WO2008147865A1

WO2008147865A1 - Point of care cervical screening system

Info

Publication number: WO2008147865A1
Application number: PCT/US2008/064500
Authority: WO
Inventors: Peter Gombrich; Mitchell Golbus
Original assignee: Diamics, Inc.
Priority date: 2007-05-22
Filing date: 2008-05-22
Publication date: 2008-12-04

Abstract

A see and treat system and method which involves screening cellular samples for lesions that can be treated at the earliest stages, in a manner where a clinician can treat the patient with information provided by the screening assay in the same visit as the sample is taken. In one embodiment, a sample is collected from the cervix using a collector, the sample is transferred to a receiving structure and assayed so as to detect HPV integration via a biological marker, and the assay results are read via a reporter molecule that associates with the biological marker. The assay results can be read directly or via an instrument. In one example, the instrument is automated or semi- automated, and dispenses liquid into the receiving structure containing cervical cells, detects the presence of marker proteins and then reports the results.

Description

Point of Care Cervical Screening System

This application claims the benefit of U.S. Provisional Application No. 60/939,533, filed May 22, 2007, and which is incorporated herein by reference in its entirety.

Field

This disclosure relates generally to cell sampling, processing and screening for use in detecting abnormal tissue in the body, for example in the cervix. More specifically, this disclosure relates to systems and methods whereby detection can be conducted within a time frame that would permit a patient to be treated in the same visit as a sample is taken.

Background

It is often necessary to collect various cell samples from patients for the purposes of screening for, detecting, and ultimate treatment of, a number of diseases and abnormalities. One of the major reasons for the collection of cellular samples is for the purpose of screening patients for cancer. For example, urine, sputum, breast nipple and fine needle aspirates, and exfoliated cells of the uterine cervix are screened by cytotechnicians and pathologists for the presence of abnormal cells suggestive of the presence of a solid tumor. When such suspicious cells are found, a more definitive diagnosis is reached by removing a sample of the tissue where a lesion is suspected, and submitting the sample for review by a pathologist.

It is generally accepted that diagnosis of cancer at its earliest stages affords the greatest opportunity for effective treatment. A corollary to this is that early diagnosis of a solid tumor corresponds to recognition of localized abnormalities, which at the cellular level are not that different from the surrounding tissue. This presents a challenge for screening of cellular samples where all context and comparison to neighboring cells is lost. One approach to this problem is to concentrate upon elements, i.e. groups of cells, which more closely approximate intact tissue elements. In fact, the presence of such clusters of cells, in and of itself, can be considered to be suggestive of a pre-cancerous or cancerous condition. However, it is also the case that normal tissue elements can be represented as cell clusters in samples collected for cytologic analysis.

Preneoplastic lesions present unique biological features. Dysplasia, the early phase of neoplastic progression, involves cells that are individually minimally different from normal cells present in the same tissue. The major difference between a dysplastic lesion and normal tissue elements undergoing changes in shape (metaplasia) or actively proliferating (hyperplasia) is an imbalance in the fractions of cells expressing characteristic proteins involving abnormal cell growth and turnover. It is well recognized by pathologists, who examine intact tissues, that the admixture of morphological (e,g, mitotic figures) or biochemical (e.g. Ki-67 proliferation antigen) markers of normal growth and function with morphological (e.g. apoptotic bodies) or biochemical (e.g. activated caspase 3) indicators of cell turnover by the process of apoptosis, is characteristic of dysplasia.

Conventional sampling methods utilized in current screening procedures acquire cells from a lesion, but then disperse these cells into a typically much larger number of normal cells obtained from outside of the boundaries of the lesion. This dispersion results in the evaluation of a sample being an exercise in the detection of a rare event; that is, finding one or a few abnormal cells within a background consisting of a very large number (e.g. 50,000-300,000) of normal cells. Furthermore, and perhaps most significantly, dispersion eliminates the information that can be gained from determining the biological characteristics of small areas that might represent preneoplastic lesions. This essential information is present in the relationship among cells, and is not apparent by examining individual cells in isolation from adjacent cells within a tissue. Dispersion also precludes using the sample to determine the location of the lesion on the patient. Even further, such conventional methods are complex, too expensive, or too slow to be useful in clinics, thereby results in a lag time between testing, diagnosis, and treatment. Given that cervical cancer is almost completely preventable through regular screening and early treatment, improvements in screening strategies would be beneficial. Summary

A "see and treat" system and method which involves screening cellular samples for lesions that can be treated at the earliest stages, in a manner where a clinician can treat the patient with information provided by the screening assay in the same visit as the sample is taken, thereby mitigating psychological distress to patients.

Systems that are designed to provide testing or screening capabilities close to a hospital bedside or a physician's office by an operator are commonly referred to as point- of-care (POC) testing. The disclosed system and method utilizes POC testing that includes evaluating biological markers useful in aiding clinicians in screening for the presence of cancerous or precancerous cells in the cervical sample analyzed.

Generally, the disclosed system includes a collector for collecting a sample from the cervix. The collector utilized is not particularly limited, and may be any of the numerous collectors available or a patient self-sampling collection system.

The disclosed system further includes a receiving structure for receiving the sample transferred from the collector. The receiving structure is also not particularly limited, and may be a slide, a vial etc.

The disclosed system also includes an instrument that contains a component for preparing the sample and another component for analyzing the cells.

The disclosed method includes collecting a sample from the cervix using the collector, transferring the sample collected by the collector to a receiving structure, conducting an assay of the sample in the receiving structure so as to detect HPV integration via at least one biological marker, and reading the assay results via at least one marker-specific reporter molecule.

In one implementation, the disclosed systems and methods integrate the fractional histological approach to examining a sample based on indices of protein expression with POC technology, thereby allowing a means to inform the clinician of a map indicating the locations that can be considered to be suspicious for the presence of preneoplastic lesions within a time frame that would permit a patient to be treated in the same visit as the sample is taken. The sample is taken by a cell collector that is designed to collect cell clusters or clumps and maintain the spatial orientation of the clusters or clumps when they are collected and transferred onto a receiving structure, for example a slide. In the case of a cervix, where the sample comes from on the cervix is maintained when the sample is transferred to the receiving structure, so that one not only can determine whether a lesion exists, but also knows the location on the cervix where the lesion is located. The receiving structure with the transferred clusters of cells may be designed to utilize capillary gap methodology in the application of antibodies, and a microfluidics process when applying a wash to the sample. In one embodiment, a slide as the receiving structure with the transferred clusters of cells is sandwiched to another slide to form a slide assembly. The slides are designed so that a channel is formed in between the slides. The channel allows application of liquids to the sample via the microfluidics process (during sample washing) and via capillary action (during antibody application).

The slide assembly, in this embodiment, is placed into a cartridge assembly that contains a blister pack provided with receptacles containing treating reagents. The receptacles are breakable so as to provide microliter quantities of the treating reagents for application to the sample. The cartridge assembly also allows wash fluids to be applied to the sample via the microfluidics process.

The cartridge assembly is then placed into an instrument for preparing the sample and scanning the prepared sample. The instrument has preferably two components, including a first component for preparing the sample for examination and a second component for processing the sample, including scanning the clusters of cells so as to map areas where distinct biological processes are occurring and where dysplasia is present.

Preferably, the instrument:

(i) applies a wash liquid to the sample on the slide assembly; (ii) after washing, breaks the receptacles to release the treating agents and treat the sample;

(iii) scans the treated sample; and

(iv) prints out results.

The concepts described herein can be implemented using admixtures of structural and biochemical analysis. Particularly useful are biological markers which recognize distinct biological processes. These include proliferation markers such as Ki-67, phosphoribosomal protein S6, phosphorylated histone H3 and p21 , apoptotic markers such as cytokeratin 18 or cCaspase3. Other markers that can be used include human papillomavirus (HPV) viral integration markers such as survivin, E6, E7, other HPV specific protein or any other cellular protein that is up-regulated as a result of HPV integration.

Alternatively, the cervical cellular sample is put into suspension, the cells are lysed and an assay is performed in solution.

Brief Description of the Drawings Figure 1 illustrates a flow diagram of one embodiment of a method of POC cervical screening.

Figure 2 illustrates a flow diagram of one implementation of the method in Figure 1.

Figure 3 A is a perspective view of a slide assembly. Figure 3B is an end view of the slide assembly of Figure 3 A.

Figure 4A is a perspective view of a cartridge assembly. Figure 4B is a perspective view of a blister pack used in the cartridge assembly. Figure 4C is an internal view of the cartridge assembly showing the sample end of the slide assembly disposed in a well of the cartridge assembly. Figure 4D is a rear view of the cartridge assembly showing how the blister pack can be accessed.

Figure 5 A is a perspective view of an instrument for preparing the sample and scanning the sample.

Figure 5B is a side view of the instrument.

Detailed Description

I. Overview

A cervical screening system and method involving POC testing. The disclosed system and method allow collecting and screening capabilities close to the bedside by a clinical practitioner or non-laboratory personnel. The POC testing utilized in the disclosed system and method provides comparable information to established laboratory devices measuring biological markers for detection of dysplasia and neoplasia and detection of HPV integration in the cervical sample analyzed.

Figure 1 is a flow diagram illustrating one embodiment of the disclosed method. The method 10 includes collecting a sample from the cervix using the collector 1 1 , transferring the sample collected by the collector to a receiving structure 12, conducting an assay of the sample in the receiving structure so as to detect HPV integration via a biological marker 15, and reading the assay results via a reporter molecule that associates with the biological marker 20. The assay results can be read directly or via an instrument. In one example, the instrument is automated or semi-automated, and dispenses liquid into the receiving structure containing cervical cells, detects the presence of marker proteins and then reports the results.

Figure 2 is a flow diagram of one implementation of the disclosed method. The method 50 includes collecting clusters of cells using a collector that is designed to enhance the ability of the collector to pick up clusters of cells, and to facilitate transfer of the collected clusters of cells onto a receiving structure, for example a slide 52. In this example, clusters of cells are transferred from the collector to the slide using a transfer station in such a way as to retain the spatial orientation that existed between the cells in the clusters prior to sampling 56. Orientation marks on the collector and the slide assist in maintaining the spatial relation during transfer. The slide is sandwiched with another slide so as to form a capillary gap between the slides, thereby forming a slide assembly. The slide assembly is then inserted into a cartridge assembly that is integrated with a blister pack and has a visible window for measuring quantities of fluorescence and color signals 58. The cartridge assembly is then placed into a microprocessor controlled instrument 60. In this example, the instrument (i) dispenses a liquid onto an area of the clusters of cells 62, (ii) pumps liquid out of the area to a disposable machine dispenser 64, (iii) breaks receptacles on a blister pack in sequence into a well where the receiving structure sits 66, (iv) wets sample by agents contained in the blister pack 68, (v) washes sample 68, (vi) scans clusters of cells 70, and then (v) reports a map and the results 70. The POC cervical screening system is one embodiment of an approach to the screening of cell clusters present in specimens in order to identify dysplastic lesions. While this specification will describe the system with respect to cervical cancer screening, it is to be realized that the concepts described herein could apply to other forms of cancer screening.

A. Collection

A collector is used for collecting a sample, for example cervical cells. The type of collector used is not particularly limited, and can be a collector commonly used by a clinician, patient, etc. In one implementation, the collector used collects a cluster of cells while maintaining the spatial orientation of the collected sample relative to the cervix. Examples of such collectors are described in published U.S. patent applications US

2006/0189893 and US 2006/0161076, which are incorporated by reference herein in their entirety. As described in these two publications, a combination of the material of the collector, the texture of the collection surface of the collector, and the use of expansion and rotation of the collector during collection facilitate the collection of the clusters of cells. The collector obtains cell clusters from the endo- and ecto-cervical regions of the cervix.

B. Transfer

Once the sample is collected, a transfer device may be used to transfer the sample from the collector to a receiving structure for subsequent analysis of the sample. The transfer device can be any mechanism, automated or manual, that is capable of transferring the sample to a receiving structure while maintaining the spatial orientation of the transferred cell clusters. An example of a suitable transfer mechanism is disclosed in published U.S. patent application US 2006/0189893, which is incorporated by reference herein in its entirety. As described in this publication, the transfer device expands the collector from a 3-dimensional configuration to a 2-dimensional configuration (i.e. when expanded, the cell clusters on the collector obtained from the endo- and ecto-cervical regions end up on a generally common plane for subsequent transfer to the receiving structure), and the cell clusters are then transferred to a receiving structure. As a result, the spatial orientation of the cell clusters transferred to the receiving structure is maintained. Alternatively, the sample may be transferred directly into a receiving structure without the use of a transfer device. In this example, the sample may be put directly into a receiving structure containing a solution, such that the sample is transferred without maintaining the spatial orientation of the cells. Receiving Structure

A receiving structure is utilized to receive the sample. The type of receiving structure used is not particularly limited, and may be a slide, a vial, etc.

C. Preparing the sample Slide Assembly

Where slides are used as the receiving structure, a unique microfluidics and gap slide assembly 100, illustrated in Figures 2A and 2B, can be utilized for washing and analyzing the sample 102. The slide assembly 100 includes a slide 104 to which a sample 102 has been transferred and a second slide 106. The slides 104, 106 are sandwiched together with the sample 102 between the facing slide surfaces 108, 1 10.

The slide assembly 100 is designed so that liquid can come into contact with the sample 102 via microfluidics and capillary action described later. In particular, the slide assembly 100 is formed so that a small gap 1 12 is created between the facing surfaces 108, 1 10 of the slides 104, 106. The gap 1 12 allows liquid to come into contact with the sample 102 during preparation of the sample.

One way in which liquid contacts the sample is via a microfluidics process used during sample washing and other sample preparation prior to antibody application. In the process, a wash liquid under high pressure is introduced into the gap 112 through the sides of the slide assembly 100. This process allows a larger volume of liquid to contact the sample during washing.

The second way in which liquid contacts the sample is via a capillary action used during application of antibodies to the sample. When an end 1 13 of the slide assembly is immersed in the antibody liquid, the liquid is drawn upward into the gap 1 12 between the slides 104, 106 and toward the sample 102 via capillary action. The specific means for forming the gap 1 12 is not critical, as long as a gap 1 12 is created that allows liquid to reach the sample 102 via the microfluidics and capillary processes. As illustrated in Figures 2 A and 2B, the gap 112 is illustrated as created by protrusions 1 14 that are formed at the corners of the slides 104, 106 at the end 1 13. The opposite ends 116 of the slides 104, 106 are devoid of protrusions 1 14 so that the slide surfaces 108, 1 10 are substantially in contact with each other. The sizes of the protrusions 114 are selected so as to form a suitable gap width. The end 116 of the slide 104 and/or the slide 106 can also include a label 1 18 for use in labeling the slide assembly. The label 1 18 can be used to keep record of the orientation of the transferred sample, as well as the identity of the patient, and further can be machine-readable.

Alternatives for forming the gap 112 are possible. For example, protrusions 114 could be formed on only one of the slides 104, 106, or one protrusion could be on the slide 104 and one protrusion on the slide 106. In addition, the protrusions 114 can have shapes other than that illustrated. The protrusions 114 need not be integrally formed with the slides 104, 106. Instead, the protrusions 114 could be initially separate from, and later secured to, either slide 104, 106.

Cartridge Assembly

Once the slide assembly 100 is created, the slide assembly 100 is inserted into a cartridge assembly 200. The cartridge assembly 200 is designed to receive the slide assembly 100 therein, and at a suitable time apply one or more test antibodies to the sample 102 under control by an instrument 300.

With reference to Figure 3A, the cartridge assembly 200 comprises a housing 202 with a slot 204 in the top of the housing through which the slide assembly 100 is inserted into the housing 202. The housing 202 also includes a window 206 through which the sample 102 on the slide assembly 100 can be detected. The window 206 is disposed toward the end of the housing 202 opposite the slot 204. Therefore, the slide assembly 100 is inserted into the housing 202 with the end 113 first, so that the sample 102 will be disposed generally adjacent the window 206.

The cartridge assembly 200 also includes a blister pack 210, Figure 3 B, which is disposed within the housing 202. The blister pack 210 contains the test antibodies and/or other liquids that are used during the testing and analysis of the sample 102. In particular, the blister pack 210 includes a plurality of sealed receptacles 212a, 212b,...212n each of which contains a reporter molecule, for example, a test antibody or other reagents. Each receptacle 212a, 21b can hold, for example, 10 μL of reagent. The receptacles 212a, 212b preferably contain different antibodies, blocking solutions such as goat serum, deionized water and other solutions or material that may be applied to the sample. The receptacles could also contain wash fluid. The receptacles 212a, 212b are located at the end of the blister pack 210, and when in the cartridge assembly 200, the receptacles 212a, 212b are positioned adjacent the end 1 13 of the slide assembly. In use, one or more of the receptacles 212a, 212b are broken open by the instrument 300 to release the antibodies for application to the sample. With reference to Figure 3C, a fluid well 214 is formed in the cartridge assembly 200 adjacent the bottom thereof. When the slide assembly is inserted into the cartridge assembly 200, the end 1 13 is received within the well 214. The blister pack 210 is positioned such that when the receptacles 212a, 212b are broken open, the antibody liquid flows into the fluid well 214. When the antibodies are released into the well 214, the antibodies are drawn up into the capillary gap 1 12 via capillary action and into contact with the sample 102, whereby the antibodies are applied to the sample.

Figure 3D illustrates the rear of the cartridge assembly 200. An access location 220 is provided through which a suitable mechanism of the instrument 300 can access the receptacles 212a, 212b to break open the receptacles. In addition, with reference to Figure 3 A, one of the side walls of the cartridge housing 202 is provided with access openings, for example an inlet opening 222 and an outlet opening 224, through which wash liquids can be introduced to the slide assembly and from which excess wash liquid can be removed.

The cartridge assembly, including the blister pack, is intended to be disposed after use. However, it is contemplated that the cartridge assembly could be re-usable, in which case the blister pack would be mounted so as to be replaceable.

Instrument

An instrument of the disclosed system and method includes a first component for preparing the sample and second component for detecting the prepared sample.

In one embodiment, the cartridge assembly 200 can be inserted into an instrument 300 shown in Figures 4A and 4B. The instrument 300 is designed to apply washes to the sample 102 and to dispense the antibodies from the blister pack 210. In addition, the instrument 300 is designed to scan the sample 102 once the antibodies are applied to the sample in order to analyze the sample. In one example, the instrument 300 is sized such that it can be placed on a desktop, for example, in a physician's office. The instrument 300 includes a housing 302 with a slot 304 in the top thereof for inserting the cartridge assembly 200 into the housing. Within the housing 302, the instrument 300 includes a fluid application section 306 and a scanning section 308. The fluid application section 306 includes reservoirs 310, shown schematically in Figure 4A, that contain washes for washing the sample 102, as well as a waste reservoir 312. The wash liquid from a reservoir 310 is applied under high pressure to the slide assembly 100 through the inlet opening 222 in the cartridge assembly. The wash liquid is applied under pressure to the side of the slide assembly, with the high pressure wash liquid entering the gap 1 12 and washing the sample. Excess wash liquid collects in the well 214 and is pumped into the waste reservoir 312 through the outlet opening 224 via a pump.

The washes can comprise any suitable wash known to those commonly used in immunohistochemistry, including wash buffers such as Tris-buffered saline tween-20 (TBST).

The fluid application section 306 also includes means to engage the receptacles 212a, 212b through the access location 220 to break open the blister receptacles 212a, 212b. When the receptacles are broken open, the antibodies or other liquids contained therein collect in the well 214. The antibodies are then applied to the sample via capillary action.

The instrument 300 is microprocessor controlled to cycle through each step. After insertion of the cartridge assembly, the instrument first conducts the wash of the sample. After the wash is complete, the instrument 300 then breaks open the receptacles on the blister pack in order to dispense the antibodies into the well and apply the antibodies to the sample.

Optionally, the instrument is designed to regulate the temperature and pressure within the instrument. For example, the slide assembly, cartridge assembly, or the liquids contained in the instrument may be individually heated. The pressure can be regulated such that high temperatures that cannot be obtained without an enclosed compartment can be achieved.

Preferably, a microprocessor controls the desk top device. The microprocessor may be programmed with desired predetermined steps. The sequence of steps may be automated, semi-automated or manually operated such that the cartridge containing the slide may be removed or inserted in the middle of the operation.

After the slide is prepared by the first component, the slide is then analyzed by a second component 308, which may be a detection mechanism 320. The detection mechanism 320 utilized is not particularly limited, and may be a scanner, microscope, spectrophotometer etc. Where the second component is a scanner, the scanner scans the sample through the window 206 of the cartridge assembly 200. In one implementation, the second component is configured to detect fluorescence generated by the antibodies. In another implementation, the second component is an automated colorimetric scanner. The fluorescence or the brightness of the color is then measured and analyzed. In another embodiment, a vial containing a transferred sample put into suspension is placed in an instrument (not shown) including a first component and a second component. The instrument may be automated or semi-automated. The first component prepares the sample for examination by dispensing reagents so as to allow detection of HPV integration via protein markers. In one example, the first component dispenses a reagent for cell lysis. In another example, the first component dispenses liquid containing a reporter molecule such as an antibody that is used to detect the presence of biological markers. In yet another example, the second component is a scanner, a microscope or a spectrophotometer. Where the second component is a scanner, the vial is scanned by the second component to detect the presence of the biological marker. In an alternative example, the vial is read directly by a clinician. One or more antibodies may be employed in order to recognize, for example, areas where distinct biological processes are occurring and where dysplasia is present. More than one antibody may be utilized for a particular cell tissue condition, and this cocktail of antibodies may be used to map and report a collected sample so as to localize areas that can be considered to be suspicious for the presence of preneoplastic legions. Different factors may be considered when choosing which antibodies to use in the cocktail. For example, in high grade cervical dysplasia (CIN2/3), which may be driven by HPV viral integration, the two most important HPV oncoproteins, E6 and E7, are expressed. E6 overexpression in turn results in survivin promoter transactivation, which is mediated by the p53 cell cycle regulatory protein degradation pathway. E7 overexpression in turn promotes the degradation of the retinoblastoma gene (Rb), resulting in disruption of the Rb cyclin D/plό¹^^4*1 cell cycle regulatory pathway. The downregulation of Rb then in turn results in the hypomethylation of the pl6^INK4a promoter, resulting in the overexpression of pl6^INK4a. In contrast, squamous maturation supports high levels of HPV episomal replication in low grade cervical dysplasia (CINl) such that the early open reading frames E1/E2 of the HPV genome repress the expression of E6 and E7. Accordingly, while viral load of HPV alone would not be indicative of genomic integration and malignant transformation, a cocktail of HPV viral integration markers such as survivin and pi 6¹^⁴*¹ specificity markers along with proliferation/apoptotic markers such as the Ki-67 proliferation marker may be used in order to reduce the chances of identifying and treating false-positives. A control marker such as pancytokeratin further may be used as a housekeeping marker when examining the sample based on the indices of protein expression.

Thus, the output of this molecular system may be a map of a cervical sample indicating the locations of the cervix that can be considered to be suspicious for the presence of preneoplastic lesions. The resulting map is both an indication of the presence of the lesion, as well as a means to inform the clinician of where on the cervix, and how to proceed with treatment. Analysis of the sample does not require any training in structural analysis or sophisticated molecular techniques. The entire system, should be less costly than conventional Pap analysis, can be run in either an automated or manual mode within a time frame that would permit a patient to be treated in the same visit as the sample is taken. The use of this approach can support a see and treat approach in areas of the world where the resources to screen and treat patients for cervical disease is limited. In addition, by focusing upon high-grade lesions, not only does this system affect a reduction in the economic cost of screening, but by eliminating unnecessary cervical biopsies, reduces the likelihood of compromising the reproductive health of younger women.

While the invention has been described in conjunction with a preferred embodiment, it will be obvious to one skilled in the art that other objects and refinements of the present invention may be made with the present invention within the purview and scope of the present invention.

The invention, in its various aspects and disclosed forms, is well adapted to the attainment of the stated objects and advantages of others. The disclosed details are not to be taken as limitations on the invention.

Claims

1. A system for detecting abnormal tissue in a cervix comprising: a collector collecting a sample from the cervix; a receiving structure for receiving the sample transferred from the collector; and an instrument comprising a first component for preparing the sample transferred to the receiving structure for examination and a second component for detecting molecular markers in the sample prepared by the first component, so as to inform a clinician of the presence of cancerous or precancerous cells in the sample.

2. The system of claim 1, further comprising a cartridge assembly that includes a housing for housing at least one receiving structure; and a holder having at least one receptacle containing treating liquids, wherein at least one receptacle provides microliter quantities of the treating liquids, and the instrument is configured to receive the cartridge assembly.

3. The system of claim 2, wherein the cartridge assembly includes first and second receiving structures, the first receiving structure being juxtaposed to a face of the second receiving structure, and at least one receptacle is breakable so as to provide the microliter quantities of the treating liquids into fluid wells, thereby allowing a space between the first and second receiving structures to draw up the treating liquids by capillary action.

4. The system of claim 1, wherein the sample is collected from an ectocervical or endocervical region of the cervix.

5. The system of claim 1, wherein the sample is clusters of cells, and the collector collects the clusters of cells so as to maintain the spatial orientation of the clusters of cells collected on the collector.

6. The system of claim 5, wherein the receiving structure and the collector are configured to maintain spatial orientation of the clusters of cells transferred to the receiving structure.

7. The system of claim 6, further comprising a transfer device for transferring the clusters of cells, wherein the transfer device is configured to maintain the spatial orientation of the clusters of cells when transferring the clusters of cells to the receiving structure.

8. The system of claim 7, wherein the instrument is configured to inform the clinician of a map of the regions of the cervix indicating locations that can be considered to be suspicious for the presence of preneoplastic lesions.

9. The system of claim 1 , wherein the instrument is a point-of-care testing device that allows detection within a time frame that would permit a patient to be treated in the same visit as the sample is taken.

10. The system of claim 1 , wherein the receiving structure is a slide or a vial.

1 1. The system of claim 1 , wherein the second component is a fluorescent scanner, a colorimetric scanner, microscope or spectrophotometer.

12. The system of claim 1 , wherein the instrument is automated or semi-automated.

13. A method for detecting abnormal tissue in a cervix, the method comprising: collecting a sample from the cervix using a collector; transferring the sample collected by the collector to a receiving structure; conducting an assay of the sample in the receiving structure so as to detect human papillomavirus (HPV) integration via at least one biological marker that facilitates detection of the HPV integration; and reading the assay results via at least one reporter molecule that associates with at least one biological marker.

14. The method of claim 1, wherein the assay results are read directly by the clinician or via an instrument.

15. The method of claim 13, wherein the instrument is automated or semi-automated.

16. The method of claim 15, further comprising placing the receiving structure containing the sample in the instrument, using the instrument, dispensing a liquid into the receiving structure containing the sample, detecting the presence of the at least one biological marker, and reporting the assay results.

17. The method of claim 1 , wherein the biological marker is a HPV specific protein or a cellular protein which is up-regulated as a result of HPV integration.

18. The method of claim 17, wherein the biological marker is at least one selected from the group consisting of: E6, E7 and survivin.

19. The method of claim 13, further comprising inserting the receiving structure containing the transferred sample into a cartridge assembly; placing the cartridge assembly into an instrument, wherein the instrument dispenses a liquid onto an area of the sample, pumps liquid out of the area to a disposable machine dispenser, breaks receptacles on a blister pack in sequence into a well where the receiving structure sits, wets sample by agents contained in the blister pack, washes the sample, scans the sample, and reports the results.