Biomedical subjects

David B Seligson

Publications and source records attributed to David B Seligson.

9 recordsLinked to original sources

PubMed2005

Global histone modification patterns predict risk of prostate cancer recurrence.

Aberrations in post-translational modifications of histones have been shown to occur in cancer cells but only at individual promoters; they have not been related to clinical outcome. Other than being targeted to promoters, modifications of histones, such as acetylation and methylation of lysine and arginine residues, also occur over large regions of chromatin including coding regions and non-promoter sequences, which are referred to as global histone modifications. Here we show that changes in global levels of individual histone modifications are also associated with cancer and that these changes are predictive of clinical outcome. Through immunohistochemical staining of primary prostatectomy tissue samples, we determined the percentage of cells that stained for the histone acetylation and dimethylation of five residues in histones H3 and H4. Grouping of samples with similar patterns of modifications identified two disease subtypes with distinct risks of tumour recurrence in patients with low-grade prostate cancer. These histone modification patterns were predictors of outcome independently of tumour stage, preoperative prostate-specific antigen levels, and capsule invasion. Thus, widespread changes in specific histone modifications indicate previously undescribed molecular heterogeneity in prostate cancer and might underlie the broad range of clinical behaviour in cancer patients.

Acetylation↗

PubMed2005

Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma.

BACKGROUND: The presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been suggested to be an important predictor of survival. The authors investigated the relation of tumor necrosis to other clinicopathologic factors known to be important prognostic indicators for patients with RCC. METHODS: The records of 311 patients undergoing treatment for RCC were evaluated for basic clinicopathologic information including TNM classification, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease recurrence, and survival. The presence and extent of histologic necrosis of the primary tumors was recorded and correlated with clinicopathologic factors, carbonic anhydrase IX and Ki-67 expression, disease recurrence, and survival. RESULTS: The presence of necrosis in the primary tumor of patients with RCC compared with patients with RCC without necrosis was associated with higher T classification (P < 0.0001), the presence of lymph node disease (P = 0.009), the presence of metastases (P < 0.0001), higher grade (P < 0.0001), greater mean tumor size (P < 0.0001), an ECOG PS score > or = 1 (P = 0.007), higher University of California-Los Angeles Integrated Staging System (UISS) category (P < 0.0001), and higher Ki-67 expression (P < 0.0001). The extent of necrosis in the primary tumor was associated with the presence of lymph node disease (P = 0.009) and the presence of metastases (P < 0.0001), and correlated with higher T classification (sigma = 0.31, P < 0.0001), poorer ECOG PS (sigma = 0.18, P = 0.002), higher grade (sigma = 0.33, P < 0.0001), greater tumor size (sigma = 0.40, P < 0.0001), higher UISS category (sigma = 0.37, P < 0.0001), and higher Ki-67 staining (sigma = 0.32, P < 0.0001). Patients with the presence of necrosis in the primary tumor demonstrated a lower 5-year disease-specific survival compared with patients without necrosis in the primary tumor (36% vs. 75%; P < 0.0001). Multivariate analysis demonstrated that T classification (P < 0.0001), distant metastases (P < 0.0001), and ECOG PS (P < 0.0001) were independent predictors of DSS, whereas the presence of necrosis was not (P = 0.1100). Substratification into localized and metastatic disease demonstrated that the presence of necrosis was an independent predictor of survival in patients with localized (P = 0.025), but not metastatic (P = 0.44), disease. The extent of necrosis was not an independent predictor of survival (P > 0.05). Patients with the presence of necrosis in the primary tumor had a lower 5-year disease recurrence-free rate compared with patients without the presence of necrosis (62% vs. 92%, P < 0.0001). CONCLUSIONS: The presence of necrosis in the primary tumor was associated with adverse prognostic factors such as high T classification, presence of lymph node disease and metastases, high grade, large tumor size, and poor ECOG PS. The extent of necrosis was found to be associated with the presence of lymph node disease and metastases and correlated with higher T classification, higher grade, greater tumor size, poorer ECOG PS, and higher UISS category. The presence of this histologic variant was an independent predictor of poor survival in patients with localized, but not metastatic, disease. In addition, Ki-67 expression served as a valuable surrogate marker for the presence of histologic tumor necrosis.

Adenocarcinoma, Clear Cell↗

PubMed2004

Epithelial cell adhesion molecule (KSA) expression: pathobiology and its role as an independent predictor of survival in renal cell carcinoma.

PURPOSE: Epithelial cell adhesion molecule (EpCAM) is a widely expressed adhesion molecule in epithelial cancers. The purpose of this study is to determine the protein expression patterns of EpCAM in renal cell carcinoma (RCC) using tissue arrays linked to a clinicopathological database to evaluate both its predictive power in patient stratification and its suitability as a potential target for immunotherapeutic treatment strategies. EXPERIMENTAL DESIGN: The University of California, Los Angeles kidney cancer tissue microarray contains specimens from 417 patients treated with nephrectomy. EpCAM protein expression in tumors and matched morphologically normal renal tissues was evaluated using anti-EpCAM immunohistochemistry. The resultant expression reactivity was correlated with clinicopathological variables. RESULTS: EpCAM is consistently expressed in the distal nephron on normal renal epithelium. Clear cell RCCs show minimal and infrequent EpCAM expression, whereas chromophobe and collecting duct RCCs both demonstrate intense and frequent expression. Of 318 clear cell carcinomas used in the analysis, 10% were EpCAM positive in > or = 50% of cells, and 8% of patients would be considered candidates for EpCAM-based therapy, based on high expression [> or = moderate intensity and frequent (> or = 50%) expression] and the need for systemic treatment. EpCAM expression was an independent prognostic factor for improved disease-specific survival, with a multivariate hazard ratio of 0.63 (P = 0.017; 95% confidence interval, 0.43-0.92). CONCLUSIONS: EpCAM is a novel prognostic molecular marker in RCC patients, and its positive expression is an independent predictor associated with improved survival. However, high expression in morphologically normal renal tissues and minimal or absent expression in clear cell carcinomas will likely limit the utility of this epithelial marker in targeted treatments of this most common RCC type.

Adenocarcinoma, Clear Cell↗

PubMed2004

Statistical methods for analyzing tissue microarray data.

Tissue microarrays (TMAs) are a new high-throughput tool for the study of protein expression patterns in tissues and are increasingly used to evaluate the diagnostic and prognostic importance of biomarkers. TMA data are rather challenging to analyze. Covariates are highly skewed, non-normal, and may be highly correlated. We present statistical methods for relating TMA data to censored time-to-event data. We review methods for evaluating the predictive power of Cox regression models and show how to test whether biomarker data contain predictive information above and beyond standard pathology covariates. We use nonparametric bootstrap methods to validate model fitting indices such as the concordance index. We also present data mining methods for characterizing high risk patients with simple biomarker rules. Since researchers in the TMA community routinely dichotomize biomarker expression values, survival trees are a natural choice. We also use bump hunting (patient rule induction method), which we adapt to the use with survival data. The proposed methods are applied to a kidney cancer tissue microarray data set.

Algorithms↗

PubMed2004

Prostate stem cell antigen expression is associated with gleason score, seminal vesicle invasion and capsular invasion in prostate cancer.

PURPOSE: Few successful therapeutic options exist for men who present with metastatic prostate cancer (CaP) or for the 30% with recurrence. The development and characterization of molecular markers are vital to the development of prognostic and therapeutic modalities in CaP. We investigated the expression and potential clinical usefulness of prostate stem cell antigen (PSCA) in CaP using tissue microarrays. MATERIALS AND METHODS: Immunohistochemical analysis using a PSCA monoclonal antibody was performed on tissue microarrays constructed from paraffin embedded specimens from 246 patients who underwent radical retropubic prostatectomy. PSCA staining was correlated with established prognostic factors, such as Gleason score, prostate specific antigen (PSA), and seminal vesicle invasion. In addition, recurrence-free survival was analyzed. RESULTS: A high PSCA intensity of 3 was associated with adverse prognostic features, such as Gleason score 7 and above (p = 0.001), seminal vesicle invasion (p = 0.005) and capsular involvement (p = 0.033). On univariate analysis tumors with a PSCA intensity of 3 carried an increased risk of PSA recurrence (p = 0.031, HR 1.77, 95% CI 1.05 to 2.96). However, after adjusting for these variables a PSCA intensity of 3 was no longer an independent predictor of PSA recurrence. CONCLUSIONS: We found that high PSCA intensity is significantly associated with adverse prognostic features such as high Gleason score and extra-organ disease. The results of this study suggest that PSCA is a promising tumor marker for the selection of patients at high risk but additional studies are necessary to assess the usefulness of PSCA in patient biopsies.

Aged↗

PubMed2003

Analysis of the Na,K-ATPase alpha- and beta-subunit expression profiles of bladder cancer using tissue microarrays.

BACKGROUND: The purpose of this study was to determine the clinical significance of Na,K-ATPase alpha- and beta-subunit expression in a histopathologically well-characterized group of patients representing a wide spectrum of tumor grades and disease stages with transitional cell carcinomas (TCC). METHODS: Na,K-ATPase alpha- and beta-subunit protein expression patterns were analyzed using immunohistochemistry on urothelial cancer tissue microarrays (TMA) of 146 patients diagnosed with urothelial carcinoma. For each subunit, the maximum staining intensity and the percentage of positive cells staining at the maximal intensity were analyzed. RESULTS: Compared with the benign fields, the mean protein expression for both Na,K-ATPase alpha- and beta-subunits were found to be decreased overall in in situ and invasive tumors, as well as in tumor-adjacent dysplastic fields. When Na,K-ATPase alpha- and beta-subunit expression levels were dichotomized into distinct groups, they were both found to be significant predictors of recurrence risk in multivariate logistic regression analysis (P = 0.0062, odds ratio [OR] = 2.6 and P = 0.013, OR = 0.43, for Na,K-ATPase alpha- and beta-subunits, respectively). The authors also found that patients with high alpha- and low beta-subunit expression had a high risk for early recurrence, whereas patients with a low alpha- and high beta-subunit expression had a significantly longer median recurrence-free time (17 months and 125 months, respectively, log rank statistics P = 0.0005). CONCLUSIONS: The results suggested that Na,K-ATPase alpha- and beta-subunit expression levels may be useful predictors of clinical outcomes such as recurrence-free time of bladder cancer patients.

Adult↗

PubMed2003

Loss of CD10 (neutral endopeptidase) is a frequent and early event in human prostate cancer.

BACKGROUND: We hypothesized that the aggressive LNCaP-derived androgen-independent cell line, CL1, might differ from LNCaP in their repertoire of cell surface markers and that these differences might typify changes that occur during clinical prostate cancer progression. METHODS: The cell surface marker expression profiles of CL1 and LNCaP were examined using flow cytometry. Markedly differential gene expression was confirmed using RT-PCR and further examined using immunohistochemistry among the prostate cancer cell lines LAPC-4, LNCaP, CL1, CL2, DU145, and PC-3. The expression of the most markedly differentially expressed surface marker, CD10, was further explored in a tissue microarray containing radical prostatectomy samples from 219 hormone naïve prostate cancer patients. RESULTS: There were marked differences in the expression of CD10, CD13, CD26, CD33, CD44, CD54, CD55, and CD104 between CL1 and LNCaP. Results from both the RT-PCR and immunohistochemistry confirmed the differential expression and found that CD10 demonstrated a pattern of expression in hormone sensitive but not hormone refractory cell lines. When CD10 expression was examined in a tissue microarray, CD10 expression was below the 25th percentile of matched normal prostate tissue in 68% of prostate cancers, below the median expression of matched normal prostate tissue in 86% of cancers, and completely absent in 34% of cancers. Samples of prostatic intraepithelial neoplasia demonstrated CD10 expression that was intermediate between normal prostatic tissue and prostate cancer. Among prostate cancer patients, CD10 expression did not correlate with Gleason score, pathological stage, or biochemical recurrence following radical prostatectomy. CONCLUSIONS: These findings demonstrate that loss or decreased expression of CD10 is an early and frequent event in human prostate cancer and implicates CD10 as a potential therapeutic target for early stage hormone sensitive prostate cancer.

Aged↗

PubMed2002

Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression.

Colony-stimulating factor-1 receptor (CSF-1R) is the major regulator of macrophage development and is associated with epithelial cancers of the breast and ovary. Immunohistochemistry analysis of murine prostate development demonstrated epithelial expression of CSF-1R during the protrusion of prostatic buds from the urogenital sinus, during the prepubertal and androgen-driven proliferative expansion and branching of the gland, with a decline in older animals. Models of murine prostate cancer showed CSF-1R expression in areas of carcinoma- and tumor-associated macrophages. Several human prostate cancer cell lines and primary cultures of human prostate epithelial cells had low but detectable levels of CSF-1R. Human prostatectomy samples showed low or undetectable levels of receptor in normal glands or benign prostatic hypertrophy specimens. Staining was strongest in areas of prostatic intraepithelial neoplasia or carcinoma of Gleason histological grade 3 or 4. The activated form of the receptor reactive with antibodies specific for phosphotyrosine modified peptide sequences was observed in samples of metastatic prostate cancer. Immunohistochemistry showed strong expression of CSF-1R by macrophage lineage cells, including villous macrophages and the syncytiotrophoblast layer of placenta, Kupper cells in the liver, and histiocytes infiltrating near prostate cancers. These observations correlate CSF-1R expression with changes in the growth and development of the normal and neoplastic prostate.

Animals↗

PubMed2002

Tissue microarrays in the study of non-neoplastic disease of the nervous system.

Tissue microarrays (TMAs), also known as "tissue chips," are a recently developed method that allows small cores or discs of tissue from dozens or hundreds of (usually paraffin-embedded) specimens to be re-embedded in a tissue block, which can then be further sectioned. The tissue cores can subsequently be studied using any combination of techniques, including immunohistochemistry, in situ hybridization (ISH). fluorescence ISH, and in situ polymerase chain reaction (PCR). To date, the technique has found greatest use in the analysis of neoplasms, including gliomas. We describe, and provide examples of, how TMAs might be utilized in investigation of autopsy (or biopsy) tissues from individuals with non-neoplastic disease, especially to address questions that require systematic review of multiple (nearly) identical brain regions across dozens or hundreds of cases. Specific questions related to patterns of protein expression (e.g. tau, Abeta, alpha-synuclein) in multiple regions of large numbers of brain specimens (from patients with neurodegenerative diseases) can be efficiently examined using TMA technology. One possible use of TMAs in the area of infectious disease might be to examine patterns of HIV-related brain injury or AIDS-related opportunistic CNS infections in the epochs before and after highly active antiretroviral therapy came into widespread use.

Humans↗