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  Molecular analysis of cellular fluid and liquid cytology specimens for clinical diagnosis, characterization, and integration with microscopic pathology evaluationUSPTO Application #: 20060141497Title: Molecular analysis of cellular fluid and liquid cytology specimens for clinical diagnosis, characterization, and integration with microscopic pathology evaluation Abstract: The application relates to methods, materials, kits, and devices for characterizing fluid specimens of any type or source that may or may not contain cells. The methods, materials, kits, and devices can be used for analyzing fluid obtained from various organs or near a purported tumor site, such as via breast ductal lavage or aspiration of a pancreatic cyst. The methods, materials, kits, and devices generate molecular information that can be used in conjunction with clinical, imaging, and microscopic pathology evaluation to provide a superior pathology diagnosis for clinical and research. (end of abstract) Agent: Drinker Biddle & Reath (dc) - Washington, DC, US Inventors: Sydney David Finkelstein, Patricia Swalsky USPTO Applicaton #: 20060141497 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20060141497. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit of U.S. Provisional Application Nos. 60/620,926 filed Oct. 22, 2004; 60/631,240 filed Nov. 29, 2004; 60/644,568 filed Jan. 19, 2005; 60/679,968 filed May 12, 2005; and 60/679,969 filed May 12, 2005, all of which are herein incorporated by reference in their entirety for all purposes. FIELD OF THE INVENTION [0002] The application relates to methods, materials, kits, and devices for characterizing biological fluid specimens that may or may not contain cells. The methods, materials, kits, and devices generate molecular information that can be used in conjunction with clinical, imaging, and microscopic pathology evaluation to provide a superior pathology diagnosis for clinical and research purposes. BACKGROUND [0003] Prevention of cancer by its diagnosis and treatment during pre-cancerous stages of development offers the most desired option for reduction and elimination of cancer morbidity and mortality. If detection cannot be achieved in the pre-cancer stage, then diagnosis at an earlier stage of cancer progression offers the best hope for complete cure. In order to achieve this end, sampling techniques such as breast ductal lavage, urine cytology, analysis of fixed cytology fluids such as but not limited to that obtained by liquid cytology preparation, pancreatic juice collection or removal of cerebrospinal fluid become increasingly used to secure representative material of the lining cells or actively proliferating cells that may contain neoplastic cellular elements. However, the effectiveness of cellular fluid analysis is diminished by the inability of a cytology evaluation to provide discriminating, definitive information on the samples obtained thereby (Huber et al., 2004 Lung Cancer 45 Suppl. 2: S209-13). Microscopic examination in increasing recognized as inadequate to address this need to for early and definitive diagnosis of cancer and so other platforms are required to achieve this objective. [0004] At the same time, advances in modern medical imaging techniques, such as but not limited to highly sensitive computerized tomography, magnetic resonance imaging, and endoscopic ultrasound, have resulted in the earlier detection of cancer in smaller sized specimens. Imaging has made possible to aspirate alterations representing precancer and early stage cancer with a high degree of precision when such lesions are small in overall size (Chen et al., 2005 Biomed. Instrum. Technol. 39(1):75-85). Representative specimens of these early cancer alterations can now be more easily obtained; however, the gains are offset by the inability to affirm a definitive diagnosis of cancer on these specimens. Hence the need for improved systems for definitive diagnosis of cancer and related states. [0005] Fluid collections that bathe and drain sites of potential cancer formation are increasingly diagnosed for earlier and better diagnosis. Examples of such fluid collection can include cyst formation within organs, breast ductal lavage fluid, urine, cerebrospinal fluid, and pleural fluid. This list can easily be extended to virtually any part of the body. As a result, pathologists are increasingly called upon to evaluate fluid specimens. However, due to the paucicellular nature of these samples, an indefinite or inadequate diagnosis is often rendered. For example, over 50% of pancreaticobiliary cytobrush cytology specimens are not definitively diagnosed (Khalid et al., 2005 Clin. Lab. Med. 25(1): 101-16). Moreover in the 50% with definitive diagnosis, the diagnosis occurs when obvious cancer has already occurred and treatment is limited or ineffective. [0006] The human genome project has led to an explosion of genetic information that will eventually lead to the full cataloging of all known human genes, including those involved in cancer development and progression. Specific DNA structural alterations, such as point mutations, genomic deletions, gene copy number losses and gains, gene rearrangements, and epigenetic DNA methylation alterations have been characterized but are not currently used in specimen diagnosis. Thus the demonstration of mutational information can serve to enhance definitive diagnosis when demonstrated to be present in correlation with cellular microscopic alterations. Yet, much of this new genetic information relating to cancer growth is not used in the context to improve definitive disease diagnosis, where it could play a most valuable role. This can be attributed to many factors including the small size and paucicellular nature of the specimen, effect of chemical fixation to optimize morphologic microscopic interpretation, and lack of definitive microscopic criteria for definitive diagnosis. [0007] A rate-limiting step in patient treatment is pathology evaluation of representative specimens wherein the pathologist can give a definitive diagnosis of the presence, type, grade, and character of the neoplasia to the treating physician. Based on this information, the treating physician can then ascertain the best course of treatment. Until recently, this fundamental aspect of disease management was based on microscopic evaluation alone, without taking advantage of the insights derived from molecular genetic analysis. The result of this is subjectivity in specimen diagnosis that often leads to an indeterminate pathology diagnosis, often labeled as "atypical", "suspicious", "not definitive for", or "inadequate for diagnosis". This is especially true for pre-cancerous conditions when microscopic criteria have not yet been universally agreed upon, but where an early diagnosis could be most beneficial (Moinfar et al., 2000 Cancer 88(9): 2072-81). [0008] For this specific reason, a patient's diagnosis is often placed on hold, resulting in great cost to the healthcare system and potentially life threatening consequences to the patient, due to delayed or improper treatment. It is not uncommon for a patient to be told by one pathologist that the lesion they may have is benign, while a second pathologist diagnoses the very same specimen as malignant. These disagreements can be objectively resolved by the incorporation of molecular analysis into pathology practice, as described herein. [0009] Yet, impediments currently exist in implementing molecular and microscopic pathology information. Current clinical research in the area of early cancer detection emphasizes mutation detection. Technologies, such as gene chip microarrays for altered RNA expression, and comparative genomic hybridization for DNA genomic deletion and/or amplification, have been instrumental in delineating a great variety of putative mutational changes in early cancer. However, these methods alone still remain ill-suited for use in assessing specimens of the type procured for the purpose of early cancer detection. For example, cDNA production for expression microarrays and comparative genomic hybridization (CGH) require abundant amounts of fresh tissue or fresh DNA. These requirements cannot be satisfied by the minute amount of cellular material and nucleic acid material present in and derived from fluid sampling techniques. [0010] Furthermore, all tissue or fluid removed for the purpose of disease diagnosis must first be evaluated by a pathologist for adequacy and representative characteristics. Pathologists require that the specimens be optimally fixative-treated and stained for microscopic review. To violate this fundamental rule for specimen processing would invite mishandling of specimens with serious therapeutic and medical malpractice implications. Effective application of molecular analysis requires that the fluid specimens be integrated into pathology practice so that no information is lost. [0011] Reliance upon mutation detection alone has limitations. Precancerous states may have few detectable mutations, but the paucity of cellular material of these states can lead to false positive artifacts in mutation detection that in turn can be misinterpreted as more advanced forms of cancer (see, e.g., Miller et al., 2002 Genetics 160(1): 357-66). Reliance upon mutation detection alone will lead to a measure of unreliability in cancer diagnosis that will only impede effective clinical translation of molecular discovery. For this reason, other parameters of early cancer formation, such as the cellular proliferation rate and quality/quantity of DNA released from actively replicating cells, may be useful in the overall molecular analysis of neoplastic and related lesions. [0012] There is also an increased need for personalized patient diagnosis and treatment to achieve better outcomes for the individual. Putting aside issues related to subjective microscopic interpretation, pre-cancer and cancer alterations do not behave in a uniform or predictable manner. Two patients may have lesions which appear to be identical under the microscope, but which may pursue radically different natural courses with one quickly progressing to cancer while the other undergoes slow or no progression over time. Discrimination cannot be reliably found in identifying unique microscopic features. Rather, the distinction relates to intrinsic molecular alterations unique to each patient's neoplasm that serves as a more rational and effective basis for neoplasia diagnosis, classification, characterization, and treatment. This need to understand precancer and cancer biology at the individual patient level has become a cornerstone of modern cancer treatment and pathology evaluation of specimens must provide the information needed to make more personalize treatment decisions (Mocellin et al., 2005 Trends Mol. Med. 2005 11 (7):327-35). [0013] One example wherein fluid specimens are frequently used is breast ductal lavage for the purpose of diagnosing a breast cancer. Breast cancer remains a leading cause of mortality despite awareness of its occurrence in the general population, as well as extensive research into its molecular pathogenesis using in vitro, animal, and clinical human systems. Pharmaceutical research directed to developing anticancer agents has proceeded actively in recent years. However, the need for effective agents and treatments to treat all types of breast cancer and metastatic breast cancer remains. [0014] Diagnosis of breast tissue is also impacted by observer variability in the subjective interpretation of the sample (Harvey et al., 2002 Pathology, 34(5): 410-6; Newman, "Ductal lavage: what we know and what we don't," 2004 Oncology 18(2): 179-85, and discussion 185-6, 189, 192). [0015] There is a general consensus, for example, that prevention of breast cancer by its diagnosis and treatment during pre-cancerous stages of development offers the most desired option for managing this disease. If detection cannot be achieved in the pre-cancer stage, then detection at an earlier stage of progression offers the best hope for complete cure. In order to achieve this end, sampling techniques such as breast ductal lavage, have been introduced to secure representative material of the breast duct lining cells or actively proliferating cells in contact with the breast ductal drainage system (O'Shaughnessy, 2003 Surg. Clin. North Am. 83(4): 753-69; Locke et al., 2004 Breast Cancer Res. 6(2): 75-81; Kenney et al., 2004 Curr. Oncol. Rep. 6(1): 69-73; Khan, 2004 Curr. Treat. Options Oncol. 5(2): 145-51; Dooley et al., 2001 J. Natl. Cancer Inst. 93(21): 1624-32). Based on a washing-out concept similar to bronchoalveolar lavage of the lung (Liloglou, "Cancer-specific genomic instability in bronchial lavage: a molecular tool for lung cancer detection," 2001 Cancer Res. 61(4): 1624-8), breast ductal lavage gathers representative material from within the breast ductal system that is then examined to arrive at a definitive diagnosis for early disease. However, the effectiveness of the breast ductal lavage approach is diminished by the inability of pathology evaluation to provide discriminating, definitive information on the samples obtained (Khan, 2004; Dooley et al., 2001). Most current clinical research in the area of early breast cancer detection emphasizes mutation detection. New technologies, such as gene chip microarrays for altered RNA expression and comparative genomic hybridization for DNA genomic deletion or amplification, have been instrumental in delineating a great variety of putative mutational changes in early breast cancer. However, these methods alone still remain ill-suited for use in assessing specimens of the type procured for the purpose of early cancer detection. For example, cDNA production and comparative genomic hybridization (CGH) generally require abundant amounts of fresh tissue to operate effectively. These needs cannot be satisfied by techniques such as breast ductal lavage and breast fine needle aspiration. Even more fundamentally, all tissue or fluid removed for the purpose of disease diagnosis must first be evaluated by a pathologist for adequacy and representative characteristics; the pathologist requires that the specimens be optimally fixative-treated and stained for microscopic review (see e.g., Lindsey, 2004 Lancet Oncol. 5(12): 704; Fabian et al., 2004 J. Nat'l. Cancer Inst.; 96(20) 1488-9). To violate this fundamental rule would be to invite mishandling of specimens with serious therapeutic and medical malpractice implications. Effective application of molecular discovery requires that it be integrated into pathology practice so that no information is lost or jeopardized. [0016] Another problem encountered with standard pathology practices is that tissue heterogeneity is often ignored when applying molecular methods to the evaluation of tissue specimens (Hollingsworth et al., 2004 Am. J. Surg. 2004 187(3): 349-62; Newman, "Current issues in the surgical management of breast cancer: a review of abstracts from the 2002 San Antonio Breast Cancer Symposium, the 2003 Society of Surgical Oncology Annual Meeting, and the 2003 American Society of Clinical Oncology meeting," 2004 Breast J. 10 Suppl. 1: S22-5). Due to the time, labor, and cost associated with cDNA or CGH analysis, usually only a single sample is evaluated for a given patient. This testing of a single sample ignores the fact that breast cancer progression is a stochastic process that proceeds heterogeneously (Kenney et al., 2004 Curr. Oncol. Rep. 6(1): 69-73; Moinfar et al., 2000 Cancer Res. 60(9): 2562-6). Averaging across the heterogeneous tissue by homogenizing a large breast tissue sample sharply contrasts with time honored methods for pathology evaluation of breast tissue, which seeks to detect and characterize microscopic cellular heterogeneity (Kenney et al., 2004; Moinfar et al., 2000). This has led to microdissection of more than one tissue target for molecular analysis (O'Connell et al., 1998 J. Nat'l Cancer Inst. 90(9): 697-703; O'Connell et al., 1994 Breast Cancer Res. Treat. 32(1): 5-12; Larson et al., 152(6): 1591-8; Sasatomi et al., 2002 Cancer Res. 62(9): 2681-9; and Finkelstein et 2003 Hepatology 37(4): 871-9). Microdissection serves to isolate and optimally purify the predetermined tissue target so that stochastic cancer-associated changes can be detected. The use of multiple targets is congruent with established principles of pathology practice that seek to better understand and correlate topographic variation across the extent of a given neoplastic process. [0017] Reliance upon mutation detection results in certain limitations. Precancerous lesions of the breast and early breast cancer may have few detectable mutations. The relative paucity of cellular material of these states can lead to false positive artifacts in mutation detection that in turn can be spuriously interpreted as more advanced forms of cancer. Reliance upon mutation detection alone will lead to a measure of unreliability in cancer diagnosis that will only serve as a further impediment to effective clinical translation of molecular discovery. [0018] Additionally, accurate diagnosis may not always occur in the instance of reactive cellular proliferative states of the breast, which often is misdiagnosed as breast cancer (see e.g., Siim et al., 1988 Br. J. Surg. 75(9): 920-1; Branton et al., 2003 Int. J. Surg. Pathol. 11(2): 83-7). Such misdiagnosis often results in unnecessary treatment and unintended morbidity of the patient. The very same integration of molecular discovery in the context of early cancer detection is ideally suited to an alternative application for reducing the misdiagnosis of reactive states for cancer. This must, however, be accomplished in a manner that is accurate and reliable. [0019] Putting aside issues related to subjective microscopic interpretation, breast pre-cancer and cancer genetic changes do not behave in a uniform or predictable manner (Tavassoli, 2001 Virchows Arch. 438(3): 221-7; Masood, 2002 Microsc. Res. Tech. 59(2): 102-8). Two patients with the same microscopic-appearing precancerous lesion may pursue radically different natural courses, with one quickly progressing to cancer, while the other patient shows slow or no progression over time. Unique microscopic features are not useful in discriminating between neoplasms. Rather, the distinction relates to intrinsic molecular alterations unique to each patient's neoplasm that serves as a more rational and effective basis for breast neoplasia diagnosis, classification, characterization, and treatment. [0020] The same paradigm holds true for early breast cancer detection. Two tumors that appear to be equivalent may behave in a vastly different manner, including different responses to the same therapy. Microscopic appearance alone is now recognized as inadequate for individual lesion characterization. [0021] Another example of where fluid specimens are taken is urinary bladder cancer via urine cytology. The urinary bladder is a common site of cancer formation which may vary in biological aggressiveness from indolent to aggressive forms with long and short survival respectively. Examination of the urine has served as a means to detect the presence of urinary bladder cancer based on shed cells from the neoplastic lesions within the organ collecting in the urine. While a positive urine cytology for cancer has great specificity (close to 100%) the sensitivity is poor (see, e.g., Bassi et al., 2005 Urol. Int. 75(3): 193-200). More importantly, the early stage of bladder cancer development tends to be universally missed which is precisely the stage of the disease where early detection would have the greatest impact. Continue reading... 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