Oncothermia summary v9

Oncothermia summary
written by Prof. Dr. Andras Szasz,
Ref: [www.SzaszAndras.hu], [www.oncotherm.de], [www.oncotherm.com]
[Last upgrade: September, 2009]
History
Hyperthermia is the oldest oncology treatment in medicine [1]. Contrary of this it is not generally
accepted as conventional therapy. The problem is its controversial performance. The controversy is
originated from the complications of the deep heating and the selection (focusing) of the heat-effect.
These challenges are based on bio-physical and engineering problems. This was the reason why the
oncotherm development was made by biophysical origins. Oncothermia is a further development of
the traditional, more than two thousand years old [2] oncological hyperthermia method. It solves such
technical problems, which were blocking the stable applications. The idea of oncothermia solves the
selective deep action on nearly cellular resolution [3]. The main idea is connected to the electric field
effect of cancer, worked out by the Karolinska Institute, Sweden [4]. The effect of electric field is a
hot topic in science, [5], [6], [7], [8], [9], used in other treatment modalities also [10]. Oncotherm
company was one of the firsts who constructed treatment unit, and shown it to the medical
community, [11]. The results were amazing, [12]. However, the method was invasive, and the request
of the non-invasive safe method was the market demand. This was the start of the oncothermia
development in early 1990s. From that time the method was rapidly developing and clearly proven
[13]. Note, the electric field effect is widely applied on lower frequencies also [14], [15]. Recently the
field became very active [16] and a clinical trials of other field methods are also in progress [17], [18].
Change of paradigm
Oncothermia is based on the paradigm of the energy-dose control, replacing the single temperature
concept [19]. The traditional hyperthermia is controlled the only single thermodynamic intensive
parameter, with the temperature. However, the requested job is to kill the malignant cells, for what a
definite energy dose is necessary [20]. The historical energy-dose-like control (temperature multiplied
by its application time), is physically incorrect, and operates with an overall energy average in the
area, instead of a directed and well measurable energy-dose (measured in kJ).
Problematic points in conventional hyperthermia:
o
make the focus artificially has many problems, because the malignant tumors have no real
boundary (only the benign tumors have boundary). So the focus never could be proper,
o
the problem is even more complex to see the technical complications of the focusing in depth of
the human body, avoid the hot-spots, and eliminate the natural and necessary movements (e.g.
breathing or other) of the patients, as well as avoid the overheating of the surfaces, when the
energy penetrates in to the body.
o
there are many theoretical problems of the heat-effects in the tumor and healthy tissues, the
interactions with the general physiology (including the HSP the hypoxia, etc.).
Oncotherm approach:
1. Apply such mechanism, which is self-selective, (the focusing in this case would be automatic);
2. Make such internal energy-distribution, which is not doing an average heating only, but
definitively works at the places where the energy could be applied on the most optimal way.
1
The first point is approached by the general mechanism of the malignancy: the malignant cells have
autonomy (renegades as Weinberg says), they are in permanent competition with the others for the
nutrition and for the life-conditions. The healthy cells are generally collective, their control is made by
“social signals”, no real competition is introduced only a labor division is active. This means, that the
active ionic exchange near the malignant cells (in most of the cases) is more intensive than in their
healthy counterpart. This allows the introduced current to find the optimal path, which goes through
the best conduction way. So the current goes self-selectively to the malignant cells [21]. Technically
(in simple speaking) this is nothing else, only to introduce current through the tissue, ant that will find
the malignant cells automatically. We had experiments in co-cultures, and observed the effect in work.
The second point is more sophisticated. Apply energy somewhere could increase the temperature of
the target but could do some other works also. Naturally, the absorbed energy increases the
temperature. It is, like in the case of ionizing radiation, only a normal “side effect” not that is the
desired effect. The expected work is to damage the DNA, to destroy the chemical bonds and rearrange
the structure. That is trivial, if the temperature is high enough, could do this rearrangement alone, but
of course than everything has this average energy. (If we have a fatty dish after the dinner, we could
was it our by very hot water only, but a clever housewife has detergent to reduce the water
temperature, and make the job where it must be done - at the surface of the dish, and not waste energy
to the non-important volumes.) To make the temperature arising alone in the tissue, could be a
problem of the safety and again comes back the selection task. So we have to give the energy not
equivalently into the target but specifically to the place where we want do the distortion (like the
ionizing radiation does). What is the target? It could not be the cellular interior (nuclei and DNA)
because that by non-ionizing radiation needs again high temperature, and the initial problem is not
solved. The target is the cellular membrane! If we keep the current in the extracellular matrix than the
energy heats up only this electrolyte, and a heat-flow starts from the extra- to intra-cellular regions
through the membrane. This heat-flow accompanied by different ionic flows and water transport,
changes the Hodgkin-Huxley equilibrium, the membrane became more transparent, and at the end
destroyed [22]. (Anyway the transparent membrane also could be helpful to kill the malignant cells,
because large concentration of the intracellular HSP could be expressed extracellularly, which has
direct effect on the apoptosis and the stimulation of the systemic immune reactions.)
So these points are realized, and called this procedure electro-hyperthermia or oncothermia [23]. Of
course many theoretical considerations were done to make this idea working. The membrane effects
by the outside electromagnetic field are shown against the old theories [24], [25], [26]. Also the modern
fluctuation analysis (fractal-physiology, [27],[28],[29]) supports the oncothermia [30], [31]; as well as
the resonance phenomenon is studied and used in the light of a new theory [32]. The hypoxia study
[33] and special vector-potential theory [34] helps to complete the method. We also study the possible
side-effects of the scattered radiation, [35] reduce the risk, and make the method as safe as possible.
The acceptance of the new paradigm is a clear demand of the theory and the practice as well [36].
Technical solution
The presently applied radiative hyperthermia devices, operating one order of magnitudes higher
frequency than oncothermia, are in fact also capacitive-coupled, because the applicators are definitely
in the near-filed arrangements. However, these are far not optimally coupled and their frequency is
also too high to be able to provide the desired effects. In oncothermia no artificial focusing needed for
selectivity, and no isotherms in space and time has to be controlled. Both effects are solved in
oncothermia with a directed electric field. It is a well designed capacitive coupling on 13.56 MHz
free-frequency, [37]. Oncothermia is controlled by the changes of the impedance, and by the absorbed
energy, which both are accurately measured. In this meaning oncothermia is very similar to the RFablation hyperthermia, where the temperature is not measured, the effects is controlled by the
measured impedance of the tissue. The power is ranging form 30 W to 150 W, which is far enough for
heating up the tumor over 42 ºC in a well controlled focusing. (You may touch a working 12 W
2
halogen lamp to be sure on its burning efficacy. Less than 20 W is enough to heat up a 5 cm diameter
tumor from 36 ºC to 44 ºC at 3 minutes! The only clue is the focusing.)
Oncothermia requests technically two definite effects: selectivity and cell-killing. [38]
Selectivity – Oncothermia is selective by the higher conductivity and higher permittivity of the
extracellular matrix of malignant tissue. (This high complex dielectric constant is effective in the
microscopic level as well.) The higher ionic concentration in the more active cellular environments
and different physiological conditions (see PET, [positron tomography]), allows even spatial
resolution by this effect (EIT [electric impedance tomography] and CDI [current density image]).
Oncothermia is selective by the higher conductivity and higher permittivity of the extracellular matrix
of malignant tissue [39]. The high complex dielectric constant is effective in the microscopic level as
well. In coculture experiments the healthy fibroblast remain intact, while the aggressively malignant
melanoma cells (A431 cell line) are destroyed (see Fig. 1) [40].
Figure 1. Selectivity in vitro experiments: only the aggressively malignant A431 cells are destroyed in a coculture with
non-malignant fibroblasts (Dr. Brunner, Clinic Horheide, Muenster, Germany)
The selectivity is well demonstrated on the brain treatment of mice, where the sharp selective focusing
on cancer area is also shown, Fig. 2. The in vivo experiments well support the in vitro results. The
excellent focusing of oncothermia can be proved by the temperature measurement in the tumor and the
surrounding healthy muscle (see Fig. 3.).
Figure 2. Selectivity in vivo experiments, (fixed sample): The definite borderline of theGL261 murine glioma (brain)
tumor in nude-mice shows the tissue selectivity
3
Two kinds of treatments were performed: local classical hyperthermia and oncothermia (see Fig. 4.)
Both of the treatments were controlled by accurately measured intratumoral temperature with fluorooptical method.
Temp (oC)
Temperature measurment
45
44
43
42
41
40
39
38
37
36
35
34
33
32
31
30
0
10
20
30
40
50
Time (min)
Treated muscle
Treated tumor
Control muscle
Control tumor
Figure 3. Selectivity in vivo experiments: A)HepG2 tumor xenografted nude mice with temperature measurement probes
in the tumors: . B) comparative energy-absorption (temperature) measurement
Hyperthermia treatment
Oncothermia treatment
Same conditions in both
treatment (treatment duration,
maximum temperature)
Continous real time
temperature measurement
with Luxtron fluoroptic
thermometer
Figure 4. Experimental setups of hyperthermia and oncothermia
The method to calculate the killing rate of the treatments is a morphological comparison based on the
observed pathological differences. The living part being in intensive proliferation microscopically
could be easily distinguished from the necrotic part containing the dead tumor cells. We compared the
area-change of the dead part of the control and treated tumor originated from the same animal. The
differences are significant, (see Fig. 5.).
43.7
kontroll
control
kezelt
treated
Efficacy of the cell-killing (%)
45
40
35
30
25
16.7
20
15
10
5
0
Hyperthermia
Oncothermia
Figure 5. The macro-evaluation of the efficacy of oncothermia in comparison to the hyperthermia in HT29 tumor
xenograft. Change of the areas of dead and vivid parts in percentage of the untreated control on the same experimental
animal (data average of 3 animals each), Similar experiments were carried out with the same results for A431 human
epidermoid carcinoma xenograft model and GL261 murine glioblastoma model
Comparison of hyperthermia and oncothermia combined both methods with mitomycin-c (MMC)
single dose chemotherapy in vivo at tissue and cellular level using histological examinations is shown
on Fig. 6. HT29 human colorectal carcinoma cell line derived xenograft tumor model in nude mouse.
4
Cell-killing effect of the method (%)
2 animals for hyperthermia (42ºC) + 3mg/kg MMC ip. (30 min before the treatment); and 2 animals
for oncothermia (42ºC) + 3mg/kg MMC ip. (30 min before the treatment).
A)
66,1
70
60
Hyperthermia (42°C)+MMC
50
Oncothermia (42°C)+MMC
40
30
20
7,7
10
0
Hyperthermia
B)
Oncothermia
Figure 6. Investigating the difference of the effects of i.p. administered Mitomycine CA)The cellkilling is relative to the
control tumor on the same animal. (Two-two animals was measured with double tumors on each for control.)
B) Hematoxilin-eosin stained microscopic images of tumor samples
The temperature dependence was also investigated [41]. The same temperature application of the two
thermal treatments was tried together with the only field application (cooled back) case (see Fig. 7.). It
was clearly shown the advantage of oncothermia where the electric field has significantly higher effect
as the temperature; as well as they have good synergy in cell-killing process (see Fig. 8.) [42].
45
44
Hyperthermia 42C
Temperature (oC)
43
42
41
Oncothermia 42C
40
39
Oncothermia 38C
38
37
Control
36
35
34
33
32
31
30
0:00:00
0:10:00
0:20:00
0:30:00
Time (min)
Figure 7. A sample of the temperature pattern of hyperthermia and oncothermia at different temperatures
57.1
60
45.9
50
40
30
17.9
20
10
6.1
0
Untreated
control
Hyperthermia Oncothermia
42°C
42°C
Oncothermia
38°C
Figure 8. Comparison of cell-killing effect of hyperthermia and oncothermia at different temperatures
Oncothermia is based on the modulated electric field effect, which works in synergy of the classical
temperature-based hyperthermia concept. In preclinical conditions (in vivo and in vitro) many
measurements were done in animals and there are many interested users who tried up till now the
temperature development by the method, which is a complex, invasive measurement approach. The
latest, sophisticated, well-controlled clinical temperature measurement was done in Nurnberg
5
(Klinikum Nord) by Prof. Dr. H. Renner. The CT-guided fluoroptic sensor was positioned by
interventional radiologist, and the patient (suffering with advanced sarcoma) was treated with the
medium applicator. The result is shown on the figure. The maximal temperature in the tumor was 44
ºC, while the surface temperature remained around 32 ºC, (Fig. 9.)
Intratumoral sensors
Figure 9. Comparison of cell-killing effect of hyperthermia and oncothermia at different temperatures
Lethal cell-disruption – The constrained thermodynamic transport effects destabilizes the cellmembrane, increases its permeability and could make its bobbling and distortion [43], [44].These are
high efficacy factors favor oncothermia over its temperature-equivalent hyperthermia counterpart, Fig.
10. [45]. It also produces higher concentration of HSPs in the outer membrane and in the extracellular
matrix. The higher HSP concentration in the vicinity of the malignant cells together with the changes
of the adherent connections between the cells induces apoptosis.
Figure 10. Lethality comparison with traditional hyperthermia in vitro experiments (fixed sample): HL-60 leukaemia cell
line
6
Figure 5. Lethality comparison with traditional hyperthermia in vivo experiments (fixed sample): HepG2 human colorectal
cancer cell line xenographt model in nude mice
The setup made possible a fine temperature control, which allowed to keep the heating, keeping and
cooling dynamist also identical, Fig. 11. This makes identical heat-shock protein induction by the
temperature changes. The temperature dependent equality was controlled by luciferase transient
transfected HEK293 cell lines [46].
Temperature measurment
44
Oncothermia
Hyperthermia
43
Temperature (oC)
42
41
40
39
38
37
36
35
34
33
32
0
5
10
15
20
25
30
35
40
45
50
Time (min)
Oncothermia
Hyperthermia
Figure 11. The dynamism of the heating and cooling is also well controlled for comparison of the two heating methods
Figure 12. HSP70 distribution in A431 epithelial cancer cell-line xenografted nude mice tumor samples treated by
hyperthermia and oncothermia (Immuno-fluorescence microscopic images, red:HSP70, blue: cell nuclei)
Despite of the equal temperature curves, oncothermia produces higher concentration of HSPs in the
outer membrane and in the extracellular matrix (see Fig. 12.) The higher HSP concentration, in the
vicinity of the malignant cells is one of the factors to induce apoptosis.
Change of adherent connections (E-cadherin and β-catenin) are also indicators of the gain of the social
signals promoting the apoptosis [47], [48]. Remarkable change could be observed on beta-catenin
dynamic development by time after the treatment, Fig. 13. on HepG2 human hepatocellular carcinoma
cell-line. This considerable change after 24 hours of the treatment is sharply different from
hyperthermia on the same temperature, and supports the other observations of the non-temperature
dependent processes [49]. The sudden regrouping the beta-catenin and its enrichment at the cell-nuclei
could be an indicator of apoptosis [50].
7
Figure 13. Development of β-catenin by time elapsed after the treatment in comparison of untreated and hyperthermia as
well as oncothermia treated samples. Sampling: 1h, 3h, 24h after the treatment; (Immuno-fluorescent microscopic images,
red: β-catenin, blue: cell nuclei)
The same relocalization of beta-catenin to the nuclei was observed in the in vivo experiments (Ht29
colorectal xenograft model, Fig. 14.)
In vivo (HT29) [xenograft]
12 hours
0.5 hour
50 µm
2 hours
24 hours
4 hours
48 hours
8 hours
72 hours
Figure 14. Development of β-catenin by time elapsed after the treatment in comparison of untreated and oncothermia
treated samples. Sampling: 0h, 0.5h, 2h, 4h, 8h, 24h, 48h and 72h after the treatment; (Immuno-histologic microscopic
images)
Detecting the double strains of DNA (DAPI staining, see Fig. 15.) and measuring the enzymatic
labeled strain-breaks of DNA (TUNEL-FICT, see Fig. 16.) the apoptosis is highly likely in
oncothermia, while at identical temperature in classical hyperthermia the necrosis is preferred.
8
Consequently the main effect in oncothermia is the apoptosis contrary to the conventional
hyperthermia, which operates mainly by necrosis.
Figure 15. DAPI staining (stains the double strains of DNA only)
Figure 16. TUNEL-FITC staining (enzymatic label of the strain-break of the DNA)
The wild p53 gene is directly promoted by oncothermia, which has probable role in the above
apoptotic indications (see Fig. 17).
Immunohistochemical image
of p53 tumor-supressor gene
Control
Oncothermia
p53 “master-switch”
Control
(untreated)
Oncothermia
Figure 17. Measurement of p53 (wild) in control and oncothermia treated samples. The mask is red, the statistical
difference is significant. (Made by Leica Bond Max fully automated IHC system, Detected by: Leica Bond Polymer
detecting kit, Primer antibody: anti-p53, DO7 clone (DAKO), dilution: 1:50)
Many in vitro and in vivo preclinical studies as well as twenty years entirely positive practice and
huge number of retrospective clinical studies are behind of oncothermia.
9
Clinical experience
Oncothermia is a complementary therapy, applied together with all the “gold standard” oncotherapies
like oncosurgery (pre- [adjuvantly, neoadjuvantly] and post-operative therapies), with radiotherapy
like booster of the blood-flow (oxygenation) oncothermia is applied pre-radiative, and like a synergic
supporter it is used as post-radiative therapy), and with chemotherapy boosting the drug delivery
oncothermia applied before, and supporting the chemo-metabolism it is applied parallel with the actual
(any drug-substances) therapies. The new therapies (like immuno-therapies, dendritic-cell treatments,
stem-cell treatments, gene-therapies, virus-therapies, etc.) are all applicable together with
oncothermia. Its application as monotherapy is only possible when the gold standards failed
(resistance, kidney of liver failure, blood-count problem, etc.). In this case it is a palliative method. In
most of the cases oncothermia is applied in high line treatments due to the possible satisfaction of the
gold-standard therapies in first-, second- and even third-line. The fourth line application of
oncothermia is general, no contraindication could be listed due to the stage of the patients.
Oncothermia could be applied in all the tumor-kinds, including the sensitive brain and the central
nervous system, as well as the well cooled lung or liver. The various cases are shown in the
Oncotherm web-sites, or could be posted in detailed electronic form upon request.
Remarkable amount of retrospective clinical studies are available to indicate the oncothermia effect in
humans [51], [52]. It is commonly used for such a complex and very frequent tumors like lung, liver,
pancreas, brain, gastrointestinal, gynecological, etc. Prospective evidence based clinical trial was not
performed till now with oncothermia. The reasons are:
(1) it is applied over the second line of treatments (far advancer cases). No evidence based trials exists
in this treatment line for pharmaceutical products also.
(2) The evidence based studies are too expensive compared to the facilities of the company.
(3) Most of the users run a private clinic, having no interest to make such studies.
Retrospective studies and case reports on huge number of patients show amazingly good results in all
the registered localizations. The best enhancements are in the brain-gliomas (n=, %). The retrospective
analyses in independent clinics show coherence in the success, and definitely and significantly higher
survival time than the large databases (SEER [53], Eurocare [54]).
100
Patient number
#
1
2
3
4
5
6
7
8
9
10
11
12
Localization
Brain glioma
Colo-rectal
Esophagus
Ovary
Corpus uteri
Kidney
Liver
Lung
Pancreas
Prostate
Soft-tissue
Stomach
Oncothermia (+%) 80
SEER
Oncothermia data
Oncothermia patient’s number
SEER
258
140
218
12
27
9
39
25
258
99
18
16
68
90.63
20.5
34
51.1
15
22.2
250.9
96.7
230.53
5.4
29.5
47.3
50.38
5
67.7
40.7
0
15.3
221.7
98.1
336.71
0.8
37.5
14
85
82
76
250
83
68
65
59
60
300
200
72
Eurocare Oncothermia 1st year 2nd year
14452
127406
18231
22929
22509
23683
9041
127487
24988
82190
5011
43082
97
89
87
71
28970
242920
18302
39383
68271
38270
12696
268106
47368
243451
11256
42813
# patients (n)
120
1st year survival (%)
The oncothermia challenge is its small fraction only of the overall survival. Oncothermia is applied
when other treatments fall, consequently the patients with long overall survival could have not
observable life-elongation, even if oncothermia was effective. The aggressive disease with short
survival is a chance to indicate the efficacy. For these reasons we compare the 1st year survivals rate
only (see Fig 18.). In this sense oncothermia is indicated as a feasible, effective method [55]; [56], [57],
[58].
150
51
40
45
114
40
99
92
36
103
100
68
17
20
16
24
0
Stomach
Colon
Rectum
Liver
50
39
25
Pancreas Lung and
bronchus
Breast
0
Kidney and Brain GBM
renal pelvis
10
Figure 18. Comparison of the first-year survival rates of various cancers with the large databases Improvement of the firstyear survival percentages of oncothermia (advanced patients) compare to SEER and Eurocare data weighted average
On brain-gliomas, the Groenemeyer Institute (Bochum Germany) was active [59], [60], [61], [62], [63],
[64], [65], together with the BioMed Clinic (Bad Bergzabern, Germany), [66], [67], [68], [69], [70]; as
well as the Empoli University had publication, [61]. Presently two German Universities (Regensburg
[Prof. Bogdahn] and Heidelberg [Prof. Wick] are working on prospective clinical study on brain
gliomas with hyperthermia. A dose escalating Phase I clinical study was made on Neurology Clinic,
University of Regensburg, showing the safe process in the brain as well, [71]. The safe treatment could
be shown by spectacularly documented near-eye cases, when the tumor disappeared by the
oncothermia treatment, while the eye remained unhurt, intact from the treatment [72]. To see more
evidences we show the retrospective data of independent clinics [73], having the same oncothermia
protocol (see Fig. 19.). The data are well correspond to each other and significantly higher than the
data of the large international databases.
Brain glioma 1y survival [% ]
Brain glioma median survival [month]
n=1578
25
n=29
23.63
n=35
n=140
23
19.8
15
11.49
11.3
n=14452
n=29
n=35
n=140
73.8
71.7
BioMed Clinic
Groenemeyer
Clinic
100
first year survival [%]
n=28970
n=28970
86.2
80
60
45.4
37.8
40
20
5
SEER
SEER
RTOG
HTT Clinic
BioMed Clinic
Eurocare
HTT Clinic
Groenemeyer
Clinic
Figure 19. The median survival and the first year survival in comparison with different clics, having the same oncothermia
treatment protocol
The metastatic liver tumor is a very complicated issue due to the effective cooling of the large blood
flow and the sensitivity of the organ due to the chemo-toxicity from previous treatments. Our results
are also exceptionally good for that organ. The colorectal liver metastasis was the topic of four
different studies on liver [74], [75], [76], [77]. The sensitivity of the liver on the chemotherapy in
advanced cases (when the other chemo-treatments were unsuccessful) is well observable on the
combined treatment compared to the oncothermia monotherapy, Fig. 20. [74].
Figure 20. Colorectal cancer liver metastases retrospective clinical study, (n=80)
11
The pancreas carcinoma is a rapid and aggressive disease, and not too many conventional
hyperthermia results can be found in this location, [78]. Oncothermia results presented on ASCO, [79],
and other conferences [80], [81] are significantly improving the achievements of the conventional
treatments. Results were repeated in six different clinics in two countries (see Fig. 21), and so the gain
definitely made on statistical evidences, [82], [83].
1 y survival [%]
60
n=42
n=73
52.4
52.1
50
n=26
n=13
46.2
46.2
n=46
n=30
41
40
31
30
n=47368 n=24988
16.2
20
14.4
10
SEER
HTT
Clinic
Eurocare Veramed
Clinic
Peterfy
Hospital
Nurnberg
Clinic
BioMed
Clinic
St.Georg
Clinic
Origin of the data
Figure 21. Comparison of six independent clinics treating with the same oncothermia protocol to the SEER and Eurocare
databases
The lung is also a complicated organ for hyperthermia because of the permanent cooling-ventilation of
the breathing. Oncothermia, due to the non-equilibrium approach, is an excellent treatment for that as
well, [84], [85], [86], [87], Fig. 22.
NSCLC 1y survival [% ]
n=268106
n=127487
n=197
n=61
85
75
64.0
65
67.2
55
45
36.1
35
29.7
25
SEER
Eurocare
HTT Clinic
Peterfy Hospital
Figure 22. Comparison of oncothermia results with large databases on NSCLC
Also remarkable effects were published on bone tumors [88], [89] using oncothermia.
Legal note
According to European Medical Device Directive (MDD) oncothermia is certified by TUV, Munich.
All the devices are manufactured according to the ISO9001 and ISO 13458 [90]. Safety and efficacy
12
are certified also by TÜV Product Service München. The device works over 100 places actively, and
the oncothermia is twenty years on the market. No serious toxicity or side effects were reported.
Minor adipose burns were happen in about 3% of all the large number of treatments. Anecdotal
benefit: patients report less side effects from the conventional treatment if oncothermia is
complementary applied. They report furthermore better quality of life and improved well-being.
NOTE:
Results in details of R&D data, description of treatments or more statistics, requested explanations of
the research, case reports etc. are available upon request from [email protected] .
Discussions, remarks, critics are very welcome ([email protected]).
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[8]
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[10]
[11]
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[14]
[15]
[16]
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