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Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration‐resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher‐grade tumors, although no significant association between HOXB13 expression and recurrence or disease‐specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor‐negative castration‐resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non‐prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration‐resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

We sought to characterize the expression level and subcellular localization of Nectin-4 and Trop-2, targets of novel antibody-drug conjugates in metastatic urothelial cancer, within variant bladder cancer from matched primary and metastatic sites. We find significant levels of the targets in histologic variants. Additionally, high levels of cytoplasmic rather than membrane staining is seen, which may have important clinical implications. Background: Nectin-4 and Trop-2 are transmembrane targets of FDA-approved antibody-drug conjugates (ADC) Enfortumab-vedotin (EV) and Sacituzumab govitecan (SG), respectively, for the treatment of metastatic urothelial carcinoma (mUC). The expression and role of Nectin-4 and Trop-2 in mUC variant histology is poorly described. Materials and Methods: We evaluate membranous and cytoplasmic protein expression, and mRNA levels of Nectin-4 and Trop-2 within matched primary and metastatic mUC samples to determine heterogeneity of ADC targets in mUC variants. Results: Patients with mUC were consented for rapid autopsy immediately after death. Tissues from matched primary and metastatic lesions were collected. A total of 67 specimens from 20 patients were analyzed: 27 were UC, 17 plasmacytoid (PUC), 18 UC with squamous differentiation (UCSD), and 5 neuroendocrine (NE); 10 from primary and 57 from metastatic sites. All histology except NE expressed moderate-high levels of Nectin-4 and Trop-2 by both immunohistochemistry and RNAseq. Nectin-4 demonstrated prominent cytoplasmic staining in metastatic PUC and UCSD. Trop-2 demonstrated strong cytoplasmic and membrane staining in primary and metastatic tumors. Interestingly, Nectin-4 and Trop-2 expression are positively correlated at both mRNA and protein levels. Conclusion: UC and non-NE variants express notable level of Nectin-4 and Trop-2 in both primary and metastatic lesions. Membrane staining of Nectin-4 and Trop-2 is present but cytoplasmic staining is a more common event in both mUC and mUC variant histology. These findings support evaluation of EV and SG in heavily treated variant histology BC and urge attention on the clinical relevance of cytoplasmic localization of ADC targets. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy (NAC) prior to radical cystectomy is associated with improved survival in patients with muscle-invasive conventional urothelial carcinoma (CUC). Sarcomatoid urothelial carcinoma (SUC) is a rare histologic variant associated with aggressive tumor behavior and poor 28 prognosis, however the role of NAC is unclear. In this study, we examined survival outcomes and response to NAC in patients with SUC treated with radical cystectomy. Introduction : To examine oncologic outcomes and response to neoadjuvant chemotherapy (NAC) in patients with sarcomatoid urothelial carcinoma (SUC) treated with radical cystectomy (RC). Materials and Methods : We retrospectively queried our institutional database (2003-18) and Surveillance, Epidemiology, and End Results (SEER)-Medicare (2004-2015) for patients with cT2-4, N0-2, M0 SUC and conventional UC (CUC) treated with RC. Clinicopathologic characteristics were described using descriptive statistics (t test, ?2-test and log-rank-test for group comparison). Overall (OS) and recurrence-free-survival (RFS) after RC were estimated with the Kaplan Meier method and associations with OS were evaluated with Cox proportional hazards models. Results : We identified 38 patients with SUC and 287 patients with CUC in our database, and 190 patients with SUC in SEER-Medicare. In the institutional cohort, patients with SUC versus CUC had higher rates of pT3/4 stage (66% vs. 35%, P < 0.001), lower rates of ypT0N0 (6% vs. 35%, P = .02), and worse median OS (17.5 vs. 120 months, P < .001). Further, patients with SUC in the institutional versus SEER-Medicare cohort had similar median OS (17.5 vs. 21 months). In both cohorts, OS was comparable between patients with SUC undergoing NAC + RC vs. RC alone (17.5 vs. 18.4 months, P = .98, institutional cohort; 24 vs. 20 months, P = .56, SEER cohor t). In Cox propor tional hazards models for the institutional RC cohort, SUC was independently associated with worse OS (HR 2.3, CI 1.4-3.8, P = .001). Conclusion : SUC demonstrates poor pathologic response to NAC and worse OS compared with CUC, with no OS benefit associated with NAC. A unique pattern of rapid abdominopelvic cystic recurrence was identified. [ABSTRACT FROM AUTHOR]

Platinum-based NAC followed by cystectomy is standard of care for MIBC, however improvement of response rates is needed. In this phase I/II trial, neoadjuvant gemcitabine-cisplatin-rapamycin combination was used to suppress response to platinum-derived DNA damage by the tumor microenvironment. Although rapamycin successfully suppressed damage response, treatment efficacy did not improve, suggesting the existence of alternative platinum resistance pathways. Introduction: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard for muscleinvasive bladder cancer (MIBC), however, NAC confers only a small survival benefit and new strategies are needed to increase its efficacy. Pre-clinical data suggest that in response to DNA damage the tumor microenvironment (TME) adopts a paracrine secretory phenotype dependent on mTOR signaling which may provide an escape mechanism for tumor resistance, thus offering an opportunity to increase NAC effectiveness with mTOR blockade. Patients & Methods: We conducted a phase I/II clinical trial to assess the safety and efficacy of gemcitabine-cisplatin-rapamycin combination. Grapefruit juice was administered to enhance rapamycin pharmacokinetics by inhibiting intestinal enzymatic degradation. Phase I was a dose determination/safety study followed by a single arm Phase II study of NAC prior to radical cystectomy evaluating pathologic response with a 26% pCR rate target. Results: In phase I, 6 patients enrolled, and the phase 2 dose of 35 mg rapamycin established. Fifteen patients enrolled in phase II; 13 were evaluable. Rapamycin was tolerated without serious adverse events. At the preplanned analysis, the complete response rate (23%) did not meet the prespecified level for continuing and the study was stopped due to futility. With immunohistochemistry, successful suppression of the mTOR signaling pathway in the tumor was achieved while limited mTOR activity was seen in the TME. Conclusion: Adding rapamycin to gemcitabine-cisplatin therapy for patients with MIBC was well tolerated but failed to improve therapeutic efficacy despite evidence of mTOR blockade in tumor cells. Further efforts to understand the role of the tumor microenvironment in chemotherapy resistance is needed. [ABSTRACT FROM AUTHOR]

Small cell bladder cancer (SCBC) is a rare histologic subtype with relative paucity of data regarding treatment response and outcomes. We reviewed 2 databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). We hypothesized that survival would be similar with these therapy approaches. We retrospectively reviewed our institutional and SEER-Medicare databases to identify patients with SCBC. Overall survival (OS) was determined from the date of diagnosis to last follow-up/death. For those with nonmetastatic disease, a multivariate Cox analysis was used to compare locoregional therapy with neoadjuvant chemotherapy (NAC) + cystectomy versus CCRT. We identified 53 patients in our institutional database and 1166 patients in SEER-Medicare with localized SCBC. Median OS (mOS) with NAC + cystectomy was 46 months (95% CI, 21-72) and 45 months (95% CI, 0-104) in the institutional and SEER-Medicare databases, respectively, whereas mOS with CCRT was 26 months (95% CI, 5-47) and 23 months (95% CI, 18-28) in the 2 series, respectively. In multivariate analysis, NAC followed by cystectomy was associated with an approximately 30% reduction in mortality compared to CCRT in both institutional and national databases but did not reach statistical significance (Institution HR 0.71, 95% CI, 0.22-2.4, P =.58; SEER HR 0.73, 95% CI, 0.49-1.08; P =.11). SCBC is very aggressive with limited survival observed in our institutional and SEER-Medicare datasets regardless of locoregional therapy used. There is an unmet need to define the optimal locoregional therapy for nonmetastatic stage and identify novel therapeutic targets. Small cell bladder cancer (SCBC) is a rare and aggressive histologic subtype of bladder cancer. We reviewed SEER-Medicare and our institutional databases to compare outcomes in patients with localized SCBC treated with cystectomy versus concurrent chemoradiotherapy (CCRT). Neoadjuvant chemotherapy followed by cystectomy was associated with a nonsignificant 30% reduction in mortality compared to CCRT. [ABSTRACT FROM AUTHOR]

However, in a phase II clinical trial of 60 patients with metastatic prostate cancer who met predefined criteria for NEPC, Beltran et al[17] found genomic alterations I BRCA2 i in 29% of patients, although only four (8%) patients had identifiable biallelic alterations. Neuroendocrine prostate cancer (NEPC) is an aggressive variant characterized by poor prognosis, increased frequency of visceral metastasis, and diminished response to hormone therapy.[1] [3] The term NEPC generally encompasses a spectrum of histology and molecular characteristics ranging from pure histologic small-cell carcinoma to mixed tumors with prostate adenocarcinoma and carcinoma with neuroendocrine features.[4] [6] Transformation of adenocarcinoma to neuroendocrine or small-cell typically emerges later in the disease course after hormonal treatment as a mechanism of resistance.[7],[8] De novo neuroendocrine or small-cell prostate cancer is rare, occurring in < 1%-2% of cases at diagnosis[3]; however, treatment-emergent neuroendocrine differentiation is present in up to 17%-25% of patients with castration-resistant prostate cancer (CRPC).[9] [11] DNA damage repair gene mutations including I BRCA2 i are common in metastatic prostate cancer, and identifying them is crucial since they predict sensitivity to therapeutics such as poly-(ADP ribose) polymerase (PARP) inhibitors and platinum chemotherapy.[12] [16] However, there have been conflicting reports regarding the frequency of I BRCA2 i mutations in NEPC.[10],[17] Here, we report the case of a patient with metastatic prostate cancer initially diagnosed with adenocarcinoma which later transdifferentiated into morphologic small-cell carcinoma. [Extracted from the article]

Bladder cancer is among the most prevalent cancers worldwide. Currently, few bladder cancer models have undergone thorough characterization to assess their fidelity to patient tumors, especially upon propagation in the laboratory. Here, we establish and molecularly characterize CoCaB 1, an aggressive cisplatin-resistant muscle-invasive bladder cancer patient-derived xenograft (PDX) and companion organoid system. CoCaB 1 was a subcutaneous PDX model reliably transplanted in vivo and demonstrated an acceleration in growth upon serial transplantation, which was reflected in organoid and 2D cell culture systems. Transcriptome analysis revealed progression towards an increasingly proliferative and stem-like expression profile. Gene expression differences between organoid and PDX models reflected expected differences in cellular composition, with organoids enriched in lipid biosynthesis and metabolism genes and deprived of extracellular components observed in PDXs. Both PDX and organoid models maintained the histological fidelity and mutational heterogeneity of their parental tumor. This study establishes the CoCaB 1 PDX and organoid system as companion representative tumor models for the development of novel bladder cancer therapies. [ABSTRACT FROM AUTHOR]

Penile cancer is an under‐studied disease that occurs more commonly in developing countries and 30–50% of cases show high‐risk human papillomavirus (HPV) infection. Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV‐related penile cancer. Ten‐week‐old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (Krt14) gene promoter and matched wild‐type controls were exposed topically to dimethylbenz(a)anthracene (DMBA) or vehicle for 16 weeks. At 30 weeks of age, mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14, and of the HPV16 oncogenes E6 and E7 was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16‐transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes E6 and E7 and showed deregulated cell proliferation, demonstrated by Ki67‐positive supra‐basal cells. HPV16‐transgenic mice exposed to DMBA showed increased PeIN incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV‐associated human penile cancers. Wild‐type mice showed no malignant or pre‐malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV‐related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique in vivo tool for studying its biology and advancing basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

PURPOSE: Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC. METHODS: Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported. RESULTS: Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common. CONCLUSION: This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors). [ABSTRACT FROM AUTHOR]

Background: Although androgens are depleted in castration resistant prostate cancer (CRPC), metastases still express nuclear androgen receptor (AR) and androgen regulated genes. We recently reported that C-terminal truncated constitutively active AR splice variants contribute to CRPC development. Since specific antibodies detecting all C-terminal truncated AR variants are not available, our aim was to develop an approach to assess the prevalence and function of AR variants in prostate cancer (PCa). Methodology/Principal Findings: Using 2 antibodies against different regions of AR protein (N- or C-terminus), we successfully showed the existence of AR variant in the LuCaP 86.2 xenograft. To evaluate the prevalence of AR variants in human PCa tissue, we used this method on tissue microarrays including 50 primary PCa and 162 metastatic CRPC tissues. RT-PCR was used to confirm AR variants. We observed a significant decrease in nuclear C-terminal AR staining in CRPC but no difference between N- and C-terminal AR nuclear staining in primary PCa. The expression of the AR regulated proteins PSA and PSMA were marginally affected by the decrease in C-terminal staining in CRPC samples. These data suggest that there is an increase in the prevalence of AR variants in CRPC based on our ability to differentiate nuclear AR expression using N- and C-terminal AR antibodies. These findings were validated using RT-PCR. Importantly, the loss of C-terminal immunoreactivity and the identification of AR variants were different depending on the site of metastasis in the same patient. Conclusions: We successfully developed a novel immunohistochemical approach which was used to ascertain the prevalence of AR variants in a large number of primary PCa and metastatic CRPC. Our results showed a snapshot of overall high frequency of C-terminal truncated AR splice variants and site specific AR loss in CRPC, which could have utility in stratifying patients for AR targeted therapeutics. [ABSTRACT FROM AUTHOR]

Testosterone and inflammation have been linked to the development of common age-associated diseases affecting the prostate gland including prostate cancer, prostatitis, and benign prostatic hypertrophy. We hypothesized that testosterone regulates components of prostate tight junctions which serve as a barrier to inflammation, thus providing a connection between age- and treatment-associated testosterone declines and prostatic pathology. We examined the expression and distribution of tight junction proteins in prostate biospecimens from mouse models and a clinical study of chemical castration, using transcript profiling, immunohistochemistry, and electron microscopy. We determined that low serum testosterone is associated with reduced transcript and protein levels of Claudin 4 and Claudin 8, resulting in defective tight junction ultrastructure in benign prostate glands. Expression of Claudin 4 and Claudin 8 was negatively correlated with the mononuclear inflammatory infiltrate caused by testosterone deprivation. Testosterone suppression also induced an autoimmune humoral response directed toward prostatic proteins. Testosterone supplementation in castrate mice resulted in re-expression of tight junction components in prostate epithelium and significantly reduced prostate inflammatory cell numbers. These data demonstrate that tight junction architecture in the prostate is related to changes in serum testosterone levels, and identify an androgen-regulated mechanism that potentially contributes to the development of prostate inflammation and consequent pathology. [ABSTRACT FROM AUTHOR]

Background: Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate gland including benign prostatic hyperplasia (BPH) and prostate carcinoma. The prostate is comprised of a functional secretory epithelium, a basal epithelium, and a supporting stroma comprised of structural elements, and a spectrum of cell types that includes smooth muscle cells, fibroblasts, and inflammatory cells. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stroma could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate microenvironment that could influence pathology. Methodology/Principal Findings: We quantitated transcript levels in microdissected glandular-adjacent stroma from young (age 4 months) and old (age 20-24 months) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding proteins associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/oxidative stress (e.g., Apod, Serpinb5) and other paracrine-acting effects (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age-associated declines. By histology, immunofluorescence, and electron microscopy we determined that the collagen matrix is abundant and disorganized, smooth muscle cell orientation is disordered, and inflammatory infiltrates are significantly increased, and are comprised of macrophages, T cells and, to a lesser extent, B cells. Conclusion/Significance: These findings demonstrate that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate. [ABSTRACT FROM AUTHOR]

Background Secondary analyses of two randomized, controlled phase Ill trials demonstrated that selenium and vitamin E could reduce prostate cancer incidence. To characterize pharmacodynamic and gene expression effects associated with use of selenium and vitamin E, we undertook a randomized, placebo-controlled phase IIA study of prostate cancer patients before prostatectomy and created a preoperative model for prostatectomy tissue interrogation. Methods Thirty-nine men with prostate cancer were randomly assigned to treatment with 200 pg of selenium, 400 lU of vitamin E, both, or placebo. Laser capture microdissection of prostatectomy biopsy specimens was used to isolate normal, stromal, and tumor cells. Gene expression in each cell type was studied with microarray analysis and validated with a real-time polymerase chain reaction (PCR) and immunohistochemistry. An analysis of variance model was fit to identify genes differentially expressed between treatments and cell types. A beta-uniform mixture model was used to analyze differential expression of genes and to assess the false discovery rate. All statistical tests were two-sided. Results The highest numbers of differentially expressed genes by treatment were 1329 (63%) of 2109 genes in normal epithelial cells after selenium treatment, 1354 (66%) of 2051 genes in stromal cells after vitamin E treatment, and 329 (56%) of 587 genes in tumor cells after combination treatment (false discovery rate = 2%). Validation of 21 representative genes across all treatments and all cell types yielded Spearman correlation coefficients between the microarray analysis and the PCR validation ranging from 0.64 (95% confidence interval [Cl] = 0.31 to 0.79) for the vitamin E group to 0.87 (95% Cl = 0.53 to 0.99) for the selenium group. The increase in the mean percentage of p53-positive tumor cells in the selenium-treated group (26.3%), compared with that in the placebo-treated group (5%), showed borderline statistical significance (difference = 21.3%; 95% Cl = 0.7 to 41.8; P= .051). Conclusions We have demonstrated the feasibility and efficiency of the preoperative model and its power as a hypothesis-generating engine. We have also identified cell type- and zone-specific tissue effects of interventions with selenium and vitamin E that may have clinical implications. [ABSTRACT FROM AUTHOR]

Background: The current study was conducted to determine the clinical characteristics and prognostic features associated with prostatic small cell carcinoma (SCC).Methods: Between January 1985 and May 2005, 83 patients with SCC of the prostate were identified. Univariate and multivariate Cox proportional hazards modeling were used to assess the prognostic significance of the clinical parameters associated with disease-specific outcomes.Results: Twenty-one patients had no evidence of distant metastasis at the time of the diagnosis of SCC, with the remaining patients demonstrating radiologic or biopsy-proven evidence of metastatic disease. Compared with patients with metastases, patients without metastases at the time of diagnosis were older (P = .001) and had a lower serum lactate dehydrogenase (LDH) level at the time of diagnosis (P = .002). On multivariate analysis, an elevated serum LDH level and low serum albumin at the time of SCC diagnosis was found to be predictive of inferior progression-free survival (P = .02 and P = .008, respectively) and inferior disease-specific survival (DSS) (P = .02 and P = .01, respectively). At the time of last follow-up, 72 patients (87%) had died of disease, with a median DSS duration of 13.1 months (range, 10.7-17.1 months). There was a statistically significant difference noted with regard to the median DSS of patients with nonmetastatic versus those with metastatic SCC (17.7 months [95% confidence interval (95% CI), 12.1-39.2 months] vs 12.5 months [95% CI, 8.1-16.1 months], respectively; P = .03).Conclusions: SCC of the prostate is a highly aggressive tumor, with serum LDH and albumin levels at the time of diagnosis believed to be predictive of disease-related outcomes. Although palliative, current systemic therapy does not result in cure and does not provide long-term survival for patients with metastases. For patients with nonmetastatic disease, a strategy utilizing systemic and local therapies should be evaluated further. [ABSTRACT FROM AUTHOR]

Bladder cancer, one of the more common cancers, is a heterogeneous disease, both morphologically and clinically. Although histological classification and extent of the disease (staging) guide treatment options, the heterogeneity in responses to therapy highlights the need for better stratification of patients for the appropriate therapy in order to achieve better outcomes. Several molecular classifications of muscle-invasive bladder cancer have been proposed but currently their use in clinical practice is limited by the complexity of the methods used and diversity of the subtypes. [ABSTRACT FROM AUTHOR]

OBJECTIVES To examine changes in prostate biopsies at different intervals after salvage cryotherapy and the effect of biopsy type (transrectal ultrasonography-guided vs transurethral resection, TUR), as the sequence and extent of histological changes occurring in the prostate after salvage cryotherapy for local failure of prostate cancer treatment are unknown. PATIENTS AND METHODS In all, 158 prostate biopsies from 150 patients were examined histologically after salvage cryotherapy for prostate cancer after radiotherapy had failed. Specimens were grouped by time from cryotherapy and biopsy technique. RESULTS Biopsies showed hyalinization, necrosis, inflammation and residual cancer. Hyalinization became predominant over time, most notably in biopsies with no residual cancer. Core biopsies showed more hyalinization and regenerating glands, while TUR biopsies showed more necrosis and inflammation. CONCLUSIONS Tissue cryo-injury and reactive changes last for >1 year; more extensive cryo-injury suggests more effective cancer ablation. A long-term follow-up is necessary, as prostate cancer might remain indolent for >1 year. [ABSTRACT FROM AUTHOR]

Background: The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers.Methods: STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided.Results: Tumors with low levels of STK15 amplification (3-4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer.Conclusion: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer. [ABSTRACT FROM AUTHOR]

Significance: Processing and diagnosing a set of 12 prostate biopsies using conventional histology methods typically take at least one day. A rapid and accurate process performed while the patient is still on-site could significantly improve the patient's quality of life. Aim: We develop and assess the feasibility of a one-hour-to-diagnosis (1Hr2Dx) method for processing and providing a preliminary diagnosis of a set of 12 prostate biopsies. Approach: We developed a fluorescence staining, optical clearing, and 3D open-top light-sheet microscopy workflow to enable 12 prostate needle core biopsies to be processed and diagnosed within an hour of receipt. We analyzed 44 biopsies by the 1Hr2Dx method, which does not consume tissue. The biopsies were then processed for routine, slide-based 2D histology. Three pathologists independently evaluated the 3D 1Hr2Dx and 2D slide-based datasets in a blinded, randomized fashion. Turnaround times were recorded, and the accuracy of our method was compared with gold-standard slide-based histology. Results: The average turnaround time for tissue processing, imaging, and diagnosis was 44.5 min. The sensitivity and specificity of 1Hr2Dx in diagnosing cancer were both >90 %. Conclusions: The 1Hr2Dx method has the potential to improve patient care by providing an accurate preliminary diagnosis within an hour of biopsy. [ABSTRACT FROM AUTHOR]