[show abstract][hide abstract] ABSTRACT: It is sometimes difficult to differentiate between type B3 thymoma from thymic carcinoma histologically. Given the rarity of these tumours, studies have been limited. A series of 66 thymic neoplasms were reviewed and classified according to the World Health Organization (WHO) scheme. We performed a tissue microarray analysis of surgically resected thymic tumour specimens including 12 thymic carcinomas, 17 type B3 thymomas and 37 thymomas of other types. Percentage and staining intensity of immunohistochemical markers were recorded. Tumour eosinophilia was recorded positive if at least one eosinophilic cell identified. Positive staining of the following markers significantly differentiated type B3 thymoma from thymic carcinoma: cytokeratin 5/6 (15 vs. 3), Mesothelin (0 vs. 5), cytoplasmic androgen receptor (10 vs. 0), CD57 (9 vs. 0), CD5 (0 vs. 7), TdT (lymphocytic) (14 vs. 1), CD1a (lymphocytic) (14 vs. 2), CD117 (1 vs. 9), MOC31 (2 vs. 6), p21 (2 vs. 8), cytoplasmic Survivin (0 vs. 4), and tumour eosinophilia (1 vs. 11). Combining two or three markers was able to differentiate these two tumours with area under the curve percentage of at least 92%. Tumour eosinophilia combined with a panel of immunohistochemistry could differentiate type B3 thymoma from thymic carcinoma.
International Journal of Experimental Pathology 11/2010; 92(2):87-96. · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: We previously reported that delayed formalin fixation (DFF) has a negative effect on immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), and HER2. The primary aim of the study was to determine if DFF affected commonly used clones of the ER and PR differentially. The specific clones evaluated were ER clones 1D5, 6F11, and SP1 and PR clones 16, 1E2, and PgR636. Ten breast cancer cases were dissected and fixed at different times (0, 10, and 30 minutes; 1, 2, 4, and 8 hours; and overnight) and were then stained with anti-ER and anti-PR antibodies. The mean Q score for ER started to decline at 2 to 4 hours for clones 1D5 and 6F11 and at 1 hour for SP1. SP1 was superior to 1D5 at the 8-hour mark (P = .03). The Q score for PR started to decline at 1 hour for clones PgR636 and 16 and 4 to 8 hours for 1E2 (P = .03). Based on our findings, it appears that regardless of the antibody clones evaluated, DFF has a negative effect on hormone receptors.
American Journal of Clinical Pathology 11/2010; 134(5):813-9. · 2.88 Impact Factor
[show abstract][hide abstract] ABSTRACT: The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)-based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb.
CSPG4 protein expression was assessed in 44 primary TNBC lesions, in TNBC cell lines HS578T, MDA-MB-231, MDA-MB-435, and SUM149, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. The effect of CSPG4-specific mAb 225.28 on growth, adhesion, and migration of TNBC cells was tested in vitro. The ability of mAb 225.28 to induce regression of tumor metastases (n = 7 mice) and to inhibit spontaneous metastasis and tumor recurrence (n = 12 mice per group) was tested in breast cancer models in mice. The mechanisms responsible for the antitumor effect of mAb 225.28 were also investigated in the cell lines and in the mouse models. All statistical tests were two-sided.
CSPG4 protein was preferentially expressed in 32 of the 44 (72.7%) primary TNBC lesions tested, in TNBC cell lines, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 μm(2); difference of mean = 121360.0 μm(2), 95% confidence interval = 91010.7 to 151709.4 μm(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis.
This study identified CSPG4 as a new target for TNBC. The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis.
[show abstract][hide abstract] ABSTRACT: The sensitivity of an intraoperative diagnosis of sentinel lymph node metastasis of invasive lobular carcinoma using conventional staining is low.
To develop a fast, modified, Alcian blue stain to decrease the intraoperative false-negative results in testing for metastatic invasive lobular carcinoma.
Modified Alcian blue was optimized. Patients who had invasive lobular carcinoma on needle biopsy were candidates for this study. Touch preparations from every sentinel lymph node were prospectively prepared in the same manner, one stained with modified Alcian blue and one with conventional staining. These slides were independently interpreted.
A total of 121 sentinel lymph nodes from 31 patients with invasive lobular carcinoma were studied. There were 11 patients (35.5%) who had at least one positive lymph node test result. There were a total of 18 positive lymph node results (14.9%). Although 10 sentinel lymph nodes with abnormalities were detected in 7 patients with conventional staining, modified Alcian blue detected 15 sentinel lymph node abnormalities in 10 patients. Modified Alcian blue increased the sensitivity compared with conventional staining from 63.6% to 90.9% (calculated based on the number of patients) and from 55.6% to 83.3% (calculated based on number of sentinel lymph nodes). The staining process takes approximately 11 minutes.
Modified Alcian blue stain is a relatively rapid, cheap, highly sensitive, and specific method of detecting metastatic invasive lobular carcinoma. This method can be used in conjunction with conventional staining methods used intraoperatively.
Archives of pathology & laboratory medicine 10/2010; 134(10):1513-9. · 2.78 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recent trials have shown remarkable efficacy from combined trastuzumab and chemotherapy in the adjuvant setting of breast cancer. In spite of these successes, refractory breast cancer has emerged as a clinically problematic outcome for a subset of patients managed this way. In an effort to clarify and optimize the treatment regimens for breast cancer patients who are candidates to receive trastuzumab, we sought to analyze whether a distinctive genetic signature could be characterized that would reliably predict the treatment outcome. The ability to predict who will respond and who will become refractory to this agent will allow for improved, rational clinical management of these patients and further stratify the personalized nature of this treatment regimen. In this study, 41 consecutive cases of breast carcinoma with well-documented amplification of the human epidermal growth factor receptor-2 gene and corresponding banked fresh-frozen tissue were identified and divided into two separate groups based on whether they received trastuzumab or not. The first group consisted of 12 patients who had received trastuzumab in the adjuvant setting, of which three later experienced tumor recurrence. The second group consisted of 10 patients not treated with trastuzumab, of which 6 were later found to have recurrence. Differentially expressed genetic profiles were determined using human genome-wide Illumina Bead Microarrays. The differentially expressed genes for non-recurrence vs recurrence in the trastuzumab-treated group were distinct from those in the same comparison group in the untreated group. Differential expression of key genes identified in this study might offer an insight into a possible mechanism of trastuzumab resistance in breast carcinoma, and may emerge as potential predictive biomarkers indicative of trastuzumab resistance.
Modern Pathology 10/2010; 23(10):1364-78. · 5.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: The histologic diagnosis of pancreatic serous cystadenoma (SCA) is straightforward in most surgically resected specimens. However, in small biopsies, diagnosis could be challenging. Given the increased use of immunohistochemistry, we sought to investigate the expression of neuroendocrine markers in this entity and compare it with pancreatic neuroendocrine tumors (NETs).
Eighteen NET and 12 SCA cases were collected from our files. The cases were stained with CD56, synaptophysin, and chromogranin A. The percentage of positive cells was recorded. A percentage greater than 10 was considered as the cutoff. Fisher exact test was used for statistical analysis.
For SCA, CD56, synaptophysin, and chromogranin A were expressed in 75%, 92%, and 0% of the cases, respectively, whereas in NET they were expressed in 89%, 100%, and 83%, respectively. Therefore, only chromogranin A could differentiate between these 2 entities based on immunohistochemistry (P=0.003). The entrapped Langerhans islets in the walls of microcysts could be a pitfall.
Our data indicate that a significant proportion of SCA shows positive immunoreaction to CD56 and synaptophysin. Therefore, these markers should be interpreted with caution, particularly in a problematic small biopsy setting.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 10/2010; 19(2):141-6. · 1.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: Thyroid transcription factor-1 (TTF-1) is a member of the homeodomain transcription family expressed in epithelial cells of the thyroid and lung. Although nuclear TTF-1 is generally considered a specific marker for lung and thyroid neoplasms, it has been reported to be positive in other types of tumors including colorectal carcinoma (CRC). During metastatic adenocarcinoma workup for patients who had a history of CRC, we identified 4 positive TTF-1 cases using clone 8G7G3/1. Three of the 4 corresponding primary carcinomas were also positive for TTF-1. Therefore, we sought to retrospectively investigate the expression of TTF-1 in 100 CRC cases constructed in tissue microarray blocks and whole tissue sections of the 4 primary tumors corresponding to the 4 positive metastases. In tissue microarray cases, all cases had negative nuclear staining. Our results suggest that during immunohistochemical workup for adenocarcinoma, especially when the differential diagnosis includes the lung and CRC, TTF-1 results should be interpreted with caution as a small percentage of CRC expresses this marker. Positive nuclear TTF-1 in a metastatic carcinoma does not rule out CRC primary. Clinicopathologic correlation, tumor morphology, and a panel of immunohistochemical markers are essential to render the correct diagnosis.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 05/2010; 18(3):244-9. · 1.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: Over-expression of HER2 in a subset of breast cancers (HER2+) is associated with high histological grade and aggressive clinical course. Despite these distinctive features, the differences in response of HER2+ patients to both adjuvant cytotoxic chemotherapy and targeted therapy (e.g. trastuzumab) suggests that unrecognized biologic and clinical diversity is confounding treatment strategies. Furthermore, the small but established risk of cardiac morbidity with trastuzumab therapy compels efforts towards the identification of biomarkers that might help stratify patients.
A single institution tissue array cohort assembled at the Clearview Cancer Institute of Huntsville (CCIH) was screened by immunohistochemistry staining using a large number of novel and commercially available antibodies to identify those with a univariate association with clinical outcome in HER2+ patients. Staining with antibody directed at TRMT2A was found to be strongly associated with outcome in HER2+ patients. This association with outcome was tested in two independent validation cohorts; an existing staining dataset derived from tissue assembled at the Cleveland Clinic Foundation (CCF), and in a new retrospective study performed by staining archived paraffin blocks available at the Roswell Park Cancer Institute (RPCI).
TRMT2A staining showed a strong correlation with likelihood of recurrence at five years in 67 HER2+ patients from the CCIH discovery cohort (HR 7.0; 95% CI 2.4 to 20.1, p < 0.0004). This association with outcome was confirmed using 75 HER2+ patients from the CCF cohort (HR 3.6; 95% CI 1.3 to 10.2, p < 0.02) and 64 patients from the RPCI cohort (HR 3.4; 95% CI 1.3-8.9, p < 0.02). In bivariable analysis the association with outcome was independent of grade, tumor size, nodal status and the administration of conventional adjuvant chemotherapy in the CCIH and RPCI cohorts.
Studies from three independent single institution cohorts support TRMT2A protein expression as a biomarker of increased risk of recurrence in HER2+ breast cancer patients. These results suggest that TRMT2A expression should be further studied in the clinical trial setting to explore its predictive power for response to adjuvant cytotoxic chemotherapy in combination with HER2 targeted therapy.
[show abstract][hide abstract] ABSTRACT: We intended to explore the relationship of CD138 with thymic tumors. A series of 64 thymic tumors were studied. Positive staining was seen in 7 of 8 (87.5%) type A, 7 of 16 (43.7%) type AB, 1 of 8 (12.5%) type B1, 1 of 5 (20%) type B2, 10 of 17 (58.8%) type B3, and 3 of 10 (30%) type C (p=0.04), respectively. In terms of subcellular location of CD138 expression, 9 of 10 (90%) CD138 positive type B3 had membranous expression, while cytoplasmic expression was identified in 7 of 7 (100%) type A, and 6 of 7 (86%) type AB (p<0.0001). Positive CD138 was noted in 20 of 31 (64.5%) cases with Masaoka stage I (p= 0.01); while negative CD138 was seen in 24 of 33 (72.7%) cases with Masaoka stages (II-IV). Tumor recurred in 4 cases (7%), all of which had negative CD138 (p=0.008). Our study suggests that CD138 could be used as an ancillary study to differentiate between WHO types. Furthermore, our findings demonstrate that advanced stage-thymic tumors as well as those with high recurrence rate tend to display a reduced expression of CD138. However, more studies with larger cohort and longer follow-up are warranted to validate the clinical utility of CD138 to assess clinical behavior and prognosis of thymic tumors.
International journal of clinical and experimental pathology 01/2010; 3(3):280-7. · 2.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: Delay to formalin fixation may invalidate hormone receptors and HER2 analyses. Invalid results of tumor markers could significantly alter the type of adjuvant therapy a patient receives and potentially impact outcome. The purpose of this study was to determine the effects of progressive delay to formalin fixation on breast cancer biomarkers. Ten palpable invasive breast cancers were resected and underwent immediate gross evaluation. For each case, the procured tumor was divided into eight parts and consecutively fixed after 0, 10, 30 min, 1, 2, 4, and 8 h; one section was kept in saline and stored overnight at 4 degrees C. Two tissue microarray blocks were constructed. Estrogen and progesterone receptors and HER2 immunohistochemistry and fluorescence in situ hybridization were carried out. Statistical analyses including non-parametric sign test, exact McNemar's test and Page's L test were used. All 10 cases were invasive ductal carcinomas. Q score > or =6 was identified in five cases for estrogen receptor and four for progesterone receptor. Mean Q score started to decline at the 2 h mark for estrogen receptor and 1 h mark for progesterone receptor. Lowest score was at 8 h mark for estrogen receptor and overnight for progesterone receptor. HER2 fluorescence in situ hybridization started to be compromised for interpretation at the 1 h mark and became statistically significant at the 2 h mark (P<0.03). To avoid delay to formalin fixation as a factor negatively affecting on breast biomarkers, we recommend not to delay formalin fixation for more than 1 h and not to store specimens overnight.
Modern Pathology 10/2009; 22(11):1457-67. · 5.25 Impact Factor
[show abstract][hide abstract] ABSTRACT: The cells of origin of mammary Paget's disease (MPD) and extra-mammary Paget's disease (EMPD) have been a controversial subject. The purpose of this study is to examine the expression of the human epidermal growth factor receptor 2 (HER2) pathway members in these two diseases.
HER2, AKT, pAKT, PTEN, epidermal growth factor receptor (EGFR) and pEGFR were examined in 16 MPD and 14 EMPD cases. HER2 was graded on a scale from 0 to 3. A score of 3 was considered positive. For AKT, pAKT, PTEN, EGFR and pEGFR, a semi-quantitative scoring system was used. A score >100 was considered positive. Fisher's exact test was used to analyze the data.
HER2 was overexpressed in 87.5% MPD and 35.7% EMPD. While AKT was expressed in all cases, pAKT was expressed in 87.5% MPD and 92.9% EMPD. Both EGFR and pEGFR were negative in all cases. PTEN was positive in 62.5% MPD and 71.4% EMPD. For pAKT+ group, HER2-/PTEN+ was recorded in 0% MPD and 38.5% EMPD (P = .01).
In a subset of EMPD, AKT is not activated by HER2 overexpression or by loss of PTEN, which is not the case in MPD. These data suggest that these two diseases are biologically different.
Journal of Cutaneous Pathology 08/2009; 37(11):1145-9. · 1.77 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cholangiocarcinomas are biliary tree neoplasms of cholangiocyte origin. Several clinical risk factors are associated with cholangiocarcinogenesis. During the last decade, there has been an increasing interest in the causative molecular mechanisms of cholangiocarcinoma because of its poor prognosis and the lack of effective therapies. A better understanding of cholangiocarcinoma tumor initiation, promotion, and progression, as well as neurotransmitter, neuroendocrine, and endocrine growth effects, may elucidate molecular targets for diagnostic and therapeutic purposes.
Anticancer research 05/2009; 29(4):1151-6. · 1.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: Our objective was to investigate the expression of survivin, Bcl-2, p53, Ki-67, and Src in thymic neoplasms and analyze their interrelationship with clinicopathologic variables.
A series of 60 thymic neoplasms was reviewed and classified according to the World Health Organization (WHO) scheme. Key clinical information, including Masaoka stage, recurrence-free survival (RFS), and overall survival (OS) was obtained. The percentage and staining intensity of listed markers were recorded. The correlation of markers and clinicopathologic variables was statistically analyzed using the Fisher exact test and log-rank test.
There were 7 type A, 15 type AB, 8 type B1, 5 type B2, 17 type B3 thymomas, and 8 thymic carcinomas. Seven patients (11.7%) died of the disease. Tumors recurred in eight patients (13.3%). Although p53 expression alone was found to be correlated with RFS with borderline significance (p = 0.056), patients with Src-positive and p53-positive coexpression had a shorter OS time than the other groups (p < 0.008). Cytoplasmic expression of survivin was present in 5 of 60 thymic neoplasms (8.3%), 4 of which were thymic carcinomas that all recurred.
Regardless of WHO type and/or tumor stage, although p53 expression may predict recurrence in thymomas, p53 and Src coexpression can predict shorter OS, and cytoplasmic localization of survivin may predict recurrence in thymic carcinoma. These findings make thymic tumors a prime target for newly developed anti-Src and anti-survivin therapies.
[show abstract][hide abstract] ABSTRACT: The addition of taxanes (Ts) to chemotherapeutic regimens has not demonstrated a consistent benefit in early-stage breast cancer. To date, no clinically relevant biomarkers that predict T response have been identified.
A dataset of immunohistochemistry stains in 411 patients was mined to identify potential markers of response. TLE3 emerged as a candidate marker for T response. To test the association with T sensitivity, an independent 'triple-negative' (TN) validation cohort was stained with anti-TLE3 antibody.
TLE3 staining was associated with improved 5-year disease-free interval (DFI) in the overall cohort (n = 441, P < 0.004), in patients treated with cyclophosphamide (C), methotrexate, and 5-fluorouracil (n = 72, P < 0.02), and in those treated with regimens containing doxorubicin (A) and a T (n = 65, P < 0.04). However, no association was shown with outcome in untreated patients (n = 203, P = 0.49) or those treated with a regimen containing A only (n = 66, P = 0.97). In the TN cohort, TLE3 staining was significantly associated with improved 5-year DFI in all patients (n = 81, P < 0.015), in patients treated with AC + T (n = 45, P < 0.02), but not in patients treated with AC (n = 17, P = 0.81). TLE3 was independent of tumor size, nodal status, and grade by bivariable analysis in both cohorts.
TLE3 staining is associated with improved DFI in T-treated patients in two independent cohorts. Since the validation study was performed in a TN cohort, TLE3 is not serving as a surrogate for estrogen receptor or HER2 expression. TLE3 should be studied in large clinical trial cohorts to establish its role in T chemotherapy selection.
Breast cancer research: BCR 04/2009; 11(2):R17. · 5.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Epstein-Barr virus (EBV) has been shown to be associated with gastric cancer. However, inconsistent findings have been reported regarding the distribution of EBV infected cells (in normal gastric epithelium vs. intestinal metaplastic cells vs. in neoplastic cells) and the characteristics of EBV-associated gastric cancer. Lymph node positive EBV-associated gastric cancer has not been systematically studied. The aims of this study were to evaluate EBV-associated gastric cancer, to assess the distribution of EBV infected cells including all positive lymph nodes, and to define the characteristics of EBV-associated gastric cancer.
The study included primary gastric cancer patients who underwent surgical resection with no preoperative treatment at M.D. Anderson Cancer Center between 1987 and 2006. Formalin-fixed paraffin-embedded tissue from these resection specimens were assessed for EBV by in situ hybridization, the gold standard for EBV detection in tissue. EBV status was analyzed along with clinicopathologic parameters including age, gender, tumor type, lymph node status, and pathologic stage of the tumor.
Among 235 patients, 12 had intranuclear expression of EBV. EBV staining was seen only in tumor cells and no detectable EBV was observed in normal gastric mucosa, intestinal metaplasia or stromal cells. Eight of 12 patients with EBV-associated gastric cancer had regional lymph node metastasis. Of note, metastatic tumor cells in all of the involved lymph nodes of these 8 cases contained EBV. The epidemiologic data showed 11 of the 12 patients with EBV-associated gastric cancer were men, ranging in age from 54 to 78 years (mean age, 60 years; median age, 62.1 years). The age distribution for non-EBV associated gastric cancer patients ranged from 21 to 93 years (mean age, 67 years; median age, 66.4 years).
Our study demonstrated that EBV is present exclusively in gastric cancer cells. The detection of EBV in tumor cells in all of the lymph nodes involved with metastatic gastric carcinoma suggests simultaneous replication of EBV and tumor cells. The predominantly male gender and relatively younger age observed for the EBV-infected gastric cancer cases suggest an association between this disease and other factors, such as life style.
Journal of Experimental & Clinical Cancer Research 03/2009; 28:14. · 3.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Eukaryotic initiation factor 4E (eIF4E) and cyclin D1, two important factors in cell-cycle progression, play key roles in the carcinogenesis of varied human cancers. However, eIF4E expression in non-small-cell lung cancer (NSCLC) and its association with cyclin D1 has received little investigation. One hundred forty-seven subjects with primary NSCLC, with long-term follow-up and essential clinicopathologic parameters (including age, sex, tumor grade, tumor stage, smoking history, performance status, weight loss, histology grade, and survival data) were evaluated based on expression of eIF4E and cyclin D1. Immunohistochemical analysis was performed using monoclonal antibodies against eIF4E and cyclin D1. While 134 of 147 cases (91%) were positive for eIF4E, 82 of 136 cases (63%) were positive for cyclin D1. Western blot results were consistent with those illustrated by immunohistochemistry. While eIF4E(+) correlated with significantly shorter patient survival (P = .03), cyclin D1(+) correlated with longer patient survival (P = .01). Assessment of coexpression of cyclin D1 and eIF4E shows greater value in determining the prognosis of NSCLC: patients with eIF4E(+)/cyclin D1(-) have poorer outcome, those with eIF4E(-)/cyclin D1(+) have a more favorable outcome, and those with eIF4E(+)/cyclin D1(+) have an intermediate outcome (P = .02). The negative effect on survival in patients with eIF4E(+) suggests its potential prognostic role in NSCLC. These results warrant further investigation to explore the value of eIF4E in identifying patients with aggressive disease for adjuvant treatments.
Clinical Lung Cancer 02/2009; 10(1):58-66. · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Colorectal cancer progression originates when accumulated genetic and epigenetic alterations cause genomic instability and a malignant phenotype. Subsequent molecular pathway deregulation leads to histopathologic changes that are clinically evident as aberrant crypt foci (ACF) and visualized by high-magnification chromoscopic colonoscopy. ACF are biomarkers of increased colorectal cancer risk, particularly those with dysplastic features. Genetic profiling using genomic instability, loss of heterozygosity, and methylation analysis has revealed a minority population of ACF genotypically analogous to cancer.
Journal of Surgical Oncology 08/2008; 98(3):207-13. · 2.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alpha-methylacyl-CoA racemase (AMACR [P504S]) is a mitochondrial and peroxisomal enzyme involved in beta-oxidation of dietary branched-chain fatty acids and their derivatives. Recent studies showed that AMACR is expressed in several neoplasms, including prostate and colon cancer. However, AMACR expression in gastric neoplasms has yet to be thoroughly investigated. Because AMACR overexpression in human solid tumors is a potential target for cancer treatment, we aimed to evaluate the expression of AMACR in a large cohort of patients with gastric adenocarcinoma. The study evaluated 249 primary gastric adenocarcinomas by immunohistochemistry. Nonneoplastic gastric tissue samples from various sites (antrum, body, fundus, and pylorus) were also examined. The immunopositivity of each sample was graded on a scale from 0 to 3 (0, no expression; 1, weak expression, 2, intermediate expression; 3, strong expression). We observed AMACR expression in 141 tumor cases: 44, 47, and 50 cases had weak, intermediate, and strong expression, respectively. Both intestinal and signet ring cell adenocarcinoma cases had overexpression of AMACR, however intestinal adenocarcinoma had significantly higher expression than did signet ring cell adenocarcinoma (p<0.05). Nonneoplastic gastric mucosa did not show AMACR expression. The results of our study demonstrate that AMACR expression is upregulated in gastric cancer, and suggest that further prospective studies to explore the potential role of AMACR as a therapeutic target for gastric cancer are warranted.
International journal of clinical and experimental pathology 02/2008; 1(6):518-23. · 2.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nuclear matrix proteins (NMPs) are important diagnostic and prognostic markers in various human cancers. The hHpr1/p84/Thoc1 protein, a key NMP, resides in the nuclear matrix and is involved in the human TREX complex, which is required for regulation of transcription elongation, pre-RNA splicing, and mRNA export of a subset of human genes. Depletion of hHpr1/p84/Thoc1 decreases growth rates in multiple cancer cell lines, and the expression levels of hHpr1/p84/Thoc1 are strongly associated with tumor size and aggressiveness of several human cancers. Little is known about the expression of this protein in human non-small cell lung cancer (NSCLC) and its association with patients' clinicopathologic characteristics and prognosis. We evaluated hHpr1/p84/Thoc1 expression in 133 NSCLC patients by immunohistochemistry of tissue microarrays using paraffin-embedded tumor tissue and we confirmed the tissue staining by Western blot analysis. The prognostic significance of hHpr1/p84/Thoc1 expression in tumor tissue was assessed by the Cox proportional hazards regression model. hHpr1/p84/Thoc1 expression was found in 51% of patients, and was more prevalent in males than females (59% vs 43%, p = 0.07) and in blacks than whites (91% vs 48%, p = 0.009). In survival analysis, hHpr1/p84/Thoc1 expression appeared to be weakly associated with elevated risk of death among patients with stage I tumors (RR = 1.53, 95% CI = 0.85-2.77, p = 0.16), squamous cell carcinomas (RR = 1.75, 95% CI = 0.73-4.21, p = 0.21), and family histories of lung cancer (RR = 1.55, 95% CI = 0.81-2.97, p=0.18), although none of these associations was statistically significant. Thus elevated expression of hHpr1/p84/Thoc1 is common in NSCLC and may have prognostic significance in subgroups of patients. Further studies with larger sample size are needed to elucidate the role of this critical nuclear matrix protein in NSCLC prognosis.
Annals of clinical and laboratory science 02/2008; 38(2):105-12. · 0.88 Impact Factor