Adenocarcinomas of the bladder are rare, with the diagnosis dependent on exclusion of secondary involvement by direct extension or metastatic spread from other sites. The recent description of an unusual form of urothelial-type mucinous prostatic adenocarcinoma raises a novel differential diagnosis between adenocarcinomas of the prostate and bladder, and investigation into the utility of classic prostatic immunohistochemical antigens in bladder adenocarcinoma is warranted. We identified 37 primary infiltrating adenocarcinomas of the bladder, which included signet ring cell carcinomas (n=11), urachal adenocarcinomas (n=5), and enteric adenocarcinoma (n=21). Also included for comparison were 3 cases, each of bladder villous adenomas and bladder adenocarcinoma in situ. Tissue microarrays were constructed from each case, with each specimen represented by multiple 1.0-mm cores to assess for tumor protein heterogeneity. Immunohistochemistry for prostate-specific antigen (PSA), prostate specific acid phosphatase (PSAP), P501S (prostein), and prostate specific membrane antigen (PSMA) was performed, and moderate to strong immunoreactivity was considered a positive result. Of the 37 adenocarcinomas, all were negative for PSA and PSAP (0/37; 0%). In contrast, a minority of bladder adenocarcinomas was labeled with the prostate antigens P501S and PSMA. P501S showed moderate diffuse cytoplasmic staining in 4/37 cases (11%), including 3 enteric-type adenocarcinomas and 1 mucinous adenocarcinoma. Additionally, 1 case of adenocarcinoma in situ demonstrated diffuse cytoplasmic staining for P501S. The granular perinuclear staining pattern of P501S typically seen in prostatic adenocarcinoma was absent in all cases of bladder adenocarcinoma. PSMA showed diffuse cytoplasmic staining in 4/37 (11%) infiltrating adenocarcinomas (including 1 signet ring carcinoma and 3 enteric-type adenocarcinomas), and in 1 case of adenocarcinoma in situ. Membranous PSMA staining was evident in an additional 3 tumors, 1 urachal mucinous adenocarcinoma, 1 nonurachal mucinous and signet ring cell adenocarcinoma, and 1 nonurachal villous adenoma. In conclusion, although all cases of bladder adenocarcinoma examined were negative for PSA and PSAP, the surprising finding that a subset of invasive and in situ adenocarcinomas of the bladder demonstrated immunoreactivity for P501S and PSMA should warrant caution when using these markers in differentiating prostatic from bladder adenocarcinomas. The lack of granular perinuclear staining for P501S and the absence of membranous PSMA staining both favor a bladder adenocarcinoma, although rare cases of villous adenoma and adenocarcinoma did show PSMA membranous staining indistinguishable from that seen in prostate cancer. Although the novel antigens P501S and PSMA are fairly specific and more sensitive in the differential diagnosis of prostate and urothelial carcinoma, care must be taken when adenocarcinomas of the bladder are considered within this differential diagnosis.
"The p501 antigen (known also as prostein) is uniquely and widely expressed in both normal and cancerous prostate tissues, and can serve as a marker for metastases of prostatic origin (Sheridan et al., 2007). It was also detected in adenocarcinomas of the bladder (Lane et al., 2008). Another vaccine candidate, containing the p501 recombinant antigen combined with the AS15 immunostimulant (p501 + AS15), was evaluated in a phase I/II clinical trial in patients with hormone-sensitive prostate cancer and rising prostate-specific antigen (PSA) (NCT00148928). "
[Show abstract][Hide abstract] ABSTRACT: Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post-mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen-specific antibody titers were determined by enzyme-linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment-related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment-free period. Transient but significant differences in biochemistry parameters were observed post-injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15-containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines.
Journal of Applied Toxicology 06/2015; DOI:10.1002/jat.3167 · 2.98 Impact Factor
"The granular perinuclear cytoplasmic expression of prostein is an important feature in establishing the prostatic origin of tumors. A recent study by Lane et al  found moderate diffuse cytoplasmic P501S staining in 11% of urinary bladder adenocarcinomas. "
[Show abstract][Hide abstract] ABSTRACT: Distinguishing urothelial carcinoma (UC) from prostate carcinoma (PC) is important due to potential therapeutic and prognostic implications. However, this can be a diagnostic challenge when there is limited tissue and in poorly differentiated tumors. We evaluated the diagnostic utility of a dual immunohistochemical stain comprising p63 and P501S (prostein), applied sequentially on a single slide and visualized by double chromogen reaction, in differentiating these two cancers. Thus far, there have been no previous studies assessing the diagnostic utility of p63 and P501S combined together as a dual immunostain in distinguishing between these two cancers.
p63/P501S dual-color sequential immunohistochemical staining was performed on archival material from 132 patients with high-grade UC and 23 patients with PC, and evaluated for p63 (brown nuclear) and P501S (red cytoplasmic) expression. Both the staining intensity and percentage of positive tumor cells were assessed.
p63 was positive in 119/132 of UC and negative in PC. P501S was positive in 22/23 of PC and negative in UC. The p63+/P501S- immunoprofile had 90% sensitivity and 100% specificity for UC. The p63-/P501S+ immunoprofile had 96% sensitivity and 100% specificity for PC.
Our results indicate that double sequential immunohistochemical staining with p63 and P501S is highly specific and can be a useful tool in distinguishing UC from PC especially when there is limited diagnostic tissue as it can be performed on a single slide.
[Show abstract][Hide abstract] ABSTRACT: Fabrication of high-k embedded capacitors on printed wiring board (PWB) is limited due to the inherent low-temperature process required for organic packaging. Current dielectrics for embedded capacitors are mostly organic with insufficient dielectric constant. Integration of high-k thin films on PWB is hindered by high processing temperature of ceramics. The goal of this work, is to develop low-cost/low-temperature, aqueous/non-aqueous based processes for embedded capacitors. Hydrothermal synthesis was used for synthesis of nanograined barium titanate films. Films synthesized at 95°C on titanium foils yielded nanograined films (<80 nm grains) with higher capacitor yield in comparison to conventional hydrothermal films from Ti precursors or sputtered Ti. Films with capacitance of more than 1.0 pF/cm<sup>2</sup> and thickness of 300 nm (corresponding to a dielectric constant of above 350) were developed. Oxygen plasma treatment of hydrothermal films was found to lower the loss significantly to 0.06 from 0.28. Sol-gel technique was also explored an alternate low cost large area process for synthesis of high K low loss films. Sol-gel derived films are typically crystallized and densified at temperatures that are not compatible with organic build-up processes. This limitation has been addressed using a modified sol-gel process to deposit films on a carrier foil that was subsequently laminated onto the printed wiring board. All high-temperature processing steps required by the oxide dielectrics were performed before the embedding process. High-k barium titanate (BaTiO<sub>3</sub>) and strontium titanate (SrTiO<sub>3</sub>) thin film capacitors were synthesized on base-metal nickel (Ni) and titanium (Ti) foils as carrier. Rapid thermal processing (RTP) lowers the process time for the development of a well-crystallized titanate film to 3 minutes as opposed to the few hours of processing time required for conventional heat treatment. Capacitance densities ranging from ∼45-700 nF/cm<sup>2</sup> have been achieved by varying the film thicknesses from ∼250 to 900 nm and the heat treatment conditions. By following the RTP with a 1 hr heat treatment in nitrogen (N<sub>2</sub>) atmosphere, the dielectric loss was reduced to 0.005. These sol-gel and hydrothermal films were su- bsequently integrated onto organic boards using conventional lamination and lithography methods, followed by low-cost wet etching.
Advanced Packaging Materials: Processes, Properties and Interfaces, 2004. Proceedings. 9th International Symposium on; 02/2004
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