Field of the Invention

The present invention relates to apparatus and methods for making penetrating radiation (e.g. X-ray) measurements, more particularly measurements in non-uniform biological tissue samples including in vivo measurements. The invention has particular, although not necessarily exclusive application in the characterisation of biological tissue, for instance characterisation of tissue as normal (e.g. healthy) or abnormal (e.g. pathological). It is useful, in the diagnosis and management of cancer, including breast cancer.

Background

Mammography is a conventional X-ray technique typically used in the early detection of breast tumours. However, the information available from the X-ray images obtained is limited.

Consequently, in order to manage suspected or overt breast cancer, potentially suspect tissue is commonly removed from the patient in the form of a biopsy specimen and subjected to expert analysis by a histopathologist. This information leads to the disease management program for the patient. Although necessary under the current approach, biopsies are intrusive, uncomfortable procedures, and it is desirable to avoid them wherever possible. The need for biopsies can also lead to considerable delays in obtaining the results and hence subsequent diagnosis and treatment.

Additional penetrating radiation techniques have the potential to fine-tune tissue characterisation to a greater degree than that currently used and hence to improve the targeted management of patients. In existing research in this field, for example x-ray diffraction effects have been shown to operate as an effective means of distinguishing certain types of tissue. However, the techniques proposed are in vitro ones that rely on the use of uniform tissue samples. The additional complications of taking such measurements in vivo, where tissue 'samples' are far from uniform have not been addressed.

Summary of the Invention

It is a general aim of the present invention to provide approaches to penetrating radiation (e.g. X-ray) measurements adapted to account for irregularities in biological tissue samples and which therefore lend themselves to use for in vivo measurements.

For the avoidance of doubt, hereinafter the term "tissue sample" is to be construed in a broad context. Specifically, this term is referred to within the context of the present invention to comprise in vivo "samples", i.e. "samples" that are part of a living human or animal body. Additionally, this term is also referred to within the context of the present invention to comprise ex vivo (which may also be referred to as in vitro), non-uniform and uniform samples, i.e. a significant lump or sample of tissue that has been removed from a patient. Non-uniform and uniform relates to the biological composition of the tissue.

Similarly, within the context of the present invention the term "biological" tissue sample is understood to comprise body tissue of human or animal origin. The body tissue samples may be in vivo also, i.e. part of a living human or animal body. Alternatively, the body tissue samples may be an ex vivo (which may also be referred to as in vitro), preferably non¬ uniform, sample that has been obtained via a surgical procedure or veterinary procedure. Alternatively, the biological tissue sample may be obtained from cell cultures or cell lines. These cell cultures or cell lines may have been grown or propagated or developed in Petri dishes or the like.

In the following, the terms "vertical", "longitudinal" and "transverse", and related terms are used for convenience and ease of understanding to define the orientation of elements of the apparatus relative to one another, but should not be taken to define an absolute orientation in space. "Vertical" is used to mean generally parallel to the incident beam of radiation. "Longitudinal" and "transverse" refer to axes that are generally perpendicular to one another and to the vertical (beam) axis.

In a first aspect the invention provides apparatus for penetrating radiation measurements on a biological tissue sample, the apparatus comprising: a tissue sample locator; a source of penetrating radiation; a collimator configured, in use, to direct radiation from the source into a vertical beam directed at the tissue sample locator; means for scanning the beam along a sample located by the tissue sample locator; and at least one detector for detecting radiation scattered by the sample; the detector being collimated so that only radiation scattered at one or more pre-determined angles is detected; and the detector being divided into multiple segments arranged in a longitudinally extending array, the collimation of the detector being such that each segment detects radiation scattered at a single pre-determined angle, whereby each segment maps onto a discrete vertical location in the plane of the radiation beam.

In this way, when a biological tissue sample is located by the sample locator and irradiated by the penetrating radiation beam, for any particular longitudinal beam location, each segment of the detector corresponds to a specific three-dimensional portion (Voxel1) of the sample. The scattered radiation detected at each detector segment can therefore be attributed to the respective voxel. In one preferred embodiment of the present invention, the tissue sample is a human breast and the sample locator may be a mammography assembly comprising suitable dimensions to locate a portion or the entire patient's breast in a desired position.

In a further preferred embodiment of the present invention, the sample is a ex vivo (which may also be referred to as in vitro), uniform or non-uniform lump of tissue that have been removed from a patient (i.e. tissue from a breast lumpectomy, or the lobe of a liver or lung, or a portion of tissue from the colon or the brain or the prostate or any other organ of the human or animal body).

In a yet further preferred embodiment of the present invention, the sample is a small piece (or pieces) of in vitro tissue samples that are considered to be substantially uniform in biological composition.

More preferably the complete breast or other body parts (including the entire human or animal body) or organs may also be irradiated using an assembly configured to operate in accordance with the method as described in co-pending PCT patent application numbers PCT/GB04/005185 and PCT/GB05/001573 and imaged as described in co-pending PCT application filed on the same day as this application that claims priority from UK patent application number 0411403.9, wherein the apparatus comprises suitable dimensions to locate the patient's tissue in a desired position.

In order to scan the beam along the sample, the sample locator may be moved. More preferably, and more practical for in vivo applications in particular, the beam is moved over the sample. In this case, the detector preferably moves with the beam. This allows the longitudinal extent of the detector to be kept to a minimum.

Preferably the radiation beam is a slit-form beam that extends laterally across the sample (it is particularly preferred that the beam can irradiate the complete width of the sample simultaneously). In this case, the detector has a corresponding lateral extent and is preferably divided into segments laterally as well as longitudinally so that the 2D array of segments thus formed map onto discrete locations in the vertical and horizontal senses in the plane of the beam. In this way, if the position of the sample relative to the beam as it scans along the sample is known, the scattered radiation incident on each detector segment can be mapped onto a corresponding discrete voxel within the sample.

An alternative is to employ a narrow beam that is scanned laterally relative to the sample as well as longitudinally (e.g. as a raster scan). The lateral scan can be uni-directional, in the sense that measurements are only collected as the beam moves in one direction across the width of the sample, the return stroke being a rapid movement during which no measurements are taken. Alternatively, the lateral scan can be bi-directional, with measurements being taken in both directions across the width of the sample (in this case the beam is preferably stepped forward in the longitudinal direction between each stroke).

Each segment of the detector is preferably a discrete detector element in order that discrete data streams representing values measured at each segment can be obtained. The detector may, for example, comprise a 2D array of detector elements mounted on a substrate carrying the required connections and signal carriers for each detector element. Each detector element corresponds to a "detector segment" above. Any of a number of suitable detectors can be used, including for example CCD arrays or large area amorphous silicon or selenium detectors.

The collimation of the detector segments can be accomplished in a conventional manner. The desired angular collimation can be achieved by setting the collimating elements at the desired angle relative to a detector intended to be mounted in a horizontal plane. More preferably, the detector is collimated to accept scattered radiation normal to the plane of the detector (or at some other easily predetermined angle). The desired angular collimation (i.e. acceptance of radiation at a particular scatter angle only) is then achieved by mounting the detector at an appropriate angle relative the direction of the radiation beam incident on the sample.

In some cases, electronic collimation may be possible. For instance, if detecting Compton scattered photons, where there is a relationship between scatter angle and photon energy, a detector can be controlled to only count photons having an energy in a particular range. This in effect, therefore, "collimates" the detector to accept photons scattered at particular angles.

In particularly preferred embodiments, the apparatus is arranged to detect scattered radiation at more than one angle and/or of more than one type. This may be achieved, for instance, using a single detector capable of detecting scattered radiation at more than one pre¬ determined angle (for example by collimating alternate detector segments at different angles), by using multiple detectors, or by using a combination of these approaches.

Another approach to obtaining measurements at different scatter angles is to provide one or more detectors with variable geometry in order that the angle of scattered radiation that they detect can be changed. This variable geometry may also be useful to adjust the detector(s) for different applications.

For example, the angle of the detector or of its associated collimator relative to the incident radiation beam can be made adjustable. Even for wide angle scatter measurements, the variation in angle is likely to be a few degrees at most, and it will generally be desirable to ensure the angle of the detector is accurately, at least to within a few minutes of the nominal angle. The angular position of a moveable detector or collimator is preferably controlled by high precision micro-actuators. Examples of suitable actuators include piezo-electric actuators, micro-actuated worm drives, electromagnetic actuators and hydraulic actuators.

It will also often be important to be able to verify the angle of the detectors and/or associated collimators relative to the incident radiation beam. In some preferred embodiments, therefore, a reference beam or signal is provided that can be used to identify misalignment of the incident radiation beam and the detector. This may be desirable, for example, to correct for temperature effects.

A variety of different measurement techniques can be employed. Examples include energy or angular dispersive x-ray (or other penetrating radiation) diffraction (EDXRD), Compton scatter densitometry, low angle x-ray (or other penetrating radiation) scattering, small angle scattering (SAXS), and ultra low angle scattering (ULAX). XRF measurements might also be used, although generally only in in vitro applications.

In addition to measuring scattered radiation, it may also be beneficial to measure linear attenuation (transmission) coefficients.

Advantageously, these measurements can be used in combination as inputs to a multivariate model to analyse and/or characterise a tissue sample, for instance as disclosed in co-pending PCT patent application numbers PCT/GB04/005185 and PCT/GB05/001573.

The approach described above can be used to more accurately characterise tissue samples and, more specifically, to identify abnormal tissue areas within an irregular 3D tissue sample. Advantageously, therefore, the approach lends itself to in vivo measurements.

Particularly where used for in vivo measurements, the apparatus can advantageously be operated at variable dose levels as described in co-pending PCT application filed on the same day as this application that claims priority from UK patent application number 0411403.9.

In some cases it will still be desirable to take a biopsy to confirm tissue characterisations determined by the measurements. Where this is the case, it is preferred that a biopsy is taken while the tissue sample (e.g. breast) is still located in the sample locator. This has the advantage that the information about the precise 3D location of the abnormal tissue region obtained through the scatter (or other) measurements in the manner described above can be used to direct the biopsy needle. It is also possible to use the apparatus to confirm the correct location of the needle prior to the tissue actually being extracted.

The invention also provides software for controlling apparatus and systems as set out above and described below. In a further embodiment of the present invention a method of analysing body tissue is provided, the method comprising: use of the apparatus as described in the first aspect of the present invention, wherein data representing a first measured tissue property of a body tissue sample is obtained from the apparatus; data representing a second, different tissue property of the tissue sample is obtained from the apparatus; and the data is used in combination to provide an analysis of the tissue sample.

In a yet further embodiment of the present invention a method for characterising body tissue is provided, the method comprising: use of the apparatus as described in the first aspect of the present invention, wherein data representing a first measured tissue property of a tissue sample is obtained from the apparatus; data representing a second, different tissue property of the tissue sample is obtained from the apparatus; and the data is used in combination to provide a characterisation of the tissue sample.

Brief Description of the Drawings

Embodiments of the invention are described below by way of example with reference to the accompanying drawings, in which:

Figure 1 is a schematic illustration of X-ray measurement apparatus in accordance with an embodiment of the present invention;

Figure 2 is a further schematic of the apparatus of figure 1 , on an enlarged scale, showing a single detector and indicating scattered radiation incident on the detector as a sample is irradiated;

Figure 3 is a schematic plan view of the detector illustrated in figure 2; and

Figure 4 illustrates a method of operating the apparatus of figure 1.

Description of Embodiments

Figure 1 illustrates and apparatus suitable for in vivo irradiation of a tissue sample (e.g. a breast). The apparatus comprises a penetrating radiation (in this example X-ray) beam source 2 that directs a beam of X-ray radiation onto the tissue sample 4 being examined. A series of detectors 6, 8, 10, 12 are arranged below and above the sample 4 to detect both transmitted and scattered X-ray radiation. In use, the source and detector arrangement is scanned across the full length of the tissue sample (e.g. breast), as indicated by arrow 'S', whilst the sample is held stationary. The scan is completed in step-wise fashion, with measurements being taken from the detectors at each step.

The incident beam can be a slit-form beam having a width (into the page as illustrated in Figure 1) sufficient to extend across the full width of the sample. Alternatively, the beam may be narrower (e.g. a pencil-form beam) and be scanned laterally across the sample at each step in the longitudinal direction.

Looking in more detail at the detector arrangement illustrated in figure 1 , it can be seen that there are a number of pairs of detectors 8,10,12 arranged to detect scattered radiation 16,18,20 and a single detector 6 for detecting transmitted radiation 14. The detectors 8 are for detecting ultra-low angle scatter (around 1 degree). The detectors 10 are for detecting wider angle scatter (of about 5 to 8 degrees in the present example) and the detectors 12 are for detecting Compton scatter at high angles (about 120 degrees and more).

Although in this example the detectors for scattered radiation are arranged in pairs, this is not essential. Single detectors may be used, or more than two detectors of for each type of measurement can be used.

In a sample 4, such as the one illustrated, having a substantial depth in the vertical direction, problems arise in determining where in that depth scattered radiation incident on a detector originates. The present invention addresses this problem by using collimated detectors. This principle will be illustrated with reference to figure 2, which shows one of the wider-angle detectors 10.

Looking at figure 2 (in which the angles are exaggerated) radiation scattered at an angle alpha (α), for example 6 degrees, from point 'a' in the plane 1P' will be incident on the detector at point 'h', from point 'b' at point T and so on, as illustrated by the dashed lines 30. However, radiation from point 'a1 scattered at an angle a little less than α will also be directed at point Y on the detector and radiation scattered from point 'b' at an angle a little greater than α will be directed at point 'h' on the detector. This would result in a very complex signal at point 'h' on the detector to be deciphered.

However, by collimating the detector 10, radiation scattered at any angle other than α can be prevented from reaching the detector surface. In this way, radiation incident at point 'h' on the detector can only be due to radiation scattered at angle α from point 'a' and so on, points T, 'k1, T, 'm', 'n' and 'p' on the detector corresponding uniquely to points 'b', 'c', 'd', 'e', T and 'g' in the sample in the plane 'P'. At any location of the plane 1P1, there will be a determinable, one-to-one relationship between points in the sample in plane 'P1 and points on the detector surface.

Furthermore, by breaking the detector down into discrete detector elements (such that each of points 'IV to 'p' is in a separate element) so that a discrete measurement can be obtained from each element, the scatter signals from the various depth locations in the sample can be measured.

If the collimated detector 10 is broken down into a 2D array of discrete detector elements as illustrated in figure 3 (extending across the width of the sample 4, as well as longitudinally with respect to it as seen in figure 2), each 'pixel' (i.e. discrete element) of the detector 10, e.g. pixel 32 identified by arrows 'x' and 'y', maps on to a discrete 'voxel' (3D location) within the sample for a given position on the plane 1P1.

By using a collimated, segmented detector 10 as described and illustrated, it is therefore possible to build up an accurate map of the scatter measurements at angle α for the complete 3D sample.

Figure 4 illustrates a method for operating the apparatus described above to scan a tissue sample such as a breast.

Specifically, the scan process is started, once the sample is in place. A first portion of the tissue sample is irradiated and measurements are taken using the detectors 6, 8, 10, 12.

The system then proceeds to the next scan step, and irradiates the next adjacent portion of the tissue sample. The scan continues until the complete sample has been scanned, i.e. the scan is complete. The scanning process is then stopped.

These measurements can be used, for example in a multivariate model as described in co- pending UK patent application GB0328870.1 , to characterise the tissue of each of the sample portions measured. The measured data may be used, for instance, to characterise tissue as normal, benign or malignant.

In some cases, it may be desirable to vary system parameters to increase the data content of measurements obtained from suspect (e.g. abnormal) tissue sample portions, to minimise the necessary data processing capacity and/or to minimise dose.

For example, a broad, slit-type beam may be used to irradiate a sample to initially determine areas of abnormal tissue, or the complete sample may be irradiated at once (e.g. using a conventional X-ray transmission measurement technique as in mammography). However, to minimise the dose during further irradiation of suspect areas for example, it may be desirable to use a more focussed beam, e.g. a pencil beam, directed only at the area of interest. In some cases, it may be desirable to restrict the number of detectors used to make an initial determination as to whether a tissue portion is normal or abnormal in order to limit the data that is processed. When examining suspect areas, however, it will generally be desirable to use more detectors, taking a greater variety of measurements (in accordance, for example, with the approach described in co-pending UK patent application GB0328870.1) to maximise the information content of the measured tissue data. So, for example, considering the exemplary apparatus of figure 1 , it might be possible to detect suspect areas using data from only transmission measurements from detector 6, or another single detector or perhaps a combination of two detectors. Once suspect areas have been identified, data from the whole arrangement of detectors can then be used to extract further information about the tissue characteristics.

Another measure that might be usefully adopted is to provide variable geometry detectors so that a detector can be optimised based, for example, on the particular tissue characteristic, type or property of interest. A single variable geometry detector might also be used to take a variety of measurements, e.g. at different scatter angles.

Looking at figure 1 , for example, detectors 10 are arranged to be variable angle (indicated by arrows 'A') so that, they can be used to detect scattered radiation at multiple selected angles. The ability to vary the angle can also be used during set up and calibration of the apparatus to make any minor adjustments to the angle of the detector needed to compensate for temperature changes for instance.

Preferably the detector angle is changed using one or more micro-actuators.

For example, the collimator assembly or the detector assembly as a whole can be mounted on a piezo driven/positioned rig/mount to allow its (angular) position to be adjusted relative to the rest of the equipment.

Taking the example of micro actuation for calibration in set up and e.g. 'equipment checking' modes, the micro-adjustment capability could be employed to change the position of the collimator assembly or detector assembly in relation to a reference beam or signal. This will enable the angle and alignment of the collimator/detector assembly (which is crucial), to be subject to verification on a regular basis (e.g. to take account of temperature effects, equipment being moved / knocked around, etc). A piezo system would enable the position to be both verified and controlled through either a continuous feedback system or (for example) every time the system (generator) is fired up or once a day or on some other regular cycle.

This micro actuation can also or alternatively be employed for setting collimator arrays or detectors at different angles to (i) the radiation source incident beam or (ii) an angle to the beam. In (i) the angle setting of the collimator beam can be considered a 'first order1 angle to the incident beam. In (ii) the angle setting of the collimator beam can be considered 'second order' because it is set in relation to the Output' angle being investigated (e.g. 6 degrees for wide angle, 120 degrees for Compton, etc).

For example, there may be clinical reasons for selecting particular angles or a number of different angles for different detectors. With piezo or other micro-actuation controls, one or both e.g. wide angle detectors 10 (or more if further detectors are provided) can be set to the same angle, or any combination of angles e.g.: all set to the same angle (e.g. 6 degrees); one (or one pair) set to at one angle (e.g. 6 degrees) and the other(s) at a second angle (e.g. 7 degrees); or, all set at difference angles (e.g. if there are four detectors, one each to 5.5 deg, 6 deg, 6.5 deg, 7 deg), etc.

Some detector angle configurations may be preferred, for example when looking for very high sensitivity (e.g. using detectors all set at the same angle), whereas other detector angle configurations might be better to maximise specificity of tissue characterisation (e.g. two, three or more angles).

Generally it will be desirable to fix the detector angles during a scan. However, there may be occasions where varying the angle of one or more detectors during a scan will be beneficial. For example, in a configuration of (say) four wide-angle detectors, all might be set at an angle (e.g. 6 degrees) in a standard mode. The angle in this standard mode may be chosen, for example, to maximise diagnostic differentiation between normal and abnormal tissue.

Where it is determined, however, that for a particular region of the tissue sample there is an increased probability that the tissue is abnormal, it may be advantageous to immediately reconfigure the angles of the collimators/detectors to, for example, maximise differentiation between abnormal benign and abnormal malignant tissue. It may be, for instance, that one of the four detectors remains at the same angle (e.g. 6 degrees) and the other three are set at three different angles (e.g. 6.8 deg., 7.0 deg. and 7.5 deg respectively).

Advantageously, the apparatus and methods described above can also be used in conjunction with a biopsy system to obtain small samples of tissue identified by the process described above as potentially malignant.

Thus, having established the 3D location of suspected malignant tissue, a needle/core biopsy is immediately taken whilst the patient is in the same position. By not having to move the patient, or her suspect breast (if that is the case), the integrity of the accuracy of the 3D location is maintained. The biopsy device is guided to this location, through the breast wall either automatically or under manual control.

In more detail, the steps to be followed by an operator of the apparatus would, by way of example, be: 1 Identify an area of suspect tissue;

2 Fix the location of this in 3D i.e. x-y-z co-ordinates ("longitudinal", "vertical" and "lateral") in relation to the physical set up of the apparatus;

3 Guide (on auto or manually) the biopsy needle/tip to this area, e.g. through a virtual display of the target location and progress of the needle (the progress of the needle and/or confirmation of its final location being determined, for example, using a transmitted x-ray measurement or x-ray scatter measurements);

4 Activate the biopsy equipment to e.g. take a core from/through the suspect area; and

5 on completion of the core, withdraw the biopsy apparatus.

This approach can potentially avoid the serious problems associated with conventional biopsies, where it can be difficult to be certain that the sample has been taken from the correct location. This can be a particular problem with small tumours / suspect tissue areas.

As the approach described above can be used to examine 3D samples, it is particularly suited to in vivo analysis and provided an attractive alternative to conventional mammography, for example.

In contrast to conventional mammography, in which the breasts are compressed to a significant extent, an approach in accordance with the present invention potentially only requires physical location / stabilising the position of the breast. This could be through the use of a number of flat panels or paddles, for example, which move up to the breast once it is in position.

Where used, the paddles could be configured such that they flatten the sides of the breast. For normal/large breasts, this could be on five sides to form an approximate cube - with the chest wall forming the sixth side. For small breasts, the configuration may be more like a four- sided pyramid, with the base of the pyramid being the chest wall.

Preferably the paddles are of a material that does not interfere with the x-ray scattering patterns that are being detected (for example, material that is substantially transparent to x- ray radiation).

Where the apparatus is to be used also for a biopsy procedure in the manner described above, the paddles can contain a matrix of small holes through which the biopsy needle/core can pass. After determining the 3D location of the suspect tissue, the operator manually, or the software controlling the biopsy needle, or the two in combination can determine the optimal hole through which the needle would pass in order to obtain the best core sample, given the position of the suspect tissue, the position of other breast structures, the (potential) need to obtain more than one biopsy sample, and other patient / clinical factors.

In the context of diagnosing breast cancer, the various aspects and embodiments of the invention described above potentially offer many advantages over conventional mammography and biopsies. Two examples of these advantages include:

a) The patient may be standing or lying flat, with breasts hanging through holes in a couch (such as those commonly used for MRI and biopsy procedures - although these procedures cannot be carried out simultaneously). Women far prefer the lying flat position for these kinds of procedures and breast imaging generally.

b) The compression of breasts in conventional mammography machines is a major issue. It makes the procedure painful for many and reduces the time available for procedures e.g. combination of imaging and biopsy. It may also reduce compliance for screening - i.e. patients may skip or drop out of screening programmes because the procedure is painful. In contrast, as discussed above, the approach described above does not require compression - or at least to anything like the same degree required for mammography.

It will be appreciated that description above is given by way of example and various modifications, omissions or additions to that which has been specifically described can be made without departing from the invention.

For instance, whilst the scanning of the beam across the sample has been described above as a step-wise process, it can also be a continuous motion along the sample for all or part of the scan. For instance, the scan may proceed in a continuous fashion until a region of suspect tissue is detected, at which point the scan may slow or stop or re-scan a portion of tissue to collect additional data and/or to carry out further measurements. It should also be noted that the angular control of detectors has been illustrated above with reference to the wide-angle detectors 10, but is also applicable to other detector positions (e.g. low angle, Compton scatter).