Publications (35)165.02 Total impact
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Article: Increasing Cytotechnologist Workload Above 100 Slides per Day Using the BD FocalPoint GS Imaging System Negatively Affects Screening Performance.
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ABSTRACT: Studies examining the effects of increased workload on the performance of individual cytotechnologists are limited. Using FocalPoint GS, the performance of 3 cytotechnologists was evaluated. The study consisted of 3 phases. In phase I, cytotechnologists were asked to screen at their usual pace. In phase II, cytotechnologists were asked to screen as fast as possible without feeling that the quality of their work was diminished. In phase III, cytotechnologists were asked to screen at least 15% more than their daily workload from phase II. Productivity was increased by decreasing the percentage of cases that underwent full manual review (from 38% to 19%) and by decreasing the time spent on each slide (from 5.5 min to 3.7 min). Overall, the total abnormal rate decreased by 31.9% from phase I to phase III of the study. In addition, the false-negative fraction increased significantly, from 1% to 6.9%. Our results indicated a negative association between increased cytotechnologist daily workload with FocalPoint GS and CT screening performance. Workloads were increased by decreasing the time spent reviewing 10 fields of view and the percentage of cases that underwent full manual review.American Journal of Clinical Pathology 12/2012; 138(6):811-5. · 2.60 Impact Factor -
Article: Comparing two methods of detection for Chlamydia trachomatis in liquid-based Papanicolaou tests.
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ABSTRACT: This study compared the performance of Chlamydia trachomatis testing using 2 methods: the BD ProbeTec Chlamydia trachomatis Q(x) Amplified DNA Assay (CTQ) on the BD Viper System with XTR technology (CTQ assay) and the Hybrid Capture (HC) 2 assay. A total of 1,054 Surepath and ThinPrep specimens were tested for C trachomatis nucleic acids using the CTQ assay and the HC2 assay. For positive and discrepant C trachomatis test results, confirmatory test for C trachomatis was performed using a reverse transcriptase-polymerase chain reaction. Of 1,054 liquid-based gynecologic cytology samples tested for C trachomatis using both assays, 1,041 tested negative on both. In 6 (0.57%) samples, findings were discordant. The CTQ assay and the HC2 assay had sensitivity rates of 100% and 66.7%, respectively, with comparable specificity (99.9%). The positive predictive values were 92.3% and 88.9% with the CTQ and HC2 assays, respectively. In this study, the CTQ assay was found to be more sensitive than the HC2 assay in detecting chlamydial infection; the CTQ assay also demonstrated a higher positive predictive value.American Journal of Clinical Pathology 08/2012; 138(2):236-40. · 2.60 Impact Factor -
Article: Quantitative Analysis of Estrogen Receptor Expression Shows SP1 Antibody Is More Sensitive Than 1D5.
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ABSTRACT: Studies comparing rabbit monoclonal SP1 antibody with 1D5 for estrogen receptor (ER) immunohistochemical testing show conflicting results. Here we use a standardized quantitative immunofluorescent (QIF) ER assay to determine the level and significance of discordance between the antibodies. Both antibodies were assessed by QIF on our Index TMA of cell lines and case controls, followed by QIF and immunohistochemical analysis on 2 retrospective cohorts from Yale. On the Index TMA, SP1 displayed stronger signal-to-noise ratio compared with 1D5. On the patient cohorts, the range of discrepancy between the 2 antibodies was 8% to 16.9%, with the majority of discrepant cases being SP1 positive/1D5 negative. Kaplan-Meier analysis of the discrepant cases showed outcomes comparable to those of double-positive cases, suggesting that SP1 is more sensitive than 1D5. A series of cases with high levels of ER-β shows that neither antibody cross-reacts, suggesting equivalent specificity. Future efforts are needed to determine whether response to endocrine therapies show superiority of either antibody as a companion diagnostic test.Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 07/2012; · 1.63 Impact Factor -
Article: Implementation of FocalPoint GS location-guided imaging system: experience in a clinical setting.
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ABSTRACT: Recently, the Food and Drug Administration approved the use of the location-guided imaging system FocalPoint GS (FPGS), on SurePath Papanicolaou (Pap) tests for primary screening. The objective of the current study was to evaluate the impact of FPGS on the following: distribution of diagnostic categories; rate of high-risk human papillomavirus (HR-HPV)-positive ASC-US cases; and quality control (QC) data before and after FPGS implementation. A search of the laboratory information system was performed to identify all SurePath Pap tests processed in our laboratory for the first 19 months after FPGS implementation. We also retrieved all SurePath specimens from a 16-month period prior to FPGS implementation to serve as the control. During the period from Janaury 2008 to April 2009, the FocalPoint Slide Profiler was used. Implementation of FPGS resulted in a significantly higher percentage of LSIL and ASC-US interpretations, as well as a significant increase in the detection of candidiasis and bacterial vaginosis. The ASC-to-SIL ratio was 1.4 and 1.9 before and after FPGS implementation, respectively. There was a decrease in the HR-HPV positive rate in ASC-US cases, and a decrease in the estimated false-negative fraction after FPGS implementation. In conclusion, our study seems to demonstrate a favorable performance of FPGS in the routine clinical setting. FPGS may have the potential to be a promising screening tool for gynecologic cytology in a low-risk patient population.Cancer Cytopathology 04/2012; 120(2):126-33. · 3.33 Impact Factor -
Article: The positive impact of simultaneous implementation of the BD FocalPoint GS Imaging System and lean principles on the operation of gynecologic cytology.
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ABSTRACT: Our cytology laboratory, like many others, is under pressure to improve quality and provide test results faster while decreasing costs. We sought to address these issues by introducing new technology and lean principles. To determine the combined impact of the FocalPoint Guided Screener (GS) Imaging System (BD Diagnostics-TriPath, Burlington, North Carolina) and lean manufacturing principles on the turnaround time (TAT) and productivity of the gynecologic cytology operation. We established a baseline measure of the TAT for Papanicolaou tests. We then compared that to the performance after implementing the FocalPoint GS Imaging System and lean principles. The latter included value-stream mapping, workflow modification, and a first in-first out policy. The mean (SD) TAT for Papanicolaou tests before and after the implementation of FocalPoint GS Imaging System and lean principles was 4.38 (1.28) days and 3.20 (1.32) days, respectively. This represented a 27% improvement in the average TAT, which was statistically significant (P < .001). In addition, the productivity of staff improved 17%, as evidenced by the increase in slides screened from 8.85/h to 10.38/h. The false-negative fraction decreased from 1.4% to 0.9%, representing a 36% improvement. In our laboratory, the implementation of FocalPoint GS Imaging System in conjunction with lean principles resulted in a significant decrease in the average TAT for Papanicolaou tests and a substantial increase in the productivity of cytotechnologists while maintaining the diagnostic quality of gynecologic cytology.Archives of pathology & laboratory medicine 02/2012; 136(2):183-9. · 2.58 Impact Factor -
Article: Use of high-risk human papillomavirus testing in patients with low-grade squamous intraepithelial lesions.
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ABSTRACT: The role of testing for high-risk human papillomavirus (HR HPV) when triaging women with a cytologic diagnosis of low-grade squamous intraepithelial lesion (LSIL) has not been well established. The objective of the current study was to correlate the status of HR HPV with the incidence of cervical intraepithelial neoplasia 2 and more severe lesions (CIN 2+) on tissue follow-up in women with LSIL. A total of 1046 women with LSIL and HR HPV testing were identified in the database of a large teaching hospital within a 12-month period. HR HPV testing was performed using the Hybrid Capture 2 assay with 1 relative light unit/cutoff as the cutoff. Of the 1046 women with LSIL and concurrent HR HPV testing, 82.3% tested positive for HR HPV, 91.1% of whom were women aged < 30 years and 73% of whom were women aged ≥ 30 years (P < .001). Cytologic and/or histologic follow-up was available in 979 (93.6%) women; 25.5% had negative follow-up, 62.5% were found to have CIN 1 lesions, and 12.0% had CIN 2+ lesions. The sensitivity and negative predictive value of HR HPV status as a marker of CIN 2+ lesions were 98.3% and 98.9%, respectively. The colposcopy rate was 73.3% and 96.9% for women aged ≥ 30 years and women aged < 30 years, respectively (P = .01). Using 1 RLU/CO as the cutoff value, HR HPV testing was found to be highly sensitive for detecting CIN 2+ lesions in women with LSIL. The colposcopy rate was significantly lower in women aged ≥ 30 years compared with women aged < 30 years. Triaging with HR HPV testing may be indicated in women aged ≥ 30 years with LSIL cytology, but not in women aged < 30 years. Cancer (Cancer Cytopathol) 2011;. © 2011 American Cancer Society.Cancer Cytopathology 08/2011; 119(4):228-34. · 3.33 Impact Factor -
Article: Standardization of estrogen receptor measurement in breast cancer suggests false-negative results are a function of threshold intensity rather than percentage of positive cells.
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ABSTRACT: Recent misclassification (false negative) incidents have raised awareness concerning limitations of immunohistochemistry (IHC) in assessment of estrogen receptor (ER) in breast cancer. Here we define a new method for standardization of ER measurement and then examine both change in percentage and threshold of intensity (immunoreactivity) to assess sources for test discordance. An assay was developed to quantify ER by using a control tissue microarray (TMA) and a series of cell lines in which ER immunoreactivity was analyzed by quantitative immunoblotting in parallel with the automated quantitative analysis (AQUA) method of quantitative immunofluorescence (QIF). The assay was used to assess the ER protein expression threshold in two independent retrospective cohorts from Yale and was compared with traditional methods. Two methods of analysis showed that change in percentage of positive cells from 10% to 1% did not significantly affect the overall number of ER-positive patients. The standardized assay for ER on two Yale TMA cohorts showed that 67.9% and 82.5% of the patients were above the 2-pg/μg immunoreactivity threshold. We found 9.1% and 19.7% of the patients to be QIF-positive/IHC-negative, and 4.0% and 0.4% to be QIF-negative/IHC-positive for a total of 13.1% and 20.1% discrepant cases when compared with pathologists' judgment of threshold. Assessment of survival for both cohorts showed that patients who were QIF-positive/pathologist-negative had outcomes similar to those of patients who had positive results for both assays. Assessment of intensity threshold by using a quantitative, standardized assay on two independent cohorts suggests discordance in the 10% to 20% range with current IHC methods, in which patients with discrepant results have prognostic outcomes similar to ER-positive patients with concordant results.Journal of Clinical Oncology 06/2011; 29(22):2978-84. · 18.37 Impact Factor -
Article: Littoral cell angioma of the spleen diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy.
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ABSTRACT: Littoral cell angiomas are uncommon primary vascular neoplasms that arise from the sinusoidal lining or littoral cells of the splenic red pulp, and hence are unique to the spleen. We report a case of littoral cell angioma in 34-year-old woman, which was diagnosed by endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB). The cytologic features of littoral cell angiomas have been described only in three previous case reports, one of which was a bench-top aspirate. In our case, we have utilized the fine-needle aspiration samples obtained by a linear endoscopic ultrasound examination for establishing the diagnosis. The characteristic cytologic features identified on the smears along with immunohistochemical analysis performed on the compact cellblock prepared from the aspirate aided in the confirmation of the diagnosis. We suggest that EUS-FNAB is a safe and reliable method in the diagnosis of vascular lesions of the spleen.Diagnostic Cytopathology 05/2011; 39(5):318-22. · 1.16 Impact Factor -
Article: Comparison of Affirm VPIII and Papanicolaou tests in the detection of infectious vaginitis.
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ABSTRACT: To compare the Affirm VPIII molecular test (Becton Dickinson, Burlington, NC) with morphologic identification used in routine Papanicolaou (Pap) test screening in the detection and identification of Candida species, Trichomonas vaginalis, and Gardnerella vaginalis, we identified 431 cases with a concomitant Pap test and Affirm VPIII assay performed from the archives of a large academic institution. The study population consisted of women ranging in age from 17 to 79 years (mean and median ages, 33 and 31 years, respectively). With a routine Pap test, 60 patients (13.9%) were found to have bacterial vaginosis, 60 (13.9%) candidiasis, and 3 (0.7%) Trichomonas infection. With the Affirm VPIII assay, 183 (42.5%) patients tested positive for G vaginalis, 70 (16.2%) positive for Candida species, and 10 (2.3%) positive for T vaginalis. The differences were statistically significant. The results demonstrate that our patient population had a high incidence of bacterial vaginosis/Candida vaginitis; however, the Affirm VPIII was a more sensitive diagnostic test for the detection and identification of all 3 organisms compared with the Pap test.American Journal of Clinical Pathology 03/2011; 135(3):442-7. · 2.60 Impact Factor -
Article: Multiplexed assessment of the Southwest Oncology Group-directed Intergroup Breast Cancer Trial S9313 by AQUA shows that both high and low levels of HER2 are associated with poor outcome.
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ABSTRACT: Assessment of key breast cancer tissue biomarkers is often done using nonquantitative methods. We hypothesized that use of continuous analysis of expression with the AQUA method of automated quantitative analysis will provide prognostic information beyond that attainable with conventional methods. A tissue microarray was made from 2123 of 3122 patients accrued to SWOG 9313, in which sequential doxorubicin (A) and cyclophosphamide (C) was compared with combination AC and in which all patients except premenopausal estrogen receptor (ER)-negative patients received tamoxifen. Multiplexed assays of 1) HER2 and estrogen receptor and 2) progesterone receptor (PgR) and p53 were performed on the two slides using the immunofluorescence-based AQUA method of automated quantitative analysis. Both ER and PgR showed unimodal distributions and significantly predicted disease-free survival when tested as continuous variables and adjusted for node status, tumor size, treatment, and menopausal status (P = 0.005 and P < 0.001, respectively). HER2, measured as a continuous variable, showed a biphasic effect on disease-free survival. Both high and low expressers of HER2 have worse outcomes (when low levels are equivalent to that seen in normal breast ducts). In patients who were uniformly treated with AC chemotherapy and tamoxifen (when indicated), both ER and PgR, assessed as continuous variables, were highly prognostic, whereas p53 expression was not. This assay method may provide a new companion diagnostic approach for targeted therapies.American Journal Of Pathology 02/2010; 176(4):1639-47. · 4.89 Impact Factor -
Article: Distinct human papillomavirus type 16 methylomes in cervical cells at different stages of premalignancy.
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ABSTRACT: Human papillomavirus (HPV) gene expression is dramatically altered during cervical carcinogenesis. Because dysregulated genes frequently show abnormal patterns of DNA methylation, we hypothesized that comprehensive mapping of the HPV methylomes in cervical samples at different stages of progression would reveal patterns of clinical significance. To test this hypothesis, thirteen HPV16-positive samples were obtained from women undergoing routine cervical cancer screening. Complete methylation data were obtained for 98.7% of the HPV16 CpGs in all samples by bisulfite-sequencing. Most HPV16 CpGs were unmethylated or methylated in only one sample. The other CpGs were methylated at levels ranging from 11% to 100% of the HPV16 copies per sample. The results showed three major patterns and two variants of one pattern. The patterns showed minimal or no methylation (A), low level methylation in the E1 and E6 genes (B), and high level methylation at many CpGs in the E5/L2/L1 region (C). Generally, pattern A was associated with negative cytology, pattern B with low-grade lesions, and pattern C with high-grade lesions. The severity of the cervical lesions was then ranked by the HPV16 DNA methylation patterns and, independently, by the pathologic diagnoses. Statistical analysis of the two rating methods showed highly significant agreement. In conclusion, analysis of the HPV16 DNA methylomes in clinical samples of cervical cells led to the identification of distinct methylation patterns which, after validation in larger studies, could have potential utility as biomarkers of neoplastic cervical progression.Virology 06/2009; 389(1-2):100-7. · 3.35 Impact Factor -
Article: Estrogen receptor co-activator (AIB1) protein expression by automated quantitative analysis (AQUA) in a breast cancer tissue microarray and association with patient outcome.
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ABSTRACT: Amplified in breast cancer (AIB1 or SRC-3) is an estrogen receptor coregulatory protein that together with other co-activators like transcription intermediary factor 2 (TIF2) and nuclear receptor co-repressor (NCoR), is implicated in estrogen signaling pathway and estrogen regulated tumor progression. We investigated the prognostic significance of AIB1, TIF2 & NCoR protein expression breast tissue microarray (TMA), and studied the relationship of coregulatory proteins to prognostic biomarkers like estrogen (ER), progesterone (PR) & HER2/neu and between coregulatory proteins. AIBI, TIF2 & NCoR were studied by fluorescent immunohistochemical staining of a TMA with 670 breast cancer specimens, using AQUA software. Using Cox univariate survival analyses, high AIB1 expression was associated with poor patient outcome (P = 0.002), while no association was noted for TIF2 (P = 0.376) & NCoR (P = 0.12). When subclassified by nodal or ER status, AIB1 was not prognostic in the node positive and ER positive subsets. However, in the ER negative and node negative subsets, high AIB1 expression was associated with poor patient outcome (P = 0.02 and P = 0.007 respectively). AIB1 retained its independent association with survival by multivariate analyses (P = 0.028). There was significant positive correlation between AIB1 and ER and PR status and with other cofators (TIF2 and NCoR) but not with HER2/neu status. High AIB1 expression was predictive of worse overall survival in our study, suggesting that AIB1 may be critical in breast carcinogenesis.Breast Cancer Research and Treatment 05/2009; 115(1):77-85. · 4.43 Impact Factor -
Article: Quantitative justification of the change from 10% to 30% for human epidermal growth factor receptor 2 scoring in the American Society of Clinical Oncology/College of American Pathologists guidelines: tumor heterogeneity in breast cancer and its implications for tissue microarray based assessment of outcome.
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ABSTRACT: The variability in scoring of immunohistochemistry, whether a result of true heterogeneity or artifacts in preparation, has led to decreased reliability in companion diagnostics and the recommendation for new standards (eg, the American Society of Clinical Oncology/College of American Pathologists [ASCO-CAP] guidelines). The basis of this problem is the amount of tissue required to be representative of an entire tumor. Because protein expression on tissue microarrays (TMAs) can be rigorously measured and one 0.6-mm spot is equivalent to two to three high-power fields, we used TMAs to assess levels of heterogeneity and to determine optimal representation as a function of outcome. We analyzed estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER-2) expression in two cohorts (n = 676 and n = 152) on a series of four to five separate TMA cores and assessed heterogeneity by linear regression analysis. Minimum, average, and maximum scores were generated for each set, which were then assessed for prognostic and predictive value. Each marker shows some heterogeneity, but average r values between 0.7 and 0.8 are seen between TMA spots. Analysis for prognostic value shows that the highest maximum score (of five spots) is the most prognostic for ER, whereas a high HER-2 minimum score is most prognostic for poor outcome and most predictive of response to trastuzumab. These results suggest that the representivity required for each biomarker may be a function of its role in tumorigenesis. Furthermore, these results provide scientific basis for the ASCO-CAP guidelines for assessment of HER-2 expression but perhaps suggest that the 30% figure is still too conservative.Journal of Clinical Oncology 01/2008; 25(34):5418-25. · 18.37 Impact Factor -
Article: Variation in breast cancer hormone receptor and HER2 levels by etiologic factors: a population-based analysis.
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ABSTRACT: Evidence suggests that breast cancer hormone receptor status varies by etiologic factors, but studies have been inconsistent. In a population-based case-control study in Poland that included 2,386 cases and 2,502 controls, we assessed ER-alpha and PR status of tumors based on clinical records according to etiologic exposure data collected via interview. For 842 cancers, we evaluated ER-alpha, ER-beta, PR and HER2 levels by semiquantitative microscopic scoring of immunostained tissue microarrays and a quantitative immunofluorescence method, automated quantitative analysis (AQUAtrade mark). We related marker levels in tumors to etiologic factors, using standard regression models and novel statistical methods, permitting adjustment for both correlated tumor features and exposures. Results obtained with different assays were generally consistent. Receptor levels varied most significantly with body mass index (BMI), a factor that was inversely related to risk among premenopausal women and directly related to risk among postmenopausal women with larger tumors. After adjustment for correlated markers, exposures and pathologic characteristics, PR and HER2 AQUA levels were inversely related to BMI among premenopausal women (p-trend = 0.01, both comparisons), whereas among postmenopausal women, PR levels were associated directly with BMI (p-trend = 0.002). Among postmenopausal women, analyses demonstrated that BMI was related to an interaction of PR and HER2: odds ratio (OR) = 0.86 (95% CI = 0.69-1.07) for low PR and HER2 expression vs. OR = 1.78 (95% CI = 1.25-2.55) for high expression (p-heterogeneity = 0.001). PR and HER2 levels in breast cancer vary by BMI, suggesting a heterogeneous etiology for tumors related to these markers.International Journal of Cancer 10/2007; 121(5):1079-85. · 5.44 Impact Factor -
Article: Bimodal population or pathologist artifact?
Journal of Clinical Oncology 07/2007; 25(17):2487-8. · 18.37 Impact Factor -
Article: Classification of breast cancer using genetic algorithms and tissue microarrays.
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ABSTRACT: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.Clinical Cancer Research 12/2006; 12(21):6459-68. · 7.74 Impact Factor -
Article: Vascular endothelial growth factor, FLT-1, and FLK-1 analysis in a pancreatic cancer tissue microarray.
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ABSTRACT: Measures of vascular endothelial growth factor (VEGF) expression in pancreatic cancer typically have been qualitative or semiquantitative. The objective of this study was to use a series of algorithms called AQUA that quantitatively assesses protein expression on tissue microarrays (TMAs) to compare in situ expression of VEGF and its primary receptors, VEGF receptor 1 (FLT-1) and VEGF receptor 1 (FLK-1), on a pancreatic cancer TMA. TMAs were constructed by arraying 1.5-mm cores from 76 samples of pancreatic adenocarcinoma (1996-2002) that were obtained from the archives of the Yale Department of Pathology. The staining for AQUA was similar to standard immunohistochemistry and involved antigen retrieval and the application of primary antibodies, but with epifluorescence detection. Slides were counterstained with 4',6-diamidino-2-phenylindole for nuclear visualization and cytokeratin for membrane visualization. The primary antibodies used were VEGF, FLT-1, FLK-1, and cytokeratin. Disease stage was highly prognostic for outcome, as expected. Total amounts of VEGF and its receptors were assessed within the tumor mask and were divided into quartiles. Kaplan-Meier survival curves showed that VEGF and FLK-1 were not associated clearly with outcome. However, the expression of FLT-1 was correlated significantly, and the patients who had tumors with the lowest expression FLT-1 levels had the worst survival (P = .0038). In multivariate analysis, FLT-1 expression was an independent prognostic factor for overall survival (P = .0044). VEGF and its 2 principal receptors were expressed to varying degrees in tumors of the pancreas. A significant association was found between low expression of FLT-1 and both poor prognosis and advanced stage, suggesting that tumor expression of this VEGF receptor is a marker of less aggressive disease.Cancer 05/2006; 106(8):1677-84. · 4.77 Impact Factor -
Article: Vascular endothelial growth factor, FLT‐1, and FLK‐1 analysis in a pancreatic cancer tissue microarray
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ABSTRACT: BACKGROUND Measures of vascular endothelial growth factor (VEGF) expression in pancreatic cancer typically have been qualitative or semiquantitative. The objective of this study was to use a series of algorithms called AQUA that quantitatively assesses protein expression on tissue microarrays (TMAs) to compare in situ expression of VEGF and its primary receptors, VEGF receptor 1 (FLT-1) and VEGF receptor 1 (FLK-1), on a pancreatic cancer TMA.METHODSTMAs were constructed by arraying 1.5-mm cores from 76 samples of pancreatic adenocarcinoma (1996-2002) that were obtained from the archives of the Yale Department of Pathology. The staining for AQUA was similar to standard immunohistochemistry and involved antigen retrieval and the application of primary antibodies, but with epifluorescence detection. Slides were counterstained with 4′,6-diamidino-2-phenylindole for nuclear visualization and cytokeratin for membrane visualization. The primary antibodies used were VEGF, FLT-1, FLK-1, and cytokeratin.RESULTSDisease stage was highly prognostic for outcome, as expected. Total amounts of VEGF and its receptors were assessed within the tumor mask and were divided into quartiles. Kaplan–Meier survival curves showed that VEGF and FLK-1 were not associated clearly with outcome. However, the expression of FLT-1 was correlated significantly, and the patients who had tumors with the lowest expression FLT-1 levels had the worst survival (P = .0038). In multivariate analysis, FLT-1 expression was an independent prognostic factor for overall survival (P = .0044).CONCLUSIONSVEGF and its 2 principal receptors were expressed to varying degrees in tumors of the pancreas. A significant association was found between low expression of FLT-1 and both poor prognosis and advanced stage, suggesting that tumor expression of this VEGF receptor is a marker of less aggressive disease. Cancer 2006. © 2006 American Cancer Society.Cancer 04/2006; 106(8):1677 - 1684. · 4.77 Impact Factor -
Article: Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis.
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ABSTRACT: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.Journal of Clinical Oncology 03/2006; 24(5):736-47. · 18.37 Impact Factor -
Article: Aberrant E-cadherin staining patterns in invasive mammary carcinoma.
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ABSTRACT: E-cadherin, a cell surface protein involved in cell adhesion, is present in normal breast epithelium, benign breast lesions, and in breast carcinoma. Alterations in the gene CDH1 on chromosome 16q22 are associated with changes in E-cadherin protein expression and function. Inactivation of E-cadherin in lobular carcinomas and certain diffuse gastric carcinomas may play a role in the dispersed, discohesive "single cell" growth patterns seen in these tumors. The molecular "signature" of mammary lobular carcinomas is the loss of E-cadherin protein expression as evidenced by immunohistochemistry, whereas ductal carcinomas are typically E-cadherin positive. We report on E-cadherin immunostaining patterns in five cases of invasive mammary carcinoma. These were five exceptional instances in which the E-cadherin immunophenotype did not correspond to the apparent histologic classification of the lesion. These cases which are exceedingly rare in our experience are the subject of this report. Findings such as those illustrated in this study occur in virtually all biologic phenomena and they do not invalidate the very high degree of correlation between the expression of E-cadherin and the classification of breast carcinomas as ductal or lobular type on the basis of conventional histologic criteria.World Journal of Surgical Oncology 12/2005; 3:73. · 1.12 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2012
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Yale-New Haven Hospital
- Department of Pathology
New Haven, CT, USA
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2005–2012
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Yale University
- School of Medicine
New Haven, CT, USA
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2002–2005
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New York Presbyterian Hospital
- Department of Pathology
New York City, NY, USA
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2004
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Weill Cornell Medical College
New York City, NY, USA
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