Oncothermia

The Oncothermia (modulated electro-hyperthermia, mEHT) method

Oncothermia is a new kind of hyperthermia [ ]. 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 [ ]. 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), [ ]. This makes the extracellular matrix around these cells more conductive, orienting the RF-current flowing there [ ]. 2. The malignant cells are autonomic, mostly breaking their cellular connections (E-cadherin, connexin formed junctions) [ ]. This creates higher dielectric permittivity in the extracellular matrix of malignant cells, which well orient the appropriately chosen RF-current [ ]. 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 [ ], [ ]. 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 [ ]. Homeostatic autocorrelation (1/f fluctuation) structure bases the amplitude modulation technique [ ], [ ]. The selective heterogenic heating has certain advantages making a certain difference from the conventional hyperthermia [ ]: 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 [ ] is also originated from the increased blood-flow, which responsible for the dissemination of the malignant cells [ ]. The selective cellular heating controls the blood-flow in the optimal fever-range level, [ ], [ ], [ ], while the temperature of the malignant cells is at least 3°C higher [ ]. 2. Active electric field absorption generates the heating effect [ ]. The electric field excites extrinsic apoptosis [ ], [ ] on the pathway starting at TRIAL-R2 (FADD-FAS) complex inducing cleaved caspase-8 and the executor caspase-3 makes the apoptosis [ ]. The proapoptotic cell-death-related gene network (EGR1, JUN, CDKN1A) is elevated which is available only in mEHT [ ]. The complete MAPK pathway (RAS→RAF→MEK→ERK), is also excited to the apoptotic processes [ ]. 3. The mEHT suppresses the proliferation rate remarkably in those parts of the tumor, which remained alive in the given session of the treatment [ ], [ ]. 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 [ ]. 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 [ ]. 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 [ ], [ ]. 7. Its application with dendritic cell therapies enhances the abscopal behavior of the mEHT, [ ], [ ]. 8. The technique of mEHT is highly efficient [ ], [ ], user-friendly, easy to operate and relatively cheap in comparison to other hyperthermia units, [ ], [ ], [ ]. 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 [ ], • Androtherm application for the Peyronie's Disease [ ], • Prostatakarzinom: Neue Aspekte für Diagnostik und Therapie [ ], • Für und Wider des Prostata-Karzinom-Screenings [ ], • Neue Studie heizt Diskussion über den Wert von PSA-Tests an [ ], • Sanfte Hilfen für die Prostata [ ], • Bestrahlung der Prostata erhöht Rektum-Ca-Risiko [ ], • Rebell gegen den Krebs. Biologische Intensivtherapie – Neue Hoffnung für Patienten? [ ], • Radiofrequency Transurethral Hyperthermia and complete Androgen Blockade. A Nonsurgical Approach to Treating Prostate Cancer [ ], • Diagnostik hyperthermia in early stage prostate cancer [ ], • Adjuvante Radiotherapie: Welcher Patient mit Prostatakarzinom profitiert? [ ], • Hoffnung bei Prostata-Beschwerden. Die neue Therapie ohne Messer [ ], • Malignus és belignus prosztatadaganatok hyperthermiája [ ], 2. Gliomas (advanced) • A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia [ ], • Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas [ ], • Glioblastoma multiforme Grad IV: Regionale Tiefenhyperthermie, Antiangiogenese mit Thalidomid, Hochdosis-Ascorbinsäureinfusionen und komplementäre Therapie [ ], • Prospective phase II trial for recurrent high-grade malignant gliomas with capacitive coupled low radiofrequency (LRF) deep hyperthermia [ ], • Retrospective clinical study of adjuvant electro-hyperthermia treatment for advanced brain-gliomas [ ], • Hyperthermia in combination with ACNU chemotherapy in the treatment of recurrent glioblastoma [ ], • The treatment of patients with high-grade malignant gliomas with RF-hyperthermia [ ], 3. Gastrointestinal (advanced) • Intra-arterial and systemic chemotherapy plus external hyperthermia in unresectable biliary cancer [ ], • Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer [ ], • Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma. A phase II study [ ] • Lebermetastasen bei kolorektalen Karzinomen [ ], • Deep electro-hyperthermia (EHY) with or without thermo-active agents in patients with advanced hepatic cell carcinoma: phase II study [ ], • 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 [ ], • Clinical study for advanced pancreas cancer treated by oncothermia [ ], • Behandlung des fortgeschrittenen Pankreaskarzinoms mit regionaler Hyperthermie und einer Zytostase mit Mitomycin- C und 5-Fluorouracil/ Folinsäure [ ], • Thermochemotherapy of the advanced pancreas carcinoma [ ], • Thermo-Chemotherapie des fortgeschrittenen Pankreaskarzinoms. Ergebnisseeiner klinischen Anwendungsstudie [ ], • Complex therapy of the not in sano respectable carcinoma of the pancreas – a pilot study [ ], 4. Lung • Current status of oncothermia therapy for lung cancer [ ], • Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: A case report [ ], • The Outcome of the Chemotherapy and Oncothermia for Far Advanced Adenocarcinoma of the Lung: Case reports of four patients [ ], • Oncothermia with chemotherapy in the patients with Small Cell Lung Cancer [ ], • Clinical study for advanced non-small-cell lung-cancer treated by oncothermia [ ], 5. Gynecology • Successful treatment of advanced ovarian cancer with thermochemotherapy and adjuvant immune therapy [ ], • Positive response of a primary leiomyosarcoma of the breast following salvage hyperthermia and pazopanib [ ], • Long-term survival of a breast cancer patient with extensive liver metastases upon immune and virotherapy: a case report [ ], • Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. [ ] • Oncothermia in HIV positive and negative locally advanced cervical cancer patients in South Africa [ ], • Treatment of advanced cervical cancer with complex chemoradio – hyperthermia [ ], • 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 [ ], 6. Bone • Posttreatment histology and microcirculation status of osteogenic sarcoma after a neoadjuvant chemo- and radiotherapy in combination with local electromagnetic hyperthermia [ ], • Successful treatment of solitary bone metastasis of non-small cell lung cancer with combination of bevacizumab and hyperthermia [ ], 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 [ ], 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 [ ], • Effect of modulated electrohyperthermia on the pharmacokinetics of oral transmucosal fentanyl citrate in healthy volunteers [ ] • Improvement of tumor oxygenation by mild hyperthermia [ ], 9. Melanoma • Malignes Melanom Stadium IV: Anwendung von regionaler Tiefenhyperthermie, Tamoxifen, Interferon-α und komplementären Therapien [ ], 10. Immuno-oncology • Oncolytic Newcastle disease virus as a prospective anti-cancer therapy. A biologic agent with potential to break therapy resistance [ ], • Hypoxia Immunity, Metabolism and Hyperthermia [ ], • Stage IV Wilms tumor treated by Korean medicine, hyperthermia and thymosin-α1: A case report [ ], • A new strategy of cancer immunotherapy combining hyperthermia/oncolytic virus pretreatment with specific autologous anti-tumor vaccination - a review [ ], • Role of HIF-1α in response of tumors to a combination of hyperthermia and radiation in vivo [ ], 11.Sarcoma • Results of oncothermia combined with operation, chemotherapy and radiation therapy for primary, recurrent and metastatic sarcoma [ ], • 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 [ ], 11. Multiple malignant diseases • Oncothermia Application for Various Malignant Diseases [ ], • Oncothermia: Emerging Therapy in Oncology [ ], • Cases that respond to oncothermia monotherapy [ ], 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). [ ], 13. Lyme-disease • Lyme Disease and Oncothermia [ ], 14. WBH • Whole body hyperthermia combined with carboplatin/paclitaxel in patients with ovarian carcinoma – Pase-II-study [ ], • Whole-body hyperthermia in combination with platinum containing drugs in patients with recurrent ovarian cancer [ ], 15. Toxicity • Tolerability of external electro-hyperthermia in the treatment of solid tumors [ ], 16. TCM • Synergy between Oncothermia and Traditional Chinese Medicine [ ], 17. ECT • Electrochemical Therapy of Tumors [ ], 18. Non-oncology • Oncothermia-Booster (Targeted Radiofrequency) Treatment – in Some Non-Oncological Diseases as Special Physiotherapy [ ],

References

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