Patent Application
20100312072
The present invention, in some embodiments thereof, relates to prostate cancer detection and grading, and, more particularly, but not exclusively, to a method and system for detecting, grading and optionally staging prostate cancer using local zinc concentrations.
Based on recent statistics, for the general population, a man has about a 17 percent chance (1 in 6) of being diagnosed with prostate cancer at some point during his lifetime (lifetime risk), and a 3 percent chance (1 in 33) of dying from prostate cancer.
Current screening methods for symptomatic prostate-cancer (PCa) detection, such as digital rectal examination (DRE), transrectal ultrasound (TRUS) or prostate specific antigen blood test (PSA), lack sensitivity and specificity. For example, elevations in PSA occur not only in cancer cases but also in some non-neoplastic conditions, such as nodular hyperplasia (approx 25% PSA>4 ng/ml) and prostatitis, leading to a considerable overlap in levels of serum PSA between that found in such conditions and that found in prostate cancer patients (approx 80% PSA>4 ng/ml). If suspicious findings are present in any of these screening tests, a trans-rectal ultrasound guided needle-biopsy examination (TRNB) is practiced [American College of Physicians 1997]. The rate of negative (non-cancerous) findings for TRNB examination is about 75%, which indicates a high over-prescription of this highly invasive and costly examination. Furthermore, none of the above screening methods provide information on tumor differentiation and/or location and/or dimensions. The lack of location information, which could serve as guidance during the needle-biopsy examination, leads to high false-negative rates in TRNB (of ˜38% in the first examination and ˜17% in repeated ones).
Clearly, an improved method for screening, imaging and staging of prostate cancer, providing reliable information on the lesion's extension and site, as well as on its pathological stage is required for the purpose of diagnosis as well as disease management (choice, monitoring and control of therapy). Numerous improvements of standard TRUS have been developed, such as the power Doppler imaging (DPI), the colour Doppler TRUS (CDUS) and the 3 dimensional Doppler (3DD). However, these modalities can not reliably provide information about the pathological stage of the lesions. Methodologies based on endo-rectal magnetic resonance imaging (ER-MRI) also exist but they are expensive and their use is limited to pre-operative staging.
Methods and devices for detection, localization and histological grading of PCa have been proposed (see PCT WO 2004/041060 to Breskin et al, filed Nov. 6, 2003), based on mapping the Zinc concentration distribution within the prostate. The proposed non-invasive method consists of local x-ray irradiation of the gland, followed by the measurement of characteristic Zinc emission with a trans-rectal X-Ray Fluorescence (XRF) probe.
Additional background art includes Zaichick et al., International Urology and Nephrology 28(5), 687-694, 1996; Zaichick et al., International Urology and Nephrology 29(5), 565-574, 1997; Habib et al., Br. J. Cancer 39 700-704, 1979; Costello et al., J. Inorg. Biochem. 78 161-165, 2000; Lahtonen R, The Prostate 6 177-183, 1985; Shilstein et al., J. Phys. Med. Biol. 49 1-15, 2004; Shilstein et al., Talanta 70 914-921, 2006; and Vartsky et al., J. Urol. 170 2258-2262, 2003.
According to an aspect of some embodiments of the present invention there is provided there is provided a method of estimating a grade of a prostate cancer from zinc data associated with the prostate, the zinc data being arranged gridwise in a plurality of picture-elements representing a zinc map of the prostate, the method comprising: clustering the zinc map according to zinc levels associated with the picture-elements; and estimating a cancer grade of at least one tissue region, based, at least in part, on zinc levels associated with a cluster of picture-elements representing the tissue region.
According to an aspect of some embodiments of the present invention there is provided a method of estimating a grade of a prostate cancer, comprising: recording zinc data from the prostate so as to generate a zinc map represented by a plurality of gridwise arranged picture-elements; clustering the zinc map according to zinc levels associated with the picture-elements; and estimating a cancer grade of at least one tissue region, based, at least in part, on zinc levels associated with a cluster of picture-elements representing the tissue region.
According to some embodiments of the invention the method further comprises segmenting the zinc data into a plurality of segments, each corresponding to a predetermined range of zinc levels, wherein the clustering is according to the segments.
According to some embodiments of the invention the method further comprises displaying at least one of the clusters.
According to some embodiments of the invention the method further comprises determining a location of a tumor in the prostate based on the at least one cluster.
According to some embodiments of the invention the method further comprises estimating a cancer stage of the tissue region.
According to an aspect of some embodiments of the present invention there is provided a method of guiding an invasive medical device in a prostate, comprising: determining a location of a tumor in the prostate using the method of claim 5; imaging the prostate to provide an image and marking the location on the image; and using the image for guiding the medical device to the location.
According to an aspect of some embodiments of the present invention there is provided a system for estimating a grade of a prostate cancer, comprising: an input module, configured for inputting zinc data associated with the prostate, the zinc data being arranged gridwise in a plurality of picture-elements representing a zinc map of the prostate; a clustering module, configured for clustering the zinc map according to zinc levels associated with the picture-elements; and a grade estimating module, configured for estimating a cancer grade of at least one tissue region, based, at least in part, on zinc levels associated with a cluster of picture-elements representing the tissue region.
According to some embodiments of the invention the system further comprising a segmentation module configured for segmenting the zinc data into a plurality of segments, each corresponding to a predetermined range of zinc levels, wherein the clustering module is configured for clustering the zinc map according to the segments.
According to some embodiments of the invention the system further comprises a staging module, for estimating a cancer stage of the tissue region.
According to some embodiments of the invention the system further comprises a mapping module for generating the zinc map using the zinc data.
According to some embodiments of the invention the system further comprises a probe device, adapted for being inserted into at least one of the rectum or the urethra of the subject, and configured for measuring the zinc data and transmitting the data to the mapping module.
According to some embodiments of the invention the system further comprises a display device for displaying at least one of the clusters.
According to some embodiments of the invention the cluster(s) comprises a cluster corresponding to a lowest range of zinc levels in the zinc data.
According to some embodiments of the invention the cluster(s) comprises a cluster corresponding to a next-to-lowest range of zinc levels in the zinc data.
According to some embodiments of the invention the segmentation and the clustering is effected by expectation-maximization technique.
According to some embodiments of the invention the estimation of the cancer grade is based on a predetermined dependence of the cancer grade on: (i) a size of the cluster and (ii) zinc levels associated with the cluster.
According to some embodiments of the invention the cancer grade is selected from a predetermined set of cancer grades, and wherein the predetermined dependence is expressed as a plurality of predictive loci in a two-dimensional plane spanned by a zinc level axis and a cluster size axis, one locus for each cancer grade in the set.
According to some embodiments of the invention an average zinc level of the cluster is classified according to a plurality of predetermined zinc level thresholds and a size of the cluster is classified according to a plurality of cluster size thresholds, and wherein the cancer grade is estimated based on both the classifications.
According to some embodiments of the invention the cancer grade is scaled according to the Gleason grading scale.
According to some embodiments of the invention an average zinc level associated with the cluster below about 40 parts per million indicates, that the cancer grade is equivalent to Gleason score 9.
According to some embodiments of the invention an average zinc level associated with the cluster below 70 parts per million indicates that the cancer grade is equivalent to a Gleason grade having a primary grade which is at least 4.
According to some embodiments of the invention an average zinc level from about 30 parts per million to about 40 parts per million indicates that the cancer grade is equivalent to Gleason grade 4+5, and an average zinc level below about 30 parts per million indicates that the cancer grade is equivalent to Gleason grade 5+4.
According to some embodiments of the invention a size of the tissue region above about 0.5 cm2, and an average zinc level associated with the cluster from about 30 parts per million to about 70 parts per million indicates that the grade is equivalent to a Gleason grade having a primary grade which is 4.
According to some embodiments of the invention an average zinc level associated with the cluster from about 40 parts per million to about 55 parts per million indicates that the cancer grade is equivalent to: Gleason grade 4+5, provided that a size of the tissue region is from about 0.5 cm2 to about 0.9 cm2, and Gleason grade 4+4, provided that a size of the tissue region is above 0.9 cm2.
Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.
For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well.
Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and images. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.
In the drawings:
The present invention, in some embodiments thereof, relates to prostate cancer detection and grading, and, more particularly, but not exclusively, to a method and system for detecting, grading and optionally staging prostate cancer using local zinc concentrations.
Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.
Some embodiments of the present invention provide means for detecting cancer in a warm-blooded male subject (animal or human) in need of such detection. Some embodiments of the present invention provide means for estimating a grade and optionally staging the cancer of the subject. In some embodiments of the present invention the grading estimation is supplemented by a determination of an approximate location of one or more tumors in the prostate of the subject.
Some embodiments of the invention can be embodied on a tangible medium such as a computer for performing the method steps. Some embodiments of the invention can be embodied on a computer readable medium, comprising computer readable instructions for carrying out the method steps. Some embodiments of the invention can also be embodied in electronic device having digital computer capabilities arranged to run the computer program on the tangible medium or execute the instruction on a computer readable medium. Computer programs implementing method steps of the present embodiments can commonly be distributed to users on a tangible distribution medium. From the distribution medium, the computer programs can be copied to a hard disk or a similar intermediate storage medium. The computer programs can be run by loading the computer instructions either from their distribution medium or their intermediate storage medium into the execution memory of the computer, configuring the computer to act in accordance with the present embodiments. All these operations are well-known to those skilled in the art of computer systems.
The present embodiments are useful for evaluating whether or not the subject has tumors in his prostate gland. The present embodiments are useful for evaluating the location of the tumor in his prostate gland. The present embodiments are useful for evaluating the size of the tumor in his prostate gland. The present embodiments are useful for evaluating the histologic grade of the tumor in his prostate gland. The present embodiments are also useful for assessing what type of treatment is suitable for a subject having a tumor of such grade and optionally size in his prostate gland. The present embodiments are further useful for determining the efficiency of the treatment by estimating the size of a prostate cancer before and after a treatment. The present embodiments may be performed with a combination of different methods, optionally and preferably including analysis of needle-biopsy in vitro.
Generally, the cancer grade is estimated from zinc data associated with the prostate of the subject.
The zinc data can be collected via X-ray fluorescence (XRF), as known in the art (to this end see, e.g., International Patent Publication No. WO2004/041060, the contents of which are hereby incorporated by reference). XRF is an analytical method widely used for analysis of trace elements in various matrices. Biological samples such as tissues can be analyzed intact by XRF without sample processing. In XRF, the analyzed tissue may be exposed to a low radiation dose of X-rays or low energy gamma rays from an X-ray tube or an isotopic radioactive source, which as described herein are non-limiting examples of irradiation systems and/or may form a component of such a system. This radiation causes the excitation of the atoms present in the tissue, which in turn decay by emission of characteristic fluorescent X-rays. The characteristic X-rays emitted from the sample are detected and counted by a high energy-resolution detector. The intensity of these X-rays is directly proportional to the concentration of the elements inside the tissue. In the case of Zinc, the characteristic fluorescent X-ray energies are 8.6 and 9.6 keV. The sensitivity of the XRF method depends on the chemical element of interest and on the experimental conditions. The limits of detection are typically below one part per million.
Since Zinc concentrations in the prostate are about 5 times lower in cancerous tissue compared to normal and benign prostate hyperplasia (BPH), the zinc data is used by the present embodiments to estimate the grading of the cancer.
The zinc data thus comprise information pertaining to the content of zinc in the prostate gland. Since different parts of the prostate generally comprise different zinc levels, the zinc data comprises a set of tuples, each comprising the coordinates of a region or a point in the prostate and a zinc numerical value (e.g., zinc concentration, zinc density) associated with the point or region. The zinc data can be transformed to visible signals, in which case the zinc map is in the form of an image.
The zinc data is typically arranged gridwise in a plurality of picture-elements (e.g., pixels, arrangements of pixels) representing a zinc map of the prostate. Each picture-element is represented by a zinc level over the grid. When the zinc data is in the form of an image, each picture-element can be represented by a grey-level which corresponds to the respective zinc level. In various exemplary embodiments of the invention the zinc map also comprise an image of the prostate.
It is appreciated that the number of different zinc levels can be different from the number of grey-levels. For example, an 8-bit display can generate 256 different grey-levels, but the number of different zinc levels can, in principle, be much larger.
The term “pixel” is sometimes abbreviated herein to indicate a picture-element. However, this is not intended to limit the meaning of the term “picture-element” which refers to a unit of the composition of the zinc map.
The terms “zinc map”, “zinc data” and “zinc image” are used interchangeably throughout the specification without limiting the scope of the present invention in any way. Specifically, unless otherwise defined, the use of the term “zinc map” is not to be considered as limited to the transformation of the information regarding zinc content in the prostate into visible signals. For example, a zinc map can be stored in the memory of a computer readable medium as a set of tuples as described above.
Representative examples of zinc maps suitable for the present embodiments are provided in the Examples section that follows (see
It is to be understood that, unless otherwise defined, the operations described hereinbelow can be executed either contemporaneously or sequentially in many combinations or orders of execution. Specifically, the ordering of the flowchart diagrams is not to be considered as limiting. For example, two or more operations, appearing in the following description or in the flowchart diagrams in a particular order, can be executed in a different order (e.g., a reverse order) or substantially contemporaneously. Additionally, several operations described below are optional and may not be executed.
Method 10 begins at 11 and optionally and preferably continues to 12 at which the zinc data are segmented into a plurality of segments, each corresponding to a predetermined range of zinc levels.
The result of the segmentation operation 12 is a plurality of segments, each defined as a range of zinc values (concentrations, amounts, grey levels, or some normalized values thereof). The segments are preferably mutually exclusives, namely that there is no overlap between segments. Each zinc value over the zinc data preferably belongs to one segment. Since the zinc data is represented by a zinc map, each picture-element of the map is also associated with one of the segments. Specifically, all picture-elements having zinc values which are within a range of zinc values defining a particular segment are said to be associated with that segment. Formally, denoting the ith segment by si and the range of zinc values which defines si by Ri the set Pi of picture-elements which are associated with si includes all picture-elements which have a zinc value g satisfying g εRi.
It is noted that although the zinc map includes zinc information as well as spatial information, the segmentation is according to the zinc values and not the spatial location of the picture-elements in the map. Therefore, picture-elements which are associated with a segment do not necessarily reside on the same region of the prostate. On the other hand, the zinc data of all picture-elements associated with a segment are within the same range of zinc values.
The number of segments can be predetermined or it can be determined by method 10. The segmentation can be done according to the range of values within the zinc data or within a portion of the zinc data which is under investigation. The segmentation can be uniform across the range of zinc values. Suppose for example that there are N segments, and that the zinc data are digitized such that there are M different zinc values. In this embodiment, each segment can be defined over a range of approximately M/N zinc values. Without loss of generality, the zinc values can be integers from 1 to N. Denoting the N segments by s1, s2, . . . , sN, the first segment s1 can include zinc data values from 1 to approximately M/N, the second segment s2 can include zinc data values from approximately M/N+1 to approximately 2M/N, etc. The special case in which N=M (i.e., each segment is defined by a single zinc value) is not excluded from the scope of the present invention. Thus, the term “range of zinc values” as used herein also encompasses the case in which the range includes a single zinc value.
The segmentation can also be non-uniform, in which case the range of values for some segments is wider than the others. This embodiment is useful when the uniform segmentation results in some segments which are associated with a small number of picture-elements.
At 13 the method clusters the zinc map according to the zinc levels associated with the picture-element. The clustering operation takes into account the spatial information in the zinc map. The operation aims at partitioning the zinc map into multiple regions each of which being substantially homogeneous with respect to the zinc values of the picture-elements within the region. Preferably, the clustering is according to the predetermined segments. As stated, the zinc data of all picture-elements associated with a segment are within the same range. At 13 the method determines, for at least one of the segments, which of the picture-elements associated with the segment are sufficiently close to each other and identifies those picture-element as belonging to the same cluster. It is appreciated that there can be more than one cluster for a single segment since there can be more than one region in the prostate with the same average level of zinc. A representative example of the result of segmentation 12 and clustering 13 is provided in the Examples section that follows (see
The clustering and the optional segmentation operations can be executed by any technique known in the art of data analysis and/or image processing. In some embodiments of the present invention the range of levels according to which the zinc data are segmented are determined dynamically during the clustering operation.
A representative example of a technique suitable for segmentation 12 and clustering 13 of the present embodiments is the expectation-maximization (EM) technique [Ramos et al., LNCS 1923 319-323, 2000]. In this embodiment the zinc data are digitized and partitioned into N homogeneous clusters classified by their average zinc values. EM is an unsupervised algorithm, which iteratively alternates between segmenting the map into N clusters and characterizing the properties of each cluster in terms of its zinc value. The output image of the EM clustering algorithm is a statistical description of the N clusters, providing the number of components in each cluster, the localization of the cluster components within the map, the average zinc value and related variances associated to each cluster. Other clustering technique, such as, but not limited to, thresholding, Markov random fields, graph theory methods, density estimation methods, scale-space clustering and the like. Several such techniques are disclosed in Pham et al., “Current methods in medical image segmentation,” Annu. Rev. Biomed. Eng. 2, 315-37, 2000.
The clustering operation is not necessarily executed for all the picture-elements of the zinc map. For example, it is not necessary to identify clusters of picture-elements which are associated with sufficiently high zinc levels (say, above 150 parts per million, since it is more likely that these picture-elements represent non-cancerous tissue regions in the prostate gland. In any event, clustering 13 results in at least one cluster of picture-elements.
At 14 a cancer grade of a tissue region represented by at least one cluster is estimated. In various exemplary embodiments of the invention the cancer grade is scaled according to the Gleason grading scale [Gleason, DF, Hum. Pathol. 23 273-279, 1992; Epstein et al., Am. J. Surg. Pathol. 29 1228-1242, 2005]. The Gleason grading scale assigns a combination of two grades (referred to herein as Gleason primary grads and Gleason secondary grade), each ranging from 1 (corresponding to highly-differentiated cells or low-aggressive cancerous pattern) to 5 (corresponding to poorly-differentiated cells or highly-aggressive cancerous pattern). Although the Gleason grading scale was developed for quantified analysis of pathological specimens, it is not intended to limit the scope of the present invention for pathology. As explained hereinunder and demonstrated in the Examples section that follows, the present Inventors discovered that the Gleason grading scale is suitable for grading the aggressiveness of the cancer based on zinc data collected in vivo. A detailed description of the Gleason grading scale is provided in the Examples section that follows.
The cancer grade is preferably estimated for clusters which correspond to a lowest range of zinc levels in the zinc data. In terms of the segmented data, s1, s2, . . . , sN the cancer grade is preferably estimated for clusters which correspond to the first segment s1 (i.e., the segments which is defined by the lowest range of zinc levels). The cancer grade is preferably estimated for other clusters as well. For example, in some embodiments of the present invention the cancer grade is estimated also for clusters which correspond to the next-to-lowest range of zinc levels (i.e., clusters corresponding to the second segment s2). Estimation of cancer grades for other clusters (e.g., clusters corresponding to the next-to-next-to-lowest range of zinc levels or third segment s3) is also contemplated. A cluster for which the cancer grade is estimated is referred to hereinunder as a “query cluster,” and a cluster for which the cancer grade is not estimated are referred to hereinunder as a “background cluster.” During execution of method 10, there can be one or more query clusters and any number (including zero) of background clusters.
The cancer grade is estimated based, at least in part, on zinc levels associated with the query cluster. Typically, but not necessarily, for the purpose of the grading, a representative zinc level is defined to for the query cluster. Such representative zinc level can be, for example, an average zinc level, including, without limitation, arithmetic average, geometric average, harmonic average, root-mean-square, generalized (arbitrary power) root-mean-power and the like. The average zinc level can be calculated as a weighted or non-weighted average. When a weighted average is calculated the weights can be related, for example, to Euclidian distances of the picture-elements of the query cluster from the center of the cluster. Also contemplated are other types of representative zinc levels, including, without limitation, a median zinc level, a zinc level of a central picture-element in the query cluster, etc.
The cancer grade of a tissue region which corresponds to the query cluster can be estimated in more than one level of estimation.
One level of estimation is a binary estimation, in which case the method roughly determines whether or not there is a malignant tumor in the prostate, and if so whether or not the cancer of the respective tissue region is aggressive. In this embodiment, it is sufficient to compare the average zinc level associated with the query cluster to a predetermined zinc level threshold. In this embodiment the method can compare the average zinc level Zn
to a predetermined zinc level threshold, L1, and determine that there is a high likelihood (above 50%) that the cancer is aggressive if the average zinc level is below L1. For example, it was found by the present inventors that an average zinc level below 75 parts per million (ppm) indicates that it there is a high likelihood (above 50%) that that the cancer grade of the respective tissue region is equivalent to a Gleason grade having a primary grade which is at least 4. Thus, the value of the threshold L1 can be 75 ppm, since a Gleason primary grade of 4 or more describes an aggressive cancer.
When it is desired to determine the likelihood for the presence of more aggressive cancer, the value of the threshold L1 is preferably lower than 75 ppm. For example, it was also found by the present inventor that an average zinc level below about 45 ppm indicates that there is a high likelihood (above 90%)) that the cancer grade is equivalent to Gleason score 9. Thus, the value of the threshold L1 can be 45 ppm, since a Gleason score of 9 describes an aggressive cancer. It was further found by the present inventor that an average zinc level below about 30 ppm indicates that there is a high likelihood (above 90%)) that the cancer grade is equivalent to Gleason grade 5+4. Thus, the value of the threshold L1 can be 30 ppm, since a Gleason grade of 5+4 describes an aggressive cancer.
The term “Gleason score”, as used herein, refers to the sum of the primary and secondary Gleason grades. Thus, for example, the Gleason score of Gleason grade 4+5 is 9.
The method can determine that the query cluster does not correspond to a malignant tumor if the average zinc level is above a predetermined threshold which is preferably higher than L1. Alternatively, if the Zn
is above L1, the method can employ a different procedure such as, but not limited to, one or more of the procedures described hereinunder.
Once a binary estimation has been made, the method can issue a report regarding the estimation. The report can be provided in any visible way, for example, on a display device or as a printed hard copy. The report can also be transmitted to a remote location to be displayed or printed at the remote location.
Combination of several predetermined zinc level thresholds, L1, L2, . . . , Lk (L1>L2> . . . >Lk) is also contemplated. This embodiment provides non-binary estimation since it allows the differentiation between different aggressiveness levels of the cancer. A representative example of this embodiment, for the case of three zinc level thresholds, L1, L2 and L3 is illustrated in Zn
to first threshold L1. If
Zn
is below threshold L1, the method compares
Zn
to second threshold L2. If
Zn
is also below threshold L2, the method further compares
Zn
to third threshold L3. Thus, the method determines whether
Zn
is between L2 and L1, between L3 and L2 or below L3, and estimates the grade as follows: If
Zn
is between L2 and L1 the method determines that there is a high likelihood (above 50%)) that the cancer grade is equivalent to a Gleason grade having a primary grade which is at least 4, if
Zn
is between L3 and L2 the method determines that there is a high likelihood (above 50%)) that the cancer grade is equivalent to a Gleason score 9, and if
Zn
is below L3, the method determines that there is a high likelihood (above 90%)) that the cancer grade is equivalent to a Gleason grade 5+4. Representative examples of the thresholds L1, L2 and L3 are about 75 ppm, about 45 ppm and about 30 ppm, respectively. Once such non-binary estimation has been made, the method can issue a report regarding the estimation; as further detailed hereinabove.
The method can determine that the query cluster does not correspond to a malignant tumor if the average zinc level is above a predetermined threshold which is preferably higher than any of the thresholds used for differentiation between different aggressiveness levels of the cancer. Alternatively, if the Zn
is above the highest threshold (e.g., L1 in the above example), the method can employ a different procedure such as, but not limited to, one or more of the procedures described hereinunder.
Another level of estimation according to some embodiments of the present invention allows a more fine differentiation between the various grades. This can be done in more than one way, as will now be explained.
In some embodiments, the estimation of cancer grade is based on a predetermined dependence of the cancer grade on: (i) a size of said cluster and (ii) zinc levels or a representative zinc level associated with the cluster. For example, the predetermined dependence can be expressed as a plurality of predictive geometrical loci in a two-dimensional plane, where each locus corresponds to a different cancer grade (e.g., a different Gleason grade or score). Thus, in this embodiment, the cancer grade can be selected from a predetermined set of cancer grades.
A representative example of such predictive loci is illustrated in
Referring to
Loci 72-75 respectively correspond to a set of four predetermined cancer grades, denoted in
To estimate the cancer grade of a tissue region, the method can determine the representative zinc level and size of the respective query cluster. The zinc level and size is a point P in the two-dimensional plane of the loci. The method then searches for the closet locus to the fit this point and estimate the grade based on the results of the search. The method can also weight the likelihood of the estimation using the distance between the point and the found locus. For example, if the point is on the locus, the method can determine that the likelihood for the corresponding tumor to have the respective grade is, say at least 70%, and if the point is near the locus, but not on it, the method can determine that the likelihood for the corresponding tumor to have the respective grade is between 50% and 70%.
In the exemplified illustration of
In various exemplary embodiments of the invention the loci can be separated by boundary lines 76-79 for delineating the boundary between two adjacent loci. In the representative example illustrated in
In regions which are above line 79 the method preferably estimates that there is a likelihood of at least 50% that the corresponding tissue region is benign or has a low cancer grade (e.g., Gleason primary grade of 3 or less). Same estimation can also be used when the average zinc level is above 80 ppm.
In various exemplary embodiments of the invention the loci include a prediction threshold line 80. Above line 80, there are regions at which some of the loci 72-75 overlap. When point P lies above line 80 and in a region that, say, locus 74 (corresponding to grade G3) and locus 75 (corresponding to grade G4) overlap, the method can determine there is a high likelihood (above 50%) that the grade of the corresponding tissue region is G3 or G4. In other words, instead of assigning one of the predetermined grades, the method assigns the sub-set {G3, G4}⊂{G1, G2, G3, G4} to the corresponding tissue region.
Generally, line 80 can be used for two-dimensional thresholding. In this embodiment, when point P is below line 80 the method determines (with likelihood of at least 50%) that the grade of the corresponding tissue region is one grade of the predetermined set of grades, but when point P is above line 80 the method assigns a set of two or more grades to the corresponding tissue region. The method can also provide weights for each of the grades in the assigned set. Typically, for smaller clusters the higher grades (e.g., G3 or G4) dominate the assigned set and for larger clusters the less high grades (e.g., G1 or G2) dominate the assigned set.
Following the estimation of the cancer grade (in cases in which the method estimates that corresponding tumor is malignant), the method can issue a report regarding the estimation, as further detailed hereinabove. Optionally, the report also includes the estimated size of the corresponding tumor, thereby estimating the stage of the cancer.
In some embodiments of the present invention, a double classification technique is employed for estimating the cancer grade. In these embodiments, the query cluster is classified according to its zinc levels as well as its size (or, equivalently, the size of the corresponding tissue region), and the cancer grade is estimated based on both classifications. Double classification can be done using a plurality of predetermined zinc value thresholds and a plurality of size thresholds. For example, the representative zinc level of the query cluster can be classified according to the zinc level thresholds and a size of the query cluster or the corresponding tissue region can be classified according to a plurality of cluster size or tissue size thresholds.
A representative example of two sets of thresholds is illustrated in
The grid defines a plurality of regions, each defined between two successive zinc level thresholds of the set and two successive size thresholds of the set. Each region in the grid provides estimation for one cancer grade. In the representative example of
Following are several examples for a double (zinc level and cluster or tissue size) classification, according to various exemplary embodiments of the present invention. The classifications are provided in terms of areas of the tissue region rather that the size of the cluster, but one of ordinary skill in the art would know how to express the classifications in terms of cluster size.
If P corresponds to a tissue region size which is above about 0.5 cm2, and an average zinc level of from about 30 ppm to about 70 ppm the method can determine that there is a high likelihood (e.g., above 50%)) that the grade is equivalent to a Gleason grade having a primary grade which is 4.
If P corresponds to a tissue region size which is from about 0.5 cm2 to about 0.9 cm2, and an average zinc level of from about 40 ppm to about 55 ppm the method can that there is a high likelihood (e.g., above 50%)) that the grade is equivalent to a Gleason 4+5.
If P correspond to a tissue region size which is not below 0.9 cm2, and an average zinc level of from about 40 ppm to about 55 ppm, more preferably from about 45 ppm to about 55 ppm the method can determine that there is a high likelihood (e.g., above 50%)) that the grade is equivalent to a Gleason 4+4.
If P correspond to a tissue region size which is above 1.3 cm2, and an average zinc level of from about 55 ppm to about 70 ppm the method can determine that there is a high likelihood (e.g., above 50%)) that the grade is equivalent to a Gleason 4+3.
Once the grade is estimated based on the geometrical loci or double classification, the method can issue a report regarding the estimation; as further detailed hereinabove. Optionally, the report also includes the estimated size of the corresponding tumor, thereby estimating the stage of the cancer.
The method can also employ an iterative procedure for determining whether or not the query cluster correspond to a malignant tumor and estimating the cancer grade if the tumor is likely to be malignant. The iterative process generally includes two or more iterations where, for a given iteration, the cluster size is re-calculated based on a previously estimated grade. It is recognized that there is a correlation between the level of accuracy of the calculated cluster size and the degree by which the cluster is distinguishable from the background. It was found by the present inventors that this the level of accuracy is higher for high cancer grades than for low cancer grades. Thus, the method can use the cancer grade which was estimated in a previous iteration as the input for calculating of the cluster size, thereby to increase the accuracy level of the calculation.
The method ends at 15.
Optionally and preferably, the method continues to 12 at which the zinc data are segmented and/or 13 at which the method clusters the zinc map as further detailed hereinabove. The method can then proceed to 14 at which the cancer grade of a tissue region represented by the query cluster is estimated, as further detailed hereinabove.
In some embodiments of the present invention the method continues to 21 at which the method estimates the stage of the cancer. Staging can be done based on the estimated size of the tissue region which corresponds to the query cluster.
In some embodiments of the present invention the method continues to 22 at which one or more of the clusters are displayed on a display device such as a computer screen, a printing device or the like. Both query clusters and background clusters can be displayed, if desired. Operation 22 can be executed before, after or during operation 14.
In some embodiments of the present invention the method continues to 23 at which the method determines a location of a tumor in the prostate. This embodiment is particularly useful for the physician, for example, when it is desired to access the tumor, e.g., for treatment or biopsy purposes. Tumor location can be calculated in any way known in the art. For example, when the boundaries of the zinc image correspond to the boundaries of the prostate gland, the location of the query cluster relative to the boundary of the zinc image can be used for determining the relative location of the tumor in the prostate.
In some embodiments of the present invention the method continues to 24 at which the method issue a report regarding the analysis. The report can include grade information and/or tumor location information and/or staging (e.g., tumor size) information. The report can be in graphical and/or alphanumeric form, as desired. For example, the report can be in the form of a map describing the prostate or a portion thereof, on which the locations of one or more tumors with their grades can be marked. The report can be provided in any visible way, for example, on a display device or as a printed hard copy. The report can also be transmitted to a remote location to be displayed or printed at the remote location.
The method ends at 15.
Reference is now made to
Method 30 begins at 31 and continues to 32 at which a location and grade of a tumor in the prostate is determined as further detailed hereinabove, e.g., by executing selected operations of method 10. Method 30 optionally continues to 33 at which the prostate is imaged and the location is marked on the produced image. The imaging can be done by employ any imaging modality, include, without limitation, ultrasound imaging, CT, MRI and the like. The imaging can also be done or be supplemented with XRF for mapping the zinc levels in the prostate and optionally using these levels to generate the image. The location of the tumor on the image can be marked by matching the location of the query cluster in the zinc map to a location in the prostate image, as further detailed hereinabove. When the zinc map used by method 10 also includes an image of the prostate, the image acquired at 33 can be used as supplementary information. Alternatively, 33 can be omitted.
The method continues to 34 at which the method uses the prostate image for guiding the biopsy or treatment device to the tumor. The device is preferably introduced into the prostate while imaging such that the image presents the location of the device relative to the marked location of the tumor. This allows the physician to monitor the procedure and advance the device within the prostate in the direction of the tumor.
The method ends at 35.
Reference is now made to
System 40 comprises an input module 42, which receives the zinc data. In various exemplary embodiments of the invention system 40 further comprises a mapping module 44 which for generates a zinc map using the zinc data, as further detailed hereinabove. Alternatively, input module 42 can receive the zinc map.
System 40 further comprises a clustering module 46 which clusters the zinc map according to zinc levels, as further detailed hereinabove. Optionally, the system comprises a segmentation module 48 which segments the zinc data as further detailed hereinabove. System 40 further comprises a grade estimating module 50 which estimates the cancer grade as further detailed hereinabove. Optionally, the system comprises a staging module 51, for estimating the stage of the cancer, as further detailed hereinabove.
In various exemplary embodiments of the invention system 40 comprises a probe device 52, adapted for being inserted into at least one of the rectum or the urethra of the subject. Probe device 52 measures the zinc data and transmits it to mapping module 44. For clarity of presentation data flow from probe device 52 to mapping module 44 is not shown. Probe device can be, for example, any of the devices described in WO2004/041060 supra. A preferred probe device is described below with reference to
In various exemplary embodiments of the invention system 40 comprises a display device 54 for displaying one or more of the clusters, as further detailed hereinabove. Display 54 can also communicate with module 50 in which case display 54 can also display the estimated grade associated with one or more of the query clusters. Display device 54 can be a computer screen, a printing device, an image projector and the like.
Reference is now made to
Apparatus 100 comprises a probe 101 adapted for being inserted into at least one of the rectum or the urethra of the subject. Probe 101 is preferably flexible so as to facilitate the insertion of probe 101 into the anus or through the urethra. Additionally and preferably probe 101 including its various components as further detailed hereinafter, is size wise and geometrically compatible with the internal cavities of the subject so as to minimize discomfort of the subject during the non-invasive in vivo examination.
It is known that in most cases, carcinoma of the prostate originates in the peripheral zone of the posterior lobe, which may be diagnosed by access through the rectum. In experiments performed by the present Inventors, it was found that about 90% of the biopsy tissue cores with cancer had cancer in the first 5 mm near the rectal wall.
As used herein, the term “probe” refers to a rectal probe, a urethral probe, an interoperative probe or a probe designed for more than one medical application, as further detailed hereinabove.
Apparatus 100 can comprise an irradiation system 103, at least a portion of which may optionally be located within probe 101, which is capable of emitting exciting radiation 104 so as to excite a chemical element (e.g., Zn atom 107) to emit characteristic radiation 105 (e.g., fluorescent X-ray radiation). Specifically, irradiation system 103 emits radiation 104 in a desired energy, flux and direction so as to impinge on the tissue of prostate 102. This radiation causes the excitation of chemical element 107, which in turn decays by emission of emitted radiation 105.
According to some embodiments of the present invention irradiation system 103 may be, for example, a conventional radioactive source such as, but not limited to, a 109Cd source, an X-ray tube such as, but not limited to, a miniature X-ray tube, a synchrotron light source, an X-ray beam guide connected to an external X-ray source, a miniature plasma X-ray generator and the like.
The energy of the incident exciting photons emitted from irradiation system 103 is dictated by the energy behavior of the cross-section for the excitation of a given element and by the absorption in the gland tissue. Preferably, the energy of the incident radiation is selected to optimize the measurement. Specifically, the energy is sufficiently high so as to be penetrative, but not too high so as not to reduce the cross-section for the excitation. In addition the energy of the incident beam is optimized to have minimum radiation dose to the patient. For example, if the chemical element is zinc, the optimized incident energy is between 18 and 23 KeV for measuring radiation from zinc atoms between 3 and 9 mm depth inside the gland. An additional consideration can be given to the background that the incident radiation produces in the spectral region of the characteristic radiation of Zn (8.6 and 9.6 keV). All factors dictate preferred incident energy.
Hence, for example, when a monoenergetic synchrotron radiation is used as an incident radiation the optimal energy is preferably about 18 keV for a 3 mm thick rectal wall and measuring zinc right behind the rectum, and 23 KeV for measuring zinc at 6 mm behind the 3 mm thick rectal wall. When a filtered X-ray tube is used the energy depends on the anode material and the filtration of the continuous bremsstrahlung radiation. In this case several anodes may be used, for example a molybdenum anode with a characteristic emission line of 17.4 keV, a Zr with a characteristic emission line of 15.8 keV or a Nb anode with a characteristic emission line of 16.6 keV.
When a filtered X-ray tube is used the energy depends on the anode material and the filtration of the continuous bremsstrahlung radiation. In this case several anodes may be used, for example a molybdenum anode with a characteristic emission line of 17.4 keV, a Zr with a characteristic emission line of 15.8 keV or a Nb anode with a characteristic emission line of 16.6 keV.
According to some embodiments of the present invention irradiation system 103 comprises a scanning mechanism, which irradiates the tissue each time at a different location so as to obtain mapping of the prostate as further detailed hereinafter. Scanning irradiation systems are known in the art. For example one or more of the above-mentioned sources may be adapted for emitting the exciting radiation in a plurality of predetermined angles and/or a plurality of predetermined locations. The scanning of the tissue may also be performed manually by the operator by directing probe 101 to different directions and/or by positioning it at different locations.
Optionally, irradiation system 103 may be coupled to a monochromatizing element so as to provide a radiation with a substantially accurate (well defined) energy. Any suitable monochromatizing element may be used, including, but not limited to, a crystal monochromator or a plurality of different absorbing films each of which being characterized by a different absorption coefficient.
Apparatus 100 further comprises a radiation detector 106 located within probe 101 and capable of detecting emitted radiation 105. Detector 106 may have any shape compatible with the shape of probe 101, such as, but not limited to, a planar shape, a spherical shape, a cylindrical shape and the like. Detector 106 is preferably suitable for mapping emitted radiation 105, e.g., for the purpose of defining a boundary of a tumor 108 present in prostate 102. More specifically, detector 106 is preferably capable of detecting radiation from a plurality of predetermined angles so as to allow the mapping of the chemical element of interest. This may be achieved in more than one way. In one embodiment, detector 106 is a scanning detector, the scan of which is preferably synchronized with the scan of irradiation system 103. In another embodiment detector 106 is a position-sensitive detector which detects the emitted radiation as a function of its position. In an additional embodiment detector 106 is preferably an array of detectors (e.g., scanning detectors and position-sensitive detectors) being optimally arranged for detecting radiation as a function of position and/or angle.
Any known type of detector, which is suitable to detect the emitted radiation, may be used. For example, radiation detector 106 may be a high energy-resolution solid state detector such as, but not limited to, detectors based on Silicon (Si), Germanium (Ge), Silicon-Lithium-drifted (Si(Li)), Ge(Li), Mercury Iodide (HgI2) or Cadmium-Zinc Telluride (CdZnTe), which can be cooled by a small thermoelectric device 154. Detector 106 may optionally be a high energy-resolution gaseous detector such as, but not limited to, a gas proportional detector or gas scintillation detector. It is to be understood that any other detector sensitive to X-rays in general and to a characteristic X-ray fluorescence emitted by chemical element 107 (shown as a zinc atom for the purpose of illustration only and without any intention of being limiting) is not excluded from the scope of the present invention. Detector 106 can optionally be a single element, a pixelized array or an array assembled of many individual elements. A solid state detector can optionally be a PIN diode, a surface barrier diode, a drift diode, a micro-strip detector, a drift chamber, a multi-pixel detector, a multi-strip detector and others. Apparatus 100 may also comprise electronic circuitry (not shown) to process signals from detector 106.
Thus, by detecting the radiation emitted from different locations of the prostate, apparatus 100 determines the level of the zinc and thereby successfully provide a zinc map of the prostate.
According to some embodiments of the present invention apparatus 100 further comprises an X-ray optical system 190, located within probe 101, for the purpose of collimating and focusing the radiation emitted by irradiation system 103 and/or chemical element 107. X-ray optical system 190 preferably prevents detector 106 from directly receiving any radiation emitted from irradiation system 103, and more preferably to receive only emitted radiation 105, which, as stated is emitted from chemical element 107. At least a portion of X-ray optical system 190 is preferably made of materials whose characteristic X-rays do not interfere with the determination of the tissue elements, in general, and Zn in particular.
Detector 106 is preferably in electrical communication (which can be either wireless communication or wired communication) with a signal recording, processing and displaying system 120 which maps the level of chemical element 107 in prostate 102 at a plurality of different points according to the mapping of detector 106. The mapping of system 120 may optionally be displayed on a display device (e.g., a monitor, a printer and the like) which is viewed by the operator for diagnostic purposes. For example, system 120 may be programmed so that zinc levels (or levels of any other chemical element) are graphically displayed on a two- or three-dimensional image of prostate 102, thereby to allow the operator to define the boundary of a cancerous region.
The electrical communication between system 120 and detector 106 is preferably controlled by electronic circuitry the size and shape of which is adapted to be compatible with the size and shape of probe 101. The electronic circuitry is designed and constructed for transmitting signals from detector 106 to system 120. The probe's head is preferably coated with a thin disposable polymer protection film 167, changed between examinations of different subjects.
The beam containing radiation 104 is preferably focused to a focal spot having a typical diameter of from about 0.5 to about 1 mm.
As stated, probe 101 comprises X-ray optical system 190 which preferably serves two purposes: (i) focusing and collimating the radiation emitted from irradiation system 103 (i.e., radiation 104) and (ii) collimating the radiation emitted from chemical element 107 (i.e., emitted radiation 105). According to some embodiments of the present invention, system 190 may optionally comprise a focusing element (not shown) for performing the focusing functionality of system 190. The focusing element may be, for example, a capillary optical device or an aperture having a suitable size. A preferred focal distance of the focusing element is from 80 mm to 100 mm.
In addition, system 190 preferably comprises a collimator (not shown) for performing the collimating functionality. The beam containing emitted radiation 105 (e.g., fluorescent radiation), emitted from a well-defined depth (focus point) is preferably collimated by the collimator into detector 106, which preferably has an annular geometry. The collimator is preferably a multichannel device having a plurality of predetermined radiation paths, e.g., thin apertures, thin capillaries, X-ray optical elements and the like. A typical but non-limiting diameter of radiation paths is about 50-200 micrometer. The collimator may have any geometrical shape, such as, but not limited to, a planar shape, a spherical shape or any other shape. The geometry of detector 106 preferably matches the geometry of the collimator. For example, a spherical collimator is used with a spherical detector and a planar collimator is used with a planar detector.
Once collimated, radiation 105 impinges on detector 106 which transmits the information via electronic circuitry 152 to system 120. Probe 101 preferably comprises a thermoelectric cooler 154 being in contact with detector 106 for maintaining detector 106 at a sufficiently low temperature.
The collimator can be configured in more than one way. Hence, in one embodiment, the collimator directs radiation emitted from the chemical element in a single location to a plurality of locations on detector 106, in another embodiment, the collimator directs the radiation emitted from the chemical element in a plurality of locations to a plurality of locations on radiation detector 106, and in an additional embodiment, the collimator directs the radiation emitted from the chemical element in a plurality of locations to a plurality of detector-elements.
In various exemplary embodiments of the invention the collimator facilities the ability of detector 106 to discriminate between radiation emitted by the chemical element which is present in the prostate and radiation emitted by chemical elements which present in tissues surrounding prostate (e.g., rectal wall). For example, the collimator may be constructed such that radiation emitted by chemical elements present in tissues other than tissues of the prostate is filtered out. In particular, the collimator preferably collimates the size and/or divergence of the primary and the fluorescent beams, such that that the intersection of these beams defines a small volume within the prostate.
One ordinarily skilled in the art would appreciate that probe 101 may be manufactured from any material suitable for endoscopic procedure, such as, but not limited to, aluminum, plastics, polymers, carbon-fibers—based materials, Cu-free stainless steel. Generally, materials from which probe 101 is manufactured are preferably selected so that the characteristic lines of these materials do not conflict with the characteristic lines of the chemical element of interest. For example, when the chemical element is zinc, probe 101 is preferably manufactured from materials other than Cu or brass because of (i) the presence of Zn in brass; and (ii) the proximity of the Cu characteristic lines (8.04 and 8.904 keV) to that of Zn. When probe 101 is made of a plastic material or includes components made of plastic materials, the plastic materials are preferably devoid of and do not conflict with the characteristic lines of the chemical element of interest.
The external dimensions of the probe are preferably selected so as to optimize the active area of detector 106 while complying with the dimension of the cavity through which it is inserted (e.g., of the rectum). A preferred diameter of probe 101 for transrectal inspection is about 25 mm, which defines a sufficiently large detector area of about 100-200 mm2, corresponding to a large detection solid angle. Large solid angles are needed for maximal reduction of the exposure time of inspection, by enhanced detection efficiency, keeping the radiation dose to the patient as low as possible.
In some embodiments of the present invention apparatus 100 employs a normalization procedure, in which the level of one element is determined relatively to another element, referred to herein as a reference element. Such normalization is known to be more accurate than a measurement of absolute concentration levels which may introduce inaccuracy due to dependence of the absolute levels on probe position (e.g., distance of the probe from the tissue), probe sensitivity and the like. A preferred normalization procedure for the purpose of qualitative determination of chemical element 107, comprises measuring the radiation emitted from element 107 in comparison to the radiation emitted from a reference element whose level is relatively constant. Alternatively the element concentration can be normalized to that of the Compton scattered part of the incident X-ray radiation.
Apparatus 100 can also be used for determining and mapping levels of chemical element introduced into the prostate for a specific medical procedure, e.g., palladium (Pd) in the form of Pd-porphyrin compounds and the like.
One such medical procedure is a photodynamic therapy (PDT), where one or more chemical elements (also known as photosensitizers) that bind to rapidly dividing cells are administered either directly to the prostate or systemically to the treated subject. The administrated photosensitizers have an inherent ability to absorb photons and transfer energy to oxygen which then converts to a cytotoxic or cytostatic species.
According to some embodiments of the present invention apparatus 100 further comprises a device 140 for illumination of the prostate with light, which preferably has a wavelength suitable for exciting the administrated photosensitizers. Once excited, the photosensitizers induce a chemical reaction which results in a production of free radicals and/or other reactive products that destroy the abnormal tissue or cell with relatively small damage to the surrounding healthy tissue.
Thus, apparatus 100 has the advantage that it may be used for diagnostic purposes as well as for therapeutic purposes. The diagnosis and the therapy may be combined in a single treatment of the subject, where in a first stage the malignant tumor is detected and its boundary is defined and in a second stage the tumor is treated, e.g., using PDT. The diagnosis/therapy combination may be further facilitated by an injecting device 160 located within probe 101, for injection a drug or a contrast agent into the prostate. The contrast agent may be used, for example, for imaging purposes, when the use of apparatus 100 is combined with an imaging apparatus. The contrast agent may also be a chemical element which is known to bind to the cancerous region in the prostate. For example, if Pd is introduced to the prostate, the Pd may be used also for diagnosis and not only to be used for PDT.
Being equipped with detector(s) 106, apparatus 100 may optionally also be used for detecting radioactive substances (e.g., radioactive 125I or Zn) introduced into the prostate for diagnostic purposes either systemically or by local administration into the prostate or proximal thereto. In such a mode of operation, the exciting radiation emanating from irradiation system 103 is typically turned off. This may optionally and preferably be done through a peripheral device or through an ON/OFF switch included within probe 101. The measurement of radioactive substances may be useful for staging the disease, as for example it is known that changes in the 125I concentration levels in the prostate may indicate a cancerous pathological condition of the prostate.
It is appreciated, that in some cases, the diagnosis of the detected tumor may have some degree of inconclusiveness, and that in such cases the real-time diagnosis should be supplemented by biopsy. In other cases, apparatus 100 is used for the purpose of locating a region of the prostate (e.g., when probe 101 is used as a radioactive detector) from which a biopsy is to be taken. According to some embodiments of the present invention, apparatus 100 comprises a biopsy device 180 for performing biopsy from a specific region of the prostate.
According to some embodiments of the present invention, probe 101 is combined with or comprises an additional mapping device 170, such as, but not limited to, an ultrasound device, a magnetic-resonance-imaging device. In this embodiment, apparatus 100 is capable of mapping the prostate by XRF and also preferably by an additional method (e.g., ultrasound waves). The advantage of such a double mapping procedure lies in the enhanced accuracy of determining the tumor location, so that the number of biopsies (if any is required) is minimized. In contrast, presently known TRUS procedures have low reliability and repeated biopsies are needed, with the risk of infections and extra costs.
As used herein the term “about” or “approximately” refers to ±10%.
The word “exemplary” is used herein to mean “serving as an example, instance or illustration.” Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.
The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments.” Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.
The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.
The term “consisting of means “including and limited to”.
The term “consisting essentially of” means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.
Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claim section below find experimental support in the following examples.
Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion.
X-ray fluorescence measurements: The methods and sample-handling protocols used in this study were described in details in PCT WO 2004/041060 to Breskin et al, filed Nov. 6, 2003, including details on calibration procedures and ways used to avoid sample drying during the measurements. Briefly, Zinc concentration in the examined tissue-segments was quantified by X-ray fluorescence (XRF). Under the measuring conditions the sensitivity of both is about 20 counts per ppm, namely Zinc concentration sensitivity better than 1 ppm. The calibration of both systems was checked against identical calibration standards, with absolute precision of a few μg/g (˜1%). The reliability was checked by repeated measurements of the same sample, during the entire study, assessed to be within sigma=5%.
The measurements were carried out, in parallel, in two locations, using two tabletop XRF systems: one a locally-assembled system at the Kaplan Medical Center (KMC) and a commercial unit, custom-modified for our application, at the Sheba MC (SMC); the later system, with fully automated operation, had about 20 fold higher X-ray flux and superior spectrum quality. Both XRF systems were calibrated with the same calibration standards, permitting to combine data from the two experiments.
At KMC, 6 needle-biopsy samples (out of 12 extracted) per patient, each being a 0.5 mm in diameter and 15-20 mm long tissue cylinders folded in two, were placed between two 2.5 micron Mylar foils, on the sample tray that incorporated wet sponges. The sample tray was designed to minimize radiation scattering and to reduce sample drying (to <1%) during the 20-30 minutes measurement per patient. The sample tray was manually linearly-translated, introducing one sample at a time into the measurement site. The entire sample was irradiated and its average Zinc content was calculated with a precision ranging from 30% to 5%, for 30 and 500 μg/g, respectively. At SMC, all extracted 8 needle-biopsy samples of same dimensions as above, were individually placed between two 2.5 microns Mylar foils in special cups, and mounted, tangentially aligned, on a rotating table. No drying was observed during the 12 minutes measurement per patient. The SMC XRF system afforded measurement of the Zinc content within four different segments, each 5 mm long, along the sample; the Zinc content precision was 15% to 5% for levels of 50 to 200 μg/g, respectively.
The clinical protocols were identical in both medical centers. The fresh needle-biopsy tissue cores were placed on their respective supports immediately after extraction, and introduced into the XRF system within minutes. Following the Zinc measurement, the samples were marked (rectal end) and stored in formaldehyde for routine histological processing: embedding in paraffin wax, slicing into 4 micrometer thick slices, and staining with hematoxylin and eosin. Pathological examination results included a diagnosis including Gleason score and the % gland, namely the fraction of surface occupied by the glandular tissue. Diagnostic categories are: PCa (adenocarcinoma), BPH (benign prostatic hyperplasia), PIN (prostatic intraephytelial neoplasia), ASAP (atypical small acinar proliferation) or GRAN (granulomatous inflammation).
Data correlations: The present mode of analysis provides three levels of data: a segment Zinc concentration and its corresponding histological classification; a core Zinc concentration and its corresponding diagnosis and a patient average Zinc concentration and its corresponding diagnosis. (The patient-average Zinc is the average of measured Zinc-concentration values over the entire volume of the extracted tissue per patient). A patient is defined as PCa one if any of his biopsy cores was diagnosed as PCa. A sample or a segment is defined as PCa only if the diagnosis of that sample or segment is PCa. All other diagnoses otherwise specified, are referred to as Non-Cancer.
Other relevant patient data from medical files, such as PSA, age, Zinc-rich nutrition supplements, prostate size, etc, has also been collected and analyzed for correlation. The data analysis included correlation of different variables (e.g. Zinc concentration) with the diagnosis, PSA, % gland, and other parameters from the patient's files; it also included the construction of sensitivity vs. specificity (Receiver Operating Characteristic=ROC) curves of some parameters or parameter combinations. PCa detection capability based on Zinc mapping has been evaluated by computer simulation of Zinc maps (using the measured data) with lesions of various sizes at random location, followed by image analysis and derivation of the respective ROC curves.
Grading of tissue samples: Tumors are labelled according to pathological grade classification as “well-”, “moderately-”, and “poorly-” differentiated, corresponding to Gleason-score values of 5-6, 7 and 8-10, respectively. The Gleason score relies on the topology of cancer cells in the gland; it evaluates their resemblance or difference to normal-gland topology and consequently describes the aggressiveness of the lesion. The Gleason score and grade scale are described in detail hereinbelow.
Gleason score and prostate cancer: The histological grade, also called pathologic grade, is an important predictive factor of malignant disease, and is commonly used to define the potential for local and/or distant progression of malignant tumours. Not all prostate carcinoma progress along the same path: the majority of PCa cases are indolent with non-clinical manifestation; in other cases, the disease is localized, well confined to the prostate, with very slow progression; other carcinomas, with metastatic potential, evolve rapidly to a life-threatening disease. The rapidity and path of the carcinoma development depend on how closely the cancerous cells resemble normal ones.
The most accepted histopathological grading system is the one proposed by Donald F. Gleason, which is presently the most practiced prognostic factor, being significantly associated with survival and/or progression of the PCa. The Gleason-grade scale is based on the histological pattern of differentiation and arrangement of carcinoma in hematoxylin-eosin (H&E)-stained sections (
It is a common practice to characterize the cancer both by the clinical stage (dimension and spread), and by the Gleason grade. Thus, updated classification based on Gleason grade defines as “well differentiated” a PCa of grade (3+3), as “moderately differentiated” the grades (3+4, 3+5, 4+3, 5+3), and as “poorly differentiated” the high Gleason grades (4+4/4+5/5+4/5+5).
Data source (KMC or SMC) is identified on each graph or table.
Table 1 summarizes the total patient statistics. Table 2 summarizes the total tissue-segments statistics.
The effect of patient age on the average Zinc concentration in the prostate is depicted in
In order to assess the possibility of a falsely-elevated Zinc concentration due to Zinc-supplements consumption (e.g. multi-vitamins. See Table 1), the effect of Zinc supplementation on the segment and on the patient-average data levels was examined.
The results are clearer when studying the Zinc-rich nutrition effect at the data level of tissue segments.
where μ and σ are the mean and standard deviation of the variable's logarithm), and analyzed with K-S test to compare the distributions of different ensembles. The Zinc-rich diet does not affect the distribution's width but it does shift its mean. The shift is negative (from 109 to 103 ppm) for Non-Cancer tissue segments, and statistically significant; it is more pronounced and positive (from 56 to 81), and statistically significant, in the PCa tissue segments. More importantly, the Non-Cancer “no-Zinc-supplement” distribution and the PCa with Zinc supplement distribution are not statistically different, clearly demonstrating the obscuring effect of Zinc-rich dietary components.
On the other hand, the local Zinc concentration (
Based on these findings, data from patients consuming Zinc-rich nutrition supplements was excluded from the statistical analysis. The effect of this exclusion on the conclusiveness of the results was deemed negligible.
Zinc Concentration in PCa Patients-Correlation with Gleason Score
In order to determine whether Zinc concentration can be used for staging PCa, Zinc-concentration in PCa-diagnosed patients confirmed to avoid Zinc-rich diet, and its correlation with the Gleason score was measured. The correlation is presented for patient average, core data level and segment data level. In almost all cases the Gleason score values assigned to all the malignant segments of a given patient were identical, and equal to the Gleason score assigned to the patient. Therefore, Non-Cancer tissue was also classified according to the Gleason score of the patient. Table 3 below provides the information on PCa-patients number per each Gleason score category (65 in total); the well-, moderately- and poorly-differentiated categories correspond to Gleason score values of 5-6, 7 and 8-9. This grouping was needed due to the low statistics. The 7 patients diagnosed for minimal volume carcinoma (MVC) were considered separately. Table 3 also summarises the statistics of tissue cores and tissue segments classified in the same way.
The diagnostic value of Zinc concentration averaged over the entire volume of the extracted tissue (patient average) may be evaluated from the sensitivity versus specificity curve (ROC curve, or True Positives rate versus False Positives rate) of this parameter (
In order to evaluate the diagnostic value of the local (e.g. segments) Zinc concentration, a large number of data points per patient (up to 32 in our case) can be converted into a single value, for which a sensitivity versus specificity (ROC) curve could be constructed, thereby permitting comparison of the quality of Zinc concentration diagnosis with other existing indicators such as PSA and its derivatives.
Alternatively, the diagnostic value of Zinc-concentration information can be assessed by assuming that a full Zinc-concentration map (two or three dimensional) could be produced, and then confirming the diagnostic value of such a map. In order to evaluate the usefulness of such data, maps have been produced by computer simulations, using the measured Zinc-concentration data of
Taken together, these results clearly indicate that the local Zinc level, measured in 1-4 mm3 fresh tissue segments, shows a clear correlation with the histological classification of the tissue, whether Non-Cancer or malignant, and a systematic positive correlation with the Gleason score classification of the cancer: the higher the Gleason score the more Zinc is depleted, and the greater the contrast between the malignant and the Non-Cancer tissue components. This indicates that the amount of Zinc depletion could be used as a measure of the Gleason score of the tumor. Further, this indicates that the higher the Gleason score, the smaller the detectable lesion. In particular, measurement of patient-average Zinc according to some embodiments of the present invention was found to be correlated with the disease grade and of greatest significance for lesions having high Gleason scores, of 8-9. Further, measurement of patient average-Zinc according to some embodiments of the present invention was found to be diagnostically significant for low Gleason grade lesions measuring ˜0.5 cm3, and higher Gleason grade lesions, measuring ˜0.1 cm3.
Further, positive correlation of the local Zinc concentration with the histological classification of the tissue, as Non-Cancer or PCa, with further correlation with the Gleason score within the PCa group is demonstrated, indicating that the specificity and sensitivity of local Zinc concentration is highest for lesions with higher Gleason grade, of clinical importance.
Significantly, it was uncovered that the Zinc depletion occurs not only in the cancerous tissue segments but also, though less pronouncedly, in the Non-Cancer components surrounding the lesion, and in correlation with the Gleason score, which may indicate that Zinc depletion is an early step in the cancer proliferation process and that Zinc depletion precedes the transformation of cells from normal to cancerous type. Thus, although PCa may not be histologically detectable in such regions, the cellular precursor for its appearance may already be present and active, and is more pronounced the more aggressive is the malignant process in the other parts of the prostate. Such pre-malignant and malignant processes in the peripheral zone may be detectable by measurement of Zinc depletion.
In addition to detection and grading of cancerous and pre-cancerous foci, it would be highly desirable to have tools for accurate and non-invasive location and imaging of prostate lesions, in order to detect both location, dimension and grade of lesions. In order to test whether Zinc depletion data generated in accordance with some embodiments of the instant invention, can be useful in location and imaging of prostate lesions, Zinc-concentration maps were generated from experimental Zinc-concentration data. The maps represent prostate-tissue with lesions of different dimensions and histological grades, at various locations within the gland. The maps are then transformed into 8-bit images and processed with a simple image processing algorithm yielding a one-parameter classifier test.
Note that all the Zinc distributions in
Two-dimensional Zinc-concentration maps, representing 1 mm thick prostatic tissue layers of area 3×3 cm2, with or without cancerous lesion, were generated using Monte Carlo tools. The experimental Zinc distributions according to the measurements as shown in Example I, hereinabove (summarized in
The analysis of the 8-bit images consisted of the following stages (i) Denoising (ii) Detection and Localization (iii) Classification and (iv) Grading
In the very first step, the image is processed with a median filter, which led to high degree of noise reduction (Denoising) but preserved the edges of the image features. This is critical to the clinical application of such an imaging tool. In the second step, an automatic detection of local Zinc-depleted features in the image was performed by an image-segmentation process, based on cluster-analysis. Image-segmentation is a low-level image-processing task that aims at partitioning an image into multiple chromatically-homogeneous regions. In recent years, many methods for improving segmentation-algorithm performance have become available, such as, for example, thresholding, clustering, or Markov random filed, etc.
Expectation-maximization (EM) technique for image segmentation was used for the analysis of Zinc concentration data: EM is a well-known unsupervised clustering algorithm, which iteratively alternates between segmenting the image into N pixels' classes (clusters) and characterizing the properties of each class. The output image of the EM clustering algorithm (segmented image) represents a statistical description of the N clusters, providing the number of components in each cluster, localization of the cluster within the map, average grey-level and related variances associated to the cluster. Using this method, the digitized Zinc-images are partitioned into 6 homogeneous clusters classified by their average grey-levels; however, only the cluster with the lowest grey-level value is identified as “suspected” cancer-lesion areas (Detection and Localization).
In
Once the lowest-Zinc cluster has been geometrically localized by image segmentation, the cluster needs to be classified as cancerous or non-cancerous (Classification) and, whenever it is classified as cancerous, it needs to be classified according its cancer-aggressiveness grade (Grading). Further, a stage can be assigned to the lesion, according to the size of the lesion detected in imaging.
The processes of classification and grading are performed by a single-parameter classification test, based on LCZn values. The performance of the classifier test was computed and evaluated by means of Receiver Operating Characteristic (ROC) analysis. The ROC curve is a two-dimensional graph in which a true-positive rate (sensitivity) is plotted versus the false-positive one (1-specificity) for each classifier's cut-off value, the so called ROC space. An ideal binary classifier test would yield a step-function shape (0,1) in the ROC space, representing a sensitivity of 100% (all true-positives found) and 100% specificity (no false-positives found). The area under the ROC curve (AUC) is a common way of depicting the classifier-test quality and comparing the performances of classifiers and their combinations. An AUC close to 1 corresponds to an excellent diagnostic test while an AUC of 0.5 corresponds to a completely random one.
Several sets, each of 10,000 synthetic maps, with and without “lesions”, were generated. The different sets were characterized by different image- and lesion-parameters, namely spatial resolution (total number of pixels), cancer-lesion size, Gleason grade. The relation between cancer detection performance and various image-parameters were evaluated, based on the image processing and ROC analysis detailed above, using the LCZn value as test classifier. For each set of lesion- and map-parameters, images (with and without lesion) were generated and processed. The presence and location of an identified cancer were then compared to the input information. Consequently each missed or identified lesion could be tagged as true/false positive or true/false negative. The process was carried out while varying the threshold of the classifier test, to construct the entire relevant ROC curves.
According to current general practice, only tumours larger than 0.5 cm3 (about one fifth of the PCa tumours detected in autopsies) are considered to be of clinical significance, with further refinement claiming that tumour volume adjusted for grade is the appropriate predictor of disease-specific survival. Malignancies with a volume of 0.5 cm3 or less and a Gleason score of less than 7, are declared clinically-insignificant and may be managed by watchful waiting. Thus, within the present study clinically-relevant tumour-sizes were defined as above 0.5 cm3 for the more aggressive prostate cancers (above or equal to Gleason grade 4+4) and above 1 cm3 for the less aggressive ones (below Gleason grade 4+4).
A systematic examination of the effect of pixel size/density is shown in
In general, the results of such simulations indicate that, under the present analysis scheme, there is an optimal spatial resolution for each lesion grade and size combination, and further improvement of the spatial resolution would not provide substantial improvement in terms of PCa detection. In order to achieve more efficient functional image processing for low Gleason grade lesions, perhaps an improved noise reduction process and a more effective image-segmentation algorithm could be employed.
The image processing scheme described in previous section, provides information on the location, size (number of pixels), average Zinc levels and variance of the Zinc distribution within each cluster. This information could be useful not only for detection and localization but also for grading and staging of the detected lesion. This is demonstrated in
In the region below the “staging/grading limit” line, the curves in
It will be noted that an actual detected cancer area will not be equal to the simulated one, but rather systematically larger, by a factor which depends on the Gleason grade. The accuracy of the area definition improves with increasing Gleason grade, due to the greater contrast between cancer and benign Zinc distributions. For a practical application of this method, the information on the detected cancer-lesion area should be evaluated together with its Zinc level (LCZn), in order to assess both the grade and the area. Then, for cancer volume above the threshold, the combination of the two could be used as an indication of the cancer-lesion location, size and grade.
In the case of low-grade cancers (3+3 and 3+4), the measured (
Counting statistics is directly related to the radiation dose administered to the patient; clearly, the radiation dose should be kept at minimum.
The counting-statistics effects, which affect the image quality, are related to random fluctuations in the measured number of Zinc XRF photons. In particular, the fluctuations degrade the precision of the image contrast, the information on the Lowest Zinc value; this affects the tumour grading and the details of the lesion-edges and hence the information on the lesion dimensions. There is a trade-off between radiation-dose and image-quality; the optimization is important for the application of the Zinc-based diagnostic approach and for the realization of an in-vivo trans-rectal prostatic-Zinc probe.
In order to study and quantitatively estimate the effects of counting statistics that result from fluctuations in the XRF photon detection, we performed a Monte-Carlo study and ROC analysis; these consisted of 15×15 and 30×30 pixels images and two sets of 1000 images each, with and without cancer lesions. Zinc-maps image were computer-simulated, using a first random number generator, as described herein. The maps were essentially pixel matrices whose elements represent Zinc concentrations associated to specific locations within the map. Each pixel's content was then converted into number-of-counts, by multiplying the corresponding Zinc-value by a specified sensitivity (counts per ppm per pixel). The effects of the sensitivity on cancer area detectability is schematically represented in
The number of counts per pixel was assumed to represent the mean value of a Poisson distribution. The final number of counts in that pixel was calculated by a second random-number generator based on Poissonian-sampling distribution with that mean; the pixel matrices resulting from this step were also processed following the procedure described herein. Examples of counting-statistics effects on processed images are shown in
As can be seen from
Taken together, the results of the simulations described herein indicate that an inclusive image of the histological-grading probability for the examined prostatic tissue could be of a prime importance for the decision-making process of needle-biopsy site selection.
Based on the relationship between total number of pixels (image spatial resolution), lesion-size, cancer aggressiveness (Gleason grade) and counting statistics, an exceptional sensitivity in detecting small PCa lesions, even with rough spatial resolution, could be reached for aggressive cancer lesions (Gleason grade 4+3 and above). The results indicate that the analysis of the Zinc maps may provide important knowledge concerning the geometry of lesions encountered in a clinical setting, and the degree of confidence in the prognostic results as function of some system parameters such as spatial resolution and sensitivity. Zinc frequency distributions for low-grade cancer lesions (primary Gleason grade 3) were similar to those of non-cancerous tissue, and are in need of possible further processing in order to provide valuable results. However, since the input Zinc frequency distributions, as shown in
Regarding counting statistics, the results disclosed herein show that the overall effect of counting statistics on cancer-lesion area detectability depends, from a qualitative point of view, on multiple factors such as image spatial resolution, intrinsic instrumental sensitivity and total irradiation time (dose) per pixel. The detectability of the cancer-lesion area is directly proportional to the Zinc-image contrast, which in turn depends on the histological grade of the detected cancer (lower Zinc concentration for higher Gleason grade). To some extent, high-spatial resolution increases detectability and, at the expense of an increase of the noise level (low statistics), it permits detecting smaller tumours.
The design of a Zinc-mapping instrument (e.g. a trans-rectal XRF probe) can be based on a compromise between dose consideration, total irradiation time and patient comfort, counting statistics effects and instrumental sensitivity of the detection system. The present Monte-Carlo study provides invaluable information on the significance of each variable to the overall diagnostic potential.
The proposed Zinc-based mapping method is expected to have significant impact on early diagnosis of prostate cancer. Zinc mapping, being a non-invasive examination, can be employed as an additional screening tool, prior to referring the patient to needle biopsy, can improve the distinction between benign and malignant conditions (e.g. BPH vs PCa), provide grading and geometrical information concerning cancer-lesion, thus refining the process of patient selection for biopsy. This can, in turn, reduce the number of unnecessary biopsy procedures performed increase the cost effectiveness of needle biopsy examination. It will thus facilitate extension of the biopsy examination to younger persons with PSA lower than 4 ng/ml, offering an improved screening strategy, and can thus have considerable impact on the life quality and expectancy of prostate-cancer patients.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claim.
All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.
This application claim the benefit of priority from U.S. Patent Application Nos. 61/006,241 and 61/095,632, the contents of which are hereby incorporated by reference as if fully set forth herein.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IL09/00006 | 1/1/2009 | WO | 00 | 8/23/2010 |
| Number | Date | Country | |
|---|---|---|---|
| 61006241 | Jan 2008 | US | |
| 61095632 | Sep 2008 | US |
