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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 3  |  Page : 1153-1159

Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver


1 Department of Nuclear Medicine and National Biological Sciences, National “F.J.C.” Research Institute for Radiobiology and Radiohygiene, Budapest, Hungary
2 Jedlik Laboratories, Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, Hungary
3 Department of Small Animal Reproduction and Obstetrics, Veterinary Faculty, Szent István University, Budapest, Hungary

Date of Web Publication4-Jan-2017

Correspondence Address:
Lajos Balogh
National “F.J.C.” Research Institute for Radiobiology and Radiohygiene, Budapest
Hungary
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.197561

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 > Abstract 

Aim of Study: Is to show the intrahepatic temperature development in anesthetized pig.
Materials and Methods: Temperature development in the liver of anesthetized pig is measured to study the thermal effects of capacitive coupled energy transfer. The treatment was made by modulated electrohyperthermia (mEHT, trade name: oncothermia ®), controlled by a fluoroptical temperature sensing positioned by the ultrasound-guided process. Various fits of coupling were studied.
Results: The intrahepatic temperature at the end of the treatment ranged 40.5–44.8°C, while the skin temperature ranged 36.8–41.8°C depending on the coupling arrangement.
Conclusion: mEHT is a feasible method to deliver deep heat to the liver of an anesthetized pig.

Keywords: Deep-tissue temperature enhancement, hyperthermia, modulated electrohyperthermia (oncothermia®)


How to cite this article:
Balogh L, Polyák A, Pöstényi Z, Kovács-Haász V, Gyöngy M, Thuróczy J. Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver. J Can Res Ther 2016;12:1153-9

How to cite this URL:
Balogh L, Polyák A, Pöstényi Z, Kovács-Haász V, Gyöngy M, Thuróczy J. Temperature increase induced by modulated electrohyperthermia (oncothermia®) in the anesthetized pig liver. J Can Res Ther [serial online] 2016 [cited 2017 Jan 24];12:1153-9. Available from: http://www.cancerjournal.net/text.asp?2016/12/3/1153/197561


 > Introduction Top


Contrary to human hyperthermia applications in oncology, the history of hyperthermia in veterinary medicine only spans 50 years. The very first veterinarian oncology case was published in 1962.[1] The number of publications then grew rapidly until the 1980s, before declining sharply in the next decades. The first hyperthermia applications concentrated on whole body heating devoted to act on advanced cases of distant metastases.[2],[3],[4],[5],[6] The results were disappointing: systemic hyperthermia does not completely destroy the primary tumor and it promotes the progression of distant metastases. The results of the clinical trial were surprisingly bad;[7],[8] the combined treatment was not effective on the primary tumor, but rapid and massive metastases were developed in distant organs, including the lung.

The so-called local current field (LCF) technique (the RF-22 Thermoprobe) was developed in the early 1970s and its results were mainly published in early 1980s. It was applied solely for small size (maximum 5–10 mm diameter) surface-located tumors (mainly squamous carcinomas). There was speculation [9] about temperatures as high as 59°C. Very good results were reported.[10],[11],[12] The LCF was successfully applied in combination with brachytherapy (Au198).[13] Special microwave application,[14] as well as radiofrequency, was in use.[15]


 > Materials and Methods Top


We applied modulated electrohyperthermia (mEHT, tradename: oncothermia). This is a local-regional approach, but its mechanism selects and targets the plasma membrane of the cancerous cells, turning the macrosize radiation to microeffects.

There has been intensive research into the effects of mEHT. This method is based on the thermal excitation of the cellular membrane.[16] Despite the idea having been developed a long time ago,[17] the details have been further investigated since. This is of no surprise of course because hyperthermia is used in oncology as a complex approach to kill tumor, as so is being investigated in fine detail. Some new, provocative papers [18] have intensified the actual debate about the place of mEHT in the spectra of hyperthermia methods. However, some researchers are questioning mEHT as a member of the treatment category of hyperthermia in oncology.

Our objective is to investigate the macroscopic temperature increase in deep-seated veterinarian targets, making decisional proofs in vivo using in situ measurements to determine the local hyperthermia effects of mEHT in veterinarian patients.

The experimental animal was a 14-week-old, 49 kg, intact female pig purchased from a commercial pig farm. She was clinically healthy; the hematological and biochemical blood panel parameters were within normal ranges. The animal was kept and treated in compliance with all applicable sections of the Hungarian Laws No. XXVIII/1998 and LXVII/2002 on the protection and welfare of animals and animal welfare directions and regulations of the European Union. The study was also approved by the Governmental Ethical Committee, permission no. 22.1/609/001/2014.

Liver temperature of the pig was measured during mEHT treatment. mEHT was provided by the EHY2000+ device (Oncotherm GmbH, Troisdorf, Germany), which is in clinical use and on the market for humans. The applied electrode was round, with a diameter of 20 cm. The temperature was measured in four places: three in the treated volume and one in a rectal location. The temperature sensors were inserted by interventional radiology (ultrasound-guided system) under general anesthesia in three positions: surface (directly on the skin, below the center of the bolus), in the liver in a shallow position, and in the liver in a deep position.

The anesthesia was a single dose intravenous injection of 1.5 ml ketamine-hydrochloride +1.5 ml xylazine +0.1 ml butomidor +3 ml dormicum/50 body weight kg i.m. It was repeated on a continuous basis when necessary to keep the pig under anesthesia. The longest and shortest periods of permanent anesthesia were at 90 and 150 min, respectively.

Systemic and local side effects were checked by veterinary clinical investigations and by repeated blood samplings 2 h after each oncothermic sessions, then 1, 5, and 14 days after completing the whole animal study.

The treatment process was performed six times with 1–3 days breaks between each treatment. The treatment protocols were different and are shown in [Table 1].
Table 1: Summary of the parameters of treatment processes

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The pig was female, 49.5 kg [Figure 1].
Figure 1: The complete arrangement of the pig treatment with the device EHY-2000 devoted for humans

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The area of the upper electrode was shaved for better matching, and the matching conditions were adjusted with and without surface-boosting-gel application [Figure 2].
Figure 2: The shaved surface with boosting gel application before treatment

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The interventional radiology process (ultrasound-guided), placing the temperature sensors on the correct places in shallow and deep areas of the liver [Figure 3].
Figure 3: Ultrasound-guided fixing of the fluoroptical temperature sensors

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The treatment conditions are shown in [Figure 4].
Figure 4: The actual treatment conditions: (a) the pig during the treatment and (b) the arrangement of the electrodes and fiber-optic temperature sensors

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Typical power patterns are shown in [Figure 5].
Figure 5: Typical power patterns of various treatment conditions. The absorbed power was always a little lower (<10%) than the input. The absorbed power was kept always at the nominal value (e.g., 150W) and the input automatically provided the efficacy loss. The efficacy from these patterns is always better than 90%. (a) Permanent 150W is absorbed, (b) step-up heating, and (c) step-down and step-up heating

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 > Results Top


The intrahepatic temperature showed a definite increase during the treatment [Table 2].
Table 2: Summary of the temperature measurements at the start during and at the end of the treatments

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The dynamism of the heating depends on the conditions and impedance-matching [Figure 6].
Figure 6: Temperature pattern in various heating conditions. (a→f) The treatments of numbered protocols 1→6 in Table 1. The four curves show the surface, the shallow and deep intrahepatic, and the power dynamic development (the power is numbered on the secondary vertical axis). The skin temperature started much lower than the intrahepatic counterparts

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The variation of the rectal temperature is low compared to the heated volumes [Table 3].
Table 3: Measured rectal temperatures observed during different types of treatments

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The dynamic patterns of temperatures measured in the rectum are shown in [Figure 7].
Figure 7: The rectal temperature pattern in various heating conditions. (a→f) The treatments of 1→6 numbered protocols in Table 1

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The wash-out period was followed by posttreatment temperature measurement [Figure 8].
Figure 8: The rectal temperature pattern in various heating conditions. (a→f) The treatments of 1→6 numbered protocols in Table 1 (the electrode is removed in the time 61 min)

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Neither local nor systemic side effects were observed after treatments in the pig, and no significant alterations were found in the hematological or biochemical blood parameters during the entire study.


 > Discussion Top


The body temperature of pigs is higher than that of humans, generally 38–39°C.[19] Under anesthesia, it could be lowered to result in a longer sleeping state.[20] The anesthetic conditions mainly affect the surface temperature, while the intrahepatic temperature together with the rectal temperature does not change too much. However, the treatments according to protocols 1 and 2 show lower starting intrahepatic temperature, so the real start time of the treatment could be important. Therefore, anesthesia has to be followed by mEHT as quickly as possible.

The power-matching conditions also modify the temperature pattern. When the matching is better, the intrahepatic temperature is higher, rising to over 42°C, while in not as well-matched conditions, it rises by about 1°C less. The physiological conditions (probably mainly the blood-flow changes which control the temperature) could be adjusted to the optimum by step-up heating. Even the short step-down and subsequent longer step-up heating appears to be more effective.

The matching quality also affects the rectal temperature too. By normalizing the pairs of treatments on the same scale with and without boosting the impedance-matching, we see that the well-matched case does not heat up the whole body systemically as much as the not well-matched case [Figure 9]. This is probably because the well-matched cases are concentrating the heat more on the target alone.
Figure 9: The same scale normalized rectal temperature patterns in various heating conditions. (a-c) Panels correspond to the numbered protocols in Table 1: 1–6, respectively (dotted curves are without gel)

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The wash-out time appears to depend more on the duration of anesthesia than anything else in the treatment.

The approximate energy-deposition (specific absorption rate [SAR]) could be calculated by the initial slope (”temperature production”) of the temperature versus time.[21] This comes from the simple thermal approximation:

Δ Q=mcΔ T

PΔ t=mcΔ T



The slopes measured in the few minutes at the start are shown in [Table 4].
Table 4: Measured set of starting development of the temperature (slope of temperature vs. time)

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Which produces the SAR as shown in [Table 5].
Table 5: Calculated specific absorption rate from the initial slopes (adiabatic assumption at start)

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This relatively large absorption is probably due to the high impedance-matching, and at the same time, a smaller targeted volume than all (focusing). Knowing the input power, which was limited to 150W, and knowing the complete energy absorption too, the initial focusing could be estimated, as is shown in [Table 6].
Table 6: Guessed initial volume where the focusing was active. The matching ratio characterizes the ratio of the matching with and without gel application

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 > Conclusion Top


The measurements show a definite increase in the temperature of the liver of a living, anesthetized pig treated with mEHT. The temperature increase depends on the impedance-matching conditions, but the efficacy of the power (ratio of absorbed and forwarded energy) remains over 90%. The intrahepatic temperature is always higher than 40°C and could reach 43°C as well. Beyond the deep-tissue temperature enhancement, mEHT proved to be a safe method in our animal model. mEHT appears to be a feasible method for biomedical research, as well as veterinary clinical hyperthermia.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Crile G Jrd. Selective destruction of cancers after exposure to heat. Ann Surg 1962;156:404-7.  Back to cited text no. 1
    
2.
Page RL, Meyer RE, Thrall DE, Dewhirst MW. Cardiovascular and metabolic response of tumour-bearing dogs to whole body hyperthermia. Int J Hyperthermia 1987;3:513-25.  Back to cited text no. 2
    
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van Rhoon GC, van der Zee J. Cerebral temperature and epidural pressure during whole body hyperthermia in dogs. Res Exp Med (Berl) 1983;183:47-54.  Back to cited text no. 3
    
4.
Thrall DE, Page RL, Dewhirst MW, Macy DW, McLeod DA, Scott RJ, et al. Whole body hyperthermia in dogs using a radiant heating device: Effect of surface cooling on temperature uniformity. Int J Hyperthermia 1989;5:137-43.  Back to cited text no. 4
    
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Thrall DE, Page RL, Dewhirst MW, Meyer RE, Hoopes PJ, Kornegay JN. Temperature measurements in normal and tumor tissue of dogs undergoing whole body hyperthermia. Cancer Res 1986;46 (12 Pt 1):6229-35.  Back to cited text no. 5
    
6.
Thrall DE, Page RL, McLeod DA. Use of insulation to reduce extremity temperature nonuniformity during whole body hyperthermia in dogs. Cancer Res 1987;47:5880-2.  Back to cited text no. 6
    
7.
Lord PF, Kapp DS, Morrow D. Increased skeletal metastases of spontaneous canine osteosarcoma after fractionated systemic hyperthermia and local X-irradiation. Cancer Res 1981;41 (11 Pt 1):4331-4.  Back to cited text no. 7
    
8.
Rice L, Urano M, Chu A, Suit HD. The Influence of Whole Body Hyperthermia on the Frequency of Metastasis in a Murine Tumour System (Abstract). Proceedings Annals of Society Therapeutic Radiology 21st Annual Meeting; 1979. p. 201.  Back to cited text no. 8
    
9.
Grier RL, Brewer WG Jr., Theilen GH. Hyperthermic treatment of superficial tumors in cats and dogs. J Am Vet Med Assoc 1980;177:227-33.  Back to cited text no. 9
    
10.
Grier RL, Brewer WG Jr., Paul SR, Theilen GH. Treatment of bovine and equine ocular squamous cell carcinoma by radiofrequency hyperthermia. J Am Vet Med Assoc 1980;177:55-61.  Back to cited text no. 10
    
11.
Kainer RA, Stringer JM, Lueker DC. Hyperthermia for treatment of ocular squamous cell tumors in cattle. J Am Vet Med Assoc 1980;176:356-60.  Back to cited text no. 11
    
12.
Kainer RA, Stringer JM. Review of Bovine Cancer Eye Therapy. Symposium Proceedings Management of Bovine Cancer Eye. Colorado State University; 1978. p. 51-9.  Back to cited text no. 12
    
13.
Neumann SM. Hyperthermia for the Treatment of Ocular Squamous Cell Carcinoma in Horses, in Proceedings. American College of Veterinary Ophthalmology (Resident Forum); 1980. p. 1-6.  Back to cited text no. 13
    
14.
Matteucci ML, Anyarambhatla G, Rosner G, Azuma C, Fisher PE, Dewhirst MW, et al. Hyperthermia increases accumulation of technetium-99m-labeled liposomes in feline sarcomas. Clin Cancer Res 2000;6:3748-55.  Back to cited text no. 14
    
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Storm FK, Harrison WH, Elliott RS, Morton DL. Normal tissue and solid tumor effects of hyperthermia in animal models and clinical trials. Cancer Res 1979;39 (6 Pt 2):2245-51.  Back to cited text no. 15
    
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Szasz A. Challenges and solutions in oncological hyperthermia. Thermal Med 2013;29:1-23.  Back to cited text no. 16
    
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Szasz A, Szasz N, Szasz O. Hyperthermia in oncology with a historical overview. Deutsche Zeitschriftfür Onkologie 2003;35:140-54.  Back to cited text no. 17
    
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Roussakow S. Critical Analysis of Electromagnetic Hyperthermia Randomised Trials: Dubious Effect and Multiple Biases. Vol. 2013. Conference Papers in Medicine. Hindawi; 2013.  Back to cited text no. 18
    
19.
Jackson PG, Cockroft P. Handbook of Pig Medicine. Amsterdam: Elsevier; 2007. Available from: http://www.elsevier.com/books/handbook-of-pig-medicine/jackson/978-0-7020-2828-1. [Last accessed on 2015 Sep 30].  Back to cited text no. 19
    
20.
Smith C. Swine Anesthesia and Analgesia, 2000-2010, Virginia-Maryland Regional College of Veterinary Medicine; 2011. Available from: http://www.awic.nal.usda.gov/awic/pubs/SwineAnesth.pdf. [Last accessed on 2015 Sep 30].  Back to cited text no. 20
    
21.
Garner AL, Deminsky M, Neculaes VB, Chashihin V, Knizhnik A, Potapkin B. Cell membrane thermal gradients induced by electromagnetic fields. J Appl Phys 2013;113:214701.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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