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Jonathan I Epstein - One of the best experts on this subject based on the ideXlab platform.
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cyclin d1 loss distinguishes prostatic small cell carcinoma from most prostatic Adenocarcinomas
Clinical Cancer Research, 2015Co-Authors: Harrison Tsai, Jonathan I Epstein, Carlos L Morais, Mohammed Alshalalfa, Hsuehli Tan, Zaid Haddad, Jessica Hicks, Nilesh S Gupta, George J Netto, William B IsaacsAbstract:Purpose:Small cell neuroendocrine differentiation in prostatic carcinoma is an increasingly common resistance mechanism to potent androgen deprivation therapy (ADT), but can be difficult to identify morphologically. We investigated whether cyclin D1 and p16 expression can inform on Rb functional status and distinguish small cell carcinoma from Adenocarcinoma. Experimental Design:We used gene expression data and immunohistochemistry to examine cyclin D1 and p16 levels in patient-derived xenografts (PDX), and prostatic small cell carcinoma and Adenocarcinoma specimens. Results:Using PDX, we show proof-of-concept that a high ratio of p16 to cyclin D1 gene expression reflects underlying Rb functional loss and distinguishes morphologically identified small cell carcinoma from prostatic Adenocarcinoma in patient specimens (n=13 and 9, respectively). At the protein level cyclin D1, but not p16, was useful to distinguish small cell carcinoma from Adenocarcinoma. Overall, 88% (36/41) of small cell carcinomas showed cyclin D1 loss by immunostaining compared to 2% (2/94) of Gleason score 7-10 primary Adenocarcinomas at radical prostatectomy, 9% (4/44) of Gleason score 9-10 primary Adenocarcinomas at needle biopsy, and 7% (8/115) of individual metastases from 39 patients at autopsy. Though rare Adenocarcinomas showed cyclin D1 loss, many of these were associated with clinical features of small cell carcinoma, and in a cohort of men treated with adjuvant ADT who developed metastasis, lower cyclin D1 gene expression was associated with more rapid onset of metastasis and death. Conclusions: Cyclin D1 loss identifies prostate tumors with small cell differentiation and may identify a small subset of Adenocarcinomas with poor prognosis.
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hepatocyte nuclear factor 1β expression in clear cell Adenocarcinomas of the bladder and urethra diagnostic utility and implications for histogenesis
Human Pathology, 2011Co-Authors: Fadi Brimo, Mehsati Herawi, Rajni Sharma, Georges J Netto, Jonathan I Epstein, Peter B IlleiAbstract:Summary The histogenesis of clear cell Adenocarcinoma of the bladder/urethra is uncertain. Hepatocyte nuclear factor–1 β is a homeodomain protein that has been reported to be frequently overexpressed in ovarian clear cell Adenocarcinoma in comparison with rare or no expression in other types of epithelial ovarian tumors. We assessed the expression of hepatocyte nuclear factor–1 β in a series of 18 clear cell Adenocarcinomas of the bladder and urethra and compared it with that of invasive high-grade transitional/urothelial carcinoma (n = 35); Adenocarcinomas of the bladder, urethra, and paraurethral glands (n = 21); as well as nephrogenic adenomas of the bladder (n = 8). Staining intensity and extent were evaluated using a 4-tiered grading system (0-3). A case was considered positive for hepatocyte nuclear factor–1 β if 10% or more of tumor cells showed at least weak nuclear staining or if any moderate or strong nuclear staining was observed. All 18 clear cell Adenocarcinomas exhibited nuclear staining in at least 50% of tumor cells (16 strong, 1 moderate, and 1 weak with focal strong nuclear staining) in comparison with positive nuclear staining (moderate) in 1 of 21 bladder Adenocarcinoma, 1 of 35 invasive high-grade transitional/urothelial carcinoma (weak to moderate staining), and 2 of 8 nephrogenic adenomas (1 weak and 1 moderate to strong staining). We concluded that hepatocyte nuclear factor–1 β is a useful marker in differentiating clear cell Adenocarcinomas of the bladder/urethra from invasive high-grade transitional/urothelial carcinoma and other types of bladder Adenocarcinomas and to a lesser extent from nephrogenic adenomas. Hepatocyte nuclear factor–1 β is of no diagnostic utility in discriminating primary bladder/urethral clear cell Adenocarcinomas from metastatic clear cell Adenocarcinomas of the female genital tract to the bladder/urethra. From a histogenesis standpoint, although the expression of hepatocyte nuclear factor–1 β in both gynecologic and urologic tract clear cell Adenocarcinomas may point to a Mullerian derivation/differentiation, this immunohistochemical evidence is insufficient to completely exclude an urothelial association.
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clear cell Adenocarcinoma of the bladder and urethra cases diffusely mimicking nephrogenic adenoma
Human Pathology, 2010Co-Authors: Mehsati Herawi, Peter A Drew, Jonathan I EpsteinAbstract:Summary Although clear cell Adenocarcinoma have been described focally mimicking nephrogenic adenoma, we have identified a subset of clear cell Adenocarcinoma that diffusely resembles nephrogenic adenoma (nephrogenic adenoma-like clear cell Adenocarcinoma). Twelve classic clear cell Adenocarcinomas of the bladder and urethra and 7 nephrogenic adenoma-like clear cell Adenocarcinomas were compared to 10 nephrogenic adenomas. Classic clear cell Adenocarcinomas and nephrogenic adenoma-like clear cell Adenocarcinomas comprised 4 men and 15 women. The following features were seen in classic clear cell Adenocarcinomas: nephrogenic adenoma-like clear cell Adenocarcinomas: predominantly solid pattern (7/12:0/7), marked nuclear pleomorphism (7/12:1/7), prominent nucleoli (5/12:1/7), clear cytoplasm in 50% or greater of tumor (7/12:0/7), and necrosis (8/12:3/7), although the necrosis in nephrogenic adenoma-like clear cell Adenocarcinomas was often focal and intraluminal. Both patterns of clear cell Adenocarcinomas showed prominent hobnail features, although more pronounced in nephrogenic adenoma-like clear cell Adenocarcinomas. Muscularis propria invasion was seen in 5 of 9 classic clear cell Adenocarcinomas and 6 of 6 nephrogenic adenoma-like clear cell Adenocarcinomas, where evaluable. Classic clear cell Adenocarcinoma was associated with urothelial carcinoma (n = 2) and endometriosis (n = 1). The Ki-67 rate in clear cell Adenocarcinomas ranged from 10% to 80% compared with 0% to 5% in nephrogenic adenoma. The following antibodies were not helpful in distinguishing nephrogenic adenoma-like clear cell Adenocarcinoma from nephrogenic adenoma: CD10, estrogen receptor, p63, high-molecular-weight cytokeratin, and α -methylacyl coenzyme-A racemase. PAX2 expression was more frequent in nephrogenic adenoma (89%) compared to both patterns of clear cell Adenocarcinoma (29%-32%). The key features discriminating between nephrogenic adenoma-like clear cell Adenocarcinoma and nephrogenic adenoma include occasional clear cells, more prominent pleomorphism especially hyperchromatic enlarged nuclei, and extensive muscular invasion. Presence of mitoses and a high rate of Ki-67 expression in lesions resembling nephrogenic adenoma require clinical correlation, close follow-up, and repeat biopsy with more extensive sampling.
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primary mucin producing urothelial type Adenocarcinoma of prostate report of 15 cases
The American Journal of Surgical Pathology, 2007Co-Authors: Adeboye O Osunkoya, Jonathan I EpsteinAbstract:Prostatic urothelial-type Adenocarcinoma arises through a process of glandular metaplasia of the prostatic urethral urothelium and subsequent in situ Adenocarcinoma sometimes associated with villous adenoma. These prostatic Adenocarcinomas are analogous to nonurachal Adenocarcinomas arising in the b
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mucinous Adenocarcinoma of urinary bladder type arising from the prostatic urethra distinction from mucinous Adenocarcinoma of the prostate
The American Journal of Surgical Pathology, 1996Co-Authors: Khanh P Tran, Jonathan I EpsteinAbstract:We describe two cases of mucinous Adenocarcinomas involving and confined to the prostate and originating from the prostatic urethra. These cases were identical to Adenocarcinomas arising within the urinary bladder and differed from mucinous Adenocarcinoma of the prostate. In both cases, an in situ Adenocarcinoma component was identified in the overlying prostatic urethra. In one case the in situ Adenocarcinoma arose in a villous adenoma of the urethra. Both cases contained lakes of mucin lined by tall columnar epithelium with varying degrees of cytologic atypia, and one case had mucin-positive signet cells. In contrast, mucinous Adenocarcinomas of the prostate demonstrate tubules and cribriform glands floating within mucin; mucin-positive signet cells are rare. Both tumors were negative immunohistochemically for prostate-specific antigen and prostate-specific acid phosphatase and positive for carcino-embryonic antigen. One case was treated by radical prostatectomy, and the patient was without evidence of disease with short follow-up. Following simple prostatectomy, the other patient did not undergo definitive therapy for several years, at which point the tumor had progressed locally to an advanced stage. In terms of therapy, the distinction between mucinous Adenocarcinoma or urinary bladder-type arising in the prostate depicted within the current study and mucinous Adenocarcinoma of the prostate is significant.
Andrew D. Sharrocks - One of the best experts on this subject based on the ideXlab platform.
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RESEARCH Open Access The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal Adenocarcinoma
2013Co-Authors: Richard Keld, Baoqiang Guo, Paul Downey, Christian Gulmann, Yeng S Ang, Andrew D. SharrocksAbstract:Background: Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers. Results: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal Adenocarcinomas and determined their role in oesophageal Adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal Adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human Adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal Adenocarcinomas. Conclusions: This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal Adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal Adenocarcinomas
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the erk map kinase pea3 etv4 mmp 1 axis is operative in oesophageal Adenocarcinoma
Molecular Cancer, 2010Co-Authors: Richard Keld, Baoqiang Guo, Paul Downey, Christian Gulmann, Yeng Ang, Andrew D. SharrocksAbstract:Background: Many members of the ETS-domain transcription factor family are important drivers of tumourigenesis. In this context, their activation by Ras-ERK pathway signaling is particularly relevant to the tumourigenic properties of many ETS-domain transcription factors. The PEA3 subfamily of ETS-domain transcription factors have been implicated in tumour metastasis in several different cancers. Results: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal Adenocarcinomas and determined their role in oesophageal Adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal Adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human Adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal Adenocarcinomas. Conclusions: This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal Adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal Adenocarcinomas.
William D Travis - One of the best experts on this subject based on the ideXlab platform.
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validation of the iaslc ats ers lung Adenocarcinoma classification for prognosis and association with egfr and kras gene mutations analysis of 440 japanese patients
Journal of Thoracic Oncology, 2013Co-Authors: Akihiko Yoshizawa, William D Travis, Shinji Sumiyoshi, Makoto Sonobe, Masashi Kobayashi, Masakazu Fujimoto, Fumi Kawakami, Tatsuaki Tsuruyama, Hiroshi Date, Hironori HagaAbstract:Introduction: This study aimed to validate the utility of the new histological classification proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) for identifying the prognostic subtypes of Adenocarcinomas in Japanese patients; correlations between the classification and the presence of EGFR or KRAS mutation status were also investigated. Methods: We retrospectively reviewed 440 patients with lung Adenocarcinoma, who underwent resection. The tumors were classified according to the IASLC/ATS/ERS classification. EGFR and KRAS mutations were detected using the established methods. Results: Five-year disease-free survival rates were: 100% for Adenocarcinoma in situ ( n = 20) and minimally invasive Adenocarcinoma ( n = 33), 93.8% for lepidic-predominant Adenocarcinoma ( n = 36), 88.8% for invasive mucinous Adenocarcinoma ( n = 10), 66.7% for papillary-predominant Adenocarcinoma ( n = 179), 69.7% for acinar-predominant Adenocarcinoma ( n = 61), 43.3% for solid-predominant adencoarcinoma ( n = 78), and 0% for micropapillary-predominant Adenocarcinoma ( n = 19). Multivariate analysis revealed that the new classification was an independent predictor of disease-free survival. EGFR and KRAS mutations were detected in 90 cases (53.9%) and 21 cases (13.3%), respectively; EGFR mutations were significantly associated with Adenocarcinoma in situ, minimally invasive Adenocarcinoma, lepidic- and papillary-predominant Adenocarcinoma, and KRAS mutations Adenocarcinomas with mucinous tumor subtypes. Conclusions: We found that the IASLC/ATS/ERS classification identified prognostic histologic subtypes of lung Adenocarcinomas among Japanese patients. Histologic subtyping and molecular testing for EGFR and KRAS mutations can help predict patient prognosis and select those who require adjuvant chemotherapy.
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international association for the study of lung cancer american thoracic society european respiratory society international multidisciplinary classification of lung Adenocarcinoma executive summary
Proceedings of the American Thoracic Society, 2011Co-Authors: William D Travis, Masayuki Noguchi, Elisabeth Brambilla, Andrew G Nicholson, Kim R Geisinger, Yasushi Yatabe, Charles A Powell, David G Beer, G J Riely, Kavita GargAbstract:Introduction: The American Thoracic Society is a cosponsor of a newly published lung Adenocarcinoma classification.Methods: An international multidisciplinary panel of experts was formed. A systematic review was performed and recommendations were graded by strength and quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results: The classification addresses both resection specimens and small biopsies/cytology. The terms bronchioloalveolar carcinoma and mixed subtype Adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as Adenocarcinoma in situ and minimally invasive Adenocarcinoma for small solitary Adenocarcinomas with pure lepidic growth and predominant lepidic growth with ≤ 5 mm invasion, respectively. Invasive Adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added. In the new ...
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evolving concepts in the pathology and computed tomography imaging of lung Adenocarcinoma and bronchioloalveolar carcinoma
Journal of Clinical Oncology, 2005Co-Authors: William D Travis, Kavita Garg, Wilbur A Franklin, Ignacio I Wistuba, Bradley S Sabloff, Masayuki Noguchi, Ryutaro Kakinuma, Maureen F Zakowski, Michelle S Ginsberg, Robert F PaderaAbstract:Purpose To review recent advances in pathology and computed tomography (CT) of lung Adenocarcinoma and bronchioloalveolar carcinoma (BAC). Methods A pathology/CT review panel of pathologists and radiologists met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The purpose was to determine if existing data was sufficient to propose modification of criteria for Adenocarcinoma and BAC as newly published in the 2004 WHO Classification of Lung Tumors, and to address the pathologic/radiologic concept of diffuse/multicentric BAC. Results Solitary small, peripheral BACs have an excellent prognosis. Most lung Adenocarcinomas with a BAC pattern are not pure BAC, but rather Adenocarcinoma, mixed subtype with invasive patterns. This applies to tumors presenting with a diffuse/multinodular as well as solitary nodule pattern. The percent of BAC versus invasive components in lung Adenocarcinomas appears to be prognosticall...
Kavita Garg - One of the best experts on this subject based on the ideXlab platform.
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international association for the study of lung cancer american thoracic society european respiratory society international multidisciplinary classification of lung Adenocarcinoma executive summary
Proceedings of the American Thoracic Society, 2011Co-Authors: William D Travis, Masayuki Noguchi, Elisabeth Brambilla, Andrew G Nicholson, Kim R Geisinger, Yasushi Yatabe, Charles A Powell, David G Beer, G J Riely, Kavita GargAbstract:Introduction: The American Thoracic Society is a cosponsor of a newly published lung Adenocarcinoma classification.Methods: An international multidisciplinary panel of experts was formed. A systematic review was performed and recommendations were graded by strength and quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results: The classification addresses both resection specimens and small biopsies/cytology. The terms bronchioloalveolar carcinoma and mixed subtype Adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as Adenocarcinoma in situ and minimally invasive Adenocarcinoma for small solitary Adenocarcinomas with pure lepidic growth and predominant lepidic growth with ≤ 5 mm invasion, respectively. Invasive Adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added. In the new ...
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evolving concepts in the pathology and computed tomography imaging of lung Adenocarcinoma and bronchioloalveolar carcinoma
Journal of Clinical Oncology, 2005Co-Authors: William D Travis, Kavita Garg, Wilbur A Franklin, Ignacio I Wistuba, Bradley S Sabloff, Masayuki Noguchi, Ryutaro Kakinuma, Maureen F Zakowski, Michelle S Ginsberg, Robert F PaderaAbstract:Purpose To review recent advances in pathology and computed tomography (CT) of lung Adenocarcinoma and bronchioloalveolar carcinoma (BAC). Methods A pathology/CT review panel of pathologists and radiologists met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The purpose was to determine if existing data was sufficient to propose modification of criteria for Adenocarcinoma and BAC as newly published in the 2004 WHO Classification of Lung Tumors, and to address the pathologic/radiologic concept of diffuse/multicentric BAC. Results Solitary small, peripheral BACs have an excellent prognosis. Most lung Adenocarcinomas with a BAC pattern are not pure BAC, but rather Adenocarcinoma, mixed subtype with invasive patterns. This applies to tumors presenting with a diffuse/multinodular as well as solitary nodule pattern. The percent of BAC versus invasive components in lung Adenocarcinomas appears to be prognosticall...
Richard A Williams - One of the best experts on this subject based on the ideXlab platform.
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does lung Adenocarcinoma subtype predict patient survival a clinicopathologic study based on the new international association for the study of lung cancer american thoracic society european respiratory society international multidisciplinary lung Adenocarcinoma classification
Journal of Thoracic Oncology, 2011Co-Authors: Prudence A Russell, Zoe Wainer, Gavin M Wright, Marissa G Daniels, Matthew Conron, Richard A WilliamsAbstract:Introduction Lung Adenocarcinoma is a heterogeneous group of tumors with a highly variable prognosis, not well predicted by the current pathologic classification system. The 2004 World Health Organization classification results in virtually all tumors encountered in clinical practice being allocated to the Adenocarcinoma of mixed subtype category. A new classification developed by an international multidisciplinary expert panel sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, is based on histomorphologic subtype and has recently been validated in a North American series of 514 stage I lung Adenocarcinomas. We investigated the relationship between the new classification and patient survival in a series of Australian patients with stages I, II, and III lung Adenocarcinoma. Methods We identified 210 patients from a surgical database who underwent resection of lung Adenocarcinoma from 1996 to 2009. Two pathologists, blinded to patient outcome, independently performed histopathologic subtyping according to the new classification. Kaplan-Meier curves were used to calculate 5-year survival for each separate histopathologic subtype/variant. Univariate and multivariate analyses were undertaken to control for validated prognostic factors. Results We confirmed that the new subtypes of Adenocarcinoma in situ, minimally invasive Adenocarcinoma and lepidic-predominant Adenocarcinoma had a 5-year survival approaching 100%, whereas micropapillary-predominant and solid with mucin-predominant Adenocarcinomas were associated with particularly poor survival. Papillary-predominant and acinar-predominant Adenocarcinomas had an intermediate prognosis. This effect persisted after controlling for stage. Conclusions Classification of lung Adenocarcinoma according to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification correlated with 5-year survival. These relationships persisted after controlling for known prognostic patient and tumor characteristics. The new classification has advantages not only for individual patient care but also for better selection and stratification for clinical trials and molecular studies.
