Introduction : Hyperthermia is a complementary therapy in oncology having various pros and contras for its application. Ascites, pleural effusion, edema and other electrolyte accumulations are frequently excluded from the treatability of the patients with heating locally or systemically. The special gathering of electrolytes is sometimes contraindicated, at times not mentioned in the clinical protocols. However, it is certainly challenging in the oncology where micro and macro edemas, as well as larger electrolyte accumulations (e.g. ascites, pleural effusion), are very frequent. Methods : Excluding patients with accumulation of free electrolytes limits the applications of hyperthermia. To find a solution we are studying the microvasculature and fluid dynamism together with the electric field effects, including the injury currents. The hyperthermia method which we investigate is the modulated electro-hyperthermia (mEHT). We use the Starling’s equation and the injury current in the frame of non-equilibrium thermodynamics and in connection with the biologically closed electric circuits. Results : It is shown that mEHT , unlike the conventional hyperthermia , is applicable for patients who have edema and other free-electrolytes in the volume which is targeted. The heterogeneous heating (unlike the ho mo geneous, isothermal conventional hyperthermia) promotes the development of tumor-specific immune actions, and so has less adverse-effects, and longer sur vival time for patients in advanced, metastatic cancers too. Conclusion : mEHT is well applicable in cases of ascites, pleural effusion, edema and other electro lyte accumulations when a patient is treated in complex (complementary) onco logical therapy.
Grannis Jr, F.W., Kim, J.Y. and Lay, L. (2017) Fluid Complications. Cancer Network. http://www.cancernetwork.com
Isikawa, T., Kokura, S., Sakamoto, N., et al. (2012) Phase II Trial of Combined Regional Hyperthermia and Gemcitabine for Locally Advanced or Metastatic Pancreatic Cancer. International Journal of Hyperthermia, 28, 597-604. https://doi.org/10.3109/02656736.2012.695428
Sharma, H.S. (2006) Hyperthermia Induced Brain Oedema: Current Status & Future Perspectives. Indian Journal of Medical Research, 123, 629-652.
Seegenschmiedt, M.H., Fessenden, P. and Vernon, C.C. (1996) Thermoradiotherapy and Thermochemotherapy. Springer Verlag, Berlin Heidelberg, 1-2.
Kosaka, M., Sugahara, T., Schmidt, K.L., et al. (2001) Thermotherapy for Neoplasia, Inflammation, and Pain. Springer Verlag, Tokyo.
Mórocz, I.A., Hynynen, K., Gudbjartsson, H., Peled, S., Colucci, V. and Jólesz, F.A. (1998) Brain Edema Development after MRI Guided Focused Ultrasound Treatment. Journal of Magnetic Resonance Imaging, 8, 136-142. https://doi.org/10.1002/jmri.1880080126
Hosotani, K., Katsumura, H., Kabuto, M., Handa, Y., Kubota, T. and Hayashji, M. (1993) Effect of Whole-Body Hyperthermia on the Development of Peritumoral Brain Oedema. International Journal of Hyperthermia, 1, 25-36. https://doi.org/10.3109/02656739309061476
Lyons, B.E., Britt, R.H. and Strohbehn, J.W. (1984) Localized Hyperthermia in the Treatment of Malignant Brain Tumors Using an Interstitial Microwave Antenna Array. IEEE Transactions on Biomedical Engineering, 31, 53-62. https://doi.org/10.1109/TBME.1984.325370
Gilly, F.N., Carry, P.Y., Bracket, A., et al. (1992) Treatment of Malignant Peritoneal Effusion in Digestive and Ovarian Cancer. Medical Oncology and Tumor Pharmacotherapy, 9, 177-181.
Neuwirth, M.G., Alexander, H.R. and Karakousis, G.C. (2015) Then and Now: Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), a Historical Perspective. Journal of Gastrointestinal Oncology, 7, 18-28.
Szasz, A., Szasz, N. and Szasz, O. (2010) Oncothermia—Principles and Practices. Springer Science, Heidelberg.
Andocs, G., Rehman, M.U., Zhao, Q.-L., Tabuchi, Y., Kanamori, M. and 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, Article ID: 16039. https://doi.org/10.1038/cddiscovery.2016.39
Szasz, O. and Szasz, A. (2014) Oncothermia—Nano-Heating Paradigm. Journal of Cancer Science and Therapy, 6, 117-121. https://doi.org/10.4172/1948-5956.1000259
Andocs, G., Renner, H., Balogh, L., Fonyad, L., Jakab, C. and 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. https://doi.org/10.1007/s00066-009-1903-1
Szasz, A., Iluri, N. and Szasz, O. (2013) Local Hyperthermia in Oncology—To Choose or Not to Choose? In: Huilgol, N., Ed., Hyperthermia, InTech, Rijeka.
West, J. (2012) Respiratory Physiology: The Essentials. 9th Edition, Lippincott Williams & Wilkins, Baltimore, 177.
Huxley, V.H. and Scallan, J. (2011) Lymphatic Fluid: Exchange Mechanisms and Regulation. The Journal of Physiology, 589, 2935-2943. https://doi.org/10.1113/jphysiol.2011.208298
De Luca Jr, L.A., David, R.B. and Menani, J.V. (2014) Homeostasis and Body Fluid Regulation, Neurobiology of Body Fluid Homeostasis. In: De Luca, L.A., Menani, J.V. and Johnson, A.K., Eds., Transduction and Integration, CRC Press/Taylor & Francis, Boca Raton, Ch. 15.
Levick, J.R. and Michel, C.C. (2010) Microvascular Fluid Exchange and the Revised Starling Principle. Cardiovascular Research, 87, 198-210. https://doi.org/10.1093/cvr/cvq062
Woodcock, T.E. and Woodcock, T.M. (2012) Revised Starling Equation and the Glycocalyx Model of Transvascular Fluid Exchange: An Improved Paradigm for Prescribing Intravenous Fluid Therapy. British Journal of Anaesthesia, 108, 384-394. https://doi.org/10.1093/bja/aer515
Carbon, M., Wübbeler, G., Mackert, B.-M., et al. (2004) Non-Invasive Magnetic Detection of Human Injury Currents. Clinical Neurophysiology, 115, 1027-1032. https://doi.org/10.1016/j.clinph.2003.12.035
McCaig, C.D., Rajnicek, A.M., Song, B. and Zhao, M. (2005) Controlling Cell Behaviour Electrically: Current Views and Future Potential. Physiological Reviews, 85, 943-978. https://doi.org/10.1152/physrev.00020.2004
Barker, A.T., Jaffe, L.F. and Vanable Jr, J.W. (1982) The Glabrous Epidermis of Cavies Contains a Powerful Battery. American Journal of Physiology, 242, 358-366.
Reid, B., McCaig, C.D., Zhao, M., et al. (2005) Wound Healing in Rat Cornea: The Role of Electric Currents. FASEB Journal, 19, 379-386. https://doi.org/10.1096/fj.04-2325com
Reid, B., Nuccitelli, R. and Zhao, M. (2007) Non-Invasive Measurement of Bioelectric Currents with a Vibrating Probe. Nature Protocols, 2, 661-669. https://doi.org/10.1038/nprot.2007.91
Mackert, B.-M., Mackert, J., Wübbeler, G., et al. (1999) Magnetometry of Injury Currents from Human Nerve and Muscle Specimens Using Superconducting Quantum Interferences Devices. Neuroscience Letters, 262, 163-166. https://doi.org/10.1016/S0304-3940(99)00067-1
Song, B., Zhao, M., Forrester, J.V., et al. (2002) Electrical Cues Regulate the Orientation and Frequency of Cell Division and the Rate of Wound Healing In Vivo. PNAS, 99, 13577-13582. https://doi.org/10.1073/pnas.202235299
Chiang, M.C., Cragoe Jr, E.J. and Vanable Jr., J.W. (1991) Intrinsic Electric Fields Promote Epithelization of Wounds in the Newt, Notophthalmus viridescens. Developmental Biology, 146, 377-85. https://doi.org/10.1016/0012-1606(91)90239-Y
Zhao, M. (2009) Electrical Fields in Wound Healing—An Overriding Signal That Directs Cell Migration. Seminars in Cell and Developmental Biology, 20, 674-682. https://doi.org/10.1016/j.semcdb.2008.12.009
Ud-Din, S., Sebastian, A., Giddings, P., Colthurst, J., Whiteside, S., Morris, J., et al. (2015) Angiogenesis Is Induced and Wound Size Is Reduced by Electrical Stimulation in an Acute Wound Healing Model in Human Skin. PLoS ONE, 10, e0124502.
Katchalsky, A. and Curran, P. (1967) Non-Equilibrium Thermodynamics in Biophysics. Harvard University Press, Cambridge-Massachusets.
Scallan, J., Huxley, V.H. and Korthuis, R.J. (2010) Capillary Fluid Exchange: Regulation, Functions, and Pathology. In: Pathophysiology of Edema Formation, Morgan & Claypool Life Sciences, San Rafael, CA, Chapter 4.
Nordenstrom, B.W.E. (1983) Biologically Closed Electric Circuits: Clinical Experimental and Theoretical Evidence for an Additional Circulatory System. Nordic Medical Publications, Stockholm.
Nordenstrom, B.W.E. (1998) Exploring BCEC-Systems, (Biologically Closed Electric Circuits). Nordic Medical Publications, Stockholm.
Nordenstrom, B.W.E. (1992) Impact of Biologically Closed Electric Circuits (BCEC) on Structure and Function. Integrative Physiological and Behavioral Science, 27, 285-303. https://doi.org/10.1007/BF02691165
Mycielska, M.E. and Djamgoz, M.B.A. (2004) Cellular Mechanisms of Direct-Current Electric Field Effects: Galvanotaxis and Metastatic Disease. Journal of Cell Science, 117, 1631-1639. https://doi.org/10.1242/jcs.01125
Pu, J., McCaig, C.D., Cao, L., et al. (2007) EGF Receptor Signalling Is Essential for Electric-Field-Directed Migration of Breast Cancer Cells. Journal of Cell Science, 120, 3395-3403. https://doi.org/10.1242/jcs.002774
Nordenström, B.E.W. (1978) Preliminary Clinical Trials of Electrophoretic Ionization in the Treatment of Malignant Tumors. IRCS Journal of Medical Science, 6, 537-540.
Nordenström, B.E.W. (1985) Electrochemical Treatment of Cancer. Annales De Radiologie, 28, 128-129.
Watson, B.W. (1991) Reappraisal: The Treatment of Tumors with Direct Electric Current. Medical Science Research, 19, 103-105.
Samuelsson, L., Jonsson, L. and Stahl, E. (1983) Percutaneous Treatment of Pulmonary Tumors by Electrolysis. Radiologie, 23, 284-287
Miklavcic, D., Sersa, G., Kryzanowski, M., et al. (1993) Tumor Treatment by Direct Electric Current, Tumor Temperature and pH, Electrode Materials and Configuration. Bioelectrochemistry and Bioenergetics, 30, 209-220. https://doi.org/10.1016/0302-4598(93)80080-E
Nordenstrom, B.W.E. (2009) Biologically Closed Electric Circuits: Activation of Vascular Interstitial Closed Electric Circuits for Treatment of Inoperable Cancers. Journal of Bioelectricity, 3, 137-154. https://doi.org/10.1080/15368378409035964
Nordenstrom, B.W.E. (1994) The Paradigm of Biologically Closed Electric Circuits (BCEC) and the Formation of an International Association (IABC) for BCEC Systems. The European Journal of Surgery. Supplement, 574, 7-23.
Dvorak, H.F. (1986) Tumors: Wounds That Do Not Heal. Similarities between Tumor Stroma Generation and Wound Healing. The New England Journal of Medicine, 315, 1650-1659. https://doi.org/10.1056/NEJM198612253152606
Schäfer, M. and Werner, S. (2008) Cancer as an Overhealing Wound: An Old Hypothesis Revisited. Nature Reviews Molecular Cell Biology, 9, 628-638. https://doi.org/10.1038/nrm2455
Singh, K. (2015) Carcinogenesis and Diabetic Wound Healing: Evidences of Parallelism. Current Diabetes Reviews, 11, 32-45. https://doi.org/10.2174/1573399811666150109122205
Goh, J. and Ladiges, W.C. (2014) Exercise Enhances Wound Healing and Prevents Cancer Progression during Aging by Targeting Macrophage Polarity. Mechanisms of Ageing and Development, 39, 41-48. https://doi.org/10.1016/j.mad.2014.06.004
Meng, X. and Riordan, N.H. (2006) Cancer Is a Functional Repair Tissue. Medical Hypotheses, 66, 486-490. https://doi.org/10.1016/j.mehy.2005.09.041
Kimberly, M.A., Opdenaker, L.M., Flynn, D. and Sims-Mourtada, J. (2015) Wound Healing and Cancer Stem Cells: Inflammation as a Driver of Treatment Resistance in Breast Cancer. Cancer Growth Metastasis, 8, 1-13.
Rybinski, B., Franco-Barraza, J. and Cukierman, E. (2014) The Wound Healing, Chronic Fibrosis, and Cancer Progression Triad. Physiological Genomics, 46, 223-244. https://doi.org/10.1152/physiolgenomics.00158.2013
Calvo, F., Randfl, R., Hooper, S., Faruggia, A.G., Moeendarbary, E., Bruckbauer, A., Batista, F., Charras, G. and Sahai, E. (2015) Cdc42EP3/BORG2 and Septin Network Enables Mechano-Transduction and the Emergence of Cancer Associated Fibroblasts. Cell Reports, 13, 1-16. https://doi.org/10.1016/j.celrep.2015.11.052
Kaspera, M., Jaksa, V., Area, A., Bergströma, Å ., Schwägera, A., Svärda, J., Teglunda, S., Barkerc, N. and Toftgård, R. (2011) Wounding Enhances Epidermal Tumorigenesis by Recruiting Hair Follicle Keratinocytes. PNAS, 108, 4099-4104. https://doi.org/10.1073/pnas.1014489108
Wolf, A.A. (1981) On a Unified Theory of Cancer Etiology and Treatment Based on the Superconduction Double-Dipole Model. Physiological Chemistry and Physics, 13, 493-510.
Giaquinta, G., Di Mauro, C., Onori, S. and Cannistraro, S. (1985) Experimental Evidence of Superconducting Properties in Human Ceruloplasmin. In: Gandolfo, G., Michaelson, S.M. and Rindi, A., Eds., Biological Effects and Dosimetry of Static and ELF Electromagnetic Fields, Springer, Berlin, 339-343. https://doi.org/10.1007/978-1-4613-2099-9_21
Calvo, F.N. (2014) Tumor Microenvironment: Unleashing Metalloproteinases to Induce a CAF Phenotype. Current Biology, 24, No 20.
Fierheller, M. and Sibbald, R.G. (2010) A Clinical Investigation into the Relationship between Increased Periwound Skin Temperature and Local Wound Infection in Patients with Chronic Leg Ulcers. Advances in Skin & Wound Care, 23, 369-739. https://doi.org/10.1097/01.ASW.0000383197.28192.98
Song, B., Zhao, M., Forrester, J., et al. (2004) Nerve Regeneration and Wound Healing Are Stimulated and Directed by an Endogenous Electrical Field In Vivo. Journal of Cell Science, 117, 4681-4690. https://doi.org/10.1242/jcs.01341
Guyton, A.C. (1976) Textbook of Medical Physiology. Saunders, Philadelphia.
Boron, W.F. (2004) A Cellular and Molecular Approach. Elsevier/Saunders, Philadelphia.
Dewhirst, M.W., Viglianti, B.L., Lora-Michiels, M., et al. (2003) Basic Principles of Thermal Dosimetry and Thermal Thresholds for Tissue Damage from Hyperthermia. International Journal of Hyperthermia, 19, 267-294. https://doi.org/10.1080/0265673031000119006
Jones, E., Thrall, D., Dewhirst, M.W. and Vujaskovic, Z. (2006) Prospective Thermal Dosimetry: The Key to Hyperthermia's Future. International Journal of Hyperthermia, 22, 247-253. https://doi.org/10.1080/02656730600765072
Thrall, D.E., Rosner, G.L., Azuma, C., Larue, S.M., Case, B.C., Samulsky, T. and Dewhirst, M.W. (2000) Using Units of CEM43oC T90 Local Hyperthermia Thermal dose Can Be Delivered as Prescribed. International Journal of Hyperthermia, 16, 415-428. https://doi.org/10.1080/026567300416712
Leophold, K.A., Dewhirst, M.W., Samulsky, T.V., Dodge, R.K., Georg, S.L., Blivin, J.L., Prosnitz, L.R. and Oleson, J.R. (1993) Cumulative Minutes with T90 Greater Than Temindex Is Predictive of Response of Superficial Malignancies to Hyperthermia and Radiation. International Journal of Radiation Oncology*Biology* Physics, 25, 841-847. https://doi.org/10.1016/0360-3016(93)90314-L
Dewey, W.C. (1994) Arrhenius Relationships from the Molecule and Cell to the Clinic. International Journal of Hyperthermia, 10, 457-483. https://doi.org/10.3109/02656739409009351
Dewey, W.C., Hopwood, L.E., Sapareto, S.A. and Gerweck, L.E. (1977) Cellular Response to Combination of Hyperthermia and Radiation. Radiology, 123, 463-474. https://doi.org/10.1148/123.2.463
Sapareto, S.A. and Dewey, W.C. (1984) Thermal Dose Determination in Cancer Therapy. International Journal of Radiation Oncology*Biology*Physics, 10, 787-800. https://doi.org/10.1016/0360-3016(84)90379-1
Moritz, A.R. and Henriques, F.C. (1947) Studies of Thermal Injury. ii. The relative importance of Time and Surface Temperature in the Causation of Cutaneous Burns. American Journal of Pathology, 23, 695-720.
Henriques, F.C. (1947) Studies of Thermal Injury v. The Predictability and the Significance of Thermally Induced Rate Processes Leading to Irreversible Epidermal Injury. Archives of Pathology, 43, 489-502.
Urano, M. and Douple, E. (1994) Chemopotentiation by Hyperthermia. Hyperthermia in Oncology, 4, 173.
Sapareto, S.A. and Dewey, W.C. (1984) Thermal Dose Determination in Cancer Therapy. International Journal of Radiation Oncology*Biology*Physics, 10, 787-800. https://doi.org/10.1016/0360-3016(84)90379-1
Pearce, J.A. (2009) Relationship between Arrhenius Models of Thermal Damage and the CEM 43 Thermal Dose. Energy-Based Treatment of Tissue and Assessment V, 7181, Article ID: 718104. https://doi.org/10.1117/12.807999
Perez, C.A. and Sapareto, S.A. (1984) Thermal Dose Expression in Clinical Hyperthermia and Correlation with Tumor Response/Control. Cancer Research, 44, 4818-4825.
Thrall, D.E., LaRue, S.M., Yu, D., Samulski, T., Sanders, L., Case, B., Rosner, G., Azuma, C., Poulson, J., Pruitt, A.F., Stanley, W., Hauck, M.L., Williams, L., Hess, P. and Dewhirst, M.W. (2005): Thermal Dose Is Related to Duration of Local Control in Canine Sarcomas Treated with Thermoradiotherapy. Clinical Cancer Research, 11, 5206-5214. https://doi.org/10.1158/1078-0432.CCR-05-0091
Maguire, P.D., et al. (2001) A Phase II Trial Testing the Thermal Dose Parameter CEM43oCT90 as a Predictor of Response in Soft Tissue Sacomas Treated with Pre-Operative Thermorasiotherapy. International Journal of Hyperthermia, 17, 283-290. https://doi.org/10.1080/02656730110039449
Dewhirst, M.W., Vujaskovic, Z., Jones, E. and Thrall, D. (2005) Re-Setting the Biologic Rationale for Thermal Therapy. International Journal of Hyperthermia, 21, 779-790. https://doi.org/10.1080/02656730500271668
de Bruijne, M., van der Holt, B., van Rhoon, G.C., et al. (2010) Evaluation of CEM43°CT90 Thermal Dose in Superficial Hyperthermia; A Retrospective Analysis. Strahlentherapy & Onkologie (Radiotherapy and Oncology), 186, 436-443. https://doi.org/10.1007/s00066-010-2146-x
Assi, H. (2009) A New cem43 Thermal Dose Model Based on Vogel-Tammann-Fulcher Behavior in Thermal Damage Processes. Ryerson University, Toronto, Ontario.
Esrick, M.A. and McRae, D.A. (1994) The Effect of Hyperthermia Induced Tissue Conductivity Changes on Electrical Impedance Temperature Mapping. Physics in Medicine & Biology, 39, 133-144. https://doi.org/10.1088/0031-9155/39/1/008
Vincze, Gy., Szasz, O. and Szasz, A. (2015) Generalization of the Thermal Dose of Hyperthermia in Oncology. Open Journal of Biophysics, 5, 97-114. https://doi.org/10.4236/ojbiphy.2015.54009
Vincze, Gy., Szigeti, Gy., Andocs, G. and Szasz, A. (2015) Nanoheating without Artificial Nanoparticles. Biology and Medicine, 7, 249.
Andocs, G., Rehman, M.U., Zhao, Q.L., Papp, E., Kondo, T. and 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, 1-9. https://doi.org/10.4172/0974-8369.1000247
Wismeth, C., Dudel, C., Pascher, C., Ramm, P., Pietsch, T., Hirschmann, B., Reinert, C., Proescholdt, M., Rümmele, P., Schuierer, G., Bogdahn, U. and Hau, P. (2010) Transcranial Electro-Hyperthermia Combined with Alkylating Chemotherapy in Patients with Relapsed High-Grade Gliomas—Phase I Clinical Results. Journal of Neuro-Oncology, 98, 395-405. https://doi.org/10.1007/s11060-009-0093-0
Sahinbas, H., Groenemeyer, D.H.W., Boecher, E. and Szasz, A. (2007) Retrospective Clinical Study of Adjuvant Electro-Hyperthermia Treatment for Advanced Brain-Gliomas. Deutsche Zeitschrift fuer Onkologie, 39, 154-160. https://doi.org/10.1055/s-2007-986020
Fiorentini, G., Giovanis, P., Rossi, S., Dentico, P., Paola, R., Turrisi, G. and Bernardeschi, P. (2006) A Phase II Clinical Study on Relapsed Malignant Gliomas Treated with Electro-Hyperthermia. In Vivo, 20, 721-724.
Hager, E.D., Sahinbas, H., Groenemeyer, D.H. and Migeod, F. (2008) Prospective Phase II Trial for Recurrent High-Grade Malignant Gliomas with Capacitive Coupled Low Radiofrequency (LRF) Deep Hyperthermia. ASCO. Journal of Clinical Oncology, Annual Meeting Proceedings (Post-Meeting Edition), 26, 2047.
Hager, E.D. and Birkenmeier, J. (2006) Glioblastoma multiforme Grad IV: Regionale Tiefenhyperthermie, Antiangiogenese mit Thalidomid, Hochdosis-Ascor-binsäureinfusionen und komplementäre Therapie. Deutsche Zeitschrift für Onkologie, 38, 133-135. https://doi.org/10.1055/s-2006-952050
Pang, C.L.K., 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. https://doi.org/10.3892/mco.2017.1221