Biomedical subjects

Raheela Ashfaq

Publications and source records attributed to Raheela Ashfaq.

At least 19 recordsLinked to original sources

PubMed2007

Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma.

PURPOSE: We determined whether the combined expression of p53, p21, p27 and pRB is associated with outcomes of patients with nonmuscle invasive bladder transitional cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for p53, p21, p27 and pRB was performed on archival bladder specimens from 9 normal controls and 74 patients who underwent transurethral bladder tumor resection for Ta, Tis and/or T1 transitional cell carcinoma. RESULTS: Normal urothelium had wild type status of p53, pRB, p21 and p27. p53 expression was altered in 34% of patients with transitional cell carcinoma, pRB in 39%, p21 in 35% and p27 in 47%. When analyzed separately, p53, pRB and p21 were each independently associated with tumor progression. Combination of biomarkers stratified patients into statistically significantly different risk groups for disease recurrence and progression. When tumor stage and grade were modeled with all 4 biomarkers, p53 and p27 were the sole independent predictors of disease recurrence and progression. After controlling for the effects of tumor grade and stage, the incremental number of altered biomarkers was associated with an increased risk of bladder cancer recurrence (p for trend = 0.011) and progression (p for trend = 0.005). The risk ratio for disease recurrence and progression increased incrementally with the number of biomarkers altered. CONCLUSIONS: Combinations of p53, pRB, p21 and p27 had cooperative/synergistic effects stratifying patients into different risk groups. Higher total numbers of altered biomarkers were independently associated with an increased risk of disease progression and death. Prospective trials are necessary to usher bladder cancer management into the age of molecular biomarkers.

Adult↗

PubMed2006

Ki-67 is an independent predictor of bladder cancer outcome in patients treated with radical cystectomy for organ-confined disease.

PURPOSE: To determine the association of the cell proliferative marker Ki-67 with pathologic features and disease prognosis in patients with transitional cell carcinoma (TCC) of the urinary bladder. METHODS: Immunohistochemical staining for Ki-67 was done on serial cuts from tissue microarrays containing cystectomy specimens from 9 patients without bladder cancer and 226 consecutive patients with bladder TCC. We also assessed malignant lymph nodes from 50 of the 226 cystectomy patients. RESULTS: Ki-67 expression was increased in 42.5% cystectomy specimens and in 54% metastatic lymph nodes. In contrast, it was absent in all nine benign cystectomy specimens. Ki-67 overexpression was associated with advanced pathologic stage, higher grade, lymphovascular invasion, and metastases to lymph nodes (P = 0.001, 0.040, 0.031, and 0.036, respectively). In multivariate analyses, pathologic stage and lymph node metastases were independent predictors of disease recurrence and bladder cancer-specific mortality. In the subgroup of patients with organ-confined disease (<pT(3) N(0); n = 91), excluding patients who received neoadjuvant or adjuvant chemotherapy, Ki-67 status was an independent predictor of both disease recurrence (risk ratio, 7.591; P = 0.001) and bladder cancer-specific mortality (risk ratio, 4.045; P = 0.041). CONCLUSIONS: Ki-67 overexpression is associated with features of aggressive bladder TCC and adds independent prognostic information to standard pathologic features for prediction of clinical outcome after radical cystectomy.

Adult↗

PubMed2006

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues.

Overexpression of urokinase plasminogen activator system or HER-2 (erbB-2) in breast cancer is associated with a poor prognosis. HER-2 overexpression is caused by HER-2 gene amplification. The anti-HER-2 antibody trastuzumab significantly improves clinical outcome for HER2-positive breast cancer. Drugs that target the uPA system are in early clinical trials. The aims of this study were to determine whether urokinase plasminogen activator receptor (uPAR) gene amplification occurs and whether analysis of individual tumor cells (TCs) in the blood or tissue can add information to conventional pathological analysis that could help in diagnosis and treatment. Analysis of individual TCs indicates that uPAR amplification occurs in a significant portion of primary breast cancers and also circulating tumor cells (CTCs) from patients with advanced disease. There was complete concordance between touch preps (TPs) and conventional pathological examination of HER-2 and uPAR gene status in primary tumors. There was also excellent concordance of HER-2 gene status between primary tumors and CTCs provided that acquisition of HER-2 gene amplification in CTCs was taken into account. Unexpectedly, gene amplification of HER-2 and uPAR occurred most frequently in the same TC and patient, suggesting a biological bias and potential advantage for coamplification. Expression of HER-2 and uPAR in primary tumors predicted gene status in 100 and 92% of patients, respectively.

Breast Neoplasms↗

PubMed2006

Correlation of cyclin D1 and E1 expression with bladder cancer presence, invasion, progression, and metastasis.

The objective of this study was to determine the correlation of the expression of cyclin D1 and E1 with the expression of commonly altered cell cycle regulators and bladder cancer presence, staging, and clinical outcomes. We performed immunohistochemical staining for cyclin D1, cyclin E1, p53, p21, p27, and retinoblastoma protein (pRB) on serial cuts from normal urothelium from 9 controls, radical cystectomy specimens from 226 consecutive patients with advanced transitional cell carcinoma, and lymph nodes with metastasis from 50 of the 226 cystectomy patients. Cyclin D1 and E1 immunoreactivity were considered low when samples demonstrated less than 10% and 30% nuclear reactivity, respectively. Normal bladder urothelium from all 9 control patients showed uniformly intense expression of cyclin D1 and E1. Cyclin D1 expression was low in 99 (43.8%) of 226 cystectomy specimens and 25 (50.0%) of 50 metastatic lymph node specimens. Cyclin D1 immunoreactivity was not associated with any pathologic characteristics or clinical outcomes. Cyclin E1 expression was low in 125 (55.3%) of 226 cystectomy specimens and 22 (44.0%) of 50 metastatic lymph node specimens. Low cyclin E1 expression was significantly associated with advanced pathologic stage, lymphovascular invasion, and lymph node metastases. In multivariate analyses, low cyclin E1 expression was significantly associated with bladder cancer-specific mortality (P = .048), but not disease recurrence (P = .056). Low cyclin E1 expression was significantly associated with altered expression of pRB, p27, and cyclin D1. Low cyclin D1 expression was significantly associated with altered expression of pRB, p21, and cyclin E1. Cyclin E1 expression stratifies patients with bladder transitional cell carcinoma into those with more "indolent" behavior and those with features of biologically and clinically aggressive disease.

Adult↗

PubMed2006

Telomerase immortalization of human mammary epithelial cells derived from a BRCA2 mutation carrier.

A novel human mammary epithelial cell line, HME348, was established from benign breast tissue from a 44-year-old germ-line BRCA2 mutation carrier with a history of stage 1 breast cancer. Mutation analysis showed that the patient had a known 6872del4 BRCA2 heterozygous mutation. The human mammary epithelial cells passaged in culture exhibited cellular replicative aging as evidenced by telomere shortening, lack of telomerase activity, and senescence. Ectopic expression of telomerase (hTERT) reconstituted telomerase activity in these cells and led to the immortalization of the cells. When grown on glass, the majority of immortalized HME348 cells expressed ESA and p63 with a small population also expressing EMA. In three-dimensional Matrigel culture, HME348 cells formed complex branching acini structures that expressed luminal (EMA, CK18) and myoepithelial (p63, CALLA, CK14) markers. Three clones derived from this culture were also p63(+)/ESA(+)/EMA(+/-) on glass but formed similar acinar structures with both luminal and myoepithelial cell differentiation in Matrigel confirming the mammary progenitor nature of these cells. Additionally, the experimentally immortalized HME348 cells formed acini in cleared mammary fat pads in vivo. As this is the first report establishing and characterizing a benign human mammary epithelial cell line derived from a BRCA2 patient without the use of viral oncogenes, these cells may be useful for the study of BRCA2 function in breast morphogenesis and carcinogenesis.

Animals↗

PubMed2006

Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells.

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-alpha (TGF-alpha) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-alpha and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma.

Autocrine Communication↗

PubMed2006

MKK4 status predicts survival after resection of gastric adenocarcinoma.

HYPOTHESIS: Lack of expression of the tumor-suppressor gene MKK4 is significantly correlated with poor survival after resection of gastric adenocarcinoma. DESIGN: Retrospective review of medical records after construction and immunolabeling of tissue microarrays for clinical correlation. SETTING: The Johns Hopkins Hospital, Baltimore, Md. PATIENTS: Patients operated on because of gastric adenocarcinoma between 1983 and 1995. Main Outcome Measure Long-term survival and MKK4 status. RESULTS: Primary tumors (N = 124) were scored as 0 (no labeling), 1+ (weak labeling), or 2+ (strong labeling) in 9 (7%), 80 (65%), and 35 (28%) patients, and 5-year survival in these patients was 0%, 21%, and 28%, respectively. Given the small size (7%) of the MKK4-negative group (as expected, given the 5%-10% incidence of genetic loss in carcinomas), a Cox proportional hazards analysis was performed, adjusting for age, sex, and tumor stage. This multivariate analysis revealed a 5-fold increased risk of death (P<.001) in patients whose primary tumors were MKK4-negative. Furthermore, the addition of MKK4 status significantly improved the Cox model, changing log likelihood from -1410 to -369, confirming that MKK4 status was truly the effector of the survival difference and not a bystander. CONCLUSIONS: The lack of expression of the tumor-suppressor gene MKK4 in resected gastric adenocarcinoma is robustly associated with poor survival. This finding may provide a useful prognostic tool in patients with gastric adenocarcinoma.

Adenocarcinoma↗

PubMed2006

Claudin-4, mitogen-activated protein kinase kinase 4, and stratifin are markers of gastric adenocarcinoma precursor lesions.

Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3sigma (stratifin), S100A4, mesothelin, fascin, topoisomerase IIalpha, HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and 111 of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions.

14-3-3 Proteins↗

PubMed2005

Selective identification of secreted and transmembrane breast cancer markers using Escherichia coli ampicillin secretion trap.

Secreted and cell surface proteins play important roles in cancer and are potential drug targets and tumor markers. Here, we describe a large-scale analysis of the genes encoding secreted and cell surface proteins in breast cancer. To identify these genes, we developed a novel signal sequence trap method called Escherichia coli ampicillin secretion trap (CAST). For CAST, we constructed a plasmid in which the signal sequence of beta-lactamase was deleted such that it does not confer ampicillin resistance. Eukaryotic cDNA libraries cloned into pCAST produced tens of thousands of ampicillin-resistant clones, 80% of which contained cDNA fragments encoding secreted and membrane spanning proteins. We identified 2,708 unique sequences from cDNA libraries made from surgical breast cancer specimens. We analyzed the expression of 1,287 of the 2,708 genes and found that 166 were overexpressed in breast cancers relative to normal breast tissues. Eighty-five percent of these genes had not been previously identified as markers of breast cancer. Twenty-three of the 166 genes (14%) were relatively tissue restricted, suggesting use as cancer-specific targets. We also identified several new markers of ovarian cancer. Our results indicate that CAST is a robust, rapid, and low cost method to identify cell surface and secreted proteins and is applicable to a variety of relevant biological questions.

Ampicillin Resistance↗

PubMed2005

Immunohistochemical evaluation of heat shock proteins in normal and preinvasive lesions of the cervix.

Heat Shock Proteins (HSPs) are molecular chaperons with multiple functions relating to cellular homeostasis. Primary, HSPs are expressed in response to cellular stresses that may also include carcinogenesis. Patterns of expression have not been extensively evaluated in the multi-step carcinogenesis of cervical cancer (Normal --> HPV infection --> Cervical Precancer --> Cancer). We evaluated the expression of HSP40, HSP60, HSP70, and HSP90 in normal tissues (N=30), in cervical intraepithelial neoplasia grade 1 (CIN1)(synonymous with productive HPV infections) (N=32), and in CIN3 (cervical precancer)(N=25) by immunohistochemistry staining (graded 0-3) and compared the results to p16INK4a, a biomarker of oncogenic HPV infections and CIN3. We found strong patterns of increased HSP40, HSP60, and HSP70 immunostaining with increasing severity of the lesion in a manner similar to p16INK4a (P(Trend)<0.0005). No difference in staining intensity by grade of lesion was observed for HSP90 (P(Trend)=0.8). Tissue patterns in CIN3 of diffuse immunostaining for HSP40 and HSP70 were analogous to those observed for p16INK4a; HSP60 immunostaining appeared more punctate within cells than for other antigens although similar tissue patterns were observed. We conclude that HSP40, HSP60, and HSP70 expressions are up-regulated in response to the development of CIN3 akin to p16INK4a expression.

Biomarkers, Tumor↗

PubMed2005

Promoter hypermethylation profile of ovarian epithelial neoplasms.

PURPOSE: Ovarian carcinomas are believed to arise de novo from surface epithelium, but the actual molecular pathogenesis is unknown. The aim of this study was to compare the promoter hypermethylation profiles of ovarian epithelial neoplasms to better understand the role of epigenetic silencing in carcinogenesis. EXPERIMENTAL DESIGN: We analyzed the DNA promoter methylation status of eight tumor suppressor and cancer-related genes (p16, RARbeta, E-cadherin,H-cadherin, APC, GSTP1, MGMT, RASSF1A) in 23 benign cystadenomas, 23 low malignant potential (LMP) tumors, and 23 invasive carcinomas by methylation-specific PCR. RESULTS: Benign cystadenomas exhibited promoter hypermethylation in only two genes, p16 (13%) and E-cadherin (13%). LMP tumors also showed p16 (22%) and E-cadherin (17%) methylation, in addition to RARbeta (9%) and H-cadherin (4%). All eight genes were hypermethylated in invasive cancers at a frequency of 9% to 30%. The mean methylation index was highest in invasive tumors [0.20 versus 0.065 (LMP) and 0.033 (cystadenomas); P = 0.001]. Promoter methylation of at least one gene was most commonly observed among invasive cancers [78% versus 44% (LMP; P = 0.03) and 26% (cystadenomas; P = 0.0009)]. Three genes exhibited higher methylation frequencies in invasive tumors: RASSF1A (30% versus 0%; P = 0.0002), H-cadherin (22% versus 2%; P = 0.013), and APC (22% versus 0%; P = 0.003). CONCLUSIONS: Promoter hypermethylation is a frequent epigenetic event that occurs most commonly in invasive epithelial ovarian carcinomas. The profile of aberrant methylation suggests that an accumulation of events at specific genes may trigger malignant transformation of some benign cystadenomas and LMP tumors.

Adenomatous Polyposis Coli Protein↗

PubMed2005

Screening methods for high-grade dysplasia in patients with anal condyloma.

UNLABELLED: Human papilloma virus (HPV) is one of the most common sexually transmitted diseases in the United States. HPV infection can cause anal condylomas and is a risk factor for dysplasia. High-grade dysplasia may progress to squamous cell carcinoma. Currently, biopsy and histological examination are required to grade dysplasia. The purpose of this study is to determine whether anal cytology, morphological characteristics, and/or the presence of high-risk oncogenic HPV-types are effective noninvasive methods to detect high-risk anal condylomas. PATIENTS AND METHODS: From November 2003 to June 2004, all patients with anal condyloma were prospectively evaluated for anal cytology, high-risk oncogenic HPV-types, and tissue biopsies. The Bethesda classification system was used to classify cytologic findings and histological examination, which were grouped as high-risk (HRL) and low-risk (LRL) lesions. Histology results served as true disease for all comparisons. RESULTS: Forty-seven patients with anal condyloma were studied; 43 (91.5%) were men, and the mean age was 39 +/- 11 years. Histology showed 19 (40.5%) patients with HRL, and 28 (59.5%) patients with LRL. Cytology correctly identified 8 patients with HRL and 27 patients with LRL (sensitivity 42% and specificity 96%). High-risk oncogenic HPV-types were found in 84.2% of HRL and 39.3% of LRL (P = 0.0029). Combining cytology with oncogenic HPV-testing, the sensitivity of detecting HRL increased to 89%, and specificity decreased to 42%. CONCLUSION: Anal cytology alone is not accurate for detecting HRL in patients with anal condylomas. Combining oncogenic HPV-testing with cytology is more sensitive in detecting HRL in patients with anal condyloma, and therefore, a more effective screening tool.

Adult↗

PubMed2005

Reproducibility of cytologic atypia in repeat nipple duct lavage.

BACKGROUND: It is believed that atypical cells identified by nipple duct lavage (NDL) indicate an increased risk for breast carcinoma similar to atypical ductal hyperplasia diagnosed by tissue biopsy, but many basic performance characteristics of NDL currently are undefined. METHODS: NDL was performed in 108 patients unselected for breast carcinoma risk and then was repeated after 2-14 months (median, 8 months) if the initial lavage was classified as atypical. Breast magnetic resonance images (MRIs) were obtained from a subset of patients who had atypical lavage results. RESULTS: Marked atypia was diagnosed in 22% of 36 breasts with an incident carcinoma compared with 7% of 172 unaffected breasts (P = 0.01). After excluding breasts with an incident carcinoma, there were 32 patients (30%) with either mild or marked atypia. The lavage was repeated in 23 of these women, and the second lavage was classified as atypical in 48%. Neither marked atypia on the initial lavage nor a 5-year Gail risk > or = 1.7% predicted atypia on repeat lavage, but there was a trend for improved reproducibility when the atypia initially was diagnosed in a fluid-producing duct. MRIs were abnormal in 13% of 24 breasts with an atypical lavage, and ductal carcinoma in situ was diagnosed subsequently in 1 breast. CONCLUSIONS: Atypia frequently is diagnosed by NDL, but the reproducibility of repeat lavage is low. Lavage atypia may be physiologic or artifactual rather than pathologic in many instances. Marked atypia occasionally may represent mammographically occult ductal carcinoma in situ.

Adult↗

PubMed2005

Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy.

Methylthioadenosine phosphorylase (MTAP) plays an important role in the salvage pathway for the synthesis of adenosine. Novel chemotherapeutic strategies exploiting the selective loss of MTAP function in cancers have been proposed. The MTAP gene, on chromosome 9p21, is frequently included within homozygous deletions of the p16INK4A/ CDKN2A gene. Biallelic deletions of the p16INK4A/CDKN2A gene are found in 40% of pancreatic cancers, suggesting that the MTAP gene may be frequently inactivated in pancreatic cancer and that selected patients with pancreatic cancer may benefit from therapies targeting this loss. We immunolabeled six xenografted pancreatic cancers with known MTAP and p16INK4A/CDKN2A gene status and found that immunolabeling mirrored gene status. Loss of expression of both MTAP and p16 was observed only in those pancreatic cancers with homozygous deletions that encompassed both the MTAP and p16INK4A/CDKN2A genes. We then immunolabeled a series of 320 microarrayed infiltrating pancreatic adenocarcinomas, 35 biliary adenocarcinomas, 54 ampullary cancers, and 35 noninvasive intraductal papillary mucinous neoplasms. Immunolabeling for MTAP was lost in 91 of the 300 (30%) evaluable pancreatic cancers, 9 of 54 (17%) ampullary cancers, 4 of 33 (12%) biliary cancers, and in 1 of 35 (3%) IPMNs. All neoplasms with loss of MTAP labeling also demonstrated loss of p16 labeling. These results suggest that MTAP expression is lost in approximately 30% of infiltrating pancreatic cancers and in a lower percentage of other periampullary neoplasms, that this loss is the result of homozygous deletions encompassing both the MTAP and p16INK4A/CDKN2A genes. Thus, pancreatic cancer is a promising cancer type in which to explore novel chemotherapeutic strategies to exploit the selective loss of MTAP function.

Adenocarcinoma↗

PubMed2005

Split sample comparison of ThinPrep and conventional smears in endoscopic retrograde cholangiopancreatography-guided pancreatic fine-needle aspirations.

Fine-needle aspiration (FNA) of pancreatic lesions is a common procedure to establish a tissue diagnosis before chemotherapy or surgery. In this study, the authors attempt to compare the diagnostic value of the ThinPrep (TP) method with conventional smears (CSs) in samples obtained by endoscopic retrograde cholangiopancreatography (ERCP)-guided pancreatic FNAs. Material obtained, prospectively, from ERCP-guided pancreatic FNAs was split to prepare CSs (2-5 slides) first, the remainder being rinsed in PreservCyte, and in the laboratory, 1 TP slide was prepared. The diagnostic categories of unsatisfactory, benign, reactive, suspicious for malignancy, and malignant were compared. Fifty-one pancreatic FNAs prepared by split sample method yielded the following results: TP yielded unsatisfactory, 6 cases; benign, 3 cases; reactive, 5 cases; suspicious for malignancy, 11 cases; and malignant, 26 cases; in contrast, CS yielded unsatisfactory, 13 cases; benign, 4 cases; reactive, 3 cases; suspicious for malignancy, 13 cases; and malignant, 18 cases. Histological follow-up was available in 21 cases (reactive, 8 cases; suspicious for malignancy, 1 case, and malignant, 12 cases). The foregoing data indicate a higher sensitivity in detection of pancreatic adenocarcinoma by the TP method (TP, 91% vs. 58% CS) with equivalent specificity (100%). In addition, TP provides better preservation and cytological detail.

Adenocarcinoma↗

PubMed2005

Management of cervical adenocarcinoma in situ during pregnancy.

OBJECTIVE: Adenocarcinoma in situ (AIS) is a precursor of invasive disease that is being more frequently diagnosed during the reproductive years. Few reports have described the treatment of this condition in gravid women. The purpose of this study was to review our collective experience managing cervical AIS during pregnancy. STUDY DESIGN: Retrospective medical record review of all women diagnosed with AIS during pregnancy from 1995 to 2004 at 3 academic institutions. RESULTS: Eleven women with a median age of 32 years were identified. Five who received a diagnosis in the early second trimester underwent uncomplicated cold knife conization (CKC) at 14 to 19 weeks' gestation. Six patients underwent postpartum CKC. All 11 women delivered at term. One patient undergoing postpartum CKC required radical hysterectomy for stage IB1 cervical adenocarcinoma. Four subsequent pregnancies occurred among patients having fertility-sparing surgery. CONCLUSION: Management of cervical AIS during pregnancy by early second trimester CKC is safe for mother and fetus.

Adenocarcinoma↗

PubMed2005

CDC2/CDK1 expression in esophageal adenocarcinoma and precursor lesions serves as a diagnostic and cancer progression marker and potential novel drug target.

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas. To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform. We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels. These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.

Adenocarcinoma↗

PubMed2005

Expression of survivin and apoptotic biomarkers in benign prostatic hyperplasia.

PURPOSE: We assessed the differential expression of survivin and other apoptotic markers in stromal and epithelial compartments of benign prostatic hyperplasia (BPH) and normal prostate tissue. MATERIALS AND METHODS: Immunohistochemical staining for survivin, and transforming growth factor-beta1 and its receptors was done in normal prostate and BPH areas from 114 consecutive patients who underwent radical prostatectomy. Moreover, staining for survivin, Bcl-2, Bax, caspase-3 and Ki-67 was performed in prostate specimens from 23 consecutive patients who underwent open prostatectomy and 4 young patients who underwent cystoprostatectomy and had a normal prostate. RESULTS: Survivin and Bcl-2 expression increased incrementally from normal prostate to epithelial BPH to stromal BPH. Caspase-3 expression was higher in BPH epithelium than in BPH stroma, which in turn was higher than that in normal prostate. Ki-67 was significantly over expressed in BPH stroma and epithelium. Survivin expression in BPH tissue correlated with International Prostate Symptom Score, quality of life, post-void residual urine volume, maximum urine flow rate and transforming growth factor-beta1 expression. CONCLUSIONS: Survivin is over expressed in BPH and it correlates with BPH parameters. Increases in proliferation and inhibition of apoptosis have a role in BPH.

Adult↗