WO2020026214A1

WO2020026214A1 - Electronic system and probe for detection of tumour masses

Info

Publication number: WO2020026214A1
Application number: PCT/IB2019/056639
Authority: WO
Inventors: Giulia MATRONE; Marco PASIAN; Maurizio BOZZI; Giovanni MAGENES; Andrea Mazzanti; Luca PERREGRINI; Francesco Svelto; Paul Eugene SUMMERS; Giuseppe RENNE; Simona DI MEO
Original assignee: Istituto Europeo Di Oncologia S.R.L.; Universita' Degli Studi Di Pavia
Priority date: 2018-08-03
Filing date: 2019-08-05
Publication date: 2020-02-06
Also published as: IT201800007825A1

Abstract

Electronic system for detecting the margin between tumour mass in a tissue and healthy tissue, comprising an electronic processing unit (U) which controls a detection probe (2) with an elongated shape and which is traversable. This probe comprises at least one electromagnetic sensor in the microwave frequency range capable of obtaining the dielectric permittivity of the tissue.

Description

ELECTRONIC SYSTEM AND PROBE FOR DETECTION OF TUMOUR MASSES

The present invention relates to a detection system and a method adapted to detect the presence of tumour tissue near or on the resection margins during surgical interventions. Thanks to imaging and screening programs, the detection of ever-smaller neoplasms has seen the emergence of minimally invasive surgery which requires a radical surgical procedure, i.e. that the surgical resection margins are free from neoplasms.

Currently the systems for the evaluation of the margins are based on the experience of the surgeon, on the intraoperative macroscopic evaluation by the pathologist and on the a posteriori histopathological examination. Unfortunately, in about 20% of cases a second intervention is needed to "enlarge" and correct the non-radicality of the first intervention.

During surgical operations to reduce tumour masses, for example for breast cancer (lumpectomy), the surgeon generally has difficulty in determining the extent of the mass itself. In most cases, the identification of the margins of the mass is therefore based on the experience of the surgeon or using a posteriori anatomical-pathological analyses on the removed tissue portions. It has been estimated that about 20% of the cases require therefore a second reduction intervention to correct the inaccuracies of the first intervention.

As an alternative to the aforementioned method based on experience, probes for detecting tumour masses are known, based on the emission of electromagnetic waves. Through the use of these probes, the extent of the tumour mass can be estimated by determining its outline. In particular, in the patent US2008021343 a probe, a system and methods for characterising the tissue by means of its dielectric properties are respectively described. The probe detects a physical characteristic of the tissue to define and delimit the volume, and its outline.

Preferably, the characterisation of the tissue takes place substantially in real time.

The probe for the characterisation of the tissue is configured to work in contact with a surface of the tissue and to apply electric signals having a predetermined wavelength to it. The electric signals reflected by the tissue are detected and measured.

In patent US6.546.787 of Schiller et al., an apparatus and a method are described for detecting and delimiting a malignant tissue enclosed in a healthy tissue. The apparatus comprises a needle having an extensometer, mounted on one of the walls of the needles. The deformation signals are collected when the needle is moved through the tissue. The needle is inserted at different points to allow the collection of data from different points within the tissue. The data is sent along with its spatial coordinates to a computerised system, which provides an image of the structure of the examined tissue.

Patent application W09712553 of Changus et al. provides an apparatus for delimiting and defining a predetermined margin or edge of healthy tissue around a tumour. The device includes a needle to be inserted into the patient's body towards the malignant tissue. The needle contains edge threads that serve to create a cage containing the malignant tissue within it. The needle must reach a predetermined distance between 7 and 13 mm and preferably 10 mm from the malignant tissue before the threads are deployed to create the cage. The cage is then used to guide the surgeon performing the removal of the portion of tissue, so that the removed tissue includes the malignant tissue with a sufficient clean margin around it.

Patent application US2006253107 describes a probe for detecting tumour masses, in particular in the breast, which has two sensors. In particular, the probe comprises a sensor realised by means of a coaxial cable adapted to determine the type of tissue around the tumour mass and a second ultrasound sensor, capable of measuring the distance from the surface where the cut is made with the scalpel for the removal of the tumour mass and the surface of the tumour mass itself.

Patent application US2018042582 describes a device with a single sensor for detecting tumour margins based on ionising mass spectrometry. Although the possibility of using an electromagnetic sensor operating in the microwave spectrum in support of the main sensor is mentioned in the text, the use of particular frequencies is not described. In fact, frequencies between 5 MHz and 3 GHz are mentioned, but without specifying whether the measurement should be considered monochrome, narrowband, or broadband. In no case, then, the possibility of using waves at millimetric frequencies is mentioned.

The present invention proposes providing a probe for detecting tumour masses and in particular margins (outlines) of the tumour masses, which is able to increase the depth of penetration into the tissue with respect to the traditional devices, thus allowing a more precise pathological evaluation (perpendicular to the surface instead of along the surface) and requiring a smaller number of measurements per sample. Such a probe uses a predetermined frequency spectrum different from that of the cited state-of-art devices, and possibly the use of elasticity measurements. In particular, the possible use of frequencies in the millimetre wave spectrum is contemplated, where by millimetre waves, in this context waves at frequencies above 10 GHz are intended. In fact, inside human tissues they can have wavelengths less than a centimetre. Furthermore, unlike the devices available to date, the information regarding the dielectric permittivity of the tissue under examination is possibly obtained starting from a broadband measurement, which allows greater precision, and greater robustness against the typical variability of the measurements themselves, compared to narrowband or monochrome measurements.

Moreover, it is possible to reach penetration depths around 2/3 mm through this probe.

The present invention relates to a system having the characteristics of the enclosed claim 1.

The present invention also relates to a probe having the characteristics of the enclosed claim 8.

The features and advantages of the present invention will be clearer and more evident from the following illustrative and non limiting description of an embodiment and its validation in murine animal models, made with reference to the attached figures illustrating respectively:

· figure 1 shows a schematic view of the system as a whole and the probe in side view according to the present invention;

• figure 2 shows a schematic section of a first embodiment of the probe; • figure 3 shows a schematic section of a second embodiment of the probe;

• figure 4 is a front view of the tip of the probe of figure 3 (tissue side).

· figure 5 illustrates the results of measurements made with an instrument realised with a commercial probe (Agilent 85070E), for the measurement of the dielectric permittivity, in mice inoculated with tumour cells.

With reference to the above figures, the tumour mass detection system comprising an electronic unit U which controls a detection probe 2 with an elongated shape, for example comparable to a pencil, but which in any case is traversable.

It is equipped with sensors in the terminal part, to be used during surgical operations to reduce tumour masses, for example for breast cancer. The probe is placed in contact with the point to be surgically removed, and thanks to the sensors provides a real-time (in vivo) indication about the healthy or tumoural nature of the point itself so as to optimise the surgeon's work. This probe can be used in an equivalent way to analyse the tissue already excised (ex vivo). Compared to normal anatomical-pathological analyses, the invention is able to provide an indication in real time, during the surgical operation. This allows the surgeon, at the side of the operating table, an extensive use of the invention on an already-excised surgical piece (ex vivo), not being limited to only analyse a few critical cases.

This probe has a tip 21 in which it comprises at least one electromagnetic sensor in the microwave frequency range, with the possible use of millimetric waves realised through a rigid, truncated coaxial cable 23 comprising an internal or central conductor 231 and an external annular conductor 232. The frequencies emitted can be selected and comprised in a range from 0.5 to 50 GHz, with a preference for a set of frequencies that allows a broadband measurement, so as to cover the spectrum at least up to 15 GHz. This allows the dielectric permittivity curve of the point under examination to be obtained in a more precise and reliable manner, since the curve itself is reconstructed starting from different measurements at different frequencies, also in the part with millimetric frequencies (broadband measurement), instead of extrapolating it from a single frequency measurement (monochrome measurement) or starting from a few points in frequency (narrowband measurement), both at low frequency.

The electronic processing unit U comprises means for generating and analysing the signal sent by the coaxial cable and measures the complex reflection coefficient of the point being measured by the probe, obtaining the dielectric permittivity of the tissue itself. The nature of the point being measured can be derived from this parameter, exploiting the fact that healthy tissues and neoplasm tissues have, statistically, different values of dielectric permittivity.

The probe further comprises at least a second sensor capable of measuring the elasticity of the tissue.

This second sensor can be of deformation and acceleration, from which the Young's modulus is obtained, which in turn provides an indication of the elasticity of the point being measured. As an example, piezoelectric, MEMS, resistive sensors, etc. can be used. This sensor is preferably associated with the rear end 22 of the probe. The connection of the probe with the processing unit is also provided in the rear end, for example by means of a cable C.

Figure 2 illustrates a first embodiment of such a probe wherein the rear end 22 is able to slide with respect to the body and to the tip 21 of the probe and is connected thereto by means of a spring mechanism 24 provided with a system for locking the sliding.

In this joining zone wherein the spring mechanism is present, the probe has the sensor 25 capable of measuring the elasticity of the tissue. This sensor is a force and/or displacement sensor. In the initial state, the open-end coaxial probe is kept in position by the spring system with the lock active.

The operator positions the tip 21 of the open-end coaxial probe on the tissue under examination and performs the electromagnetic measurement.

Subsequently, the locking system is unlocked, allowing the upper part 22 of the probe to slide axially when the operator exerts pressure against the tissue under examination.

The elasticity measurement is read by the force and displacement sensors, which measure these quantities during the compression of the open coaxial probe and return the Young module.

The main advantages of this option are that the elasticity measurement is less influenced by third factors, such as friction, and the evaluation of the elastic properties allows solving a series of ambiguous cases not identifiable with the sole electromagnetic waves. Figures 3 and 4 illustrate a second embodiment of this probe wherein the probe comprises an outer covering 2' or a cup shaped jacket inside which the body of the probe 2 can slide. The rear end 22 is associated with the bottom of the cup by means of a spring mechanism 24' provided with a system for locking the sliding, while the tip 21 of the probe is located at the open end of the cup.

In this way the operator gripping the lining and pressing the tip by exerting pressure against the tissue under examination causes a compression of the spring mechanism.

In this joining zone wherein the spring mechanism is present, the probe has the sensor 25' capable of measuring the elasticity of the tissue. This sensor is a force and/or displacement sensor. In this embodiment, in the initial state, the tip 21 of the coaxial probe slightly protrudes from the outer jacket.

The operator positions the tip 21 of the open-end coaxial probe on the tissue under examination and performs the electromagnetic measurement with the spring lock active.

The locking system is subsequently unlocked and the coaxial probe is compressed in the outer jacket.

The main advantages of this option are the fact that the electromagnetic and elastic sensors are protected by the external jacket and the vertical dimensions are reduced.

Figure 5 illustrates the results of a measurement activity carried out with an instrument realised with a commercial probe (Agilent 85070E) for measuring dielectric permittivity. Four mice were used, inoculated in the rear dorsal areolar area with tumour cells according to the following scheme: i) 2 CD1 mice inoculated with 4T1 cells (murine mammary tumour cells); ii) 1 CD1 mouse inoculated with HCT116 cells (human colorectal tumour cells); iii) 1 NSG mouse (NOD scid gamma mouse) inoculated with NB4 cells (human acute myeloid leukaemia cells). For each animal, a single in vivo measurement was performed, in situ measurements at 2, 4, 6, 8, 10 and 20 minutes after animal sacrifice and, for one of the two mice inoculated with 4T1, ex vivo measurements after removal of the tumour mass with and without skin. In particular, figure 5 illustrates by way of example the measurements of the real part of the relative dielectric permittivity carried out on a portion of neoplasm tissue of one of the two mice inoculated with 4T1, wherein measurements were performed in vivo, in situ and ex vivo without skin. In figure 5, the horizontal axis represents the frequency range from 0 to 50 GFIz, while the vertical axis is a real part of the relative dielectric permittivity, from 0 to 50 (pure number, without unit of measurement).

The comparison of all the in vivo, in situ and ex vivo measurements does not show substantial differences, demonstrating that the present invention can be used both for in vivo and ex vivo measurements. Furthermore, a histological analysis revealed that the measured tumour masses are characterised by a maximum diameter ranging from 6 to 25 mm and a thickness ranging from 3 to 8 mm. The skin overlying the neoplasm mass had an average thickness of 0.6 +/- 0.02 mm. The growth pattern of the neoplasms was of expansive type except for mouse 4, (with the greater neoplasm) which presented an infiltrative aspect in the muscle tissue. The mean neoplasm cellu larity in the measurement area was at least 95% with a cell density of 1300 cells/HPF (40x) +/- 200 cells. These characteristics are analogous to high-grade neoplasms measured in ex vivo patients.

Compared to normal anatomical-pathological analyses, the invention is able to provide an indication in real time, during the surgical operation. This allows the surgeon an extensive use of the invention, not limiting to analyse only a few critical cases.

The dielectric properties of the tissues offer a new diagnostic tool for discriminating mammary lesions and extend the domain of this capacity to microwaves, as at a given frequency, the degree to which the dielectric properties differ between healthy and tumour tissues is more evident.

The frequency range used between 0.5 and 50 GHz and the shape of the probe allow the probe to receive information in the tissue up to a depth of 3 mm. In this way it is possible to precisely identify the "border" between the tumour tissue and the healthy tissue.

Claims

1. Electronic system for detecting the margin between a tumour mass in tissue and healthy tissue, comprising an electronic processing unit (U) which controls a detection probe (2) with an elongated shape and which is traversable,

characterised in that such probe comprises at least one electromagnetic sensor in the millimetre wave frequency range capable of obtaining the dielectric permittivity of the tissue.

2. System according to claim 1, wherein the probe comprises at least one second sensor capable of measuring the elasticity of the point of tissue being measured.

3. System according to claim 1, wherein the processing unit comprises means for generating and analysing the signal sent by the probe and measures the complex reflection coefficient of the point of tissue being measured.

4. System according to claim 1, wherein the electromagnetic sensor is a rigid, truncated coaxial cable (23).

5. System according to claim 1, wherein the electromagnetic sensor operates within the frequency range from 0.5 to 50 GHz.

6. System according to claim 1, wherein the electromagnetic sensor operates with a set of frequencies below 15 GHz (broadband measurement).

7. System according to claim 1, wherein the electromagnetic sensor is associated with the tip (21) of the probe while the second sensor is positioned in its rear end (23).

8. System according to claim 2, wherein the second sensor is a piezoelectric or MEMS or resistive sensor.

9. System according to claims 2 and 4, wherein the rear end (22) of the probe is slidable with respect to the body and to the tip (21) of the probe itself and is connected thereto through a spring mechanism (24) provided with a system for locking the sliding, in this joining zone wherein the spring mechanism is present, the probe comprising the sensor (25) capable of measuring the elasticity of the tissue, said sensor being a force and/or displacement sensor.

10. System according to claims 2 and 4, wherein the probe comprises an external covering (2') or a cup-shaped jacket inside which the probe body (2) can slide, the rear end (22) of the probe being associated with the bottom of the cup by means of a spring mechanism (24') provided with a system for locking the sliding, while the tip (21) of the probe is located at the open end of the cup, in said joining zone wherein the spring mechanism is present, the probe provides the sensor (25') capable of measuring the elasticity of the tissue, said sensor being a force and/or displacement sensor.

11. Electronic probe for detecting tumour masses in tissues comprising at least one electromagnetic sensor in the millimetre wave frequency range capable of obtaining the dielectric permittivity of the tissue.

12. Probe according to claim 11, further comprising at least one second sensor capable of measuring the elasticity of the point of tissue being measured.

13. Probe according to claim 12, wherein the electromagnetic sensor is associated with the tip of the probe while the second sensor is positioned in its rear end.

14. Probe according to claim 13, wherein its rear end (22) is slidable with respect to the body and to the tip (21) of the probe itself and is connected thereto through a spring mechanism (24) provided with a system for locking the sliding, in said joining zone wherein the spring mechanism is present, the probe comprising the sensor (25) capable of measuring the elasticity of the tissue, this sensor being a force and/or displacement sensor.

15. Probe according to claim 13, comprising an outer covering (2') or cup-shaped jacket inside which the probe body (2) can slide, the rear end (22) of the probe being associated with the bottom of the cup by means of a spring mechanism (24') provided with a system for locking the sliding, while the tip (21) of the probe is located at the open end of the cup, in this joining zone wherein the spring mechanism is present, presenting the sensor (25') capable of measuring the elasticity of the tissue, said sensor being a force and/or displacement sensor.