Biomedical subjects

Emina Torlakovic

Publications and source records attributed to Emina Torlakovic.

At least 19 recordsLinked to original sources

PubMed2006

Tumor-associated antigen 90K/Mac-2-binding protein: possible role in colon cancer.

The tumor-associated antigen 90K (TAA90K)/Mac-2-binding protein implicated in cancer progression and metastasis is modified by beta1-6 branched N-linked oligosaccharides in colon cancer cells, glycans shown to contribute to cancer metastasis. To elucidate the role of TAA90K in colon cancer, we examined its expression and function in human colon tumors and colon carcinoma cell lines. Immunohistochemical analyses of colon tumors revealed elevated expression of TAA90K in all samples analyzed compared to normal colon. To examine the function of TAA90K in colon cancer, we carried out protein and cell binding assays using TAA90K-His purified from HT-29 cells colon carcinoma cells infected with recombinant vaccinia virus expressing TAA90K containing a C-terminal poly-histidine tag. TAA90K-His bound to fibronectin, collagen IV, laminins-1, -5, and -10 and galectin-3 (Mac-2) but poorly to collagen I and galectin-1. As expected, binding of TAA90K to galectin-3 was dependent on carbohydrate since it was inhibitable by lactose and asiolofetuin, and a TAA90K-His glycoform purified from HT-29 cells treated with the glycosylation inhibitor 1-deoxymannojirimycin bound poorly to galectin-3. Unlike TAA90K isolated from other cell types, TAA90K-His isolated from colon cancer cells failed to mediate adhesion of colon cancer and normal cell lines, possibly due to cell-type specific glycosylation of TAA90K-His and/or its putative cellular receptor. However, at low concentrations, TAA90K-His enhanced galectin-3-mediated HT-29 cell adhesion while at high concentrations, it inhibited cell adhesion. Thus, a possible mechanism by which TAA90K may contribute to colon cancer progression is by modulating tumor cell adhesion to extracellular proteins, including galectin-3.

Antigens, Neoplasm↗

PubMed2006

Pax-5 expression in nonhematopoietic tissues.

We evaluated 123 formalin-fixed, paraffin-embedded samples, including neuroendocrine tumors, adult brain, mesonephric tissues, and from various other sites. A pre-B lymphoma cell line, Daudi, and a small cell carcinoma cell line, NCL-H128, were evaluated by Western blot. All tissues were immunostained by mouse monoclonal anti-Pax-5 antibody by using standard, synthetic polymer-based detection methods. Our study describes for the first time distribution of Pax-5 in adult brain tissue, including periaqueductal gray matter of the midbrain, area postrema of the medulla oblongata, and occasional cells of the spinal trigeminal nucleus (caudal nucleus). We confirm that Pax-5 is expressed regularly in poorly differentiated neuroendocrine tumors but never in well-differentiated classic carcinoid tumors. Pax-5 expression also was found readily in benign and malignant mesonephric tissues and focally in müllerian duct-derived tissues and tumors. Expression of Pax-5 in the Daudi and NCL-H128 cell lines was confirmed by Western blot. Together, these results are important for correct interpretation of results in immunophenotyping of undifferentiated tumors, for diagnosis of mesonephric carcinoma, and, potentially, for correct classification of neuroendocrine tumors in small biopsy samples.

Adult↗

PubMed2006

Sessile serrated adenoma: a brief history and current status.

Sessile serrated adenoma (SSA) is a polyp of the large intestine, which was first described in 1996. It presents as a solitary lesion or in a setting of a polyposis previously coined as "serrated adenomatous polyposis." The importance of correct recognition of this lesion and distinction from other serrated polyps of the colon is in that the newly described "serrated pathway" of colorectal carcinogenesis seems to apply mostly to SSA and not to other serrated polyps of the colon. This review describes the history of morphologic discovery of SSA and reports on current status of this lesion.

Adenomatous Polyps↗

PubMed2005

Differential expression of steroid receptors in prostate tissues before and after radiation therapy for prostatic adenocarcinoma.

The expression, distribution and the role of steroid receptors in benign and malignant untreated prostate tissues is well recognized, however, the status of steroid receptors in prostate after radiotherapy (RT) for adenocarcinoma has not yet been studied fully. Immunohistochemical evaluation of androgen receptor (AR), estrogen receptor-alpha (ER-alpha), estrogen receptor-beta (ER-beta), and progesterone receptor (PR) was carried out in prostate needle biopsies obtained before and after radiotherapy from 60 patients with adenocarcinoma. The ER-beta transcripts were also studied by RT-PCR in LNCaP prostate carcinoma cell line before and 24 hr after gamma-irradiation at 0.5 Gy and 8.0 Gy. Significantly higher level of ER-beta expression was found in post-radiation samples of prostate adenocarcinoma and benign epithelium. After RT, all steroid receptors were upregulated in prostatic stroma. Tumor AR expression did not change significantly. Although a positive association between AR and ER-beta expression was observed in pre-treatment prostate adenocarcinoma, it was lost after RT suggesting that these 2 steroid receptors respond differently to RT. High levels of pretreatment tumor ER-beta were associated with local recurrence after RT and decreased biochemical recurrence-free survival (p = 0.028). LNCaP cell line that expressed no ER-beta mRNA before gamma-irradiation, clearly expressed ER-beta mRNA 24 hr after 0.5 Gy and 8.0 Gy. Upregulation of all steroid receptors in the prostate stroma and upregulation of ER-beta in the tumor epithelium after RT, may represent a protective tissue response to radiation-induced tissue injury. Although stromal AR was doubled after RT, the tumor and benign epithelium expression of AR seemed resistant to change by RT.

Adenocarcinoma↗

PubMed2005

CD10+ stromal cells form B-lymphocyte maturation niches in the human bone marrow.

In adult mammals, early B-lymphopoiesis takes place in the bone marrow in close association with stromal cells. Both the phenotype of the stromal cells and the molecules involved in this essential interaction are as yet inadequately described. In this study, all benign, differentiating B-cells (Pax-5+ lymphoid cells) are shown, by using two-colour immunohistochemistry on biopsies from human bone marrow, to be in close contact with scant dendritic CD10+ stromal cells until they leave via the sinusoids. This CD10+ stromal cell population does not fully overlap with the VCAM-1+ stromal cell population. Furthermore, using a set of B-cell differentiation markers (TdT, Pax-5, and CD20), B-cell development is shown to be spatially oriented, with maturation progressing towards bone marrow sinusoids. In conclusion, CD10+ stromal cells form distinct B-lymphocyte maturation niches in the human bone marrow.

B-Lymphocytes↗

PubMed2005

PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor.

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development.

Antigens, CD↗

PubMed2005

Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen.

Tamoxifen treatment substantially improves the 10-year survival of women with estrogen-receptor (ER)-alpha-positive tumors. However, approximately one-third of all breast cancer patients with ER-alpha-positive tumors progress on antiestrogen therapy. The molecular mechanism(s) involved in antiestrogen-resistant phenotype of breast carcinoma is not completely understood. The PTEN (phosphatase and tensin homolog deleted on chromosome Ten) gene is a novel candidate tumor suppressor that plays an important role in cell cycle regulation and apoptosis by regulating Protein kinase-B/Akt activity. Previous studies have shown that PTEN downregulation in breast cancer is associated with high-grade tumor, distant metastases and poorer disease-free survival. Decreased PTEN and/or increased protein kinase B/Akt activity in breast cancer cells has recently been associated with resistance to tamoxifen-induced apoptosis. In this study, we have evaluated PTEN expression by immunohistochemistry in 100 tamoxifen-treated ER-alpha-positive breast cancer patients. Reduced PTEN protein expression was associated with shorter relapse-free survival. When stage I patients were analyzed separately, reduced PTEN expression was a strong predictor of both, shorter relapse-free survival and shorter disease-specific survival. An association of reduced PTEN expression with shorter relapse-free survival and disease-specific survival in stage I patients was still observed after stratification by stage, axillary lymph node status, tumor size, grade, and expression of ER-alpha, progesterone receptor, and Her-2/neu. In summary, our results showed a strong association between downregulation of PTEN expression in ER-alpha-positive tumors and failure to tamoxifen treatment.

Adult↗

PubMed2005

Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients.

This study characterizes the clinicopathological spectrum of lymphoproliferations involving the breast nipple and/or areola. Morphologic, immunohistochemical, molecular-genetic, and clinical features of 58 specimens from 56 patients were analyzed. They were re-diagnosed as cutaneous lymphoid hyperplasia (CLH, n = 44); other benign lymphoid infiltrates (OBLI, n = 8); peripheral T-cell lymphoma, not otherwise specified (n = 1); cases with overlapping features of CLH and B-cell lymphoma (n = 3), one of them composed of spindle cells. Cutaneous lymphoid hyperplasia infiltrates were dense, composed mainly of B cells forming follicles with germinal centers (GC). Cutaneous lymphoid hyperplasia frequently showed features suggesting a malignancy as coalescing follicles with non-polarized germinal centers lacking mantle zones, and smudged infiltrates of lymphoid cells spreading into collagen (often as "Indian files"), smooth muscle, vessel walls, and nerve sheaths. Only two cutaneous lymphoid hyperplasias recurred; otherwise all patients are without disease (mean follow-up 62 months). Monoclonal rearrangement of immunoglobulin heavy chain gene was detected in five, and of T-cell receptor gamma gene in two cutaneous lymphoid hyperplasias using polymerase chain reaction (PCR), but the patients fared well too. In 47% of cases Borrelia burgdorferi was detected by polymerase chain reaction and/or serology, of which one was monoclonal. We conclude that cutaneous lymphoid hyperplasia is the most common lymphoproliferation of the breast nipple, rarely recognized clinically, and often overdiagnosed histologically as lymphoma.

Adolescent↗

PubMed2005

Simultaneous bilateral breast carcinomas: a category with frequent coexpression of HER-2 and ER-alpha, high Ki-67 and bcl-2, and low p53.

The aim of this study was to evaluate clinicopathological characteristics and immunophenotypes of simultaneous bilateral adenocarcinomas of the breast and their axillary metastases. Immunohistochemical analysis and in situ hybridization were performed using formalin-fixed/paraffin-embedded tissues. In total, 15 primary and 9 metastatic tumors from 8 patients were evaluated. The expression of estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), Ki 67, p53, bcl-2, and bax were evaluated by immunohistochemistry. Her2 gene amplification was evaluated by chromogenic in situ hybridization (CISH). Four patients were younger that 40 years of age (mean 47 years). Six patients had pleomorphic lobular carcinoma in 1 breast. Four of these had invasive ductal carcinoma in the contralateral breast. One patient had atypical medullary carcinoma in both breasts and 1 patient had atypical medullary carcinoma in 1 breast and pleomorphic lobular carcinoma in the other. The phenotype of the primary tumors and corresponding metastatic tumors was similar for the expression of ER-alpha (p=0.001), PR (p=0.03), and HER-2 (p=0.018). While strong coexpression of HER-2 and ER-alpha is exceptional in hereditary breast carcinoma and sporadic breast carcinoma, 6/8 (75%) patients in this study had tumors with strong coexpression of HER-2 and ER-alpha. P53 protein expression was found in only 2/15 (13%) primary tumors, which is in contrast to BRCA1-related hereditary bilateral breast carcinomas, which often express p53 protein. Most of the patients presented with axillary metastases and had very aggressive course. Characteristically, the tumors showed high levels of expression of ER-alpha and Her2 amplification, were bcl-2 positive, and had high Ki-67 fraction. However, in patients with atypical medullary carcinoma there was no expression of ER-alpha or amplification of Her-2.

Adenocarcinoma↗

PubMed2005

Antibody selection in immunohistochemical detection of cyclin D1 in mantle cell lymphoma.

An assessment in Nordic immunohistochemical Quality Control (NordiQC) revealed that only 23% participant laboratories performed optimal staining for detection of cyclin D1 (CyD1) in mantle cell lymphoma (MCL). False-negative results were secondary to suboptimal protocols. We compared the 5 anti-CyD1 antibodies (monoclonal SP4, P2D11F11, and DCS-6 and polyclonal CP236 and 06-137) used in the Scandinavian laboratories. Evaluated were 31 MCLs, 16 other malignant lymphomas, and 19 samples of normal tissues. Sensitivity was as follows: CP236, 100%; SP4, 95%; P2D11F11, 90%; DCS-6, 84%; and 06-137, 53%. SP4 produced the strongest staining. Correlation of CyD1 with the proliferative index was best with polyclonal antibodies CP236 and 06-137. The use of heat-induced epitope retrieval in an alkaline buffer such as 1/10 mmol/L of Tris-EDTA buffer, pH 9, seemed mandatory. For the optimal detection of CyD1 expression, both SP4 and CP236 antibodies should be available in the laboratory.

Cyclin D1↗

PubMed2005

Nordic immunohistochemical quality control.

The use of immunohistochemistry by pathologists has been steadily, almost logarithmically increasing during the last decade. There is no scientific indication that this trend will reverse or slow down. At the same time, quality control issues have not followed this tempo. In particular, external quality control has been neglected. In 1999, nine Scandinavian laboratories established organization, Nordic Quality Control (NordiQC), to provide external quality control in immunohistochemistry for Denmark, Norway, Sweden, and Finland. This commentary briefly describes the work of this organization.

Humans↗

PubMed2005

Easy method of assessing volume of prostate adenocarcinoma from estimated tumor area: using prostate tissue density to bridge gap between percentage involvement and tumor volume.

AIM: To determine prostate carcinoma tumor volume in routine pathology practice by using prostate tissue density. METHODS: Prostate tissue density was determined experimentally by using picnometry in 57 unfixed prostate tissue fragments of different size. The percentage of prostate involvement was converted to tumor volume using the equation V=m/rho (g/mL). Additionally, all tumor foci were outlined in 46 prostates. A high grade component was also designated. The percent of prostate involvement by the tumor and separately by the high-grade component was determined using the fine grid method (0.9 mm resolution) in all cases. Pathologist's estimated square area method was applied for comparison in 27 cases. All tumor foci were evaluated for Gleason grades. RESULTS: Prostate tissue density (rho) was 0.98 or approximately 1.0 (g/mL). Quicker estimated square area method was fully comparable to more laborious fine grid method for determination of percent of prostate involvement. The percentage of prostate involvement by the tumor as measured by the grid method was not significantly associated with the Gleason sum of the tumor. However, the total tumor volume that was calculated from the percent tumor involvement, mass of the prostate, and tissue density was positively associated with the Gleason sum (P=0.035, linear-by-linear association). CONCLUSION: Our results show that prostate tissue density can be used to determine prostate carcinoma tumor volume in routine pathology practice.

Adenocarcinoma↗

PubMed2005

Volume-related sequence of tumor distribution pattern in prostate carcinoma: importance of posterior midline crossover in predicting tumor volume, extracapsular extension, and seminal vesicle invasion.

AIM: To evaluate intraprostatic distribution of prostate carcinoma as a function of increasing tumor size and its potential clinical relevance. METHODS: Forty-six prostates with different tumor extent were three dimensionally reconstructed and analyzed with emphasis on number of separate tumors (multifocality) and its distribution on both sides of the urethral midline (laterality). RESULTS: Three tumor distribution patterns were identified: multiple bilateral without posterior midline crossover, multiple bilateral with crossover, and single bilateral (global) tumors. Unilateral tumors were rare (2%). The pattern of tumor distribution was associated with total tumor volume, presence and volume of high grade component, presence of extracapsular extension, and seminal vesicle involvement. Bilateral tumors with crossover were larger than bilateral tumors without crossover (Spearman's rho=0,728, P<0.001) and were associated with adverse pathological features including capsular penetration, seminal vesicle invasion, and surgical margin involvement. However, only high-grade volume was independently and highly associated with seminal vesicle involvement (OR=2.64, 95%, CI=1.181-5.340, P<0.001). Total (OR=2.53 [1.23-3.74], P<0.001) and index tumor (OR=2.54 [1.31-4.93], P<0.001) volumes were independently associated with capsular penetration. CONCLUSIONS: The distribution of bilateral prostatic carcinomas with and without crossover may have clinical relevance because of their relation to total and high-grade volume.

Adenocarcinoma↗

PubMed2004

The early transcription factor GATA-2 is expressed in classical Hodgkin's lymphoma.

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin's lymphoma (cHL) are thought to be derived from germinal centre B-cells in almost all cases. However, expression profiling has revealed that HRS cells do not show a germinal centre B-cell-like phenotype. Although the nature of this aberrant phenotype and the underlying molecular mechanisms remain largely unknown, it has been reported that the activity of NOTCH1 plays an important role in the growth and survival of HRS cells. In some leukaemic cell lines, the effect of Notch signalling is mediated by the early transcription factor GATA-2. This and the fact that HRS cells lack expression of PU.1, which can repress Gata-2, led to an investigation of GATA-2 expression in HRS cells. GATA-2 expression was found in all the cHL-derived cell lines studied, but not in a Burkitt lymphoma-derived cell line. In addition, 50% of biopsies from patients with cHL contained GATA-2-expressing HRS cells. In contrast, neither normal germinal centre B-cells nor malignant cells of nodular lymphocyte-predominant Hodgkin's lymphoma, Burkitt lymphoma or diffuse large B-cell lymphoma expressed GATA-2. Thus, GATA-2 expression was found specifically in HRS cells of cHL, suggesting that GATA-2 is important in establishing the abnormal B-cell phenotype of HRS cells.

Adult↗

PubMed2004

Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis.

Nonspecific interstitial pneumonia, a recently described form of idiopathic interstitial pneumonia, is characterized by uniform involvement of the alveolar septae with interstitial inflammation and variable amounts of fibrosis. Histological observations differentiate nonspecific interstitial pneumonia from usual interstitial pneumonia and clinically, patients with a nonspecific interstitial pneumonia pattern show better prognosis than those with usual interstitial pneumonia. We have genetically analyzed a family with a history of usual interstitial pneumonia. Most of the patients presented as adults and their biopsies showed a pattern consistent with usual interstitial pneumonia. However, three family members presented in early childhood and their biopsies revealed a nonspecific interstitial pneumonia pattern. The inheritance pattern of usual interstitial pneumonia is consistent with autosomal dominant inheritance with variable expression. DNA sequence analyses of the surfactant protein C gene in children with nonspecific interstitial pneumonia and adults with usual interstitial pneumonia exhibit a common heterozygous mutation located in exon 5. The mutation causes a Leu188 to Gln188 change in the carboxy-terminal region of prosurfactant protein C, possibly affecting peptide processing. These observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types.

Adolescent↗

PubMed2004

Simultaneous EBV-positive lymphoepithelioma-like carcinoma and EBV-negative intestinal-type adenocarcinoma in a patient with Helicobacter pylori-associated chronic gastritis.

We report the case of a 72-year-old man with 2 simultaneous gastric carcinomas. The larger, ulcerated mass in the antrum was a conventional infiltrating intestinal-type adenocarcinoma. The associated antral-type mucosa showed moderate chronic gastritis, foci with complete and incomplete intestinal metaplasia, and mild to moderate Helicobacter pylori infection. The second, smaller tumor was found within fundic-type mucosa and was a lymphoepithelioma-like carcinoma associated with Epstein-Barr virus (EBV) infection shown by the EBV-encoded small RNA (EBER) test. The EBER test result was negative in the intestinal type adenocarcinoma. To our knowledge, this is the first report of simultaneous gastric carcinomas with 2 different morphologic phenotypes, in which only one tumor was associated with EBV infection, while the second tumor was related to H pylori-associated chronic gastritis. Our report demonstrates 2 different but simultaneous etiologic pathways of gastric carcinogenesis in the same patient.

Adenocarcinoma↗

PubMed2004

Expression of bcl-6 and CD10 protein is associated with longer overall survival and time to treatment failure in follicular lymphoma.

Follicular lymphomas (FLs) are a heterogeneous group of tumors, but prognostic factors are evaluated insufficiently in this common hematologic neoplasm. While bcl-6 and CD10 are expressed characteristically in FLs, their significance for biologic behavior of FL has not been studied previously. Samples from 73 patients with FL and clinical follow-up from 7 to 231 months were evaluated by immunohistochemical analysis. Patients with high levels of bcl-6 expression had favorable overall survival (OS) (P = .003), disease-specific survival (DSS) (P = .033), and time to treatment failure (P = .003) compared with patients with low levels of bcl-6 expression. Multivariate analysis showed that the results for OS, DSS, and time to treatment failure were independent of the international prognostic index. Patients with CD10+ FLs also had longer OS (P = .001), DSS (P = .007), and time to treatment failure (P = .004), and grade 1 FL was associated with better OS (P = .01) and a statistical trend for longer DSS (P = .05) and time to treatment failure (P = .05), but these results were not independent of bcl-6 expression or the international prognostic index in multivariate analysis.

Adolescent↗

PubMed2003

Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and T-cell/histiocyte-rich B-cell lymphoma (T/HRBCL) are distinct tumors and are treated differently. They are linked by a morphologic and probably a biologic continuum, which renders the differential diagnosis difficult. To develop criteria to distinguish the entities along the morphologic continuum, we correlated the lymph node architecture and immunophenotype of both tumor cells and reactive components of 235 neoplasms in the spectrum of NLPHL and T/HRBCL with clinical data. Two hundred and eighteen cases fitted the World Health Organization (WHO) criteria of NLPHL (139) or T/HRBCL (79). While tumor cells in both entities were immunophenotypically similar, background composition differed: in NLPHL small B cells and CD3+CD4+CD57+ T cells were common, whereas in T/HRBCL, CD8+ cytotoxic T cells and histiocytes dominated. Follicular dendritic cells (FDCs) formed expanded meshworks in NLPHL, whereas they were absent in T/HRBCL. Seventeen cases represented a gray zone: within FDC meshworks, neoplastic B cells resided in a background depleted of small B cells but rich in T cells and histiocytes. Tumor cells either were loosely scattered or formed clusters, thus resembling areas of either T/HRBCL or inflammatory diffuse large BCL (DLBCL) within the nodules. Patients with these NLPHLs with T-cell/histiocyte-rich nodules presented at a high stage and with B symptoms, as in T/HRBCL, but had an excellent survival, as in NLPHL. This morphologic pattern suggests a biologic continuum between NLPHL and T/HRBCL.

Adult↗