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ABSTRACT: For the first time, the use of fiber-optic color Doppler optical coherence tomography (CDOCT) to map in vivo the three-dimensional (3-D) vascular network of airway segments in human lungs is demonstrated. Visualizing the 3-D vascular network in the lungs may provide new opportunities for detecting and monitoring lung diseases such as asthma, chronic obstructive pulmonary disease, and lung cancer. Our CDOCT instrument employs a rotary fiber-optic probe that provides simultaneous two-dimensional (2-D) real-time structural optical coherence tomography (OCT) and CDOCT imaging at frame rates up to 12.5 frames per second. Controlled pullback of the probe allows 3-D vascular mapping in airway segments up to 50 mm in length in a single acquisition. We demonstrate the ability of CDOCT to map both small and large vessels. In one example, CDOCT imaging allows assignment of a feature in the structural OCT image as a large (∼1 mm diameter) blood vessel. In a second example, a smaller vessel (∼80 μm diameter) that is indistinguishable in the structural OCT image is fully visualized in 3-D using CDOCT.
Journal of Biomedical Optics 05/2013; 18(5):50501. · 3.16 Impact Factor
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ABSTRACT: To improve ploidy analysis in the detection of high-grade cervical dysplasias by combining it with anti-Ki-67 immunocytochemistry in a double staining procedure to distinguish between cells with abnormal DNA content and normal cycling cells.
Cervical cytology specimens from 49 patients with various diagnoses, mostly dysplasias, from a previous study were used. Samples were double stained with Feulgen-thionin and anti-Ki-67 immunocytochemistry. Ki-67-negative cells were noncycling, so nondiploid Ki-67-negative cells were likely truly abnormal cells.
The area under the receiver operating characteristic curve for the ability to identify high-grade dysplasias was 0.73 for double staining and 0.74 for thionin-only ploidy analysis on Cytospin specimens. At 90% specificity, sensitivities for double staining and thionin alone were 45% and 32%, respectively, but the difference was not statistically significant.
Double staining with Feulgen-thionin and anti-Ki-67 immunocytochemistry does not improve the ability of ploidy analysis of cervical cytology specimens to separate high-grade and low-grade dysplasias, but our insights into the technical aspects of double staining, especially the effects of antigen retrieval, give hope that this technique could be applied to other immunocytochemical stains that would have a greater ability to improve ploidy analysis.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 10/2012; 34(5):273-84. · 0.41 Impact Factor
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ABSTRACT: The successful management of oral cancer depends upon early detection, which relies heavily on the clinician's ability to discriminate sometimes subtle alterations of the infrequent premalignant lesions from the more common reactive and inflammatory conditions in the oral mucosa. Even among experienced oral specialists this can be challenging, particularly when using new wide field-of-view direct fluorescence visualization devices clinically introduced for the recognition of at-risk tissue. The objective of this study is to examine if quantitative cytometric analysis of oral brushing samples could facilitate the assessment of the risk of visually ambiguous lesions. About 369 cytological samples were collected and analyzed: (1) 148 samples from pathology-proven sites of SCC, carcinoma in situ or severe dysplasia; (2) 77 samples from sites with inflammation, infection, or trauma, and (3) 144 samples from normal sites. These were randomly separated into training and test sets. The best algorithm correctly recognized 92.5% of the normal samples, 89.4% of the abnormal samples, 86.2% of the confounders in the training set as well as 100% of the normal samples, and 94.4% of the abnormal samples in the test set. These data suggest that quantitative cytology could reduce by more than 85% the number of visually suspect lesions requiring further assessment by biopsy.
Journal of Biomedical Optics 08/2012; 17(8):86004-1. · 3.16 Impact Factor
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ABSTRACT: Deregulated cell proliferation is a hallmark of cancer, and Ki67 immunostaining can be used to identify proliferating cells. Evaluation of cell proliferation may have utility as a biomarker of epithelial malignant transformation risk. To date, most analyses of Ki67 staining have been restricted to semiquantitative estimations of the degree of staining or the measurement of the fraction of Ki67-positive cells within the epithelium. We sought to develop a robust, objective means of quantitatively evaluating Ki67 immunostaining for lung precancerous lesions.
We quantified the spatial distribution of Ki67-expressing cells within the epithelium by means of (1) a cell-based Voronoi tessellation and (2) a basement membrane-referenced distance transform. This was undertaken in a large cohort of 613 lung biopsy sections representing normal, hyperplasia, squamous metaplasia and mild, moderate and severe dysplasia. For each section 21 features quantifying different aspects of the Ki67 staining were calculated. Intraobserver and inter-observer variation were recorded for a subset of the biopsy sections. We examined the behavior of each feature with respect to histopathological grade.
These measures demonstrated that proliferation is generally limited to layers 2, 3 and 4 of the epithelium (layer 1 being the basal layer). The proliferation in the basal layer is limited and does not increase with increasing grade of dysplasia. Interobserver and intraobserver effects on these features were assessed, and several were more robust with respect to measuring Ki67 expression pattern than the commonly used fraction of Ki67-positive cells.
Many of these quantitative features showed associations with histological grade that were as strong as the association that exists based on the fraction of Ki67-positive cells while being much more robust to interobserver- and intraobserver-associated variations. The measured spatial distribution of proliferating cells statistically demonstrated asymmetric cell division behavior in cells in the basal layer, a pattern attributed to stem cells giving rise to transient amplifying cells.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 06/2012; 34(3):120-38. · 0.41 Impact Factor
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ABSTRACT: Optical spectroscopy has been proposed as an accurate and low-cost alternative for detection of cervical intraepithelial neoplasia. We previously published an algorithm using optical spectroscopy as an adjunct to colposcopy and found good accuracy (sensitivity=1.00 [95% confidence interval (CI)=0.92 to 1.00], specificity=0.71 [95% CI=0.62 to 0.79]). Those results used measurements taken by expert colposcopists as well as the colposcopy diagnosis. In this study, we trained and tested an algorithm for the detection of cervical intraepithelial neoplasia (i.e., identifying those patients who had histology reading CIN 2 or worse) that did not include the colposcopic diagnosis. Furthermore, we explored the interaction between spectroscopy and colposcopy, examining the importance of probe placement expertise. The colposcopic diagnosis-independent spectroscopy algorithm had a sensitivity of 0.98 (95% CI=0.89 to 1.00) and a specificity of 0.62 (95% CI=0.52 to 0.71). The difference in the partial area under the ROC curves between spectroscopy with and without the colposcopic diagnosis was statistically significant at the patient level (p=0.05) but not the site level (p=0.13). The results suggest that the device has high accuracy over a wide range of provider accuracy and hence could plausibly be implemented by providers with limited training.
Journal of Biomedical Optics 04/2012; 17(4):047002. · 3.16 Impact Factor
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ABSTRACT: Optical spectroscopy has been studied for biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness.
We sought to identify health care provider attitudes or practices that might act as barriers or to the dissemination of this new technology.
Through an academic-industrial partnership, we conducted a series of focus groups to examine physician barriers to optical diagnosis. The study was conducted in 2 stages. First, a pilot group of 10 physicians (8 obstetrician gynecologists and 2 family practitioners) was randomly selected from 8 regions of the United States and each physician was interviewed individually. Physicians were presented with the results of a large trial (N = 980) testing the accuracy of a spectroscopy-based device in the detection of cervical neoplasia. They were also shown a prototype of the device and were given a period of time to ask questions and receive answers regarding the device. They were also asked to provide feedback on a questionnaire that was then revised and presented to 3 larger focus groups (n = 13, 15, and 17 for a total N = 45). The larger focus groups were conducted during national scientific meetings with 20 obstetrician gynecologists and 25 primary care physicians (family practitioners and internists).
When asked about the dissemination potential of the new cervical screening technology, all study groups tended to rely on established clinical guidelines from their respective professional societies with regard to the screening and diagnosis of cervical cancer. In addition, study participants consistently agreed that real-time spectroscopy would be viewed positively by their patients. Participants were positive about the new technology's potential as an adjunct to colposcopy and agreed that the improved accuracy would result in reduced health care costs (due to decreased biopsies and decreased visits). Although all participants saw the potential of real-time diagnosis, there were many perceived barriers. These barriers included changes in scheduling and work-flow, liability, documentation, ease of use, length of training, device cost, and reimbursement by third-party payers.
Barriers exist to the dissemination of optical technologies into physician practice. These will need to be addressed before cervical screening and diagnosis programs can take advantage of spectroscopy-based instruments for cancer control.
Gender Medicine 02/2012; 9(1 Suppl):S67-77; quiz 77.e1-6. · 2.10 Impact Factor
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ABSTRACT: Optical spectroscopy devices are being developed and tested for the screening and diagnosis of cancer and precancer in multiple organ sites. The studies reported here used a prototype of a device that uses white light, green-amber light at 545 nm, and violet light at 405 nm. Given that oral neoplasia is rare, the need for a device that increases the sensitivity of comprehensive white light oral screening is evident. Such a device, in the hands of dentists, family practitioners, otorhinolaryngologists, general surgeons, obstetrician gynecologists, and internists, could greatly increase the number of patients who have lesions detected in the precancerous phase.
The objective of this study was to present a case series of oral precancers and cancers that have been photographed during larger ongoing clinical trials.
Over 300 patients were measured at 2 clinical sites that are comprehensive cancer centers and a faculty practice associated with a major dental school. Each site is conducting independent research on the sensitivity and specificity of several optical technologies for the diagnosis of oral neoplasia. The cases presented in this case series were taken from the larger database of images from the clinical trials using the aforementioned device. Optical spectroscopy was performed and biopsies obtained from all sites measured, representing abnormal and normal areas on comprehensive white light examination and after use of the fluorescence and reflectance spectroscopy device. The gold standard of test accuracy was the histologic report of biopsies read by the study histopathologists at each of the 3 study sites.
Comprehensive white light examination showed some lesions; however, the addition of a fluorescence image and a selected reflectance wavelength was helpful in identifying other characteristics of the lesions. The addition of the violet light-induced fluorescence excited at 405 nm provided an additional view of both the stromal neovasculature of the lesions and the stromal changes associated with lesion growth that were biologically indicative of stromal breakdown. The addition of 545 nm green-amber light reflectance increased the view of the keratinized image and allowed the abnormal surface vasculature to be more prominent.
Optical spectroscopy is a promising technology for the diagnosis of oral neoplasia. The conclusion of several ongoing clinical trials and an eventual randomized Phase III clinical trial will provide definitive findings that sensitivity is or is not increased over comprehensive white light examination.
Gender Medicine 02/2012; 9(1 Suppl):S25-35. · 2.10 Impact Factor
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ABSTRACT: Optical spectroscopy and imaging devices are being developed and tested for the screening and diagnosis of cancer and precancer in multiple organ sites.
The aim of the study reported here is to optimize the capability of an optical imaging device to discriminate precancerous tissue from other lesions by identifying ideal excitation wavelengths.
The studies reported here used a prototype of a direct fluorescence imaging device that uses 405-nm illumination to excite tissue.
There is ample evidence in the literature that 405 nm can distinguish oral cancers from normal tissue. Higher wavelengths may be necessary to differentiate potential confounding lesions, such as abrasions, burns, viral infections, inflammation, and gingivitis.
Imaging at 405 nm could help doctors detect precancerous and cancerous oral lesions. Such imaging could be used by dentists, family practitioners, otorhinolaryngologists, general surgeons, obstetrician gynecologists, and internists, and could greatly increase the number of patients who have lesions detected in the precancerous phase.
Gender Medicine 02/2012; 9(1 Suppl):S78-82.e1-8. · 2.10 Impact Factor
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ABSTRACT: Despite the benefits of early lung cancer detection, no effective strategy for early screening and treatment exists, partly due to a lack of effective surrogate biomarkers. Our novel sputum biomarker, the Combined Score (CS), uses automated image cytometric analysis of ploidy and nuclear morphology to detect subtle intraepithelial changes that often precede lung tumours.
2249 sputum samples from 1795 high-risk patients enrolled in ongoing chemoprevention trials were subjected to automated quantitative image cytometry after Feulgen-thionin staining. Samples from normal histopathology patients were compared against samples from carcinoma in situ (CIS) and cancer patients to train the CS.
CS correlates with several lung cancer risk factors, including histopathological grade, age, smoking status, and p53 and Ki67 immunostaining. At 50% specificity, CS detected 78% of all highest-risk subjects-those with CIS or worse plus those with moderate or severe dysplasia and abnormal nuclear morphology.
CS is a powerful yet minimally invasive tool for rapid and inexpensive risk assessment for the presence of precancerous lung lesions, enabling enrichment of chemoprevention trials with highest-risk dysplasias. CS correlates with other biomarkers, so CS may find use as a surrogate biomarker for patient assessment and as an endpoint in chemoprevention clinical trials.
Analytical cellular pathology (Amsterdam) 01/2012; 35(3):187-201. · 0.92 Impact Factor
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ABSTRACT: The tools and techniques developed for analytical cytology have become invaluable in expanding the development of cancer screening programs and biomarker discovery for personalized medicine. Detecting cellular, molecular, and functional changes of diseased tissue as defined by quantitative analytical methodologies has enhanced the field of medical diagnostics and prognostics. The focus of this review is to outline applications and recent technical advances in flow cytometry, laser scanning cytometry, image cytometry, and quantitative image analysis, as they pertain to clinical, research, and drug discovery applications.
Journal of Biophotonics 01/2012; 5(4):313-26. · 4.34 Impact Factor
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Timon P H Buys,
Scott B Cantor,
Martial Guillaud,
Karen Adler-Storthz,
Dennis D Cox,
Clement Okolo,
Oyedunni Arulogon,
Oladimeji Oladepo,
Karen Basen-Engquist,
Eileen Shinn, [......],
Edward Neely Atkinson,
Luc Bidaut,
Pierre Lane,
J Lou Benedet,
Dianne Miller,
Tom Ehlen,
Roderick Price,
Isaac F Adewole, Calum MacAulay,
Michele Follen
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ABSTRACT: There is an urgent global need for effective and affordable approaches to cervical cancer screening and diagnosis. In developing nations, cervical malignancies remain the leading cause of cancer-related deaths in women. This reality may be difficult to accept given that these deaths are largely preventable; where cervical screening programs have been implemented, cervical cancer-related deaths have decreased dramatically. In developed countries, the challenges of cervical disease stem from high costs and overtreatment. The National Cancer Institute-funded Program Project is evaluating the applicability of optical technologies in cervical cancer. The mandate of the project is to create tools for disease detection and diagnosis that are inexpensive, require minimal expertise, are more accurate than existing modalities, and can be feasibly implemented in a variety of clinical settings. This article presents the status and long-term goals of the project.
Gender Medicine 09/2011; 9(1 Suppl):S7-24. · 2.10 Impact Factor
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Scott B Cantor,
Jose-Miguel Yamal,
Martial Guillaud,
Dennis D Cox,
E Neely Atkinson,
John L Benedet,
Dianne Miller,
Thomas Ehlen,
Jasenka Matisic,
Dirk van Niekerk, [......],
Karen Adler-Storthz,
Michael E Scheurer,
Karen Basen-Engquist,
Eileen Shinn,
Loyd A West,
Anne-Therese Vlastos,
Xia Tao,
J Robert Beck, Calum Macaulay,
Michele Follen
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ABSTRACT: Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.
International Journal of Cancer 03/2011; 128(5):1151-68. · 5.44 Impact Factor
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ABSTRACT: To study the possible mechanisms of epithelial preneoplastic development we developed an integrated platform using a 3D agent-based model (ABM). This platform, named idefics, allows for the implementation of normal biological rules at the cell level that interact and generate the usual homeostatic equilibrium of epithelium as well as other abnormal processes that can disrupt this equilibrium. The structure of this model is based on data from multi-scale quantitative analysis of a unique collection of preneoplastic lesions of the lung, cervix, and oral epithelium, that have been collected in our lab in the last 25 years. In this paper, we are describing the different components of this platform and will present results from different simulations generated by the model.
Bio Systems 10/2010; 102(1):22-31. · 1.27 Impact Factor
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ABSTRACT: The availability of high resolution array comparative genomic hybridization (CGH) platforms has led to increasing complexities in data analysis. Specifically, defining contiguous regions of alterations or segmentation can be computationally intensive and popular algorithms can take hours to days for the processing of arrays comprised of hundreds of thousands to millions of elements. Additionally, tumors tend to demonstrate subtle copy number alterations due to heterogeneity, ploidy and hybridization effects. Thus, there is a need for fast, sensitive array CGH segmentation and alteration calling algorithms. Here, we describe Fast Algorithm for Calling After Detection of Edges (FACADE), a highly sensitive and easy to use algorithm designed to rapidly segment and call high resolution array data.
Nucleic Acids Research 08/2010; 38(15):e157. · 8.03 Impact Factor
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William W Lockwood,
Raj Chari,
Bradley P Coe,
Kelsie L Thu,
Cathie Garnis,
Chad A Malloff,
Jennifer Campbell,
Ariane C Williams,
Dorothy Hwang,
Chang-Qi Zhu,
Timon P H Buys,
John Yee,
John C English, Calum Macaulay,
Ming-Sound Tsao,
Adi F Gazdar,
John D Minna,
Stephen Lam,
Wan L Lam
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ABSTRACT: Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes--adenocarcinoma (AC) and squamous cell carcinoma (SqCC)--respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy. Please see later in the article for the Editors' Summary.
PLoS Medicine 07/2010; 7(7):e1000315. · 16.27 Impact Factor
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ABSTRACT: Preinvasive bronchial lesions defined as dysplasia and carcinoma in situ (CIS) have been considered as precursors of squamous cell carcinoma of the lung. The risk and rate of progression of preinvasive lesions to invasive squamous cell carcinoma as well as the mechanism of progression or regression are incompletely understood. While the evidence for the multistage, stepwise progression model is weak with relatively few documented lesions that progress through various grades of dysplasia to CIS and then to invasive carcinoma, the concept of field carcinogenesis is strongly supported. The presence of high-grade dysplasia or CIS is a risk marker for lung cancer both in the central airways and peripheral lung. Genetic alterations such as loss of heterozygosity in chromosome 3p or chromosomal aneusomy as well as host factors such as the inflammatory load and levels of anti-inflammatory proteins in the lung influence the progression or regression of preinvasive lesions. CIS is different than severe dysplasia at the molecular level and has different clinical outcome. Molecular analysis of dysplastic lesions that progress to CIS or invasive cancer and rare lesions that progress rapidly from hyperplasia or metaplasia to CIS or invasive cancer will shed light on the key molecular determinants driving development to an invasive phenotype versus those associated with tobacco smoke damage.
CANCER AND METASTASIS REVIEW 03/2010; 29(1):5-14. · 9.35 Impact Factor
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Xin Dong,
Jun Guan,
John C English,
Julia Flint,
John Yee,
Kenneth Evans,
Nevin Murray, Calum Macaulay,
Raymond T Ng,
Peter W Gout,
Wan L Lam,
Janessa Laskin,
Victor Ling,
Stephen Lam,
Yuzhuo Wang
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ABSTRACT: Current chemotherapeutic regimens have only modest benefit for non-small cell lung cancer (NSCLC) patients. Cumulative toxicities/drug resistance limit chemotherapy given after the first-line regimen. For personalized chemotherapy, clinically relevant NSCLC models are needed for quickly predicting the most effective regimens for therapy with curative intent. In this study, first generation subrenal capsule xenografts of primary NSCLCs were examined for (a) determining responses to conventional chemotherapeutic regimens and (b) selecting regimens most effective for individual patients.
Pieces (1x3x3 mm(3)) of 32 nontreated, completely resected patients' NSCLCs were grafted under renal capsules of nonobese diabetic/severe combined immunodeficient mice and treated with (A) cisplatin+vinorelbine, (B) cisplatin+docetaxel, (C) cisplatin+gemcitabine, and positive responses (treated tumor area <or=50% of control, P < 0.05) were determined. Clinical outcomes of treated patients were acquired.
Xenografts from all NSCLCs were established (engraftment rate, 90%) with the retention of major biological characteristics of the original cancers. The entire process of drug assessment took 8 weeks. Response rates to regimens A, B, and C were 28% (9 of 32), 42% (8 of 19), and 44% (7 of 16), respectively. Certain cancers that were resistant to a particular regimen were sensitive to others. The majority of responsive tumors contained foci of nonresponding cancer cells, indicative of tumor heterogeneity and potential drug resistance. Xenografts from six of seven patients who developed recurrence/metastasis were nonresponsive.
Models based on first generation NSCLC subrenal capsule xenografts have been developed, which are suitable for quick assessment (6-8 weeks) of the chemosensitivity of patients' cancers and selection of the most effective regimens. They hold promise for application in personalized chemotherapy of NSCLC patients.
Clinical Cancer Research 02/2010; 16(5):1442-51. · 7.74 Impact Factor
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ABSTRACT: We examined intensity and shape differences in 378 repeated spectroscopic measures of the cervix. We examined causes of variability such as presence of precancer or cancer, pathologic tissue type, menopausal status, hormone or oral contraceptive use, and age; as well as technology related variables like generation of device and provider making exam. Age, device generation, and provider were statistically significantly related to intensity differences. Provider and device generation were related to shape differences. We examined the order of measurements and found a decreased intensity in the second measurement due to hemoglobin absorption. 96% of repeat measurements had classification concordance of cervical intraepithelial neoplasia.
Biomedical Optics Express 01/2010; 1(2):641-657. · 2.33 Impact Factor
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ABSTRACT: Non-small cell lung cancer (NSCLC) presents as a progressive disease spanning precancerous, preinvasive, locally invasive, and metastatic lesions. Identification of biological pathways reflective of these progressive stages, and aberrantly expressed genes associated with these pathways, would conceivably enhance therapeutic approaches to this devastating disease.
Through the construction and analysis of SAGE libraries, we have determined transcriptome profiles for preinvasive carcinoma-in-situ (CIS) and invasive squamous cell carcinoma (SCC) of the lung, and compared these with expression profiles generated from both bronchial epithelium, and precancerous metaplastic and dysplastic lesions using Ingenuity Pathway Analysis. Expression of genes associated with epidermal development, and loss of expression of genes associated with mucociliary biology, are predominant features of CIS, largely shared with precancerous lesions. Additionally, expression of genes associated with xenobiotic metabolism/detoxification is a notable feature of CIS, and is largely maintained in invasive cancer. Genes related to tissue fibrosis and acute phase immune response are characteristic of the invasive SCC phenotype. Moreover, the data presented here suggests that tissue remodeling/fibrosis is initiated at the early stages of CIS. Additionally, this study indicates that alteration in copy-number status represents a plausible mechanism for differential gene expression in CIS and invasive SCC.
This study is the first report of large-scale expression profiling of CIS of the lung. Unbiased expression profiling of these preinvasive and invasive lesions provides a platform for further investigations into the molecular genetic events relevant to early stages of squamous NSCLC development. Additionally, up-regulated genes detected at extreme differences between CIS and invasive cancer may have potential to serve as biomarkers for early detection.
PLoS ONE 01/2010; 5(2):e9162. · 4.09 Impact Factor
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Junichi Soh,
Naoki Okumura,
William W Lockwood,
Hiromasa Yamamoto,
Hisayuki Shigematsu,
Wei Zhang,
Raj Chari,
David S Shames,
Ximing Tang, Calum MacAulay,
Marileila Varella-Garcia,
Tõnu Vooder,
Ignacio I Wistuba,
Stephen Lam,
Rolf Brekken,
Shinichi Toyooka,
John D Minna,
Wan L Lam,
Adi F Gazdar
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ABSTRACT: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes.
We determined 1) mutational status, 2) copy number gains (CNGs) and 3) relative ratio between mutant and wild type alleles of KRAS, BRAF, PIK3CA and EGFR genes by direct sequencing and quantitative PCR assay in over 400 human tumors, cell lines, and xenografts of lung, colorectal, and pancreatic cancers. Examination of a public database indicated that homozygous mutations of five oncogenes were frequent (20%) in 833 cell lines of 12 tumor types. Our data indicated two major forms of MASI: 1) MASI with CNG, either complete or partial; and 2) MASI without CNG (uniparental disomy; UPD), due to complete loss of wild type allele. MASI was a frequent event in mutant EGFR (75%) and was due mainly to CNGs, while MASI, also frequent in mutant KRAS (58%), was mainly due to UPD. Mutant: wild type allelic ratios at the genomic level were precisely maintained after transcription. KRAS mutations or CNGs were significantly associated with increased ras GTPase activity, as measured by ELISA, and the two molecular changes were synergistic. Of 237 lung adenocarcinoma tumors, the small number with both KRAS mutation and CNG were associated with shortened survival.
MASI is frequently present in mutant EGFR and KRAS tumor cells, and is associated with increased mutant allele transcription and gene activity. The frequent finding of mutations, CNGs and MASI occurring together in tumor cells indicates that these three genetic alterations, acting together, may have a greater role in the development or maintenance of the malignant phenotype than any individual alteration.
PLoS ONE 01/2009; 4(10):e7464. · 4.09 Impact Factor
