinical

results(response rates)and actual survival time.The direct local response in itself does not necessarily

guarantee survival time,because metastasis potential could be gained.If it is the case,then local

hyperthermia increases dissemination of malignant cells and therefore causes metastases .

At last but not least,control of dosing is also a large problem in local hyperthermia.Observing

importance of temperature and its action time,a complicated dose-unit is introduced in the relevant

literature:the cumulative equivalent minutes(CEM) .This unit is measured in minutes,which is

tightly connected to the heating time.According to experiments and clinical data ,the equivalence

is realistic when we set a base line of equivalent to 43℃ (denoted CEM43C)and it notes how many

percentile of the temperature was equal to 43℃ (CEM43CT90 is equivalent time that the 10th percentile

temperature was equal to 43℃).Its correct measurement needs correct percentile of temperature pattern

and stable(equilibrium)thermodynamic conditions,which is almost impossible in deep-seated tumors.

Why do we need such a complicated dose definition? Why don’t we use for dosing locally pumped

energy,as we dose ionizing radiation(Joule/kg＝Gy)? The reason is simple,because we have no idea

how to evaluate locally absorbed energy.The difficulty has many reasons,all of which are of technical

ones.First of all,focusing of non-ionizing radiation is far more complex than that of ionizing one.

Second,while in ionizing radiation case we can pump a large energy portion into the focused volume

within a short time,it takes a lot of time to do so in non-ionizing radiation,which opens the possibility

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Thermal Med,29〔1〕:1-23,2013.

of smearing energy in the volume.Third,the largest technical challenge of energy dosing in local

hyperthermia is the necessity of surface cooling,due to safety reasons.The cooling takes away unknown

portion of energy from heating power forwarded,and consequently really pumped energy remains to be

unknown as well.Fourth,the surface blistering is time-dependent,and for avoiding blistering on the

skin it is not possible to apply more than approx.0.45 W/cm for 60 min.duration.If we apply 1 W/cm,

then the treatment time should be reduced to approx.40 min.The surface blistering value limits

available energy for heating up a larger volume of a tumor inside the body.This explains why higher

incident power even over 1,000 W energy is used in most local treatments.We know that such high

power is used for boiling a few hundred ml volume and boiling itself takes only a few minutes Then,why

is it possible for local hyperthermia to use such a high energy for so long time? The fact clearly shows

that from the tremendous amount of energy produced,more than the 90％ is wasted.This makes

difficult to evaluate energy-dosing of the treatment.Temperature measurement might help to guess the

real energy-intake in the tumor.However,blood-flow and physiological counter-reactions again make

this possibility unrealistic.

Besides the challenges described above,we have to emphasize the general disadvantage of local

treatments which limits efficacy of local hyperthermia.Malignant diseases seem to be only local.

However,it is not true.In fact malignant diseases are systemic which have high potential of

dissemination and metastases.Prognosis of patients is drastically worsening due to metastatic growth,

which should be taken into account when calculating survival time.From this reason whole body

hyperthermia(WBH)as a systemic solution is used.Its advantage lies in whole body heat-action with

easy temperature measurement(dose)and in additional immune support,which is well known in the

phenomenon of natural fever,too.

In spite of these advantages challenges in WBH have also serious problems like in the case of local

hyperthermia.Heating the whole body neglects the physiologic temperature control by increasing all the

relevant physiological parameters drastically together with changes of electrolyte-equilibrium in the

human body.Here the main disadvantage is also the possible support of malignant dissemination.

Therefore,WBH needs to be applied only with simultaneous systemic chemotherapy,which might limit

metastatic potential of the method.From a technical standpoint,WBH has an entirely different heating

mechanism from local hyperthermia.The systemic heating is provided by blood-heating and heated

blood heats up the tumor through the elevated body temperature.In case of local hyperthermia the

targeted volume tissues are locally heated,and blood-stream remains in the level of body-temperature.

Here,blood itself is a cooling media of the heated tumor,which is entirely the opposite of that of WBH.

Solution of the problems

As long as the problems described above are not solved appropriately,local hyperthermia remains

to be an incorrect medical approach.All the problems relating to local hyperthermia are connected to

proper and controlled energy delivery to the place where it should be active.We have to destroy the

targeted malignant cells without promoting their dissemination activity.The challenging assignment of

development in hyperthermia technology might be similar to the technological innovation of

light-sources.

Challenges and solutions in hyperthermia・A.Szasz

― ―5

The incandescent light-source(standard bulb)uses a heated tungsten filament that reaches about

2,500℃ where it has white-hot radiation,and interestingly enough,for example,a 60 W bulb uses only

10％ (6 W)of the energy consumed for emitting light.Lighting comes from excitation of tungsten

particles which radiate white-light in such a high temperature.However,if the excitation be smaller,it

would radiate in red,or radiate only heat without making visible light.In this excitation process the

high temperature of wire is crucial,because 90％ of the energy is wasted for heating everything:wire,

bulb body and environment.

A major innovation of changing traditional lighting is the discovery of fluorescent lamp.The idea

is to excite particles which make chemical changes(electron-transfer)in the material which radiates light.

Compared with previous light sources,this technology has 43％ usefulness of light in the same

luminousness with less than fourth of the power to standard bulb.This technology doesn’t waste so

much energy to heat up the environment as the previous technology,it concentrates energy selectively on

molecules,which have to be excited to radiate.

The latest innovation is the discovery of the light-emission-diode(LED)light-source,which uses

95％ of energy for useful light and uses only 3 W for the same luminosity for what the incandescent bulb

uses 60 W.What is essential for the latest development of lighting technology? Here is the clue to our

question,too.

What we can learn from the development of lightning is that we have to excite only those chemical

bonds which are necessary for the desired effect and thus we should not waste energy for useless processes,

which might have several contra-effects.Similar innovation is taking place in car-engine technologies,

where the development concentrates on energy-saving by avoiding heat-waste through cooling circuits of

the engine.This is nothing but the development of fuel-cell technology.The essential technological

novelty of all these new technologies lies in microscopic energy liberation,which is not only more

effective,but can be also more accurately controlled.This type of energy-saving is naturally well

developed in biology too,when energy of nutrients is liberated step-by-step in small and controlled

amounts thus avoiding a loss of excess energy caused in case of immediate macroscopic energy liberation.

In hyperthermia applications macroscopic heating is typical where achievement of overall

temperature(homogeneous)is the main target in the entire targeted volume,irrespective of its content and

ratio of tumor-cells in the target.However,the target volume has only a small fraction of active

malignant cells,and therefore selective heating should be enough for heating malignant cells and thus can

avoid heating(energy waste)other part of the target-volume.If the nano-heating can be possible for

selective heating,then only the selected malignant cells absorb energy in the target.The selective

nano-heating technically and biologically realizes step-by-step energy-liberation on the place where it is

necessary,i.e.in the cellular membrane of malignant cells.This new nano-heating technology can be

called Oncothermia or Nanothermia,after its heating action in nano-range of malignant cells.This

technology can be realized by using impedance matching(similar to capacitive one)and by delivering

modulated radiofrequency(RF)current which flows through the malignant target volume.In case of

simple capacitive solutions potential of electrodes is decisional,while in case of RF-current impedance

coupling is decisional in heating.Moreover,in case of modulated RF current multiple actions at the

cellular membrane are caused by non-equilibrium heat-flows and electro-osmosis processes.

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Thermal Med,29〔1〕:1-23,2013.

There are essential differences between malignant and healthy cells that we can use for their

recognition.Selection of malignant cells can be based on the next three complex and interacting effects.

1.Differences of metabolic rate of the malignant and healthy cells(Warburg effect)

2.Differences of dielectric constant of extracellular electrolyte in immediate vicinity of malignant

and healthy cells(Szent-Gyorgyi effect)

3.Structural differences(pathological pattern recognizing)of malignant and healthy tissues(fractal

physiology effect)

These biophysical differences make possible the accurate selection of cancer-cells and contribute to

actively destroy them without damaging their healthy neighborhood.Here also dosing is crucial.If we

provide too much energy,all components of the target will be heated up,and then we lose selection and

its consequent healing effects,which used to happen in traditional hyperthermia.Therefore,the classical

wisdom is valid:the difference between the medicine and poison is only the applied dose.

Selection by metabolic rate of cells

Otto Warburg discovered definite metabolic deviation in malignant cells from that of healthy cells,

which is originated from mitochondrial dysfunction .Malignant cells use fermentation in utilizing

glucose to produce 2ATPs,while normal Krebs cycle uses oxidative way to produce 36ATP with high

efficacy .Despite 18 times difference in ATP production,simplicity of the process let malignant cells

favor this way,and therefore this massive energy production could support malignant cell.This process

is similar to the well-known change of glucose metabolism in sport-medicine when muscles are

overloaded and oxygen is not enough to supply ATP demand by mitochondria.In this point muscles

start to metabolize glucose fermentatively,causing muscular strain after activity.

The high glucose influx,which is necessary for supporting malignancy,creates a distinguishable

difference in the composition of the extracellular electrolyte in the vicinity of cells.It is the difference

that is used in modern diagnostics(positron emission tomography,PET).The ionic concentration of

extracellular solution changes robustly by highly concentrated metabolites.The composition change is

measurable by conduction of various liquids which direct electric current to a more conductive path.

The process clearly selects cells of different metabolic forms and automatically focuses RF-current on

close extracellular electrolyte of malignant cells.This irregular behavior of electric conduction can be

measured and imaged by the Electric Impedance Tomography(EIT).The same methods are applied

in prophylactics like mammography ,too.Intensive auto-selected RF-current delivers more energy to

the malignant target through cellular selection in nano-meter range of cellular membrane.Moreover,

targeted energy-delivery prefers combination with chemotherapy,which results in robust synergy and

increases absorption of cytotoxines .This process is supported by heat-flow through membrane of

malignant cells,which heats the cytoplasm from hotter extracellular milieu.The heat-flow relaxes the

anyway rigid cell-membrane of malignant cells and increases its permeability for membrane-associated

HSPs.Furthermore,the increase of selectivity by conduction is a positive feedback of conductivity in

growing temperature .The measured gain of selectivity is 2％ in℃ ,therefore the gain in the range

of 36→43℃ is 14％ increase.

The increase of current density in tumor could be visualized by measurement of real processes,i.e.

Challenges and solutions in hyperthermia・A.Szasz

― ―7

by using image of radiofrequency current density(RF-CDI) .

Selection by dielectric properties of cells

The living matter exists in aqueous solution,which is partly well ordered .The ordered

electrolyte state is suggested to be as much as 50％ of total amount of aqueous solution in living

systems.Recently the order is shown as dominant ,and is probably oriented(ordered)by the

membrane potential of cells.Rearranging(disordering)electrolyte structure needs energy ,similarly to

melting ice with latent heat.This drastic change(phase transition)modifies actual physical properties

(like dielectric constant)of a material without changing the composition of the medium itself.

Malignant cells have lower membrane potential than their healthy counterpart.The low membrane

potential disorients the ordered bond-structure in the extracellular matrix .The disorder of structure

increases electric permeability(elevates dielectric loss) and at the same time reduces the cell-cell

adhesion ,and consequently the structure becomes boggy.This order-disorder phase-transition induces

two different states of cells:one which has a disordered extracellular matrix and therefore has autonomy

status(called alpha-state)and the other which has ordered matrix form in connected and collective status

(beta-state).These states of cells are recognized by evolutional biology:alpha state cells were present

in the early development of life,when the aggressive electron acceptor was not present and life was

energized only by a fermentative(non-aerobic)way.When differentiation was available via oxygen in

the atmosphere,cooperative cell-structures(beta-state cells)appeared.Cancer-cells are in their alpha

state mimicking the early development of life-evolution .Based on this theory,electromagnetic

properties of alpha and beta states of cells are well connected with the Warburg’s theory described above.

The significantly larger permittivity(alpha state)and high conductivity(fermentation metabolism)in

tumor-tissue is explained on this theoretical basis .The high dielectric constant allows additional

selection(focusing):higher dielectric constant absorbs more RF-energy,due to their disordered

behavior.The ordered structure makes possible for“channeling”energy-flow,while the disordered

structure always absorbs energy in a“friction like”manner.

The significantly higher water content of malignant tissue than that of their healthy counterpart

makes the dielectric selection more precise.Proliferating cells control their cell-volume by their water

content in the malignant growth and make more biophysical distinction for properly applied

electromagnetic treatment.

Furthermore,dielectric selection factor is derived from the applied frequency and its modulated

forms.There are various forms of energy-absorption mechanisms and one of them is calledβ

-dispersion (Maxwell-Wagner effect).It is active in the band between 0.1-100 MHz.This effect

involves bound water and other adhesive bonds on outer membrane.Water bound to membrane forms

the upper part ofβ-dispersion which is denoted byδ ,and this part is well selective for various

cell-membrane states.Selection in the frequency-range ofβ-dispersion excites special signal receptors

on malignant membrane,inducing apoptosis.For choosing receptors which transmit apoptotic signal,

modulated carrier frequency is desired.In summary:all the electrolyte and membrane properties differ

in malignant tissues from healthy tissues .The proper selection uses dipole relaxation ofβ-dispersion

connected to membrane bounded water ,as well as chooses apoptotic signaling pathways by the

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Thermal Med,29〔1〕:1-23,2013.

modulation of the RF-carrier.

Selection by pathological pattern of tissues

Modern physiology is essentially an interdisciplinary discipline ,which combines the knowledge

of various fields,like electronic structure approach of solid-state physics ,superconductivity ,

electromagnetism ,and thermodynamics .Various modern approaches have been developed in

the last decades based on this complexity,for example self-organization ,fractal physiology ,and

bioscaling .Due to the physiological differences,various tissues have distinguishable structures and

therefore experienced pathologist can well recognize malignancy in the tissue sample by their deviated

structures.Moreover,tumor is highly complex in its pattern,too.It has no definite boarder that makes

it complicated to distinguish healthy tissue from cancerous one.This is the reason why such a visible

curative method as surgery has to be controlled with immediate pathology in order to prove surgical

excise successful and to confirm that no any malignant cells remained.

Healthy cells work collectively;energy-consumption as well as their life-cycles and availability of

resources are controlled in a collective way by various forms of self-organization .Healthy cells have

special“social”signals for commonly regulating and controlling their life.Therefore,healthy living

systems have characteristic fractal dynamism ,as a consequence of their self-similar stochastic behavior.

The healthy dynamism fluctuates according to a certainly identified pattern .Healthy communication

has fractal behavior both in space and time.The healthy time fractal is scale-independent

fractal-fluctuation(called as pink noise),which can be also identified by dielectric properties .

The collective order is missing in malignancy.The cancerous cells behave non-collectively;they

are autonomic.They are“individual fighters”;common control over them is missing,and only

available nutrients regulate their life.In malignant tissue cellular communication has disappeared .

Consequently there is a well recognizable pattern of cancer in pathological morphology.Malignancy

has a different fractal structure compared to its healthy counterpart ,and therefore pathologic difference

between the two tissues can be described as a basic structure-pattern.Fractal analysis could be used for

better pathologic description and for prophylactics as well.Analysis of fractal structures of

malignancies could even indicate stages of the disease .

Unlimited proliferation is not the only characteristics of malignancy,but rather missing of apoptosis

and the loss of programmed cell-death might be its main characteristics,which makes it difficult to

activate natural controls and error-corrections of the organism.The dynamic(time-fractal)behavior in

space and time provides effective information exchange between cells.Due to malignant autonomy,

collective communication signals(called social signal)are broken among cells .The social signals

and their correlation length are determined by different factors,for example by an energy-pack-like

information-transfer .Consequently,the normal(healthy homeostatic)biological processes could

be described by self-similar function-classes,based on dynamical observations of long-range correlation

lengths .The lost information exchange could be reestablished by constrainedly delivered

information,and the modulation of RF-carrier is the best way for the purpose.The famous

Adey-window published in the early 1990s is the first proof of special modulation effects .

Modulation of RF-carrier frequency has started to be used since then,and has become an important

Challenges and solutions in hyperthermia・A.Szasz

― ―9

new method for cancer therapies .Numerous clinical results show its efficacy ,and oncothermia

has been applying it for dynamic selection since the late 1980s.The carrier frequency delivers

information(modulation frequencies)for targeting cancer cells which are much less“transparent”than

their healthy counterpart.Malignant cells are heated up by selectively absorbed energy.The applied

modulation helps localize the tumor-boarder,clear the contours and(most importantly)select(self-focus)

energy-intake,and thus makes exciting numerous signal pathways on the outer cell membrane.

Action on far-distant metastases

The real life-threatening danger is the metastatic growth of malignancy,when cells are disseminated

from tumor-lesion by various transport systems(lymph,blood),or their effect becomes systemic by one

of the general mechanisms of the organism(Fig.1).

Primary tumor-growth arises dominantly from

lack of apoptotic processes.The main purpose of

tumor therapies is to make the primary tumor shrink

and disappear.It is clearly not enough for curing

diseases,because the most important of oncology is

to block dissemination and metastatic growth of

tumor.Dissemination is caused mainly by lazy or

missing cellular connections,while forming of

metastases is attributed mainly to problem of

immune-deficiency.The effective treatment should take into account these processes together with the

elimination of primary tumor.

Characteristics and advantages of oncothermia(nanothermia)

A s d e sc ri b e d ab o ve,

oncothermia is the method that

can venture to fight against both

dissemination and metastases by

utilizing energy liberation and

consequent heating at the

immediate vicinity of the outer

cell-membrane of malignant cells.

The whole working mechanism

of oncothermia (nanothermia)

can be illustrated in Fig.2.

The main task is to excite

various signal-pathways in the

nano-scope range of cellular

membrane of cancer-cells.

Numerous in-silico, in-vitro,

Fig.1.The three main steps of malignancy:primary

tumor,dissemination and metastatic growth.

Fig.2.Oncothermia works in four main areas:selective on cellular level,

natural method,safety without side-effect and systemic effect in spite

of its local application.

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Thermal Med,29〔1〕:1-23,2013.

in-vivo and preclinical experiments have to be performed before clinical applications as it is the

conventional way in the medical world .The determinant point for oncothermia(nanothermia)is to

be as natural as it can be,which

means that the intervention o

2

oncothermia should not

i n i t i al i z e an y n e g a t i v e

physiological feedbacks.The

classical local hyperthermia

concentrates on the constrained

temperature increase in a

volume,which induces definite

contra-reaction of the body in

order to reestablish homeostatic

body-temperature . Onco-

thermia is invented to avoid the

contra-reaction of the body of traditional

hyperthermia and rather to activate natural

physiologic feedback loops(Fig.3)for eliminating

extraneous structures and reestablishing cooperative

harmony which were destroyed by cancer

cells.

The nano-scale energy-liberation by modulated

RF-current can be proven.We have acquired the

result in suspension cell-culture (HL60 human

leukemia cell-line);definite 28％ better selection

than classical hyperthermia can be shown in same

temperature .One of the results is the definite

selection of malignant cells in co-cultures.The

effect on healthy human keratinocytes(HCK)

co-cultured with human fibroblasts(Fig.4)was

marginal and was regenerated in time.The

co-culture with immortalized(but not malignant)

HaCaT keratinocytes was effected slightly,but the

malignant A431 cell-line was selected from the

co-culture.The co-culture with immortalized(but

not malignant)HaCaT keratinocytes is effected

slightly,but the malignant A431 cell-line was

selected from the co-culture.Cellular metabolic

activity was measured using the MTT assay

(standard colorimetric test)and quantitated at 630

Fig.3.Oncothermia helps the natural feedback loop.

Fig.4.Oncothermia in silico.Co-culture with normal

human skin fibroblasts as a model of a squamous

carcinoma growing within connective tissue

cells(100 ml)were exposed to oncothermia.

Incubated for 24 h at 37℃,fixed and stained with

crystal violet. Cellular metabolic activity was

measured using the MTT assay (standard

colorimetric test)and quantitated at 630 nm.

Data represent the mean value±S.E.M.of 4-6

separate experiments assayed in triplicate,but

some experiments were repeated up to 12 times to

obtain reliable data.(A:4 h post-oncothermia;

B:48 h post-oncothermia. HCK:healthy

human keratinocytes;HaCaT:malignant

keratinocytes;A431:lung cancer cells.)

Challenges and solutions in hyperthermia・A.Szasz

― ―11

nm(Fig.5).This experiment well demonstrates the effective

selectivity on malignancy and not simple sensitivity on

proliferation rate.

A sophisticated experiment was performed in order to

study the synergy of temperature and modulated electric

field .The model is a HT-29 human colorectal carcinoma

cell-line given to xenografted to nude mice(BALB(nu/nu)).

Classical hyperthermia destroyed 17.9％ of the tumor by

single shot(30 min),while oncothermia showed drastic 57.1％

distortion rate.For a comparison we performed a low

temperature oncothermia experiment,where the bolus of the

upper-electrode was cooled down.The intensive cooling

kept the tumor near physiological temperature(38℃),while

the oncothermia field was identical with heating conditions to 42℃.The electric field made only

nano-range heating,by which 45.9％ distortion was shown at body temperature.The effect of the

oncothermia experiment shows that efficacy was more than 2.5-times higher than hyperthermia on 42℃.

All of the facts show us that the overall temperature has a minor role in cell-killing mechanism.

The multiple fractal physiological effects are also proven by oncothermia experimental results.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 non-modulated(passive arm)).The

single shoot experiment was done for 30 min,but tumors were treated only on 40℃.We know from our

experiments that level of temperature is generally not satisfactory condition to make hyperthermia effect

according to a classical heating approach.The animals were sacrificed after 48 h,and the results shows

well the modulation effect:the treated arm in modulated cases

had 45.8％ higher cell-distortion than the non-treated part,while

the effect in the non-modulated mice was only 3.9％.The fractal

modulation selects and re-establishes the apoptotic signal

path-ways.A day after oncothermia treatment a definite

difference can be detected between modulated and non-modulated

effects.The difference became more significant when two days

passed after the treatment:the tumor treated by modulated signal

continued the cell-death in an extended portion,while the

non-modulated tumor started to regrow.

The difference between classical hyperthermia and

oncothermia is also well demonstrated by HEK293 cell-lines.

The HSPA1A chaperone (HSP70 family) was used for

characterizing the stress difference .Oncothermia had induced

the presence of this chaperone robustly,while hyperthermia was

not active at the same temperature in this line(Fig.6).This

experiment well shows how the overall heating has definite

Fig.5.Cellular metabolic activity of A431

tumorigenic (●) and HaCaT

non-tumorigenic,but immortalized(◆)cell-lines.The cell density used for

experiments was 10 cells/ml (as

indicated by the arrow).

Fig.6.Oncothermia treatment induces

HSPa1a,which is not expressed by

hyperthermia in HEK293,but

oncothermia induces it on the

identical temperature. This effect

directly proves that oncothermia

stress is thermal providing the

selected and microscopic heating,which is different from overall and

macroscopic heating that depends

only on temperature(Samples from

two independent experiments).

― ―12

Thermal Med,29〔1〕:1-23,2013.

difference from nano-heating process o

oncothermia.

The difference of the stress-development

can be also measured by Luciferase

transcription .Luciferase as a heat-shock

recovery sensor was measured after 15 min

and 30 min heat-shock at 42.5℃,and detected

slower recovery by oncothermia than by

hyperthermia in the same temperature.

Luciferase was used as a heat-shock reported

N3-Luc (HSE-HSE-HSE-Luc) transient

transected as“switch detector”and measured

after 30 min heat-shock at 42.5℃.It was

again more HSP70 after 4,6,8,and 12 h

recovery time.The difference was the largest and significant(50％)after 8 hours recovery time(Fig.7).

Molecular changes show natural processes which are dominantly apoptotic(Fig.8) .The time

delay indicates the long-duration processes,which were identified as programmed cell-death(apoptosis):

macro-and micro-morphology,enhanced activity of p53 tumor-suppressor,cleaved caspase 3

Fig.7.Oncothermia makes higher heat-shock than classical

hyperthermia.

Fig.8.Early molecular reactions(up to 24 h after single shot［30 min］

treatment)show definite apoptotic signs .

Challenges and solutions in hyperthermia・A.Szasz

― ―13

involvement,tunnel reaction,DNA fragmentation

(laddering),and etc.were carefully measured .

Massive presence of apoptotic bodies can be also

observed together with the typical tunnel effect(Fig.

9).Apoptosis became dominant after 24 h(Fig.10).

Oncothermia also suppresses proliferation rate in

the remaining living part of treated tumor.

Measurement was done by Ki67 proliferation marker

(Fig.11).The surviving-living malignant cells in the

treated tumor had definitely and significantly suppressed Ki67 marker compared to its untreated

counterpart in all the time-scale investigated.

Together with the certain suppression of proliferation the adherent connections are reestablished

Fig.9.TUNEL reaction in full cross-section of the untreated and treated samples after

48 h of single shot(30 min)treatment.Appearance of the apoptotic bodies is

observed.(HE＝hematoxylin-eosine stain).

Fig.10.Typical time-delay by apoptotic processes.The

cell-distortion appears 24 h after the single shot

(30 min)treatment.

Fig.11.Colon26(murine colorectal cancer)cell line

derived allograft(CID mice),single shoot.

Ki-67:proliferation marker protein,

expressed in the nuclear membrane only in

the dividing cells.The samples were chosen

from the definitely living cancer part in both

(treated and untreated) tumors.Ki-67

expression in untreated control tumor(A),

and in the still living part of the treated

tumor(B).

― ―14

Thermal Med,29〔1〕:1-23,2013.

(Fig.12)by blocking disseminative processes.New connections also make possible the missing

signal-transmissions reestablished.

Local rearrangement is observed by long-time effects(measured by 216 hours after the single shot

treatment)(Fig.13).

Fig.12.Oncothermia can reestablish adherent cell connections(E-cadherin and

β-catenin)as well as gap-junctions(Connexin-43).

Fig.13.The long-time effect after the single shot(30 min)oncothermia treatment .

CD3＋ and CD8＋ has been observed after two days,while HSP70 is permanently

presented for 5 days.The Ki67 proliferation indicator protein is suppressed in the

living,non-destroyed part of the treated tumor,Surprisingly an invasion ring was

detected after 5 days of the treatment,representing monocyte and neutrophil activity

(MPO is indicated in the ring).

Challenges and solutions in hyperthermia・A.Szasz

― ―15

Immune activation of oncothermia is shown,measuring the CD3 and CD8 expressions the invasion

ring forming around the treated tumor and the neutrophil and monocytes activity in the region.

Based on these changes certain abscopal(bystander)effect can be induced by local oncothermia,

which is also clinically proven .

Together with molecular effects oncothermia is a good complementary treatment for any

gold-standard therapies.It increases oxygenation of the treated volume(Fig.14),as well as increasing

effect of chemotherapy(Fig.15).

Conclusion

Oncothermia is a new kind of hyperthermia in oncology.It selects and robustly heats the malignant

cells in their membrane.This nano-scale heating of oncothermia solves classical challenges of

hyperthermic oncology:

Challenge 1:“The biology is with us while the physics is against us” .Nanothermia solution solves

the antagonism of the two sciences:“The biophysics is with us”

Challenge 2:“The biology and the physics are with us while the physiology is against us”.

Nanothermia solution solves the antagonism of the three sciences:“The fractal physiology is with us”

Challenge 3:“Reference point is needed!” .Nanothermia solution definitely proposes:“Back to the

gold standards,use energy instead of temperature as reference point”.

As a new paradigm of hyperthermia,Oncothermia(Nanothermia)would be feasible and efficient

method to treat solid malignant diseases,which gives us new era of hyperthermia treatment.

Fig.14.The oncothermia effect on the ionizing

radiation therapy. Fig.15.Oncothermia drastically enhances the

antitumor effect of the Mitomycine-C.Effects

are measured on identical temperature for

hyperthermia and oncothermia.Percentage of

cell-killing is in comparison to untretead

tumors.

― ―16

Thermal Med,29〔1〕:1-23,2013.

Acknowledgement

I am thankful for Dr.Morita T.,Dr.Andocs G.,Dr.Meggyeshazi N.,Dr.Brunner G.,Professor

Kampinga H.H.,Professor Okamoto Y.,and Professor Szasz O.,for their outstanding support and help

in the above results.This work is devoted to the memory of Reka Szasz.

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