• State the objective of the project, benefits of its realization for the actual level of profession

 The objective of this project is to create an apparatus and a covering patent that increases the efficiency of chemotherapy in the field of oncology and can be applied in a wider range. This will be achieved with use of subcontractors and services in the appointed sessions.

It is widely known that the early recognition of the tumorous disorder is not yet completely solved due to complex evaluation of various areas. The different screening procedures are highly expensive and not too dependable. CT and MR technologies can only diagnose the evolved tumor, and are usually used when late stadium is evolving. The correct diagnosis is difficult due to inadequate contrast substance. In addition there are areas where proper diagnosis can be put up only after several technological processes have been carried out. The undermentioned methods signify an enormous step in early screening of tumorous diseases. These methods are expensive and there is no worked out coordination for generating a nationwide database that would help confronting the various diagnoses. With the application we would like to work out a new joint diagnosis opportunity. The point of the procedure is allocating the known MR contrast matter joined with nanomolecules into the system of the study person. These products have been already produced for years and can be ordered from a catalogue. The process continues analogous to the MR and with the new system more magnetic sensors (SQUID) sweep the body of the patient. The superior magnetic sensibility and magnetic vector sensibility of the sensors enable making a high resolution 3D map of the pent-up contrast matter. An automated system points the microwave head to the points given by the 3D vectors. Then using microwave energy we heat the allocated MR contrast matter to cell disintegration state. The induced temperature will be higher in the tumorous areas because the contrast matter glued to the tumorous cells absorbs energy more intensely than its ambience. The nano-iron molecule in the MR contrast matter facilitates this process. By this process we can generate higher temperature differences than the extant procedures. Healthy cells are not put out to deteriorative impactand the immune-reaction of the system does not decrease. Furthermore the new procedure can be conveniently set to comparing MR to vector graphical images thus giving chance to new research areas in oncology.

  Do a comparison between the actual domestic and international level of profession and describe how does the objective interlock with the subject of the tender, the drawn up professional demands

 Nowadays the 9 kHz-400 GHz so-called radio-frequency (RF) range (bounds defined by International Radio Regulation of Schedule of Dividing Frequency Ranges) is getting saturated by fast evolution of newscast, radiolocation, industrial, scientific, medical and other purpose utilization. This is especially true for the lower range, the part spreading to a few 10 GHz.

The biomedical use of RF radiation can be divided into three groups: diagnosis, therapy and other applications hard to classify into one of the first two groups. The medical research area of using non-thermal and athermal impacts for medical intent has been previously led by Eastern-European researchers, but from the mid-80’-s the research of these impacts and applying in biomedicine has begun all over the world. The passive apparatus developed for diagnostic purpose working in the entire range of the RF-spectrum (microwave thermographs) use the “silent frequency bands” also liked by radio astronomers due to low level of radiation coming from the biological examination matter. The usual bands used for microwave thermography are 2655-2700 MHz, 4800-5000 MHz and 10,68-10,7 GHz. The therapeutical purpose RF-irradiation frequency bands have been assigned by ITU: International Telecommunication Union along with the industrial and scientific purpose bands – ISM: Industrial-Scientific-Medical. ITU’s international radio regulation categorizes the continents into three sectors and assigns the frequency ranges used for various purposes differently in these sectors. Out mother country being European, falls into sector 1 of ITU, thus the frequency bands from Schedule of National Division of Frequencies are applied.

The appointed frequencies belong to the short waves (6 MHz < f <= 30 MHz), ultra short waves (30 MHz < f <= 1 GHz) and microwaves (f > 1 GHz) ranges. The short wave diathermic apparatus well known in physiotherapy of rheumatic diseases works in the 27,120 MHz central band range while most of the microwave hyperthermic apparatus uses the 2450 MHz central band range (this corresponds to the microwave oven used in households). Increasing the central band frequency the penetration depth (the distance which the wave can travel before its intensity reduces by a factor of 1/e) of electromagnetic (EM) waves decreases, at the same time with apparatus using higher frequency radiation is easier directed onto the target and the geometric sizes of energy radiating instruments is smaller.

For industrial, scientific and medical purposes power from the RF signal source is allocated into the radiation matter by use of special antennas so-called applicators. In case of passive application the radiation coming from the matter is taken by applicators. Applicators differ from conventional antennas by the immediate nearness of the high permittivity biological matter being irradiated. Their goal is the same: they have to get the highest fraction of power from the RF signal source onto the target area. In case of passive applications, microwave thermography the purpose is to get the highest fraction of weak radiation coming from the biological matter. The applicator can be contact or not depending on whether it comes or not in contact with matter. Design of applicators for medical purposes happens adaptively. This is the reason why various applicators designed for different purposes differ so much. For example the microwave applicators for balloon-angioplasty (will be reviewed later) used for healing surface cancerous tumours have notably different geometrical parameters: size, shape, etc. The applicator denomination also implies antennas used for given task. The EM radiation coming from the applicator is dispersed, reflected from the surface of matter and the part entering it is absorbed. For perpendicular incidence there is no dispersion. Then power density of the entering wave is the difference between power difference of entered and reflected waves. This also means that in case of perpendicular incidence (the propagation direction of waves is perpendicular to matter) and minimal reflection the highest proportion of RF power can be entered into the biological matter. The spatial distribution of entering waves depends of the all-time scope. In microwave hyperthermic treatment of local cancerous tumours the purpose is that radiation hits the tumour directly. In whole-body RF-hyperthermia or heating up cooled blood-bags with microwaves we need uniform spatial distribution.

  The RF-apparatus connected to the applicators

 

The RF-apparatus connected to the applicators depends on the medical application. In case of microwave thermography there is a special set-up low noise microwave receiver-meter (will be later reviewed at microwave thermography subchapter) attached to the applicator. The apparatus feeding the RF-hyperthermy applicator is a few times 10–100W power RF signal source. Such power can be generated economically at 2,45 GHz by intensifying a small-level oscillator signal with semiconductor amplifiers and assessment of output signals or by attenuating the signal of a cheap mass-fabricated 600-800 W magnetron-oscillator designed for household microwave ovens. In case of RF-hyperthermia or any other radiofrequency medical application based on thermal effect the radiated biological matter has to be kept at appointed temperature. Therefore the temperature of matter has to be measured constantly and power of RF signal source has to be controlled with a signal proportional to the temperature. This is achieved by different implementations in the various equipments.

 

Diagnostic use of RF-radiation, microwave thermography

 

Microwave thermography is a non-invasive examination method for measuring the temperature distribution of the body. Abnormal temperature distribution implicates cancerous tumour, circulation anomalia or inflammation. As a diagnostic method it is drawn up beside other image-generative methods (conventional and digital X-Rays, CT [Computer Tomography], MRI [Magnetic Resonance Imaging], ultrasound and PET [Positron Emission Tomography]). Cardiovascular system and cancerous disorder are among the first mortality causes in the world. On the first place of occurrence and mortality cause are lung-cancer at men and breast-cancer at women. The mortality-rate of women breast-cancer is almost constant from 1930, but new occurrences are constantly growing. Survival chances are increasing with earlier detection of the tumour. Diagnostical methods for detecting breast-tumour are: feeling of the tumour by gynecologist-oncologist in the course of medical examination, mammography (X-Ray monitoring of breast with use of contrast-matter), ultrasound examination, diaphonography (use of sparks of light) and thermography. There are two sorts of thermography: infrared radiometry (thermovision) and microwave radiometry (thermography). The collective or combined use of the enumerated methods helps the early recognition.

 

Evolution direction of microwave thermography

 

The successful diagnostic with the single-antenna microwave thermograph has opened the way for further evolution of the procedure. The multi-antenna radiometry has been developed for shortening of the examination time. Enhanced reliability can be reached by using multi-frequency (cm and mm band simultaneously) and multi-antenna radiometry (deeper in the cm-band and better spatial resolution in the mm-band), or using microwave and infrared thermography together. Correlation radiometry also uses several antennas (in row or matrix configuration) with the phase-controlled antennas. One can prove theoretically that in loss-suffering homogenous matter the correlation radiometry mends the thermogradient resolution. Microwave thermography is often used as “thermometer” of hyperthermic apparatus, it is used for automatic regulating power of hyperthermic microwave signal sources, for the temperature of heated tissue has to be kept on constant value between close bounds.

 

Microwave hyperthermy

 

In medical practice there are three kinds of hyperthermy: local, regional (with impact on body parts) and general or artificial fever. Body or body part heating can be done in many ways, such as bailing in hot water, blowing of hot air, infrared radiation, ultrasound, RF-energy that can be allocated into the body by inductive, capacitive bonding and radiating in microwave band. Microwave hyperthermy is a heating procedure using microwave radiation as therapy, with important application in destroying cancerous tumours. It is more favorable than in situ short wave and ultrashort wave radiation used for this purpose because it is more dirigible. It has shorter penetration depth, this is why the applicator has to be set near the tumour for deep-lying tumours. This can be done non-invasively through natural cavities and openings in the body in some cases of cancer. By using hyperthermy in some cases the cancerous cell proliferation can be stopped or the previously non-operable tumours can be depressed into operable ones. Pre-surgery hyperthermia serves for this. The post-surgery hyperthermia increases healing chances by destroying the scattered cancerous cells furthermore the surgeon has to cut out smaller part of healthy tissue that encompasses the tumour. Used as combined treatment it enhances the effect of medication (it can put an end to medication-resistence of cells resisting medication), combined with radiotherapy with smaller dose of X-Rays further results can be achieved. Almost every combined treatment is in the first or second phase of clinical tests.

 

• Justify the economic and professional necessity of the project

 

Since modern medicine has accomplished notable successen in healing infectious diseases the malign cancerous diseases have reached the second place on the mortality list.

 

Medical Journal

 

“7 million people are affected by tumorous disease in the world, 160 thousand in Hungary. In 70% of late stage patients pain is the main complaint.”

 

“…while 60 thousand new tumorous patients are detected, 160 thousand are under active oncologic treatment, and 300 thousand under post-nursing. … doctors reach recovery at 35-40 percent of treated tumorous patients, however 35 thousand patients – 20 thousand men and 15 thousand women – die every year. With this hungarian men lead the tumour-mortality statistics in the world, while women are on the second place.”

 

2005-07-20

Kökény Mihály, health protection cabinet deputy said Hungary is on the first place in cancerous disease occurrence. 30-35 thousand people die every year in the country from tumorous disease, 40 percent of whom are under 65 years. The 21 steps in ten years would cut down the number of tumorous patients by 15 percent – the national anti-cancer program with screening-buses and organised travelling is planned to raise onto 65 percent the rate of breast-screening participants until the end of the year.

 

It is important to know that absolute number of cancerous patients has also increased. There is a huge effort around the world for healing, but the results have not brought the expected breakthrough yet. Unfortunately Hungary leads in statistics considering prevalence and mortality of the disease. That is most people get sick by cancer and most die from the disease around the world in Hungary. The limits and side-effects of nowadays traditional surgery, radiotherapy and chemotherapy treatments give way to searching for new possibilities, other mentalities. Safekeeping, supporting the capacity of the patient’s self-protection, improving the quality of life, maintaining the results of therapy is anew important.

 

Hyperthermy – thermotherapy, fevertherapy – is not a novelty. We are aware for a few thousand years of the application of healing heat and our system “applies” it whenever is needed. At the beginning of the century the “new radiation”, the ionizing rays have overshadowed thermotherapy. The subsequent movement started in the seventies and its evolution is unbroken since. Hyperthermy is equal to other conventional therapeutical methods in leading oncotherapy institutions in many countries around the world.

 

Electrohyperthermy is a method where thermal impact comes from electric frequency. Heat is only one component of therapy, effect of electrohyperthermy is more complex. Electrohyperthermy increases efficiency of radiation therapy, thus by mean of complexity it makes possible decreasing of applied doses without insufficiency impact, thus moderating the side effects.

 

Thermic and electromagnetic effect destroys the tumor, blocks its growing, stimulates the functioning of the immune-system and effects the transforming tumorous cells, helps the redifferentiation (the cell will evolve normally, it will not become a tumorous one). The temperature needed for the cells and destroying of tumorous cells is above 42,5 °C. Above this value the structure of cell protein starts to change, to decay, but the cell membrane, cell parts, DNA and RNA chains deteriorate, the metabolic process changes, the cell reconditioning system decays. The initial assumption that tumorous cells are basically more sensitive than normal cells is only partially proven – the increased growing rate does not allow complete cell generation, the quantity and quality of blood vessels is inferior, thus the blood provision.

The anyway increased metabolism of the tumour increases its activity, the anyway inferior blood provision decreases to a critical level, is out of step with the increasing needs, thus the rate of anaerob processes grows, the cell accumulates acid effect, the pH decreases. By continuous thermic impact the distance between metabolic needs and supply increases gradually, the cell perishes after a while. Method of heating is an essential issue: aim is heating the tumorous cells selectively, sparing the normal tissue, no pain. There are several methods and many instruments appliable for heating.

The difference between dielectric constants of tumorous and normal tissue gives opportunity for absorbing energy in tumorous cells to be multiple of the normal cells. This energy absorption can be measured. Tumorous tissue stands of cells in different growing phases, with different blood circulation areas, with different sensitivity for X-Rays, chemotherapy and hyperthermy. This makes it possible to apply different therapeutical methods combined.

One has to consider that cells not destroyed by therapeutical methods get more sensitive for new methods, thus one method helps the other. This is why membrane and metabolic changes caused by hyperthermy allow a bigger quantity of cytostatic matter to get into the tumour and concentration to get efficient in areas with inferior blood provision. Hyperthermy also decreases the proportion of otherwise hard to handle static cells by activating them and making them more sensitive to healing methods. Hyperthermy decreases the proportion of cells resisting X-Rays. It can be told that by combining hyperthermy with same X-Ray and cytostatic matter a better therapeutic answer is probable and the same result can be achieved by decreasing the dose. For tumours not reacting to chemo- or X-Ray-therapy both chemo- and X-Ray-therapy can get efficient after hyperthermy. New research has shown that tumorous cells make up typical proteins on their surface at constant 42°C thermic impact (thermic shock proteins). Although these proteins originally protect the cells from deteriorative outer impact, they also activate the cytokin system and play an important role in activating through the so-called killer-cells the immune system being responsible for healing and keeping up the results. Separate research topic is how can hyperthermy increase efficiency of non-specific immune system stimulating matter, playing a role in handling tumours hardly visible for the immune system.

Hyperthermy’s rich, almost unreviewable literature contains widespread use and clinical observations on many methods from almost every area of oncology, using before surgery for decreasing the body of tumour, making inoperable tumours operable, handling mutations affecting more organs. Hyperthermy is a non-invasive, painless, humane curing method. It significantly increases the chances of patients applied as part of complex oncological therapy with chemo- or X-Ray-therapy or immune system stimulating procedures. 2500 PET/CT examinations will be financed by the healthcare department next year. Jenő Rácz, minister of health care would like this number to be quadrupled in five years. Doctors say there is need for at least 25 thousand PET/CT examinations. Director of PET/CT center says the examination enabling early identifying of cancerous tumours would be reasonable every two years after reaching a certain age.

With this system decreasing healthcare expenses are probable because identification of early stadium and therapy for it is less expensive.

 

Justify on professional and economical level, as well as underlay it with numerical data, if the project will be realized, in that case, what kind of scientific, professional and economical benefits would be predicted and how those can contribute for the designated goal accomplishment?

On combined treatment, curing cancer with conventional cancer treatments and with hyperthermy simultaneously, I mean the hyperthermy and the radiology (microwave and ionizing ray) or the hyperthermy and chemotherapy ( radiation of microwaves and medicinal treatment) would work together. In case of combined treatment the superimposition will not be prevail, the effects can make stronger or weaker each other. In our case, we aim to destroy the cancerous tumour with high efficiency so we will examine the synergic effects. The combination of the microwave and ionizing ray they examined through mice experiments and they experienced synergic effect.

 

During the experiments, mice have gotten human fibroblast (youth connective tissue),

that was handled with cytomegalovirus and it produced tumour.

By considering the partial or the entire regression of the tumour, the combined microwave and X-ray radiation turn out as the most efficient method. The reason is, that the 2 types of radiation can complement each other because the DNA-synthesising cells are more resistant face the X-ray, however they are more sensitive to temperature.

 

The hyperthermy blocks the self-correcting mechanism of the damaged cancerous cells during the radiation. After the promising results of the animal experiments, it has begun the combined hyperthermy-radiology treatment deployment in the human therapy.

Moros and Co. reports that, the microwave hyperthermy and the cobalt-60 therapy clinical application simultaneously has been successful.

 

They used two types of radiation, one of them has a RF radiation and (radiation has one way, and the other has perpendicular way). The experience of preclinical treatment, beside the effectiveness of the medical treatment says, the equipments are technically dependable, they work without interference. This treatment combination is also called thermoradiotherapy. At the combined application of the microwave hyperthemy and the chemotherapy the mechanism of effect is diverge. The radiation of microwave, according to the expansion of the micro-tubes of the cell membrane, it increases the cells permeability for the circulating chemotherapy materials in the bloodstream.

The procedure of testing the treatment has been started in end of the 1970`s with animal experiments. The effectiveness of this combination was tested by Szmigielszki and Co., in based on the treatment of the mouse sarcoma. On the effect of the microwave hyperthermy, the sarcoma was decreased with 50% in the mouse colony, and the interferon and the radiation of microwave simultaneous application has been decreased it by 66%.

After the successful animal experiments, the procedure has begun the in clinical practice. The microwave hyperthermy and chemotherapy is applied together successfully in the Institution of Haematology in Munich, they treated local tumours and metastatic cancer patient as well.

 

Combined treatment of RF hyperthermy and chemotherapy for pancreas cancerous tumour was reported in Germany, 1997 by Migeod and Co.

The symptoms stopped temporarily by 49% of treated patient, the CT examinations have proven it. The hyperthermycal effect not only because of the hot temperature causes hypoxia (the tissue has lack of oxygen because of the blood has reduced oxygen saturation ) and the effect of the acidosis ( cells has hyperacidity), but the result of the bioelectrical cell resonance. The research of the effects is under process recently as well.

 

They treated the metastatic cancer with the entire body hyperthermy and systhematic chemotherapy simultaneously and the local tumours ( melanoma, tissue sarcoma etc. ) were treated by systematical chemotherapy and regional hyperthermy.

The systematic chemotherapy includes the conventional medicinal treatment as well. There are remarkable results at leukemia, after medulla transplantation they used high dose chemotherapy and the entire body hyperthermy simultaneously.

 

The combination of the microwave hyperthermy and the chemotherapy treatment is called thermo-chemotherapy as well, that is very effective treatment, enable to stop the cancer cells from growing. Recently , the method is before the clinical application, it is in the stage of preclinical , however it seems very promising treatment to extend the life expectancy of the cancer patient.

 

The hyperthermy technical characteristics

Among the hyperthermy technical characteristics, the most important parameter the hyperthermy capacity. Transmitting energy (when the radiated materials totally devour the RF capacity )in this case at the 20 mm diameter tumour ,1.5 W microwave capacity theoretically causes 5 ^o C/minute temperature increasing. As previously mentioned it will help to establish mechanism of effect, that the cancerous tissues have a big loss, they are able to absorb much more microwave capacity, than the healthy tissues.

 

The reason of the bigger loss is the bigger content of the water. It is important to mention, that the X-ray and microwave radiation applied for combined treatment the ionizing ray ( the radiation with 15 Gy radiation dose) has no effect on the tissue dielectric feature in the 0,2-2,45 GHz frequency range.

Beyond the radiation frequency, the wave entry and the tissue temperature increasing, depend on the applicator and on the capacity of the generator. At the one part of the human arm, on f=2,45 GHz frequency, calculated with the method of the finite element, based on the isotherm, to get the optimal capacity density 200 mW/cm^2 a 42-43,5^o C.

 

When the cancerous tissue treated by microwave hyperthermy, it is important to keep the optimal treatment temperature because the healthy tissue should not be damaged.

The healthy tissue burning hazard factors: cause hot punctum ( specially surrounding osseous distend), the low blood supply fatty tissue could be heated up faster, the external bigger water content organs bigger absorption. For this, it is very important, that the radiation has to be controllable, it can be caught by the proper applicator designing.

To design applicator, it depends on where the treated tumour is located in the body and we need to know whether we apply external or internal hyperthermy for the treatment. For the external treatment we would use external applicator and for the internal treatment we would use internal applicator or special applicator that will be inserted in the tissue.

 

When we design the applicator we need to consider the following requirements: the go in and/or remarked microwave radiation would not pollute the environment in improper quantity.(the staff protection needs to be work out) , on behalf of the patient it will be important, that induced local field and temperature distribution in time and space need to be adjustable. By considering the performance requirement of hyperthermy treatment, the occurring losses in the system would expand form 10W to 100 W.

To control the radiatation RF performance we need to measure the radiated tissue temperature distribution. There is another way to measure the temperature, that in the tissue we place a temperature sensor in invasive mode.

For this task, we would be applying the fiber optics thermometer, it is the best. The developed device for treatment needs to perform with the EM compatibility with the surrounding devices, it has to meet with the EMC(electromagnetic compatibility) specification.

 

Other medical applications

 

This subchapter deals with the radiofrequency energy in the diagnostics or in the therapy section or the disputed classifiable medical application, in order to be applied many-sided, through radiation the energy goes into biological substance in this professional field.

 

The executive, who is responsible for the project

 

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The executive of the project is Steve Abonyi, who is director of the relevant research and development ABN-tech LLC. He graduated in 1996 at College of Kando Kalman, as an electric engineer. In 1999, he has become a member of the New York Academy of Sciences for his results with superconductor at the KFKI.