OBJECTIVE
To identify the precise location of prostate cancer within the gland and thus possibly permit more aggressive therapy of the lesion, while potentially sparing the noncancerous gland from ...ablative therapy.
MATERIALS AND METHODS
Three‐dimensional ‘solid’ computer models were reconstructed for 86 autopsy specimens and 20 stage T1c radical prostatectomy specimens. Transperineal biopsies were simulated for grid sizes of 5‐mm (method A) and 10‐mm (method B) with an 18 G, 23‐mm long biopsy needle. One or two biopsies per grid point were obtained for a total of 12–108 biopsies, depending on the size of the prostate. Clinically threatening cancers were defined as having volumes of ≥ 0.5 mL or Gleason sum ≥ 7.
RESULTS
Method A detected significantly more carcinomas than method B in both the autopsy and prostatectomy specimens (autopsy, 72 vs 51; prostatectomy, 50 vs 32, both P < 0.001). Method A also detected more clinically threatening cancers found at autopsy (38/40 vs 31/40, P = 0.008). Among autopsy patients with negative sextant biopsies whose disease was localized to one side, method A detected 72% and method B detected 29–43% (P < 0.001).
CONCLUSIONS
The results of this computer simulation show that 5‐ and 10‐mm grid biopsies detect three‐quarters and a third, respectively, at autopsy, of patients with the disease localized to one side of the prostate, which may be useful when planning highly selective ablative treatments in the future.
Vitamin D and dihydrotestosterone pathways interact to promote the growth of prostatic tissue. The nuclear vitamin D receptor (VDR) moderates the actions of vitamin D. 5alpha-Reductase type II ...(SRD5A2) codes for the enzyme that converts testosterone to dihydrotestosterone in the prostate. This study tested the interactions of VDR (CDX2, FokI) and SRD5A2 (V89L, A49T) polymorphisms, and their associations with prostate cancer.
This genetic association study included 932 non-Hispanic White (NHW) men and 414 Hispanic White (HW) men from South Texas. Cases had biopsy-confirmed cancer; controls had normal digital rectal exams and serum prostate-specific antigen levels of <2.5 ng/mL.
Using logistic regression analyses to test associations with prostate cancer, only the V89L polymorphism (VV genotype compared with LL/LV) in HW men was statistically significant odds ratios (OR), 0.64; 95% confidence intervals (95% CI), 0.41-0.99. The interaction terms for FokI and V89L in NHW men and CDX2 and V89L in HW men in the logistic model were significant (P = 0.02 and 0.03, respectively). When stratified by V89L genotype, the FokI polymorphism (TT/TC versus CC) was significantly associated with prostate cancer in NHW men with the V89L VV genotype (FokI OR, 1.53; 95% CI, 1.06-2.23). The CDX2 polymorphism (GG versus AG/AA) was significantly associated with prostate cancer only in HW men with the V89L VV genotype (CDX2 OR, 3.16; 95% CI, 1.39-7.19; interaction term P = 0.02).
Our results indicate that the SRD5A2 V89L VV genotype interacts with VDR FokI TT/CT genotypes in NHW men and VDR CDX2 GG genotypes in HW men to increase the risk for prostate cancer.
The RNASEL gene at 1q25 has been identified as a hereditary prostate cancer susceptibility gene, but to date, no study has investigated the role of RNASEL variants in Hispanic Caucasian men with ...prostate cancer.
Two RNASEL common variants, located at amino acids 462 and 541, were genotyped in non-Hispanic Caucasian, Hispanic Caucasian, and African American prostate cancer cases and controls.
The RNASEL 462 AA genotype was found to increase prostate cancer risk over 4-fold in Hispanic Caucasians odds ratio (OR), 4.43; 95% confidence interval (95% CI), 1.68-11.68; P = 0.003 and over 10-fold in African Americans (OR, 10.41; 95% CI, 2.62-41.40; P = 0.001) when compared with the GG genotype. Analysis of the RNASEL 541 variant showed that Hispanic Caucasian patients with the GG genotype had a statistically significant increase in their risk for developing prostate cancer when compared with the TT and GT genotypes (OR, 1.91; 95% CI, 1.16-3.14; P = 0.01). A common G-T haplotype for the combination of the RNASEL 462 and 541 variants was found to occur more frequently in controls compared with cases in African Americans (P = 0.04) but not in non-Hispanic Caucasians or Hispanic Caucasians.
This is the first study that investigates the association of prostate cancer risk with RNASEL variants in Hispanic men. Our data support the role of RNASEL as a predisposition gene for prostate cancer and showed a significant association between the RNASEL 462 variant and prostate cancer risk in African Americans and Hispanic Caucasians.
Triple-negative breast cancers (TNBC) are among the most aggressive and heterogeneous cancers with a high propensity to invade, metastasize and relapse. Here, we demonstrate that the anticancer ...compound, AMPI-109, is selectively efficacious in inhibiting proliferation and inducing apoptosis of multiple TNBC subtype cell lines as assessed by activation of pro-apoptotic caspases-3 and 7, PARP cleavage and nucleosomal DNA fragmentation. AMPI-109 had little to no effect on growth in the majority of non-TNBC cell lines examined. We therefore utilized AMPI-109 in a genome-wide shRNA screen in the TNBC cell line, BT-20, to investigate the utility of AMPI-109 as a tool in helping to identify molecular alterations unique to TNBC. Our screen identified the oncogenic phosphatase, PRL-3, as a potentially important driver of TNBC growth, migration and invasion. Through stable lentiviral knock downs and transfection with catalytically impaired PRL-3 in TNBC cells, loss of PRL-3 expression, or functionality, led to substantial growth inhibition. Moreover, AMPI-109 treatment, downregulation of PRL-3 expression or impairment of PRL-3 activity reduced TNBC cell migration and invasion. Histological evaluation of human breast cancers revealed PRL-3 was significantly, though not exclusively, associated with the TNBC subtype and correlated positively with regional and distant metastases, as well as 1 and 3 year relapse free survival. Collectively, our study is proof-of-concept that AMPI-109, a selectively active agent against TNBC cell lines, can be used as a molecular tool to uncover unique drivers of disease progression, such as PRL-3, which we show promotes oncogenic phenotypes in TNBC cells.
Little is known about the practice patterns of primary care providers as they relate to assessing risk of and screening for chlamydial infections, an important cause of preventable reproductive ...morbidity in young women in the United States. The present cross-sectional study was undertaken to assess levels of chlamydia testing, sexual history taking, and prevention practices by Colorado primary care physicians, nurse practitioners, and physician assistants who provide gynecologic care to adolescent females (13-19 years old).
Between July 1998 and October 1998, an anonymous, self-administered questionnaire was mailed to a 25% random sample (n = 1265) of Colorado physicians (family practitioners, internal medicine specialists, obstetrician-gynecologists, and pediatricians), nurse practitioners, and physician assistants. Practitioners were identified through professional organization membership, state-licensing bodies, and listings in the yellow pages.
After estimating the eligibility rate among non-respondents, the adjusted response rate was 71.5%. Only 53.8% of providers reported regularly testing sexually active female adolescents for chlamydia; 71.8% of providers regularly took a sexual history. Female providers reported significantly higher levels of regularly taking a sexual history (87. 2% vs 60.6% of males), feeling comfortable discussing sex (94.4% vs 77.8%), discussing sexually transmitted disease (STD) prevention (81. 5% vs 71.3%), and testing for chlamydia (64.4% vs 38.6%). Among provider types, obstetrician-gynecologists, nurse practitioners, and pediatricians were most likely to report regularly taking a sexual history (90.1%, 88.6%, and 76.0%, respectively). Internal medicine specialists were the least likely to report taking a sexual history (43.9%). Pediatricians and nurse practitioners were the most likely to report testing sexually active adolescent females for chlamydia (74.1% and 70.1%, respectively), whereas physician assistants and internal medicine specialists were the least likely (46.0% and 38.5%, respectively). In multivariate analysis, variables independently associated with regularly taking a sexual history included female provider gender (odds ratio OR: 5.5; 95% confidence interval CI: 2.9-10.9), obstetrics/gynecology specialty (OR: 4.0; 95% CI: 1.7-10. 3; referent group: family practitioners), and provider comfort level in discussing sex (OR: 4.9; 95% CI: 2.3-11.1). Variables independently associated with regularly testing adolescent females for chlamydia included female provider gender (OR: 2.8; 95% CI: 1. 6-4.8), regularly discussing STD prevention (OR: 2.1; 95% CI: 1.1-4. 1), and regularly discussing limiting the number of patients' sex partners (OR: 2.4; 95% CI: 1.4-4.1).
Only a little over one half of providers (54%) reported regularly performing chlamydia tests on adolescent females who are sexually active by history. Because this falls well short of the recommendations of the Centers for Disease Control and Prevention to test all sexually active female adolescents, efforts are needed to improve STD clinical practices of Colorado physician and nonphysician providers of primary care for adolescent females. Particular efforts are needed to close the provider gender gap.
B7-H4, a member of the B7 family, is involved in the regulation of antigen-specific immune responses. Its expression in a range of breast pathology and correlation to the number of CD3 and CD8 tumor ...infiltrating T-lymphocytes in invasive carcinomas were explored. The proportion of B7-H4 positive cells, staining pattern, and intensity were evaluated within diagnostic groups (normal and benign lesional, potentially premalignant and in situ carcinoma, and invasive carcinoma) on archival tissue blocks by immunohistochemistry. The proportion and intensity of B7-H4 expression was progressively increased across the major diagnostic groups. There was a significant association between a high proportion of B7-H4 positive cells in invasive ductal carcinomas and decreased number of tumor infiltrating lymphocytes (P=0.002). The cellular distribution of B7-H4 appears altered in the spectrum of normal to malignant breast. Its overexpression may help cancers avoid immune detection.
Members of the p160 steroid receptor cofactor family, including AIB1 (Amplified in Breast Cancer 1) (also known as SRC-3/RAC3/ACTR/pCIP/TRAM-1), are of interest in endometrial carcinoma as they ...affect the function of estrogen (ER) and progesterone receptors (PR). Since it is feasible that alterations in the expression levels of coregulators can either augment ER activity or reduce the ability of PR to oppose ER action in endometrial cancers, our primary aim was to analyze expression of the AIB1 protein in endometrial carcinoma, carcinoma-associated complex atypical hyperplasia, and carcinoma-associated normal endometrium using immunohistochemistry and tissue microarrays. Expression of AIB1 was compared with other biomarkers and clinicopathologic parameters. We also tested AIB1 expression in non-carcinoma associated hyperplastic, normal secretory and proliferative endometrium to determine baseline AIB1 levels. In endometrial carcinoma, there is a higher expression of AIB1 compared to carcinoma-associated complex atypical hyperplasia (0.007) or carcinoma-associated normal endometrium (<0.001). AIB1 expression correlates with older age (P=0.003), peri- or postmenopausal status (P=0.002) and a higher grade of carcinomas (P=0.04). There were no differences in the expression of additional steroid hormone receptor co-activators (SRC-1 and p300/CBP) and the co-repressor SMRT between histologic categories. AIB1 expression correlated with ER (r=0.30, P=0.006). The strongest correlation was between ER and PR-B isoform nuclear expression (r=0.52, P<0.0001). AIB1 levels were higher in non-carcinoma associated normal and hyperplastic endometrium compared to carcinoma-associated complex atypical hyperplasia and carcinoma-associated normal endometrium, and were the highest in normal secretory endometrium. In conclusion, high AIB1 expression in endometrial carcinoma is associated with parameters of poor prognosis. We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy. Future studies correlating expression with response to hormonal therapy may be beneficial.
Objectives Contemporary prostate carcinoma is frequently of small volume and early stage. Subtotal gland ablation by minimally invasive therapies such as cryotherapy demands preoperative prediction ...of unifocal, unilateral, margin-negative, and small volume (less than 0.5 mL) cancer. Methods We examined matched biopsy and prostatectomy and clinical data from 393 patients at two institutions who underwent surgery in 2000 through 2003. Radical prostatectomy specimens were uniformly sectioned at 5-mm intervals and completely embedded. Numerous clinical and biopsy variables were correlated by regression analysis with unifocal, unilateral, margin-negative, and 0.5 mL or less volume cancer in the prostatectomy specimen. Odds ratios (OR) were determined. Results At prostatectomy, 92 (23%) had unifocal cancer, 90 (23%) had unilateral cancer, 348 (89%) had organ-confined cancer, and 106 (31%) had small volume cancer. Unilateral cancer occurred in 71% to 76% of cases of unilateral cancer in the biopsy (OR, 4.30; if 9 or more cores were sampled, OR rose to 6.83), and was predicted by unifocality in the biopsy (OR, 2.63). Unifocal cancer was predicted by unilateral (OR, 2.66) but not unifocal, cancer present in the biopsy. Negative surgical margins were predicted by unilateral (OR, 2.53; positive predictive value, 82%) cancer in the biopsy and by serum prostate specific antigen (OR, 5.33). Small volume cancer was predicted by unilateral (OR, 5.50) and unifocal (OR, 7.98) cancer in the biopsy; Gleason score greater than 7 predicted a non–small volume cancer (OR, 7.52). Conclusions Unilateral or unifocal cancer on biopsy are among the strongest predictors of unilateral, unifocal, and small volume prostate cancer in contemporary practice.
Studies suggest that SNPs within
ESR1 may be associated with an increased risk of prostate cancer. We evaluated the association of the
XbaI and
PvuII
ESR1 SNPs and prostate cancer risk in 3 different ...racial/ethnic populations.
A total of 1,603 volunteers from the SABOR study (285 black, 876 white and 442 Hispanic men) were genotyped to assess allelic frequencies of the
ESR1 SNPs. Case-control analysis was performed on 598 prostate cancer cases and 1,098 controls (260 black men, 1,013 non-Hispanic white men and 423 Hispanic white men) to assess the association between these polymorphisms and prostate cancer risk.
Allelic frequency was significantly different across ethnic/racial groups for both SNPs. Logistic regression analysis adjusted for age and stratified by race and ethnicity demonstrated an association between the AG genotype or presence of the G allele (GG or AG genotype) in the
XbaI SNP and prostate cancer risk within black men (OR 2.25, 95% CI 1.07–4.70, p = 0.031; OR 2.14, 95% CI 1.05–4.35, p = 0.035, respectively). No association was observed among Hispanic and non-Hispanic white men for this SNP. Furthermore, there was no association between the
PvuII SNP and prostate cancer risk across all groups.
Our study demonstrates an association between the AG genotype, as well as presence of the G allele within the
XbaI
ESR1 SNP and prostate cancer risk among black men.
This study compared p53 expression with B7-H4, a novel cancer biomarker, in pancreatic ductal adenocarcinoma (PDA) resection specimens and in a pilot series of endoscopic ultrasound-guided ...fine-needle aspirations (EUS-FNAs).
B7-H4 and p53 expression were evaluated by immunoperoxidase methods in 36 PDA and 15 EUS-FNA specimens and were scored for intensity and proportion of positive cells; cases were then assigned a final sum score.
B7-H4 was detected in 33 (92%) of 36 PDA sections, 8 (89%) of 9 cytologically positive EUS-FNAs, and 1 (20%) of 5 cytologically negative EUS-FNAs. p53 was detected in 30 (83%) of 36 PDA sections, 4 (44%) of 9 cytologically positive EUS-FNAs, and 1 (20%) of 5 cytologically negative cases. One EUS-FNA case that was cytologically atypical but not diagnostic of malignancy expressed B7-H4 and p53. Some benign tissue components (intercalated cells/ducts, main pancreatic ducts, and acinar cells) were also positive for B7-H4 and/or p53. Overall expression of B7-H4 in benign tissues, however, was relatively low compared with that seen in most carcinoma cases.
B7-H4 was expressed more often in PDA than was p53. Despite potentially problematic expression in benign/normal cells, the 2 markers target different cellular components and demonstrate potential diagnostic use for detection of PDA in resected and EUS-FNA specimens.
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