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The Oncothermia method
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The Oncothermia (modulated electro-hyperthermia, mEHT) method
'''Oncothermia''', i. e. the '''modulated deep [[Hyperthermia therapy|electro-hyperthermia]]''' system is a fast-developing supportive, complementary treatment method against different types of [[tumor]]s. The principles are based on the classical method of [[hyperthermia]], but the aim, beside the absolute increase in temperature, is especially the direct electric-field energy absorption in the extracellular liquid and destroying the membrane of the cancer cells. Oncothermia's effect is synergic to [[radiotherapy]] and to numerous [[Chemotherapy|chemotherapies]]. Furthermore, it leads to an increased [[immunogenicity]] and effectively reduces the pain of the patient.


Oncothermia is a new kind of hyperthermia [<ref>Szasz A, Szasz N, Szasz O (2010) Oncothermia – Principles and practices. Springer Science, Heidelberg, http://www.springer.com/gp/book/9789048194971 </ref>]. The generic (scientific) name of oncothermia is modulated electro-hyperthermia (mEHT). It is a further development of the heating method, heating selectively the malignant cells instead of the complete isothermal heating of the tumor-mass [<ref>Szasz A (2013) Electromagnetic effects in nanoscale range. Cellular Response to Physical Stress and Therapeutic Applications (eds. Tadamichi Shimizu, Takashi Kondo), chapter 4. Nova Science Publishers, Inc </ref> ].
Hyperthermia has been described as the "oldest identified weapon against cancer."<ref name="SzaszSzasz2010">{{cite book|last1=Szasz|first1=Andras|last2=Szasz|first2=Nora|last3=Szasz|first3=Oliver|title=Oncothermia: Principles and Practices|url=https://books.google.com/books?id=Ek-2nEe1HpwC|accessdate=31 July 2011|date=2010-12-03|publisher=Springer|isbn=978-90-481-9497-1}}</ref>
Four effects form the selection of malignant cells:

1. The malignant cells metabolize much intensively than their healthy counterpart. Positron Emission Tomography (PET) measures the massive glucose intake, (Warburg effect), [<ref>Szigeti GP, Szasz O, Hegyi G (2017) Connections between Warburg’s and Szentgyorgyi’s Approach about the Causes of Cancer. Journal of Neoplasm 1(2:8):1-13; http://neoplasm.imedpub.com/connections-between-warburgs-and-szentgyorgyis-approach-about-thecauses-of-cancer.pdf </ref> ]. This makes the extracellular matrix around these cells more conductive, orienting the RF-current flowing there [<ref> Szasz A, Vincze Gy, Szasz O, Szasz N (2003) An energy analysis of extracellular hyperthermia. Magneto- and electro-biology 22(2):103–115, http://www.tandfonline.com/doi/abs/10.1081/JBC-120024620 </ref> ].
It has been used since at least 1989.<ref name="pmid19811397">{{cite journal |vauthors=Andocs G, Szasz O, Szasz A |title=Oncothermia treatment of cancer: from the laboratory to clinic |journal=Electromagn Biol Med |volume=28 |issue=2 |pages=148–65 |year=2009 |pmid=19811397 |doi= 10.1080/15368370902724633|url=}}</ref>
2. The malignant cells are autonomic, mostly breaking their cellular connections (E-cadherin, connexin formed junctions) [ <ref> Vincze Gy, Szigeti Gy, Andocs G, Szasz A. (2015) Nanoheating without Artificial Nanoparticles, Biology and Medicine 7(4):249, http://www.omicsonline.com/open-access/nanoheating-without-artificial-nanoparticles-0974-8369-1000249.php?aid=61783 </ref> ]. This creates higher dielectric permittivity in the extracellular matrix of malignant cells, which well orient the appropriately chosen RF-current [ <ref> Szasz O (2013) Essentials of oncothermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 159570, http://www.hindawi.com/archive/2013/159570/ </ref> ].

3. The plasma-membrane of the malignant cells has numerous transmembrane proteins and their clusters (membrane rafts). These absorb the well applied RF-current selectively (beta and delta dispersion). The absorbed energy on the proteins creates a definite heating and triggers various signal transduction via the corresponding receptors [<ref> Szasz O, Andocs G, Kondo T, et.al. (2015) Heating of membrane raft of cancer-cells, ASCO Annual Meeting, J Clin Oncol 33, (suppl, abstr e22176), http://meetinglibrary.asco.org/content/151213-156 </ref> ], [<ref> Szasz A (2013) Electromagnetic effects in nanoscale range. Cellular Response to Physical Stress and Therapeutic Applications (eds. Tadamichi Shimizu, Takashi Kondo), chapter 4. Nova Science Publishers, Inc </ref> ].
Oncothermia in general is not used as sole therapy. It is usually combined with chemotherapy, radiotherapy or other therapies and their combination. The method transfers energy using the principle of [[capacitive coupling]] (like a condenser) of [[radio waves]] of 13,56-MHz. No external shielding is needed. Oncothermia utilizes the special absorption rate of the near-membrane extracellular liquid of the tumor. The tumor tissue has lower impedance than the surrounding tissues, so most of the energy is transmitted and absorbed by the cancerous lesion. This selection of the tumour tissues (self-focusing) renders external focusing unnecessary.
4. The homeostatic harmony is broken by the malignancy. The structural differences (which is the pathological proof anyway) allow a differentiation of the inharmonic cells by modulation technique [<ref> Szasz O, Andocs G, Meggyeshazi N (2013) Modulation effect in oncothermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 395678, http://www.hindawi.com/archive/2013/398678/ </ref> ]. Homeostatic autocorrelation (1/f fluctuation) structure bases the amplitude modulation technique [<ref> Szendro P, Vincze Gy, Szasz A (1999) Response of bio-systems on white noise excitation. Hungarian Agricultural Engineering 12:31-32 </ref> ], [<ref> Szendro P, Vincze Gy, Szasz A (1998) Origin of pink-noise in bio-systems. Hungarian Agricultural Engineering 11: 42-43 </ref> ].

The selective heterogenic heating has certain advantages making a certain difference from the conventional hyperthermia [<ref> Yang K-L, Huang C-C, Chi M-S, Chiang H-C, Wang Y-S, Andocs G, et.al. (2016) In vitro comparison of conventional hyperthermia and modulated electro-hyperthermia, Oncotarget, oi: 10.18632/oncotarget.11444, http://www.ncbi.nlm.nih.gov/pubmed/27556507 </ref> ]:
Oncothermia achieves a permanent increase of the temperature in the extracellular liquid of the tumour tissue. Due to the constant energy-supply, a temperature gradient (temperature drop) between the extra- and intracellular [[electrolyte]]s develops until the [[thermal equilibrium]] is reached at the end of the therapy. This (in absolute numbers very low) temperature difference acts on the likewise small distance through the [[cellular membrane]] (from extra- to intracellular) and that leads to a destabilizing [[thermal stress]] on the membrane of the tumour cells, leading those into [[necrosis]] or [[apoptosis]].
1. The blood-flow is controversial by isothermal heating, igniting a competition between the thermal cell-damage and the cellular support by glucose delivery. The classical controversy of hyperthermia which is usually very effective in the local response and less efficient in the overall survival [<ref> Sergey Roussakow (2013) The History Of Hyperthermia Rise And Decline. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 428027, http://www.hindawi.com/archive/2013/428027/ </ref> ] is also originated from the increased blood-flow, which responsible for the dissemination of the malignant cells [<ref> Szasz A (2013) Challenges and Solutions in Oncological Hyperthermia. Thermal Med 29(1):1-23, https://www.jstage.jst.go.jp/article/thermalmed/29/1/29_1/_article </ref> ]. The selective cellular heating controls the blood-flow in the optimal fever-range level, [<ref> Balogh L, Polyak A, Postenyi Z, Kovacs-Haasz V, Gyongy M, Thuroczy J. (2016) Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver, Journal of Cancer Research and Therapeutics, 12(3):1153-1159, http://www.cancerjournal.net/article.asp?issn=0973-1482;year=2016;volume=12;issue=3;spage=1153;epage=1159;aulast=Balogh </ref> ], [<ref> Jung Kyung Kim, Bibin Prasad, Suzy Kim (2017) Temperature mapping and thermal dose calculation in combined radiation therapy and 13.56 MHz radiofrequency hyperthermia for tumor treatment. Proc. SPIE 10047, Optical Methods for Tumor Treatment and Detection: Mechanisms and Techniques in Photodynamic Therapy XXVI, 1004718; http://spie.org/Publications/Proceedings/Paper/10.1117/12.2253163?origin_id=x4318 </ref> ], [<ref> Nagy G, Meggyeshazi N, Szasz O (2013) Deep temperature measurements in oncothermia processes. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 685264, http://www.hindawi.com/archive/2013/685264/ </ref> ], while the temperature of the malignant cells is at least 3°C higher [<ref> Andocs G, Rehman MU, Zhao QL, Papp E, Kondo T, Szasz A. (2015) Nanoheating without Artificial Nanoparticles Part II. Experimental support of the nanoheating concept of the modulated electro-hyperthermia method, using U937 cell suspension model, Biology and Medicine 7(4):1-9, http://www.omicsonline.com/open-access/nanoheating-without-artificial-nanoparticles-part-ii-experimental-support-of-the-nanoheating-concept-of-the-modulated-electrohyperthermiamethod-using-u937-cell-suspension-model-0974-8369-1000247.php?aid=60362 </ref> ].
2. Active electric field absorption generates the heating effect [<ref> Andocs G, Renner H, Balogh L, Fonyad L, Jakab C, Szasz A (2009) Strong synergy of heat and modulated electro- magnetic field in tumor cell killing, Study of HT29 xenograft tumors in a nude mice model. Strahlentherapie und Onkologie 185:120–126, http://www.ncbi.nlm.nih.gov/pubmed/19240999 </ref> ]. The electric field excites extrinsic apoptosis [<ref> Meggyeshazi N, Andocs G, Spisak S, Krenacs T (2013) Early changes in mRNA and protein expression related to cancer treatment by modulated electro-hyperthermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 249563, http://www.hindawi.com/archive/2013/249563/ </ref> ], [<ref> Meggyeshazi N, Andocs G, Krenacs T (2013) Programmed cell death induced by modulated electro-hyperthermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 187835, http://www.hindawi.com/archive/2013/187835/ </ref> ] on the pathway starting at TRIAL-R2 (FADD-FAS) complex inducing cleaved caspase-8 and the executor caspase-3 makes the apoptosis [<ref> Meggyeshazi N, Andocs G, Balogh L, Balla P, Kiszner G, Teleki I, Jeney A, Krenacs T (2014) DNA fragmentation and caspase-independent programmed cell death by modulated electrohyperthermia. Strahlenther Onkol 190:815-822, http://www.ncbi.nlm.nih.gov/pubmed/24562547 </ref> ]. The proapoptotic cell-death-related gene network (EGR1, JUN, CDKN1A) is elevated which is available only in mEHT [<ref> Andocs G, Rehman MU, Zhao Q-L, Tabuchi Y, Kanamori M, Kondo T. (2016) Comparison of biological effects of modulated electro-hyperthermia and conventional heat treatment in human lymphoma U937 cell, Cell Death Discovery (Nature Publishing Group), 2, 16039, http://www.nature.com/articles/cddiscovery201639 </ref> ]. The complete MAPK pathway (RAS→RAF→MEK→ERK), is also excited to the apoptotic processes [<ref> Szasz O, Szasz A.M. Minnaar C, Szasz A (2017) Heating preciosity - trends in modern oncological hyperthermia. Open Journal of Biophysics 7:116-144, http://www.scirp.org/journal/PaperInformation.aspx?PaperID=77458 </ref> ].
3. The mEHT suppresses the proliferation rate remarkably in those parts of the tumor, which remained alive in the given session of the treatment [<ref> Szasz O, Szasz A.M. Minnaar C, Szasz A (2017) Heating preciosity - trends in modern oncological hyperthermia. Open Journal of Biophysics 7:116-144, http://www.scirp.org/journal/PaperInformation.aspx?PaperID=77458 </ref> ], [<ref> Jeon T-W, Yang H, Lee CG, O ST, et.al. (2016) Electro-hyperthermia up-regulates tumour suppressor Septin 4 to induce apoptotic cell death in hepatocellular carcinoma, Int. J. Hyp., 7:1-9, http://dx.doi.org/10.1080/02656736.2016.1186290 </ref> ].
4. The mEHT strengths the cellular connections of the malignant area (E-cadherin-beta-catenin complex is developed), decreasing the invasion and dissemination of malignant cells, suppressing the probability of the metastases [<ref> Jihye Cha, Tae-Won Jeon, Chang Geol Lee, Sang Taek Oh, Hee-Beom Yang,Kyung-Ju Choi, Daekwan Seo, Ina Yun, In Hye Baik, Kyung Ran Park,Young Nyun Park, Yun-Han Lee; (2015) Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis, Int. Journal Hyperthermia, 31(7):784-792, http://www.ncbi.nlm.nih.gov/pubmed/26367194 </ref> ]. This effect remarkably increases the overall survival time of the patient as it is verified by clinical results below.
5. The controlled energy absorption makes it possible to define the same energy absorption dose as used in the ionizing radiation, J/kg. This way the complicated and unpractical cumulative equivalent minutes related to necrosis at 43°C, and representing the T temperature homogeneity at X% of the target (CEM43°CTx) is not considered necessary ever more.
6. The method mEHT induces damage associated molecular pattern (DAMP) in proper spatiotemporal order (calreticulin, free-ATP, membrane and extracellular HSPs and liberated HMBG1 protein) in an immunogenic cell-death (ICD) process [<ref> Andocs G, Szasz O, Szasz A (2009) Oncothermia treatment of cancer: from the laboratory to clinic. Electromagn Biol Med 28(2):148–165, http://www.ncbi.nlm.nih.gov/pubmed/19811397 </ref> ]. These effects used complementary with some general immune supporting therapies. This combination transforms the general immune-surviallance to tumor-specific immune actions by antigen presenting cells (APC) and creates vaccination-like behavior of mEHT [<ref> Andocs G, Meggyeshazi N, Balogh L, Spisak S, Maros ME, Balla P, Kiszner G, Teleki I, Kovago Cs, Krenacs T (2014) Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modualted electrohyperthermia. Cell Stress and Chaperones 20(1):37-46, http://www.ncbi.nlm.nih.gov/pubmed/24973890 </ref> ], [<ref> http://www.google.com/patents/EP2703001A1?cl=en </ref> ].
7. Its application with dendritic cell therapies enhances the abscopal behavior of the mEHT, [<ref> http://www.freepatentsonline.com/20150217099.pdf </ref> ], [<ref> Qin W, Akutsu Y, Andocs G, Sugnami A, Hu X, Yusup G, Komatsu-Akimoto A, Hoshino I, Hanari N, Mori M, Isozaki Y, Akanuma N, Tamura Y, Matsubara H (2014) Modulated electro-hyperthermia enhances dendritic cell therapy through an abscopal effect in mice. Oncol Rep 32(6):2373-2379, http://www.ncbi.nlm.nih.gov/pubmed/25242303 </ref> ].
8. The technique of mEHT is highly efficient [<ref> Szasz O, Szasz A (2016) Heating, efficacy and dose of local hyperthermia. Open Journal of Biophysics, 6:10-18, http://www.scirp.org/journal/PaperInformation.aspx?paperID=62874 </ref> ], [<ref> Szasz A, Szasz O, Szasz N (2006) Physical background and technical realization of hyperthermia. In: Baronzio GF, Hager ED (eds) Locoregional Radiofrequency-Perfusional- and Wholebody- Hyperthermia in Cancer Treatment: New clinical aspects, Ch. 3., Springer, New York, NY, pp 27–59 </ref> ], user-friendly, easy to operate and relatively cheap in comparison to other hyperthermia units, [<ref> Szasz O, Andocs G, Meggyeshazi N (2013) Oncothermia as personalized treatment option. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 2941364, http://www.hindawi.com/archive/2013/941364/ </ref> ], [<ref> Hegyi G, Szigeti GP, Szasz A (2013) Hyperthermia versus oncothermia: Cellular effects in complementary cancer therapy. Evid Based Complement Alternat Med 2013:672873, http://www.hindawi.com/journals/ecam/2013/672873/ </ref> ], [<ref> Baronzio G, Parmar G, Ballerini M, Szasz A, Baronzio M, Cassutti V (2014) A brief overview of hyperthermia in cancer treatment. Journal of Integrative Oncology, 3:1 </ref> ].
Based on the above research facts and publications, oncothermia has various clinical results used as verification of the research results:
1. Andrology and Prostate
• Long-term remission of prostate cancer with extensive bone metastases upon immune- and virotherapy: A case report [<ref> Volker Schrrmacher, Akos-Sigmund Bihari, Wilfried Stücker, Tobias Sprenger (2014) Long-term remission of prostate cancer with extensive bone metastases upon immuno- and virotherapy: A case report. Oncology Letters 8:2403-2406, http://www.ncbi.nlm.nih.gov/pubmed/25364402 </ref> ],
• Androtherm application for the Peyronie's Disease [<ref> Ballerini M, Baronzio G F, Capito G, Szasz O, Cassutti V (2013) Androtherm application for the Peyronie's Disease. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 962349, http://www.hindawi.com/archive/2013/962349/ </ref> ],
• Prostatakarzinom: Neue Aspekte für Diagnostik und Therapie [<ref> Douwes FR (2008) Prostatakarzinom: Neue Aspekte für Diagnostik und Therapie. Facharzt Gynakologie/Urologie, 2:23-29 </ref> ],
• Für und Wider des Prostata-Karzinom-Screenings [<ref> Douwes FR (2011) Für und Wider des Prostata-Karzinom-Screenings. Prostata Newsletter (PNL) Ausgabe August 2011 </ref>],
• Neue Studie heizt Diskussion über den Wert von PSA-Tests an [<ref> Douwes FR (2011) Neue Studie heizt Diskussion über den Wert von PSA-Tests an. Prostata Newsletter (PNL) Ausgabe August 2011 </ref> ],
• Sanfte Hilfen für die Prostata [<ref> Douwes FR (2008) Sanfte Hilfen für die Prostata. CO’Med, 4:1-2 </ref> ],
• Bestrahlung der Prostata erhöht Rektum-Ca-Risiko [<ref> Douwes FR (2005) Bestrahlung der Prostata erhöht Rektum-Ca-Risiko. Klinik St. Georg </ref> ],
• Rebell gegen den Krebs. Biologische Intensivtherapie – Neue Hoffnung für Patienten? [<ref> Maar K (2004) Rebell gegen den Krebs. Bioogische Intersivtherapie – Neue Hoffnung für Patienten? Neomedica GmbH, Klosterneuburg </ref> ],
• Radiofrequency Transurethral Hyperthermia and complete Androgen Blockade. A Nonsurgical Approach to Treating Prostate Cancer [<ref> Douwes FR, Lieberman S (2002) Radiofrequency Transurethral Hyperthermia and complete Androgen Blockade. A Nonsurgical Approach to Treating Prostate Cancer. Alternative & Complementary Therapies, 8(3):149-156, http://connection.ebscohost.com/c/articles/83564104/radiofrequency-transurethral-hyperthermia-complete-androgen-blockade-nonsurgical-approach-treating-prostate-cancer </ref> ],
• Diagnostik hyperthermia in early stage prostate cancer [<ref> Douwes FR (2001) Transurethral hyperthermia in early stage prostate cancer. Focus Alternat Complement Ther 6(1):77-78 </ref> ],
• Adjuvante Radiotherapie: Welcher Patient mit Prostatakarzinom profitiert? [<ref> Douwes FR (2001) Adjuvante Radiotherapie: Welcher Patient mit Prostatakarzinom profitiert? Prostata Newsletter (PNL), Ausgabe August 2011 </ref>],
• Hoffnung bei Prostata-Beschwerden. Die neue Therapie ohne Messer [<ref> Douwes F, Sillner L, Köhnlechner M (1999) Hoffnung bei Porstata-Beschwerden. Die neue Therapie ohne Messer. Herbig Verlagsbuchhandlung GmbH, http://www.zvab.com/9783776620863/Hoffnung-Prostata-Beschwerden-neue-Therapie-Messer-3776620862/plp </ref> ],
• Malignus és belignus prosztatadaganatok hyperthermiája [<ref> Szasz A (2003) Malignus és belignus prosztatadaganatok hyperthermiája. Magyar Urológia 15:87-88 </ref> ],
2. Gliomas (advanced)
• A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia [<ref> Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, Bernardeschi P (2006) A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia. In Vivo 20(6A):721–724, http://www.ncbi.nlm.nih.gov/pubmed/?term=fiorentiniA+phase+II+clinical+study+on+relapsed+malignant+gliomas </ref> ],
• Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas [<ref> Wismeth C, Dudel C, Pascher C, Ramm P, Pietsch T, Hirschmann B, Reinert C, Proescholdt M, Rümmele P, Schuierer G, Bogdahn U, Hau P (2010) Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas – Phase I clinical results. J Neurooncol 98(3):395–405, http://www.ncbi.nlm.nih.gov/pubmed/?term=Transcranial+electro-hyperthermia+combined+with+alkylating+chemotherapy+in+patients+with+relapsed+high-grade+gliomas+%E2%80%93+Phase+I+clinical+results </ref>],
• Glioblastoma multiforme Grad IV: Regionale Tiefenhyperthermie, Antiangiogenese mit Thalidomid, Hochdosis-Ascorbinsäureinfusionen und komplementäre Therapie [<ref> Hager ED, Birkenmeier J. (2006) Glioblastoma multiforme Grad IV: Regionale Tiefenhyperthermie, Antiangiogenese mit Thalidomid, Hochdosis-Ascorbinsäureinfusionen und komplementäre Therapie, Deutsche Zeitschrift für Onkologie 38(3):133-135, DOI: 10.1055/s-2006-952050, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2006-952050 </ref> ],
• Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia [<ref> Hager ED, Sahinbas H, Groenemeyer DH, Migeod F (2008) Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia. ASCO, J Clin Oncol, Annual Meeting Proceedings (Post-Meeting Edition) 26:2047, http://www.portmoodyhealth.com/resource/prospective-phase-ii-trial-for-recurrent-high-grade-malignant-gliomas-with-capacitive-coupled-low-radiofrequency-lrf-deep-hyperthermia/ </ref> ],
• Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas [<ref> Sahinbas H, Groenemeyer DHW, Boecher E, Szasz A (2007) Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas. Deutsche Zeitschrift fuer Onkologie 39:154–160, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2007-986020 </ref> ],
• Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma [<ref> Douwes F, Douwes O, Migeod F, Grote C, Bogovic J (2006) Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma. St. Georg Klinik, Germany </ref> ],
• The treatment of patients with high-grade malignant gliomas with RF-hyperthermia [<ref> Hager ED, Dziambor H, App EM, Popa C, Popa O, Hertlein M (2003) The treatment of patients with high-grade malignant gliomas with RF-hyperthermia. Proc ASCO 22:118, #47;Proc Am Soc Clin Oncol 22: 2003 </ref> ],
3. Gastrointestinal (advanced)
• Intra-arterial and systemic chemotherapy plus external hyperthermia in unresectable biliary cancer [<ref> Mambrini A, Del Freo A, Pacetti P, Orlandi M, Torri T, Fiorentini G, Cantore M (2007) Intra-arterial and systemic chemotherapy plus external hyperthermia in unresectable biliary cancer. Clin Oncol (R coll Radiol) 19(10):808-806, http://www.ncbi.nlm.nih.gov/pubmed/?term=Intra-arterial+and+systemic+chemotherapy+plus+external+hyperthermia+in+unresectable+biliary+cancer </ref> ],
• Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer [ <ref> Hager ED, Dziambor H, Höhmann D, Gallenbeck D, Stephan M, Popa C (1999) Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer. Anticancer Res 19(4C):3403–3408, http://www.ncbi.nlm.nih.gov/pubmed/10629627 </ref> ],
• Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma. A phase II study [ <ref> Gadaleta-Caldarola G, Infusino S, Galise I, Ranieri G, Vinciarelly G, Fazio V, Divella R, Daniele A, Filippelli G, Gadaleta CD (2014) Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma. A phase II study. Oncol Lett, 2014 Oct,8(4):1783-1787, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156230/ </ref>]
• Lebermetastasen bei kolorektalen Karzinomen [ <ref> Hager ED. (2004) Lebermetastasen bei kolorektalen Karzinomen, Deutsche Zeitschrift für Onkologie, 36:132-134 </ref>],
• Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: phase II study [<ref> Ferrari VD, De Ponti S, Valcamonico F, Amoroso V, Grisanti S, Rangoni G, Marpicati P, Vassalli L, Simoncini E, Marini G (2007) Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: phase II study. J Clin Oncol 25:18S, 15168, http://meeting.ascopubs.org/cgi/content/short/25/18_suppl/15168 </ref> ],
• Second-line chemotherapy with gemcitabine and oxaliplatin in combination with loco-regional hyperthermia (EHY-2000) in patients with refrctory metastatic pancreatic cancer - preliminary results of a prospective trial [ <ref> Hager ED. (2004) Lebermetastasen bei kolorektalen Karzinomen, Deutsche Zeitschrift für Onkologie, 36:132-134 </ref> ],
• Clinical study for advanced pancreas cancer treated by oncothermia [ <ref> Dani A, Varkonyi A, Magyar T, Szasz A (2008) Clinical study for advanced pancreas cancer treated by oncothermia. Forum Hyperthermie 1:13–20, http://www.pyatthealth.com/wp-content/uploads/2015/03/Hyperthermia-Pancreatic-Cancer.pdf </ref>],
• Behandlung des fortgeschrittenen Pankreaskarzinoms mit regionaler Hyperthermie und einer Zytostase mit Mitomycin- C und 5-Fluorouracil/ Folinsäure [ <ref> Douwes F, Migeod F, Grote C (2006) Behandlung des fortgeschrittenen Pankreaskarzinoms mit regionaler Hyperthermie und einer Zytostase mit Mitomycin- C und 5-Fluorouracil/ Folinsäure. Onkologische Fachklinik St. Georg, Bad Aibling, https://www.researchgate.net/publication/237633519_Behandlung_des_fortgeschrittenen_Pankreaskarzinoms_mit_regionaler_Hyperthermie_und_einer_Zytostase_mit_Mitomycin_C_und_5FluorouracilFolinsaure </ref> ],
• Thermochemotherapy of the advanced pancreas carcinoma [ <ref> Douwes FR (2006) Thermochemotherapy of the advanced pancreas carcinoma. Biologische Medizin 35:126–130, https://www.researchgate.net/publication/287861898_Thermo-chemotherapy_of_the_advanced_pancreas_carcinoma </ref> ],
• Thermo-Chemotherapie des fortgeschrittenen Pankreaskarzinoms. Ergebnisseeiner klinischen Anwendungsstudie [<ref> Douwes FR (2004) Thermo-Chemotherapie des fortgeschrittenen Pankreaskarzinoms. Ergebnisseeiner klinischen Anwendungsstudie. Onkologische Fachklinik St. Georg, Bad Aibling </ref>],
• Complex therapy of the not in sano respectable carcinoma of the pancreas – a pilot study [ <ref> Hager ED, Süsse B, Popa C, Schritttwieser G, Heise A, Kleef R (1994) Complex therapy of the not in sano respectable carcinoma of the pancreas – a pilot study. J Cancer Res Clin Oncol 120:R47,P1 </ref>],
4. Lung
• Current status of oncothermia therapy for lung cancer [ <ref> Szasz A (2014) Current status of oncothermia therapy for lung cancer. Korean J Thorac Cardiovasc Surg 47:77-93, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000888 </ref>],
• Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report [ <ref> Seung-Gu Yeo (2015) Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report. Experimental and Therapeutic Medicine pp. 1-4, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509030/ </ref>],
• The Outcome of the Chemotherapy and Oncothermia for Far Advanced Adenocarcinoma of the Lung: Case reports of four patients [ <ref> Doo Yun Lee, Joon Seok Park, Hae Chul Jung, Eun Seol Byun, Seok Jin Haam, Sung Soo Lee (2015) The Outcome of the Chemotherapy and Oncothermia for Far Advanced Adenocarcinoma of the Lung: Case reports of four patients. Advances in Lung Cancer 4:1-7, http://www.scirp.org/journal/PaperInformation.aspx?PaperID=54620 </ref> ],
• Oncothermia with chemotherapy in the patients with Small Cell Lung Cancer [ <ref> Doo Yun Lee, Seok Jin Haam, Tae Hoon Kim, Jae Yoon Lim, Eun Jung Kim, and Na Young Kim (2013) Oncothermia with chemotherapy in the patients with Small Cell Lung Cancer. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 910363, http://www.hindawi.com/archive/2013/910363/ </ref> ],
• Clinical study for advanced non-small-cell lung-cancer treated by oncothermia [ <ref> Dani A, Varkonyi A, Magyar T, Szasz A (2009) Clinical study for advanced non-small-cell lung-cancer treated by oncothermia. Forum Hyperthermie; DGHT, 2009 </ref>],
5. Gynecology
• Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy [ <ref> Kleef R, Kekic S, Ludwig N (2012) Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy. Case Rep Oncol 5:212-215, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369243/ </ref> ],
• Positive response of a primary leiomyosarcoma of the breast following salvage hyperthermia and pazopanib [ <ref> Lee SY, Lee N-R. (2016) Positive response of a primary leiomyosarcoma of the breast following salvage hyperthermia and pazopanib, Korean J Intern Med, doi: 10.3904/kjim.2015.242, http://www.ncbi.nlm.nih.gov/pubmed/27079325 </ref> ],
• Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report [ <ref> SchrrmacherV, Stücker W, Lulei M, et.al. (2015) Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report; Immunotherapy 7: 855–860, http://www.ncbi.nlm.nih.gov/pubmed/26020523 </ref> ],
• Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. [ <ref> Lee S-Y, Lee N-R, Cho D-H, Kim J-S; (2017) Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation; Oncology Letters, DOI: 10.3892/ol.2017.6117 http://www.spandidos-publications.com/10.3892/ol.2017.6117 </ref> ]
• Oncothermia in HIV positive and negative locally advanced cervical cancer patients in South Africa [ <ref> Carrie Strauss, Jeffrey Kotzen, Ans Baeyens, Irma Maré (2013) Oncothermia in HIV positive and negative locally advanced cervical cancer patients in South Africa. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 293968, http://www.hindawi.com/archive/2013/293968/ </ref> ],
• Treatment of advanced cervical cancer with complex chemoradio – hyperthermia [<ref> Lajos Pesti, Zsófia Dankovics, Péter Lorencz, and András Csejtei (2013) Treatment of advanced cervical cancer with complex chemoradio – hyperthermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 192435, http://www.hindawi.com/archive/2013/192435/ </ref> ],
• Update on phase III randomized clinical trial investigating the effects of the addition of electro-hyperthermia to chemora-diotherapy for cervical cancer patients in South Africa [ <ref> C Minnaar, A Baeyens, J Kotzen (2016) Update on phase III randomized clinical trial investigating the effects of the addition of electro-hyperthermia to chemora-diotherapy for cervical cancer patients in South Africa. Physica Medica 32(2):151-152; http://www.physicamedica.com/article/S1120-1797(16)30175-2/abstract </ref> ],
6. Bone
• Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia [ <ref> Bogovic J, Douwes F, Muravjov G, Istomin J, (2001) Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia, Onkologie 24(1):55-58, http://www.ncbi.nlm.nih.gov/pubmed/11441282 </ref>],
• Successful treatment of solitary bone metastasis of non-small cell lung cancer with combination of bevacizumab and hyperthermia [ <ref> Rubovszky G, Nagy T, Godeny M, Szasz A, Lang I (2013) Successful treatment of solitary bone metastasis of non-small cell lung cancer with combination of bevacizumab and hyperthermia. Pathol Oncol Res. 2013 Jan;19(1):119-22, http://www.ncbi.nlm.nih.gov/pubmed/22752712 </ref> ],
7. Malignant ascites
• Pang CLK, Xinting Z, Zhen W, Junwen O, Yimin L, Roussakow R, et.al. (2017) Local modulated electro-hyperthermia in combination with traditional Chinese medicine vs. intraperitoneal chemoinfusion for treatment of peritoneal carciomatosis with malignant ascites: a phase II randomized trial [<ref> Pang CLK, Xinting Z, Zhen W, Junwen O, Yimin L, Roussakow R, et.al. (2017) Local modulated electro-hyperthermia in combination with traditional Chinese medicine vs. intraperitoneal chemoinfusion for treatment of peritoneal carciomatosis with malignant ascites: a phase II randomized trial, Molecular and Clinical Oncology, 6:723-732, doi.org/10.3892/mco.2017.1221; http://www.ncbi.nlm.nih.gov/pubmed/28529748 </ref> ],
8. Temperature effects
• The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study [ <ref> Lee SY, Kim M-G (2015) The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study, Int J Hyp, 28:1-6, http://www.ncbi.nlm.nih.gov/pubmed/26507458 </ref> ],
• Effect of modulated electrohyperthermia on the pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers [<ref>Lee SY, Kim M-G. (2016) Effect of modulated electrohyperthermia on the pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers, Clinical Therapeutics, 38(12):2548-2554, https://www.ncbi.nlm.nih.gov/pubmed/27866658 </ref> ]
• Improvement of tumor oxygenation by mild hyperthermia [ <ref> Chang W Song, Heonjoo Park, Robert J Griffin (2001) Improvement of tumor oxygenation by mild hyperthermia. Radiation Research 155:515-528, https://www.ncbi.nlm.nih.gov/pubmed/11260653 </ref> ],
9. Melanoma
• Malignes Melanom Stadium IV: Anwendung von regionaler Tiefenhyperthermie, Tamoxifen, Interferon-α und komplementären Therapien [ <ref> Hager ED, Birkenmeier J. (2006) Malignes Melanom Stadium IV: Anwendung von regionaler Tiefenhyperthermie, Tamoxifen, Interferon-α und komplementären Therapien, Deutsche Zeitschrift für Onkologie, 38(1):32-34, https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2006-932313 </ref> ],
10. Immuno-oncology
• Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance [ <ref> Schirrmacher V (2015) Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance. Expert Opic Biol Ther 15(12):1757-1771; http://www.ncbi.nlm.nih.gov/pubmed/26436571 </ref> ],
• Hypoxia Immunity, Metabolism and Hyperthermia [ <ref> Baronzio G, Kiselevsky M, Ballerini M, Cassuti V, Schwartz L, Freitas I, Fiorentini G, Parmar G (2013) Hypoxia Immunity, Metabolism and Hyperthermia. Hindawi Publishing Corporation Conference Papers in medicine, Volume 2013, Article ID 528909; http://www.hindawi.com/cpis/medicine/2013/528909 </ref> ],
• Stage IV Wilms tumor treated by Korean medicine, hyperthermia and thymosin-α1: A case report [<ref> Donghyun Lee, Sung Su Kim, Shin Seong, Wonjun Cho, Hyejin Yu (2016) Stage IV wilms tumor treated by Korean medicine, hyperthermia and thymosin-α1: A case report. Case Rep Oncol 9:119-125, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899649/ </ref> ],
• A new strategy of cancer immunotherapy combining hyperthermia/oncolytic virus pretreatment with specific autologous anti-tumor vaccination - a review [<ref> Schirrmacher V, Lorenzen D, Van Gool SW, Stuecker W (2017) A new strategy of cancer immunotherapy combining hyperthermia/oncolytic virus pretreatment with specific autologous anti-tumor vaccination - a review. Austin Oncol Case Rep 2(1):1-8, http://www.iozk.de/aktuelles/iozk_austin_oncology_case_reports_2017.pdf </ref> ],
• Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo [ <ref> Kim W, Kim MS, Kim HJ, Lee E, Jeong JH, Park I, Jeong YK, Jang WI (2017) Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo. Int J Hyperthermia 28:1-8, http://www.ncbi.nlm.nih.gov/pubmed/28659004 </ref> ],
11.Sarcoma
• Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma [ <ref> Tae Sig Jeung, Sun Young Ma, JiHoon Choi, Jeasang Yu, Su Yong Lee, Sangwook Lim (2015) Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma. Case Reports in Clinical Medicine 4:157-168, http://www.scirp.org/journal/PaperInformation.aspx?PaperID=56280 </ref> ],
• The results of combination of ifosfamid and locoregional hyperthermia (EHY 2000) in patients with advanced abdominal soft-tissue sarcoma after relapse of first line chemotherapy [ <ref> Volovat C, Volovat SR, Scripcaru V, Miron L, Lupascu C (2014) The results of combination of ifosfamid and locoregional hyperthermia (EHY 2000) in patients with advanced abdominal soft-tissue sarcoma after relapse of first line chemotherapy. Romanian Reports in Physics, 66(1):175-181, https://www.researchgate.net/publication/273968670_The_results_of_combination_of_ifosfamid_and_locoregional_hyperthermia_EHY_2000_in_patients_with_advanced_abdominal_soft-tissue_sarcoma_after_relapse_of_first_line_chemotherapy </ref>],
11. Multiple malignant diseases
• Oncothermia Application for Various Malignant Diseases [ <ref> Youngsuk Lee (2013) Oncothermia Application for Various Malignant Diseases. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 245156, http://www.hindawi.com/archive/2013/245156/ </ref>],
• Oncothermia: Emerging Therapy in Oncology [ <ref> Marwan Akasheh (2010) Oncothermia: Emerging Therapy in Oncology. J Med J 44(4):456-465, http://journals.ju.edu.jo/JMJ/article/view/2088 </ref> ],
• Cases that respond to oncothermia monotherapy [<ref> Jeung TS, Ma SY, Yu J, Lim S. (2013) Cases that respond to oncothermia monotherapy, Conf. Papers in Medicine, Vol. 2013, Article ID 392480, Hindawi, http://dx.doi.org/10.1155/2003/392480 </ref> ],
12. Low-back pain
• Low back pain – complex approach of treatment by different CAM modalities (Acupuncture and other type of dry-needling, “Targeted RF non invasive physiotherapy” for low back pain). [<ref> Hegyi G, Jian Li (2013) Low back pain – complex approach of treatment by different CAM modalities (Acupuncture and other type of dry-needling, “Targeted RF non invasive physiotherapy” for low back pain). Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 326595, http://www.hindawi.com/archive/2013/326595/ </ref> ],
13. Lyme-disease
• Lyme Disease and Oncothermia [ <ref> Zais O (2013) Lyme Disease and Oncothermia. Hindawi Publishing Corporation Conference Papers in Medicine, Volume 2013, Article ID 275013, http://www.hindawi.com/archive/2013/275013/ </ref> ],
14. WBH
• Whole body hyperthermia combined with carboplatin/paclitaxel in patients with ovarian carcinoma – Pase-II-study [ <ref> Strobl B, Rjosk D, Janni W, etlal. (2004) Whole body hyperthermia combined with carboplatin/paclitaxel in patients with ovarian carcinoma – Pase-II-study, J Clin Oncol, 22(14):5128, http://ascopubs.org/doi/abs/10.1200/jco.2004.22.14_suppl.5128 </ref>],
• Whole-body hyperthermia in combination with platinum containing drugs in patients with recurrent ovarian cancer [ <ref> Douwes F, BogoviC J, Douwes O, Migeod F, Grote C. (2004) Whole-body hyperthermia in combination with platinum containing drugs in patients with recurrent ovarian cancer; Int J Clin Oncol. 2004 Apr;9(2):85-91, http://www.ncbi.nlm.nih.gov/pubmed/15108039 </ref> ],
15. Toxicity
• Tolerability of external electro-hyperthermia in the treatment of solid tumors [<ref> Cremona F, Pignata A, Izzo F, Ruffolo F, Delrio P, Fiore F, D'Angelo R, Palaia R, Daniele B, Grazano F, Puppio B, Guidetti GM, Parisi V, (2003) Tolerability of external electro-hyperthermia in the treatment of solid tumors; Tumori 2003 Jul-Aug;89(4 Suppl):239-40, Tumori 2003 Jul-Aug;89(4 Suppl):239-40, http://www.ncbi.nlm.nih.gov/pubmed/12903605 </ref> ],
16. TCM
• Synergy between Oncothermia and Traditional Chinese Medicine [ <ref> Hegyi G (2014) Synergy between Oncothermia and Traditional Chinese Medicine. EANU Special pp. 1-25, http://www.maot.hu/wp-content/uploads/2014/09/Heft_SPECIAL_eng.pdf </ref>],
17. ECT
• Electrochemical Therapy of Tumors [ <ref> Li Jing-Hong, Xin Yu Ling (2013) Electrochemical Therapy of Tumors. Hindawi Publishing Corporation Conference Papers in medicine, Volume 2013, Article ID 858319; http://www.hindawi.com/archive/2013/858319/ </ref> ],
18. Non-oncology
• Oncothermia-Booster (Targeted Radiofrequency) Treatment – in Some Non-Oncological Diseases as Special Physiotherapy [<ref> Mate M, Molnar I, Petrovits G, Hegyi G (2017) Oncothermia-Booster (Targeted Radiofrequency) Treatment – in Some Non-Oncological Diseases as Special Physiotherapy. International Journal of Complementary and Alternative Medicine 6(3):00191; http://juniperpublishers.com/jcmah/pdf/JCMAH.MS.ID.555572.pdf </ref> ],


==References==
==References==
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==External links==
==External links==

Revision as of 12:18, 18 September 2017

The Oncothermia (modulated electro-hyperthermia, mEHT) method

Oncothermia is a new kind of hyperthermia [[1]]. The generic (scientific) name of oncothermia is modulated electro-hyperthermia (mEHT). It is a further development of the heating method, heating selectively the malignant cells instead of the complete isothermal heating of the tumor-mass [[2] ]. Four effects form the selection of malignant cells: 1. The malignant cells metabolize much intensively than their healthy counterpart. Positron Emission Tomography (PET) measures the massive glucose intake, (Warburg effect), [[3] ]. This makes the extracellular matrix around these cells more conductive, orienting the RF-current flowing there [[4] ]. 2. The malignant cells are autonomic, mostly breaking their cellular connections (E-cadherin, connexin formed junctions) [ [5] ]. This creates higher dielectric permittivity in the extracellular matrix of malignant cells, which well orient the appropriately chosen RF-current [ [6] ]. 3. The plasma-membrane of the malignant cells has numerous transmembrane proteins and their clusters (membrane rafts). These absorb the well applied RF-current selectively (beta and delta dispersion). The absorbed energy on the proteins creates a definite heating and triggers various signal transduction via the corresponding receptors [[7] ], [[8] ]. 4. The homeostatic harmony is broken by the malignancy. The structural differences (which is the pathological proof anyway) allow a differentiation of the inharmonic cells by modulation technique [[9] ]. Homeostatic autocorrelation (1/f fluctuation) structure bases the amplitude modulation technique [[10] ], [[11] ]. The selective heterogenic heating has certain advantages making a certain difference from the conventional hyperthermia [[12] ]: 1. The blood-flow is controversial by isothermal heating, igniting a competition between the thermal cell-damage and the cellular support by glucose delivery. The classical controversy of hyperthermia which is usually very effective in the local response and less efficient in the overall survival [[13] ] is also originated from the increased blood-flow, which responsible for the dissemination of the malignant cells [[14] ]. The selective cellular heating controls the blood-flow in the optimal fever-range level, [[15] ], [[16] ], [[17] ], while the temperature of the malignant cells is at least 3°C higher [[18] ]. 2. Active electric field absorption generates the heating effect [[19] ]. The electric field excites extrinsic apoptosis [[20] ], [[21] ] on the pathway starting at TRIAL-R2 (FADD-FAS) complex inducing cleaved caspase-8 and the executor caspase-3 makes the apoptosis [[22] ]. The proapoptotic cell-death-related gene network (EGR1, JUN, CDKN1A) is elevated which is available only in mEHT [[23] ]. The complete MAPK pathway (RAS→RAF→MEK→ERK), is also excited to the apoptotic processes [[24] ]. 3. The mEHT suppresses the proliferation rate remarkably in those parts of the tumor, which remained alive in the given session of the treatment [[25] ], [[26] ]. 4. The mEHT strengths the cellular connections of the malignant area (E-cadherin-beta-catenin complex is developed), decreasing the invasion and dissemination of malignant cells, suppressing the probability of the metastases [[27] ]. This effect remarkably increases the overall survival time of the patient as it is verified by clinical results below. 5. The controlled energy absorption makes it possible to define the same energy absorption dose as used in the ionizing radiation, J/kg. This way the complicated and unpractical cumulative equivalent minutes related to necrosis at 43°C, and representing the T temperature homogeneity at X% of the target (CEM43°CTx) is not considered necessary ever more. 6. The method mEHT induces damage associated molecular pattern (DAMP) in proper spatiotemporal order (calreticulin, free-ATP, membrane and extracellular HSPs and liberated HMBG1 protein) in an immunogenic cell-death (ICD) process [[28] ]. These effects used complementary with some general immune supporting therapies. This combination transforms the general immune-surviallance to tumor-specific immune actions by antigen presenting cells (APC) and creates vaccination-like behavior of mEHT [[29] ], [[30] ]. 7. Its application with dendritic cell therapies enhances the abscopal behavior of the mEHT, [[31] ], [[32] ]. 8. The technique of mEHT is highly efficient [[33] ], [[34] ], user-friendly, easy to operate and relatively cheap in comparison to other hyperthermia units, [[35] ], [[36] ], [[37] ]. Based on the above research facts and publications, oncothermia has various clinical results used as verification of the research results: 1. Andrology and Prostate • Long-term remission of prostate cancer with extensive bone metastases upon immune- and virotherapy: A case report [[38] ], • Androtherm application for the Peyronie's Disease [[39] ], • Prostatakarzinom: Neue Aspekte für Diagnostik und Therapie [[40] ], • Für und Wider des Prostata-Karzinom-Screenings [[41]], • Neue Studie heizt Diskussion über den Wert von PSA-Tests an [[42] ], • Sanfte Hilfen für die Prostata [[43] ], • Bestrahlung der Prostata erhöht Rektum-Ca-Risiko [[44] ], • Rebell gegen den Krebs. Biologische Intensivtherapie – Neue Hoffnung für Patienten? [[45] ], • Radiofrequency Transurethral Hyperthermia and complete Androgen Blockade. A Nonsurgical Approach to Treating Prostate Cancer [[46] ], • Diagnostik hyperthermia in early stage prostate cancer [[47] ], • Adjuvante Radiotherapie: Welcher Patient mit Prostatakarzinom profitiert? [[48]], • Hoffnung bei Prostata-Beschwerden. Die neue Therapie ohne Messer [[49] ], • Malignus és belignus prosztatadaganatok hyperthermiája [[50] ], 2. Gliomas (advanced) • A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia [[51] ], • Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas [[52]], • Glioblastoma multiforme Grad IV: Regionale Tiefenhyperthermie, Antiangiogenese mit Thalidomid, Hochdosis-Ascorbinsäureinfusionen und komplementäre Therapie [[53] ], • Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia [[54] ], • Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas [[55] ], • Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma [[56] ], • The treatment of patients with high-grade malignant gliomas with RF-hyperthermia [[57] ], 3. Gastrointestinal (advanced) • Intra-arterial and systemic chemotherapy plus external hyperthermia in unresectable biliary cancer [[58] ], • Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer [ [59] ], • Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma. A phase II study [ [60]] • Lebermetastasen bei kolorektalen Karzinomen [ [61]], • Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: phase II study [[62] ], • Second-line chemotherapy with gemcitabine and oxaliplatin in combination with loco-regional hyperthermia (EHY-2000) in patients with refrctory metastatic pancreatic cancer - preliminary results of a prospective trial [ [63] ], • Clinical study for advanced pancreas cancer treated by oncothermia [ [64]], • Behandlung des fortgeschrittenen Pankreaskarzinoms mit regionaler Hyperthermie und einer Zytostase mit Mitomycin- C und 5-Fluorouracil/ Folinsäure [ [65] ], • Thermochemotherapy of the advanced pancreas carcinoma [ [66] ], • Thermo-Chemotherapie des fortgeschrittenen Pankreaskarzinoms. Ergebnisseeiner klinischen Anwendungsstudie [[67]], • Complex therapy of the not in sano respectable carcinoma of the pancreas – a pilot study [ [68]], 4. Lung • Current status of oncothermia therapy for lung cancer [ [69]], • Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report [ [70]], • The Outcome of the Chemotherapy and Oncothermia for Far Advanced Adenocarcinoma of the Lung: Case reports of four patients [ [71] ], • Oncothermia with chemotherapy in the patients with Small Cell Lung Cancer [ [72] ], • Clinical study for advanced non-small-cell lung-cancer treated by oncothermia [ [73]], 5. Gynecology • Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy [ [74] ], • Positive response of a primary leiomyosarcoma of the breast following salvage hyperthermia and pazopanib [ [75] ], • Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report [ [76] ], • Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. [ [77] ] • Oncothermia in HIV positive and negative locally advanced cervical cancer patients in South Africa [ [78] ], • Treatment of advanced cervical cancer with complex chemoradio – hyperthermia [[79] ], • Update on phase III randomized clinical trial investigating the effects of the addition of electro-hyperthermia to chemora-diotherapy for cervical cancer patients in South Africa [ [80] ], 6. Bone • Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia [ [81]], • Successful treatment of solitary bone metastasis of non-small cell lung cancer with combination of bevacizumab and hyperthermia [ [82] ], 7. Malignant ascites • Pang CLK, Xinting Z, Zhen W, Junwen O, Yimin L, Roussakow R, et.al. (2017) Local modulated electro-hyperthermia in combination with traditional Chinese medicine vs. intraperitoneal chemoinfusion for treatment of peritoneal carciomatosis with malignant ascites: a phase II randomized trial [[83] ], 8. Temperature effects • The effect of modulated electro-hyperthermia on the pharmacokinetic properties of nefopam in healthy volunteers: A randomised, single-dose, crossover open-label study [ [84] ], • Effect of modulated electrohyperthermia on the pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers [[85] ] • Improvement of tumor oxygenation by mild hyperthermia [ [86] ], 9. Melanoma • Malignes Melanom Stadium IV: Anwendung von regionaler Tiefenhyperthermie, Tamoxifen, Interferon-α und komplementären Therapien [ [87] ], 10. Immuno-oncology • Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance [ [88] ], • Hypoxia Immunity, Metabolism and Hyperthermia [ [89] ], • Stage IV Wilms tumor treated by Korean medicine, hyperthermia and thymosin-α1: A case report [[90] ], • A new strategy of cancer immunotherapy combining hyperthermia/oncolytic virus pretreatment with specific autologous anti-tumor vaccination - a review [[91] ], • Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo [ [92] ], 11.Sarcoma • Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma [ [93] ], • The results of combination of ifosfamid and locoregional hyperthermia (EHY 2000) in patients with advanced abdominal soft-tissue sarcoma after relapse of first line chemotherapy [ [94]], 11. Multiple malignant diseases • Oncothermia Application for Various Malignant Diseases [ [95]], • Oncothermia: Emerging Therapy in Oncology [ [96] ], • Cases that respond to oncothermia monotherapy [[97] ], 12. Low-back pain • Low back pain – complex approach of treatment by different CAM modalities (Acupuncture and other type of dry-needling, “Targeted RF non invasive physiotherapy” for low back pain). [[98] ], 13. Lyme-disease • Lyme Disease and Oncothermia [ [99] ], 14. WBH • Whole body hyperthermia combined with carboplatin/paclitaxel in patients with ovarian carcinoma – Pase-II-study [ [100]], • Whole-body hyperthermia in combination with platinum containing drugs in patients with recurrent ovarian cancer [ [101] ], 15. Toxicity • Tolerability of external electro-hyperthermia in the treatment of solid tumors [[102] ], 16. TCM • Synergy between Oncothermia and Traditional Chinese Medicine [ [103]], 17. ECT • Electrochemical Therapy of Tumors [ [104] ], 18. Non-oncology • Oncothermia-Booster (Targeted Radiofrequency) Treatment – in Some Non-Oncological Diseases as Special Physiotherapy [[105] ],

References

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