NON-INVASIVE ELECTROMAGNETIC DETECTION OF PROSTATIC CANCER BY
THE TRIMPROB
Andrea Tubaro, Cosimo De Nunzio, Roberto Miano°, Alberto Trucchi, Hassan Fattahi,
Stefano Petta and Lucio Miano
Department of Urology, Sant’Andrea Hospital – 2nd School of Medicine, “La Sapienza”
University of Rome, Italy
° Department of Urology, Policlinico Tor Vergata, “Tor Vergata” University, Rome, Italy
ABSTRACT
Prostate cancer is the most common neoplasm diagnosed in men and digital rectal examination
(DRE) and elevated Prostate Specific Antigen (PSA) are commonly used to suspect the presence of prostate cancer. However, due to PSA low specificity some authors have questioned that the PSA era is over for the detection of prostate cancer. The characteristic dielectric properties observed in cancer tissue are also related to a different metabolism and a characteristic intercellular adhesion mechanism as proposed by several authors. So far it has been postulated that the measurement of the dielectric constant may provide a practical method for diagnosing the malignancy of a tumor. In
1992, C Vedruccio, an Italian physicist, invented and patented a device for the electromagnetic
(EM) detection of biologic tissues anomalies. This equipment is composed by a nonlinear oscillator concealed into a cylindrical probe and a radiofrequency spectrum analyser, and is named TRIMprob
(Tissue resonance interaction method probe). The TRIMprob has been investigated in several studies evaluating its capability for the early detection of prostate cancer. TRIMprob presented an high sensitivity and the highest specificity, positive and negative predictive value and accuracy rate to serum PSA and PSA ratio. TRIMprob seems to be a promising technology for the detection of prostate cancer; however larger studies and series of patients are required to confirm its use in clinical practice and to improve and extend its application.
Key words: prostate cancer, electromagnetism, diagnosis, TRIMprob 1 INTRODUCTION
Prostate cancer is the most common neoplasm diagnosed in men in the United States. It is estimated that 232000 new cases will be diagnosed in 2005 [1]. Autopsy studies have shown that approximately 30% of men over the age of 50 have histologic evidence of prostate cancer and data from public health records showed that men in the United States have a 1 in 6 lifetime risk of developing prostate cancer [2]. Digital rectal examination (DRE) and elevated Prostate Specific
Antigen (PSA) and its derivates (Total PSA, free PSA and Free/Total PSA ratio), are used to suspect the presence of prostate cancer. However for the diagnosis of prostate cancer it is necessary an histological confirmation of a biopsy specimen of the prostate obtained under ultrasound guidance (TRUS). The use of PSA as a diagnostic test in the late 1980’ was associated with a dramatic rise in the incidence of prostate cancer. Since its introduction in clinical practice PSA measurement considerably improved the early detection of prostate cancer and has been vastly used as a screening test. The ideal screening test should have a high sensitivity and specificity, should be easily available and accepted by the patients and physician and should be not expensive. The ideal test should be not too sensible to detect cancer as early as possible but when they are curable. [2]. A positive screening test is followed by a diagnostic procedure. Transrectal ultrasoud prostatic biopsy is the procedure of choice for the detection of prostate cancer and unfortunately for its related side effects is not well tolerated by the patients. The simplicity of PSA testing made its use very attractive despite its low specificity. However PSA is not considered as a cancer marker but as a marker of prostate tissue. Several disease as benign prostatic hyperplasia, chronic prostatitis, ejaculation, physical activity, cystoscopy, prostate biopsy can increase serum PSA [3]. Another controversial point is the definition of the best cut-off value for serum PSA that should be used in order to reduce the number of unnecessary biopsies, avoid the detection of un-significant cancers, and avoid the non-diagnosis of high aggressive prostate cancer. A value of PSA more than 4 ng/ml has been generally considered as the threshold value to recommend prostatic biopsy unless some 2 authors [4-5] recently proposed a slightly lower value. The PSA range 4-10 ng/ml is commonly referred as the diagnostic gray zone with a 12-32% positive predictive value. A biopsy with its costs and morbidity would reveal no cancer in about three of four men biopsied for a PSA between 4 and
10 ng/ml [3]. Several authors have recently showed as the detection of prostate cancer for a PSA between 2.5- 4 ng/ml was identical to the detection rate for PSA between 4 and 10 ng/ml [6].
Therefore with this data some authors have questioned that the PSA era is over for the detection of prostate cancer [7]. A single PSA cut-point for biopsy is not recommended and that a new marker or tools for the early detection of prostate cancer in the current PSA era are urgently needed [7]. In this historical period in 1992, Clarbruno Vedruccio, an Italian physicist, invented and patented a device for the electromagnetic (EM) detection of biologic tissues anomalies. This equipment is composed by a nonlinear oscillator concealed into a cylindrical probe and a radiofrequency spectrum analyser, and is named TRIMprob (Tissue resonance interaction method probe) [8]. The TRIMprob has been investigated in several studies evaluating its capability for the early detection of prostate cancer.
Aim of this report is to evaluate this new equipment its working system, the results of related clinical studies and its future applications.
ELECTROMAGNETIC DETECTION OF CANCER TISSUE
The biological effects of microwave radiation have always been divided into a large, predominant chapter of thermal interactions (e.g. trans-urethral microwave thermotherapy) and a small, non- dominant part consisting of non-thermal interactions (e.g. Magnet Resonance Imaging) where the
TRIMprob belongs to.
Malignant and normal tissue presented different electric properties, which can be revealed through a non-linear resonance interaction. The response of any material to electric fields is defined by two frequency dependent functions: the dielectric constant (relative to vacuum, it represents the possibility of the surface charges of a non electrical conductor to be polarized by an external electric
3 field) and the conductivity (the capability of a any electrical conductor to be crossed by an electric filed and is measured in siemens/meter). [9].
In 1926 Fricke and Morse [10], evaluated the electric properties of malignant breast tumors to those of normal tissue and benign breast tumors. Measurements were performed at 20 kHz and showed a clearly difference for the dielectric constant . The dielectric constant was on the average 10 times larger for cancer tissue than for normal tissue. The conductivity had always the same value. These features are the result of a membrane effect. An electric field that polarizes different media will determinate surface charges on both sides of cell membrane. These surface charges produces a secondary electric field that works on all charges like an elastic restoring force, and this accounts for the appearance of resonance effects. The increase of for malignant tumors was attributed to an increased proportion of membrane surfaces for unit volume. The most probable modification was related to intracellular membranes, associated with an intensity energy household (in mitochondria) and protein synthesis (at the endoplasmatic reticulum). The presence of angiogenesis and the related membranes of capillaries, the high polarizability of the adjacent fluid and the effect of red blood cells should also be considered [9].
In 1983 Chaudhary and co-workers [11] evaluated and of breast cancer and normal tissue between 3 Mhz and 3 GHz. Both functions are always greater for tumors in this frequency range, but increases towards lower frequencies (below 30 MHz), while increases towards higher frequencies (above 300 MHz). While the first effect was related to the membrane effects the second one was considered the result from reorientations of dipolar particles ant to the increased water content of tumors [9-11]. Joines WT and co-workers [12] also showed in rats that tumors have a greater absorption with a broad peak between 300-400 Mhz. Since the resonance frequency of free water molecules is 25 GHz at 37 C°, these particles could not explain the different absorption observed in cancer tissue under 1 GHz. A major surface of membran proteins that attracts water molecules (bound water) as observed in cancer tissue could explain these phenomena. [12-14].
4 The characteristic dielectric properties observed in cancer tissue are also related to a different metabolism, and a characteristics intercellular adhesion mechanism as proposed by several authors [15-
18]. So far it has been postulated that the measurement of the dielectric constant may provide a practical method for diagnosing the malignancy of a tumor. [19]. When an electric field is in close contact with a biological tissue, its dielectric properties are related to its size and shape, to its conductivity and to the presence of other electric material. Evaluation of the electric field in several points of the related tissue can be used to identify the dielectric characteristics of the different biological materials which constitutes its structure.
The existence of significant differences between the electrical properties of malignant and normal tissue and the possibility to measure their related changes after an exposition to an electric field was the first step for the development of the TRIMprob by Vedruccio at the end of the 1980’s [8-9].
Tissue Resonance Interaction Method Probe (TRIMprob)
TRIMporb is a diagnostic device developed and produced by Galileo Avionica S.p.A. and distributed by TRIMProb S.p.A., under dr Vedruccio’s patent [8]. Actually the technology on which the device is based is well known as masers were first described by Nikolay Basov and Alexander
Prokhorov, Noble Prize in Physics, in 1952 [20] The device consists in a probe which emits a very weak electromagnetic field, performs a non invasive tissue analysis, allowing to detect the presence of pathological states, and in a receiver that, by means of a dedicated software program, allows to observe the electromagnetic field behavior and to save the relevant readings. The TRIMprob does not give morphologic image of the organ under examination, but carries out a functional analysis of it [21].
5 The detection probe is about 30 cm long; it contains a tuneable autonomous oscillator and a quarter wavelength antenna, axially center in a partially reflecting cylindric cavity; it generates a complex of electromagnetic wave of low intensity with several frequency components and with a high degree of spatial and temporal coherence. The beam form the probe is narrow measuring no more than 0.5 cm across. The emitted wave is very weak, since the receiving antenna of the spectrum analyzer catches only 1.58W at 200 cm from the probe and consists in three frequencies in UHF (around 460, 920, 1350 MHz), each of them is associated to the possible answer generated by tissues of different typology; in particular the first frequency signal interacts with the metabolism of structures (Fig 1). “At the resonance of the spectral line two different effects are detectable: the first is related to the transfer of an mount of radiofrequency from the generator probe to the diseased tissue, that absorb a part of the signal on the proper frequency line; the second effect is related to the deformation of the electromagnetic pattern emitted by the probe, due to the interaction with a resonating agglomerated of cells that produces in the near field a sort of parasisting resonating element able to deflect, on other spatial direction the waves, in the same way like the a beam antenna for radio communications works” [9]
Bellerofonte C et al [22] firstly explained the physical principles of this new device and experimented the possibility of electromagnetic detection of prostate cancer. They observed that an extracorporeal scan of the perineum by the TRIMprob could identify patients at risk for prostate cancer, and recognize those in whom the risk is extremely low. A spectrum analyser, fed by a small receiving antenna that was situated about two meters away from the probe, displays the corresponding spectral liens. Their relative intensities were fixed, but when the probe was brought close to biological tissue, one or several lines can be strongly reduced, according to the pathological state of the tested tissue and the consequent non-linear resonance interaction. The non-linear resonance interaction at 465 MHz frequency range seems to be important in distinguishing cancerous from benign prostate tissue. Resonance values are representative of power measured on a logarithmic scale but are expressed in arbitrary units ranging between 0 and 255 [22]. Bellerofonte 6 and co-workers [22] firstly described the TRIMprob scanning technique. The room were the
TRIMprob was installed and used was made free from electromagnetic interference in the 400-1000
Mhz band. The TRIMprob was installed far away from radio, television and telecommunication transmitters or repeaters. No other electro medical devices were used in a three-metre radius surrounding the TRIMprob, to avoid reciprocal interference. Mobile phone or cordless were forbidden and switched off during the entire duration of the test. The prostate area was scanned with the TRIMprob while the patient standing, normally dressed, 2 meters in front of the receiver at the level of the prostate. The patient should remove all metallic object (keys, wallet) or electric/electronic devices (remote controls, CD player, mobile phones) from his pockets or from areas of the body near the area under test. The probe is brought in close contact with the perineum and the gland explored tilting and rotating the probe on is long axis (maximum allowed rotation:
15° to the left and 15° to the right). Interaction of the TRIMprob electromagnetic field with biological tissue is shown in the form of simple bar charts [21-22]. The height of the spectral line is related to the entity of the biological response of the area under evaluation. When decrease of signal intensity in the 465 MHz frequency is observed, the probe is finely moved searching the lowest possible signal intensity. Once the lowest signal intensity at 465 MHz is obtained, the signal is freezed and automatically stored in the TRIMprob software (Fig 2).
CLINICAL TRIAL WITH THE TRIMPROB
Bellerofonte and co-workers firstly evaluated the feasibility of prostate cancer detection using the
TRIMprob [22]. 211 men with abnormal digital rectal examination or PSA more than 4 ng/ml were evaluated with the TRIMprob and than underwent six cores transrectal ultrasound biopsy of the prostate. ROC analysis from this group of patients resulted in an high sensitivity and moderate specificity (95,4% and 42,7%). The negative predictive value (NPV) of TRIMprob was the highest
(89%) when compared to the other diagnostic tools as PSA, DRE, TRUS (Table 1). Other investigators who used the TRIMporb for the early detection of prostate cancer in patients with 7 elevated PSA (more than 4 ng/ml) in prospective, single center or multi center studies have also confirmed this data [23-25]. The results of this studies seem to confirm the good sensitivity of the
TRIMprob test and the highest specificity, positive and negative predictive value to serum PSA and
PSA ratio Preliminary data on the evaluation of diagnostic accuracy demonstrates how TRIMprob analysis provides the highest accuracy rate (60-73%) for the detection of prostate cancer when compared to PSA (Table 2). However its specificity should be still improved before considering the
TRIMprob as a useful screening test.
According to this data TRIMprob has been suggested as a simple, useful and non invasive tool for the early detection of prostate cancer; in particular its high negative predictive could be used to avoid unnecessary biopsies in patients with elevated PSA and suspected prostate.
The possibility to differentiate with the TRIMprob patients with prostate cancer and normal patients
(controls) has been also evaluated in two studies. Bellerofonte and co-workers [22] enrolled as controls one hundred and sixty three men volunteers aged less than 35 years with a normal PSA and no lower urinary tract symptoms. Analysis of resonance value at 465 MHz showed a significant difference between controls and patients with prostate cancer. No differences were observed for the
920, 1350 MHz frequencies. In order to exclude the possible presence of electromagnetic differences in patients with different age, Tubaro and coworkers in a preliminary report evaluated the data obtained from the TRIMprob test in patients with prostate cancer and in a control group composed of age matched patients with a PSA level below 1 ng/ml [25]. The risk of prostate cancer in this group of patients should be considered around 7%. [6]. A significant difference in resonance level at 465 Mhz frequency was observed between cancer patients and controls (25,6 36,8 vs
80.748.4; p = 0.03). No differences were observed at 930 MHz (91,3 35,8 vs 79,733,9, p =0,32) and at 1395 MHz ( 94,2 32,2 vs 85 32, p =0,72 ) resonance levels [25]. This data seems to confirm that only the 465 MHz signal is of interest for the diagnosis of prostate cancer.
8 Itraobesrver variability and interobserver variability of the TRIMprob test has been also tested by
Bellerofonte and co-workers [22] who showed a 100% consistency between two TRIMprob tests performed by a single investigator at 24 hours interval. An 8% discrepancy (2 of 25 patients) was found in the results of the TRIMprob test performed by two separate investigators. Differences observed where related to two patients with benign prostatic hyperplasia who were diagnosed as prostate cancer by one investigator; no differences were observed in patients with prostate cancer.
Recently several studies are ongoing to evaluate the use of the TRIMprob for the detection of prostate cancer in patients with a PSA between 2 and 4 ng/ml who are actually considered patients at risk of prostate cancer [6] and to also test the possibility to detect prostate cancer recurrences after radical treatment as radical prostatectomy. Experimental studies in the mouse model are currently underway and results will soon became available. They can help us to better understand the detection of prostate cancer by the TRIMprob and to define the size, grade and shape of cancer that should be detected.
CONCLUSION
Electromagnetic detection of cancer is a fascinating subject which is finally turning from an hypothesis into a real possibility. From a clinical perspective, the TRIMprob seems to be a promising technology for the detection of prostate cancer. Data available suggests that a significant improvement of diagnostic accuracy can be obtained as long as the experience on this technology increases. However larger studies and series of patients are required to confirm its use in clinical practice and to improve and extend its application.
9 a) b) c)
FIGURE 1: TRIMprob: non-invasive diagnostic system composed of an emitting maser (a), a receiver (b) for data acquisition and analysis of EM waves (c )
10 FIGURE 2:
TRIMprob is composed of an emitting maser (Bioscanner) and a receiver for data acquisition and analysis of EM waves. When the probe is brought close to biological tissue (prostate), the 465 MHz EM waves can be strongly reduced, according to the pathological state of the tested tissue (cancer).
Receiver
EM Bioscanner
Cancer
Prostate
465 930 1395 MHz
11 Sensitivity Specificity PPV NPV TRIMprob 0.95 0.42 0.63 0.89 PSA 0.94 0.07 0.47 0.60 PSA ratio< 18 % 0.68 0.80 0.76 0.73 DRE 0,68 0.80 0.76 0.73 TRUS 0.84 0.52 0.62 0.78
TABLE 1: Sensitivity, specificity, positive and negative predictive value of TRIMprob, PSA and Free/Total PSA ratio [22]
12 Authos Patients PSA TRIMprob Bellerofonte C (2005) [24] 705 37 60,6 Tubaro A (2006) [25] 111 45 73 Da Pozzo L (2006) [23] 188 - 63
TABLE 2: TRIMprob and PSA accuracy
13 REFERENCES
1) Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al.: Cancer statistics. CA
Cancer J Clin. 2005, 55, 10-30.
2) Schroder FH, Albertsen P, Boyle P et al. Early detection and screening of prostatic cancer,
In Prostate Cancers. L Denis, G Bartsch, S Khoury et al. Health Publications, 2003, 17-49
3) Haese A and Partin AW. Total, complexed and free PSA form and human glandular
Kallikrein 2. Clinical application for early detection and staging of prostatic cancer. In
Management of Prostate Cancer. EA Klein. Human press, 2004, 5-36
4) Antenor JA, Ham A, Roehl K, Nadir RB, Catalona WJ. Relationship between initial
prostate specific antigen level and subsequent prostate cancer detection in a longitudinal
screening study. J. Urol.; 2004,172(1):90-3
5) Krumholtz JS, Carvalhal GF, Ramos CG, Smith DS, Thorson P, Yan Y, Humphrey PA,
Roehl KA, Catalona WJ. Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer
screening is associated with favorable pathologic tumor features. Urology; 2002, 60(3):469-
73.
6) Thompson IM, Pauler DK, Goodman PJ et al.: Prevalence of prostate cancer among men
with a prostate-specific antigen level < or =4.0 ng per milliliter. N.Engl.J.Med. 2004,
350:2239-2246
7) Stamey TA, Caldwell M, McNeal JE et al. The prostate specific antigen era in the United
States is over for prostate cancer : what happened in the last 20 years?. J Urol. 2004, 172,
1297-1301
8) Vedruccio, C. Electromagnetic analyzer of anisotropy in chemical organized systems. Patent
WO 01/07909A1, February 1, 2001; July 26, 2000.
14 9) Vedruccio C, Meessen, A. EM cancer detection by means of nonlinear resonance
interaction. In: Extended Papers Book of PIERS2004. Progress in Electromagnetics
Research Symposium, Pisa, Italy, 2004, p. 909–912.
10) Fricke H, Morse S. The electric capacity of tumors of the breast. J Cancer Res 1926; 10, 340
11) Chaudhary SS, Mishra RK, Swarup A, et al. Dielectric properties of normal and malignant
human breast tissue at radiowave and microwave frequencies. Indian J Biochem Biophys
1983; 21, 76.
12) Joines WT, Jurtle RL, Rafal MD, et al. Microwave power absorption differences between
normal and malignant tissue. Int J Radiol Oncol Biol Phys 1980; 6, 681
13) Purdom L, Ambrose EJ, Klein G. A correlation between electrical surface charge and some
biological characteristics during the stepwise progression of a mouse sarcoma. Nature 1958;
181, 1586
14) Van Lamsweerde-Gallez D, Meessen A. The role of proteins in a dipole model for steady
ionic transport through biological membranes. J Membr Biol 1975; 23,103.
15) Jossinet J. Variability of impeditivity in normal and pathological breast tissue. Med Biol
Eng Comput 1996; 34, 346.
16) Jossinet J. The impeditivity of freshly excised human breast tissue. Physiol Meas 1998; 19,
61.
17) Burdette E, Cain FL, Seals J. In vivo probe measurement technique for determining
dielectric properties at VHF through microwave frequencies. IEEE Trans Microw Theory
Techn 1980; 28, 414.
18) Rogers JA. The dielectric properties of normal and tumour mouse tissue between 50 MHz
and 10 GHz. Br J Radiol 1983; 56, 335.
19) Vedruccio C, Mascia E, Martines V. Uktra high frequency and microwave non linear
interaction cancer detection and tissue characterization, a military research approach to
15 prevent health diseases. Internat. Review of the Armed Forces Medical Service, 2005, 78/2,
120-6
20) J.R. Singer, Masers, John Whiley and Sons Inc. (1959)
21) Trimprob. Portable system for non invasive diagnostics. Issue 1, User’s manual, Galileo
Avionica, Torino, Italy, Sett 2004.
22) Bellerofonte C, Vedrucio C, Tombolino P, Ruoppolo M and Tubaro A. Non-Invasive
Detection of Prostate Cancer by Electromagnetic Interaction. Eur. Urol. 2005, 47, 29-37.
23) Da Pozzo L, Mazzoccoli B, Rigatti P et al. Tissue resonance interaction method (TRIMprob)
for non invasive diagnosis of prostate cancer: a multicenter clinical evaluation. Eur Urol
suppl. 2005, 5 (2), Abs 748
24) Bellerofonte C, Tubaro A, Guarnieri A, De Nunzio C et al. The accuracy of the TRIMprob
for the diagnosis of prostate cancer : two year experience. Eur Urol suppl4, 2005, n°3, pp
110
25) Tubaro A, De Nunzio C, Trucchi A, Miano L. Early diagnosis of prostate cancer: Trimprob
versus PSA, DRE, TRUS: a toss-up control study. Eur Urol suppl. 2005, 5 (2), 277, Abs
1020
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