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Background: Objective and standardized evaluation of surgical skills in robot-assisted surgery (RAS) holds critical importance for both surgical education and patient safety. This study introduces machine learning (ML) techniques using features derived from electroencephalogram (EEG) and eye-tracking data to identify surgical subtasks and classify skill levels. Method: The efficacy of this approach was assessed using a comprehensive dataset encompassing nine distinct classes, each representing a unique combination of three surgical subtasks executed by surgeons while performing operations on pigs. Four ML models, logistic regression, random forest, gradient boosting, and extreme gradient boosting (XGB) were used for multi-class classification. To develop the models, 20% of data samples were randomly allocated to a test set, with the remaining 80% used for training and validation. Hyperparameters were optimized through grid search, using fivefold stratified cross-validation repeated five times. Model reliability was ensured by performing train-test split over 30 iterations, with average measurements reported. Results: The findings revealed that the proposed approach outperformed existing methods for classifying RAS subtasks and skills; the XGB and random forest models yielded high accuracy rates (88.49% and 88.56%, respectively) that were not significantly different (two-sample t-test; P-value = 0.9). Conclusion: These results underscore the potential of ML models to augment the objectivity and precision of RAS subtask and skill evaluation. Future research should consider exploring ways to optimize these models, particularly focusing on the classes identified as challenging in this study. Ultimately, this study marks a significant step towards a more refined, objective, and standardized approach to RAS training and competency assessment.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P= 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Background. Nuclear shape analysis of histologic sections from radical prostatectomy specimens has retrospectively predicted outcome in patients with clinically localized prostate carcinoma. If outcome could be predicted preoperatively by nuclear shape analysis, patients might be selected better for definitive surgical therapy. Morphometric analysis of preoperative biopsies, however, has not correlated positively with values obtained from analysis of prostatectomy specimens. Methods. The nuclear shapes of histologic specimens of 20 organ-confined carcinomas, 10 periprostatic fat-invasive carcinomas, 10 seminal vesicle-invasive carcinomas, and 12 lymph node-metastatic carcinomas from 52 patients who had undergone radical prostatectomy for clinically localized disease were evaluated. Results. Nuclei from areas of extraprostatic invasion or regional lymph node metastases were less round than those from the corresponding intraprostatic portion of the tumor (nuclear roundness factor (mean [+ or -] SD) PPF, 51.2 [+ or -] 3.1 vs. 31.2 [+ or -] 3.2; SV, 52.4 [+ or -] 4.1 vs. 31.6 [+ or -] 2.5; and LN, 57.3 [+ or -] 3.1 vs. 36.4 [+ or -] 1.8; paired Student's t tests, P 0.001). Cells sampled from the periphery of organ-confined tumors had a greater nuclear roundness factor (49.1 [+ or -] 1.5) than did those sampled from the center (34.5 [+ or -] 2.0; P < 0.001) or randomly throughout the tumor (37.8 [+ or -] 1.6; P < 0.001). Nuclear roundness factors for all extraprostatic tumor foci and for peripheral tumor cells in organ-confined disease were similar (analysis of variance, P 0.05). The intraprostatic portions of randomly sampled primary tumors had similar nuclear roundness factors, regardless of pathologic stage (P > 0.05). Among organ-confined carcinomas, nuclear shape was unrelated to tumor volume. Conclusions. Pathologic stage in clinically localized prostate carcinoma cannot be determined by the nuclear shape profiles of intraprostatic tumor cells. Thus, patients with a poor prognosis or high pathologic stage can be recognized only when samples for morphometric analysis include high proportions of nuclei from the extraprostatic carcinoma and nuclei from the periphery of organ-confined carcinoma that may not be sampled routinely by prostate biopsy. Cancer 1994; 74:2996-3001.

Background: Numerous studies have associated bladder cancer with exposure to carcinogens present in tobacco smoke and other environmental or occupational exposures. Approximately 50% of all humans inherit two deleted copies of the GSTM1 gene which encodes for the carcinogendetoxification enzyme glutathione S-transferase M1. Recent findings suggest that the GSTM1 gene may modulate the internal dose of environmental carcinogens and thereby affect the risk of developing bladder cancer. Purpose: We investigated whether the absence of the GSTM1 gene affects bladder cancer risk and whether there are racial differences in GSTM1 genotype frequency. Methods: Using a polymerase chain reaction (PCR)-based method, we examined the frequency of the homozygous deleted genotype (GSTM1 0/0) in 229 patients with transitional cell carcinoma of the bladder and 211 control subjects who were enrolled from the Urology Clinics at Duke University Medical Center and the University of North Carolina Hospitals. Control subjects were urology clinic patients who primarily presented with benign prostatic hypertrophy or impotence, who had no history of any cancer other than nonmelanoma skin cancer, and who were frequency matched to case patients on race, sex, and age (10-year age intervals). In order to explore racial differences in GSTM1 gene frequency, genotype was also determined in a community-based sample of 466 paid, healthy, unrelated volunteers from Durham and Chapel Hill, N.C. The presence or absence of the GSTM1 gene locus was determined by using a differential PCR, a semiquantitative technique in which multiple genes are coamplified. Results: Overall, the GSTM1 0/0 genotype conferred a 70% increased risk of bladder cancer (odds ratio [OR] = 1.7; 95 % confidence interval [CI] = 1.2-2.5; P = .004). Absence of the GSTM1 gene encoding the glutathione S-transferase M1 enzyme significantly increased risk to persons with exposure to the carcinogens in tobacco smoke (OR = 1.8; 95% CI = 1.2-3.0; P = .01) but poses little increased risk to persons without such exposure. Persons with smoking exposure of more than 50 pack-years who had the GSTM1 0/0 genotype had a sixfold greater risk relative to persons in the lowest risk group (i.e., nonsmokers who were GSTM1 +/+ or +/0). In the pooled clinic control and community sample groups (677 individuals), the GSTM1 0/0 genotype occurred less frequently among Blacks (35%) than among Whites (49%, P

AbstractThe present study investigated the effects of childhood physical neglect (CPN), childhood physical abuse (CPA), and the moderator role of perceived resilience on adult life satisfaction (LS). The National Longitudinal Study of Adolescent Health public-use Wave 3 dataset were used, which included a nationally representative sample (N = 4,397) whose ages ranged from 21 to 28 (M = 21.83, SD = 1.81). The factor structure of the perceived resilience scale was examined using exploratory and confirmatory factor analysis. Ordinal logistic regression (OLR) analysis was used for data analysis, and McFadden's Pseudo R-squares were reported to compare the OLR models. Age, gender, and education were controlled in the study. The results showed that CPA and CPN had a negative direct effect on adult LS. Although the effect of resilience on adult LS was found highly significant in this study, the moderator role of resilience was not found significant. Gender differences were found in adult LS when perceived resilience was taken into account. These findings suggest that childhood adversity is a critical factor in adult LS. Future studies should focus on protective factors, strategies for establishing, building, reinforcing resilience, and gender dynamics in childhood adversities and well-being.

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ. Materials and methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC. Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings. Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Background: Many men diagnosed with prostate cancer are active surveillance (AS) candidates. However, AS may be associated with increased risk of disease progression and metastasis due to delayed therapy. Genomic classifiers, e.g., Decipher, may allow better risk-stratify newly diagnosed prostate cancers for AS. Methods: Decipher was initially assessed in a prospective cohort of prostatectomies to explore the correlation with clinically meaningful biologic characteristics and then assessed in diagnostic biopsies from a retrospective multicenter cohort of 266 men with National Comprehensive Cancer Network (NCCN) very low/low and favorable-intermediate risk prostate cancer. Decipher and Cancer of the Prostate Risk Assessment (CAPRA) were compared as predictors of adverse pathology (AP) for which there is universal agreement that patients with long life-expectancy are not suitable candidates for AS (primary pattern 4 or 5, advanced local stage [pT3b or greater] or lymph node involvement). Results: Decipher from prostatectomies was significantly associated with adverse pathologic features (p-values &lt; 0.001). Decipher from the 266 diagnostic biopsies (64.7% NCCN-very-low/low and 35.3% favorable-intermediate) was an independent predictor of AP (odds ratio 1.29 per 10% increase, 95% confidence interval [CI] 1.03–1.61, p-value 0.025) when adjusting for CAPRA. CAPRA area under curve (AUC) was 0.57, (95% CI 0.47–0.68). Adding Decipher to CAPRA increased the AUC to 0.65 (95% CI 0.58–0.70). NPV, which determines the degree of confidence in the absence of AP for patients, was 91% (95% CI 87–94%) and 96% (95% CI 90–99%) for Decipher thresholds of 0.45 and 0.2, respectively. Using a threshold of 0.2, Decipher was a significant predictor of AP when adjusting for CAPRA (p-value 0.016). Conclusion: Decipher can be applied to prostate biopsies from NCCN-very-low/low and favorable-intermediate risk patients to predict absence of adverse pathologic features. These patients are predicted to be good candidates for active surveillance.

Sustained reliance on androgen receptor (AR) after failure of AR-targeting androgen deprivation therapy (ADT) prevents effective treatment of castration-recurrent (CR) prostate cancer (CaP). Interfering with the molecular machinery by which AR drives CaP progression may be an alternative therapeutic strategy but its feasibility remains to be tested. Here, we explore targeting the mechanism by which AR, via RhoA, conveys androgen-responsiveness to serum response factor (SRF), which controls aggressive CaP behavior and is maintained in CR-CaP. Following a siRNA screen and candidate gene approach, RNA-Seq studies confirmed that the RhoA effector Protein Kinase N1 (PKN1) transduces androgen-responsiveness to SRF. Androgen treatment induced SRF-PKN1 interaction, and PKN1 knockdown or overexpression severely impaired or stimulated, respectively, androgen regulation of SRF target genes. PKN1 overexpression occurred during clinical CR-CaP progression, and hastened CaP growth and shortened CR-CaP survival in orthotopic CaP xenografts. PKN1’s effects on SRF relied on its kinase domain. The multikinase inhibitor lestaurtinib inhibited PKN1 action and preferentially affected androgen regulation of SRF over direct AR target genes. In a CR-CaP patient-derived xenograft, expression of SRF target genes was maintained while AR target gene expression declined and proliferative gene expression increased. PKN1 inhibition decreased viability of CaP cells before and after ADT. In patient-derived CaP explants, lestaurtinib increased AR target gene expression but did not significantly alter SRF target gene or proliferative gene expression. These results provide proof-of-principle for selective forms of ADT that preferentially target different fractions of AR’s transcriptional output to inhibit CaP growth.

Background: To evaluate efficacy and morbidity prospectively in a contemporary multi-institutional salvage radical prostatectomy (SRP) series. Methods: Forty-one men were enrolled between 1997 and 2006, who suffered biopsy-proven recurrent prostate cancer (CaP) after receiving?=?60c Gy radiation as primary treatment for cT1–2NXM0disease. Surgical morbidity, quality of life, biochemical progression-free survival (BPFS) and overall survival (OS) were evaluated. Results: Twenty-four men had undergone external beam radiotherapy, 11 brachytherapy, and six both. Median time between radiation and SRP was 64 months. Median age at SRP was 64 years. Pathologic staging revealed 44% pT2, 54% pT3, and 3% pT4. Surgical margins were positive in 17 and 88% were pN0. Twenty-two percent required intraoperative blood transfusion. Three rectal and one obturator nerve injuries occurred. Seventeen of 38 evaluable patients (45%) had urinary incontinence (?=?3 pads/day) prior to SRP; 88% reported urinary incontinence at 6 months, 85% at 12 months, 63% at 24 months after SRP. Furthermore, 37% of men reported impotence prior to SRP; 78% reported impotence at 6 months, 82% at 12 months, and 44% at 24 months after SRP. The 2-, 5- and 10-year BPFS rates were 51, 39, and 33% respectively; the 2-, 5- and 10-year OS rates were 100, 89, and 52%, respectively, at median follow-up 91 months. Conclusions: Modern surgical techniques continue to be associated with significant peri-operative complication rates. Nevertheless, SRP may benefit carefully selected patients through durable oncologic control

Prostate cancer (PCa) growth and progression rely on the interaction between the androgen receptor (AR) and the testicular ligands, testosterone and dihydrotestosterone (DHT). Almost all men with advanced PCa receive androgen deprivation therapy (ADT). ADT lowers circulating testosterone levels, which impairs AR activation and leads to PCa regression. However, ADT is palliative and PCa recurs as castration-recurrent/resistant PCa (CRPC). One mechanism for PCa recurrence relies on intratumoral synthesis of DHT, which can be synthesized using the frontdoor or primary or secondary backdoor pathway. Androgen metabolism inhibitors, such as those targeting 5α-reductase, aldo-keto-reductase family member 3 (AKR1C3), or cytochrome P450 17A1 (CYP17A1) have either failed or produced only modest clinical outcomes. The goal of this review is to describe the therapeutic potential of combined inhibition of 5α-reductase and 3α-oxidoreductase enzymes that facilitate the terminal steps of the frontdoor and primary and secondary backdoor pathways for DHT synthesis. Inhibition of the terminal steps of the androgen metabolism pathways may be a way to overcome the shortcomings of existing androgen metabolism inhibitors and thereby delay PCa recurrence during ADT or enhance the response of CRPC to androgen axis manipulation.

Charcoal-stripped fetal bovine serum (CS-FBS) is commonly used to study androgen responsiveness and androgen metabolism in cultured prostate cancer (CaP) cells. Switching CaP cells from FBS to CS-FBS may reduce the activity of androgen receptor (AR), inhibit cell proliferation, or modulate intracellular androgen metabolism. The removal of proteins by charcoal stripping may cause changes in biological functions and has not yet been investigated. Here we profiled proteins in FBS and CS-FBS using an ion-current-based quantitative platform consisting of reproducible surfactant-aided precipitation/on-pellet digestion, long-column nanoliquid chromatography separation, and ion-current-based analysis. A total of 143 proteins were identified in FBS, among which 14 proteins including insulin-like growth factor 2 (IGF-2) and IGF binding protein (IGFBP)-2 and -6 were reduced in CS-FBS. IGF-1 receptor (IGF1R) and insulin receptor were sensitized to IGFs in CS-FBS. IGF-1 and IGF-2 stimulation fully compensated for the loss of AR activity to maintain cell growth in CS-FBS. Endogenous production of IGF and IGFBPs was verified in CaP cells and clinical CaP specimens. This study provided the most comprehensive protein profiles of FBS and CS-FBS and offered an opportunity to identify new protein regulators and signaling pathways that regulate AR activity, androgen metabolism, and proliferation of CaP cells.

The World Wide Web is a communication media tool that is highly useful in classroom education. At Purdue University's Department of Technical Graphics, courses being given are already utilizing the Web. However, courses being offered within the department are classified either as dependent or supplementary courses, but are not completely delivered on the Web.

MAGEA11 is a cancer germline (CG) antigen and androgen receptor co-activator. Its expression in cancers other than prostate, and its mechanism of activation, has not been reported. In silico analyses reveal that MAGEA11is frequently expressed in human cancers, is increased during tumor progression, and correlates with poor prognosis and survival. In prostate and epithelial ovarian cancers (EOC), MAGEA11expression was associated with promoter and global DNA hypomethylation, and with activation of other CG genes. Pharmacological or genetic inhibition of DNA methyltransferases (DNMTs) and/or histone deacetylases (HDACs) activated MAGEA11in a cell line specific manner. MAGEA11promoter activity was directly repressed by DNA methylation, and partially depended on Sp1, as pharmacological or genetic targeting of Sp1 reduced MAGEA11promoter activity and endogenous gene expression. Importantly, DNA methylation regulated nucleosome occupancy specifically at the -1 positioned nucleosome of MAGEA11. Methylation of a single Ets site near the transcriptional start site (TSS) correlated with -1 nucleosome occupancy and, by itself, strongly repressed MAGEA11promoter activity. Thus, DNA methylation regulates nucleosome occupancy at MAGEA11, and this appears to function cooperatively with sequence-specific transcription factors to regulate gene expression. MAGEA11regulation is highly instructive for understanding mechanisms regulating CG antigen genes in human cancer.

The progression of prostate cancer to the castration-recurrent phenotype remains a major problem medically.  The present study examined the transcriptomics of de novoandrogen synthesis as a potential mechanism to escape from dependence on circulating androgen. VCaP, LNCaP and LAPC4 cells were acclimated to 1 nM testosterone for 5 generations before subjecting them to a reduced level of 0.03 nM testosterone. Changes in gene expression were quantified using qRT-PCR.  Analyses of the cholesterol biosynthesis pathway and the D4, D5 and backdoor steroidogenic pathways were carried out.  VCaP cells showed no change in the transcriptome of cholesterol biosynthesis.  However, several receptors for cholesterol transport were up-regulated.  The D4 and D5 steroidogenic pathways, but not the backdoor pathway, were stimulated.  Additionally, androgen receptor (AR) expression was increased.  Taken together, the above changes might allow recovery of AR activity to a near normal level. In contrast, LNCaP cells showed only minimal adjustment in the transcriptome of steroidogenesis. LAPC4 cells were equally unresponsive to boosting the machinery of androgen production.  In brief, our results suggest that the VCaP model is an appropriate model for further investigation of targeting the androgen-AR axis to block the emergence of castration-resistant prostate cancer.

INTRODUCTION:Many genes are differentially expressed between androgen-dependent and androgen-independent prostate cancer (CaP). Differential expression analysis and subtractive hybridization previously identified nine genes expressed in intact mice bearing CWR22 tumors and castrated mice bearing recurrent CWR22 tumors but not in regressed tumors. The objectives of this study were to develop an immunostaining method to dual-label foci of proliferating tumor cells [the origin of castration-recurrent CaP (CR-CaP)], to determine which of the nine candidate proteins were differentially expressed in proliferating versusnonproliferating cells at the onset of growth after castration, and to test preclinical findings using clinical specimens of androgen-stimulated benign prostate (AS-BP) and CaP (AS-CaP) and CR-CaP. METHODS:Paraffin-embedded, bromodeoxyuridine-injected CWR22 tumors were hydrated, antigen-retrieved using high heat and high pressure, labeled for each of the nine antigens of interest, visualized using peroxidase, and counterstained with hematoxylin. Mean optical density was calculated for proliferating and nonproliferating areas using automated (nuclear staining) or manual (cytoplasmic staining) image analysis. Prostate tissue microarray sections were immunostained and visually scored. RESULTS:Immunohistochemistry revealed higher nuclear expression of thioredoxin reductase 1 (TrxR1) in proliferating cells than nonproliferating cells (P< .005). There were no statistical differences between cell types in the expression of other proteins. TrxR1 expression was higher (P< .01) in CR-CaP compared with AS-BP or AS-CaP. CONCLUSIONS:Increased TrxR1 expression in CR-CaP was consistent with increased TrxR1 and BrdU expression at the onset of growth in the CWR22 model. Thioredoxin reductase 1 should be targeted in an attempt to delay or prevent CaP recurrence after castration.

We performed a comprehensive survey of annexin I, II and VII protein expression in patient matched benign prostatic epithelium (BPE), androgen stimulated prostate cancer (AS-CaP) and recurrent prostate cancer (R-CaP).

Black American men experience disproportionate mortality from prostate cancer (CaP) compared with white American men. Differences in outcome may stem from differences within the androgen axis. Since serum testosterone levels appear to be similar by race in men with CaP, we measured and compared androgen receptor (AR) protein expression in malignant and benign prostate tissue from black and white men who underwent radical prostatectomy for clinically localized CaP.

The androgen receptor (AR) is highly expressed in androgen dependent and recurrent prostate cancer, suggesting that it has a role in tumor growth and progression after androgen deprivation. AR amplification may contribute to androgen receptor activation in relative androgen absence.

Overexpression of Bcl-xL, an anti-apoptotic member of the Bcl-2 family, negatively correlates with the sensitivity of various cancers to chemotherapeutic agents. We show here that high levels of expression of Bcl-xL promoted apoptosis of cells treated with an antisense oligonucleotide (5′Bcl-x AS) that shifts the splicing pattern of Bcl-x pre-mRNA from the anti-apoptotic variant, Bcl-xL, to the pro-apoptotic variant, Bcl-xS. This surprising finding illustrates the advantage of antisense-induced modulation of alternative splicing versusdown-regulation of targeted genes. It also suggests a specificity of the oligonucleotide effects since non-cancerous cells with low levels of Bcl-xL should resist the treatment. 5′Bcl-x AS sensitized cells to several antineoplastic agents and radiation and was effective in promoting apoptosis of MCF-7/ADR cells, a breast cancer cell line resistant to doxorubicin via overexpression of the mdr1gene. Efficacy of 5′Bcl-x AS combined with chemotherapeutic agents in the PC3 prostate cancer cell line may be translated to clinical prostate cancer since recurrent prostate cancer tissue samples expressed higher levels of Bcl-xL than benign prostate tissue. Treatment with 5′Bcl-x AS may enhance the efficacy of standard anti-cancer regimens and should be explored, especially in recurrent prostate cancer.

Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed <1% immunostained cells on day 6. Androgen receptor immunostained cells increased to 63% on day 6 and 84% on day 32 although immunostaining remained weak. Cellular proliferation was undetectable beyond day 6 after castration until multiple foci of 5 to 20 proliferating cells became apparent on day 120. These foci expressed increased levels of prostate-specific antigen, an androgen receptor-regulated gene product. In tumors recurrent 150 days after castration androgen receptor-immunostaining intensity was similar to CWR22 tumors from intact mice although the percentage of cells immunostained was more variable. The appearance of proliferating tumor cells that expressed androgen receptor and prostate-specific antigen 120 days after castration suggests that these cells represent the origin of recurrent tumors.

Human tissue xenograft models are currently the only tool for conducting in vivoanalyses of intact human tissue. The goal of the present study was to develop reliable methods for successful generation of short-term primary tissue xenografts from benign and tumor-derived human prostate tissue. Primary human prostate xenografts were established in athymic nu/numice from eight of eight benign and five of five prostate cancer tissues, collected from a total of 10 patients who underwent radical prostatectomy for the treatment of prostate cancer. An average of 13 xenografts was established per specimen. Two tissue specimens were cryopreserved for 1 month before successful generation of prostate xenografts. After 1 month in vivo, xenograft tissues were harvested and examined regarding: gross evidence of vascularization; tissue morphology; proliferation; apoptosis; and expression of androgen receptor, prostate-specific antigen, and high molecular weight cytokeratins specific for basal cells in the prostate. Direct comparison of the original tissue specimen and the 1-month xenografts revealed similar histology; similar apoptotic and proliferative fractions in most cases; and comparable expression levels and expression patterns of androgen receptor, prostate-specific antigen, and high molecular weight cytokeratins. These data demonstrate that primary human prostate xenografts, benign and malignant, can be established routinely from human prostate tissue surgical specimens, and that the xenografts maintain tissue architecture and expression of key prostatic markers. The development of this methodology, including the technique for cryopreservation of human tissue, will allow multiple (successive) analyses of human prostate tissue to be conducted throughout time using a tissue sample derived from a single patient; and simultaneous analysis of human prostate tissues derived from a cohort of patients.

VISUAL COMMUNICATION is vitally important to a variety of disciplines. Generally information is communicated in a way deemed appropriate for the discipline, governed by established rules based on prior research. However, when communicating to general audiences en masse, it is imperative that information be presented as simply as possible—the rules governing specialized scientific communication may or may not be applicable. In short, accessing information should be straightforward, allowing the user to efficiently gain the knowledge for which they are searching. Visual content that is presented should be clear, concise, and accurate. With this in mind, this contribution discusses issues related to delivering spatially oriented data to the general populace. Communication through computer graphics should be for the masses as much as it is for individual disciplines. As such, the first half of this paper examines issues related to visual communication for the mass population. The later half provides an update on one such resource,The Purdue University Virtual Visit, being used for visualization and communication at Purdue University and abroad.

IN THE SUMMER OF 1998, the Department of Computer Graphics began developing a Web-based informational and marketing resource for individuals interested in attending and visiting Purdue University’s West Lafayette campus. The result is an interactive campus map that provides information about the various campus buildings using text, photographs, and VR movie clips. It also provides the ability to search for specific buildings and locations and an on-line guided tour. The site allows the user to navigate the campus using a unique, vector-based graphical user interface. The completed interactive map, titledThe Purdue University Virtual Visit, became available in August of 1998 (http://www.tech.purdue.edu/resources/map/). This contribution will discuss the planning, development, and implementation of the site and the related technologies that were used.

Accurate preoperative staging is important for proper selection of patients for radical retropubic prostatectomy. Preoperative staging by digital rectal examination, transrectal ultrasound, magnetic resonance imaging (MRI), Gleason grade and prostate specific antigen was compared to pathological stage for 25 patients who underwent radical retropubic prostatectomy. The predictive value for tumor confinement was 36% by rectal examination, 37% by ultrasound and 30% by MRI. The predictive value for extracapsular disease was 100% by rectal examination, 83% by ultrasound and 66% by MRI. Preoperative determinations of tumor volume by any modality did not correlate with pathological tumor volume. Digital rectal examination, ultrasound and MRI clinically understage the disease in most patients but they may be reliable to predict extracapsular disease.

A method for accurate prediction of prognosis in human prostatic cancer does not exist. The limitations of pathologic grading systems may result from the failure of standard pathological examination of fixed dead tissue to accurately assess the biological behavior of live tumor cells. Many of the sublines of the Dunning R-3327 rat adenocarcinoma are histologically similar yet differ widely in their metastatic potential. The nonmetastatic G, occasionally metastatic AT-1 and AT-2, and highly metastatic AT-3 and MAT-Lu Dunning sublines, and normal dorsal prostate were grown in culture and filmed by time-lapse videomicroscopy. Cell membrane ruffling, undulation and pseudopodal extension, vectoral translation, irregularity of pathway, and overall subjective motility (gestalt) were visually graded. Intra-assay, intra-observer, and inter-observer reproducibility were 75, 80 and 75% respectively. The combination of ruffling, pseudopodal extension and vectoral translation was most successful in identifying the six sublines. To validate this technique prospectively, five tumor sublines and two normal prostates were graded by 10 observers unfamiliar with the technique. Fifty-nine percent of unknowns were correctly identified when motility profiles were compared to previously developed standards by least sum of squares analysis. We devised a new technique for characterizing the motility of living prostate cells which was more accurate in identifying normal rat prostate and the Dunning sublines than standard pathological examination. Prostatic cancer cell motility may reflect biological behavior and metastatic potential and thus contribute to the assessment of an individual patient’s prognosis.

The role of nutritional assessment and support in patients with bladder carcinoma undergoing radical cystectomy is controversial. Morphometric, visceral protein and cell-mediated immune statuses were measured in 33 patients with bladder cancer treated by radical cystectomy. Malnourished patients had greater operative morbidity, operative mortality and days of intensive care than their nutritionally normal counterparts. Kaplan-Meier survival plots showed a tendency to early death of disease in the malnourished patients with convergence of survival rates after 36 months. Of the malnourished patients 7 had extensive nutritional support, and 6 had no parenteral and minimal enteral or oral support. Operative morbidity and mortality rates were higher in the nutritionally supported than in the unsupported groups. Nutritional support in the immediate perioperative period probably does little to alter operative complications.

Pathological grading systems have failed to assess accurately the prognosis of patients with prostatic carcinoma. A visual grading system of cancer cell motility has described successfully the metastatic potential of sublines of the Dunning R-3327 rat prostatic adenocarcinoma model maintained in vitro and in vivo. Clinical application of this technique would be facilitated if it could be performed upon aspirated cells. We compared the motility of cells obtained by biopsy and fine needle aspiration from in vivo Dunning tumors and determined if the motility of aspirated cells could predict metastatic potential. Specimens from the same tumor were obtained by fine needle aspiration and incisional biopsy from three sublines of low (<10%) and three sublines of high (>90%) metastatic potential. Membrane ruffling, pseudopodal extension and cellular translation of 100 cells were graded using time-lapse videomicroscopy. Cells obtained by biopsy and aspiration had similar average (analysis of variance, p >0.7) and variation (coefficient of variation, aspirated = 18.6%, biopsy = 17.7%) of motility. Aspirated cells from three low metastatic sublines (membrane ruffling 5.20 ± SEM 0.41, pseudopodal extension 4.10 ± 0.57 and cellular translation 3.07 ± 0.45) were distinguished from cells of three high metastatic sublines (membrane ruffling 7.10 ± 0.15, pseudopodal extension 6.93 ± 0.22 and cellular translation 5.47 ± 0.25). Cellular translation, the best discriminator, correctly classified the metastatic potential of the subline of origin in 82% of 60 individual cells. A grading system based upon the motility of aspirated cancer cells should be studied in human prostatic carcinoma.

The efficacy of radionuclide bone scans in monitoring metastatic bone activity remains controversial. Objective measurement of bone tumor burden would be useful for the evaluation of new therapies for metastatic carcinoma of the prostate. The recent discovery of the urinary excretion of pyridinoline (cross-link of mature collagen found in cartilage and bone) and deoxypyridinoline (collagen cross-link specific to bone) measured by high pressure liquid chromatography has provided sensitive specific indexes of cartilage and bone breakdown in rheumatoid arthritis, osteoporosis and metabolic bone diseases.

The renal function of spinal cord injury patients frequently is overestimated by 3 commonly used equations to predict creatinine clearance. Overestimation of creatinine clearance may result in aminoglycoside overdosage and resultant nephrotoxicity. Three newer prediction equations have been developed from creatinine clearances measured in neurologically abnormal patients. These 6 equations were tested in 77 male and 9 female spinal cord injury patients (48 quadriplegics and 38 paraplegics, including 38 with acute and 48 with chronic injuries). The equation developed by Sawyer and Hutchins was superior to 2 other equations developed in spinal cord injury patients and 3 equations developed in neurologically normal patients. However, creatinine clearances predicted by this equation were within 30ml. per minute of measured creatinine clearances in only two-thirds of the spinal cord injury patients. Errors ranged from overestimation by 95ml. per minute (151 per cent) to underestimation by 106ml. per minute (45 per cent). The potential for large errors in creatinine clearance prediction necessitates measurement of creatinine clearance as soon as possible when renal excreted and toxic pharmaceuticals are administered to spinal cord injury patients.

Metabolic acidosis developed frequently after ureterosigmoidostomy and rectosigmoid bladder construction but has been reported rarely after the newer methods of continent urinary diversion which also employ intestinal reservoirs. We created an animal model in which to compare the metabolic effects of bladder replacement with segments of ileum or colon and the potential for reversing these derangements with nicotinic acid and chlorpromazine. One year after six dogs’ bladders were replaced by colon (three) or ileum (three), all dogs appeared in excellent health and were free of urinary tract obstruction and clinical infection. Both groups of dogs were severely acidotic with diminished arterial pH and arterial and venous total CO2concentrations although normal serum electrolytes and creatinine concentrations were maintained. Both groups of dogs absorbed approximately one half the urinary sodium, chloride and urea presented to their intestinal reservoirs. After treatment with nicotinic acid and chlorpromazine, the metabolic status of both groups of animals improved. Although nicotinic acid reduced urinary excretion of electrolytes more effectively than chlorpromazine, nicotinic acid was not more effective for reversing metabolic acidosis. When nicotinic acid was provided as an adjunct to sodium bicarbonate therapy in two animals acidosis was corrected at reduced doses of sodium bicarbonate. Based upon this work in an animal model, there does not appear to be a metabolic advantage to intestinal reservoirs which incorporate ileum versus colon. However, asymptomatic patients with normal serum electrolytes and creatinine concentrations may be acidotic. The effects of long term mild acidosis are unknown. However, if therapy is required to prevent diminution of whole body buffers or changes in bone density specific therapy with nicotinic acid or chlorpromazine may reduce the requirement for alkali for correction of metabolic acidosis.

The parameters of age, height, weight, serum creatinine and 24-hour urinary creatinine production were measured in 101 consecutive spinal cord injury patients (79 men and 22 women, 43 quadriplegics and 58 paraplegics) admitted to a rehabilitation hospital. Creatinine production was significantly lower than that of age and sex-matched hospitalized controls, upon whom commonly used nomograms for evaluation of endogenous creatinine clearance are based. Therefore, these nomograms grossly overestimate the creatinine clearance in paralyzed patients, which often results in aminoglycoside overdosage. Regression analysis identified the interval since injury and age as important determinants of creatinine production. We propose 2 simple equations and nomograms that should allow more accurate prediction of creatinine clearance in spinal cord injury patients.

A nuclear shape descriptor, nuclear roundness factor, predicted outcome in patients with prostatic carcinoma whereas standard pathological grading by Gleason’s architectural pattern did not. The inability of others to duplicate those successes warranted a reevaluation of the technique for NRF measurement. We previously described our digitization system and measured the perimeter and area of a microscopic circle similar in size to prostatic carcinoma nuclei with a reproducibility and accuracy of greater than 95%. We have applied our improved system to nuclear contour digitization and standardized our method for NRF measurement. In order to calculate accurately the NRF for prostatic carcinoma, the histologic section must have been reviewed by a pathologist and 150 nuclei traced after random selection. NRF measurement reproducibility within and between observers exceeded 90%. This system for NRF measurement successfully predicted outcome in 13 of 15 patients with stages A2, B1, and B2 prostatic carcinoma. Our success with a carefully tested and improved system for NRF determination warrants further evaluation of NRF for assessment of prognosis of patients with prostatic carcinoma.

Standard pathological grading systems for prostatic carcinoma based upon glandular architectural pattern or nuclear anaplasia have failed to predict the prognosis of individual patients. Quantitative morphometric analysis of nuclear shape has predicted the outcome of patients with prostatic carcinoma when evaluated by some but not all reported studies. Calculation of nuclear roundness factor by different investigators was complicated by equipment differences and lack of standardized methods for acquiring and reporting data. We have improved our system for nuclear contour digitization and determined its theoretical limitations by digitizing standardized objects. Measurement errors were independent of orientation or location of an object within a microscopic or digitizer tablet field, speed of digitization and introduction of a microscope extension tube and light emitting diode cursor. Perimeters and areas of circles and squares of actual or digitizer-projected diameter or sidelength greater than five mm. were measured with a reproducibility and accuracy of greater than or equal to 90 %. When a microscopic circle of diameter similar to prostatic carcinoma nuclei was digitized at a magnification of 2580 X perimeter and area measurements differed within or between observers by less than 5 % and were more than 95% accurate. In order to calculate accurately and evaluate NRF for use in assessing the prognosis of patients with prostatic carcinoma investigators must precisely describe their digitization system, standardization method and observer reproducibility and accuracy when measuring circles that approximate the projected size of prostatic carcinoma nuclei.

The natural history of stage A2 prostate cancer is unknown. Previous studies from this institution have shown that, without treatment, a third of the men with clinically localized stage A2 prostatic adenocarcinoma will have disease progression within 4 years. Presently, most patients who present with stage A2 prostate cancer receive surgical or radiation therapy. The degree of differentiation of the tumor (Gleason score) presently is used to predict the prognosis among patients with clinically localized prostate cancer. The Gleason score does well to predict the prognosis for patients with scores of 2 to 4 and 8 to 10. Unfortunately, the majority of patients fall within the range of Gleason scores of 5 to 7. Better methods are needed to predict which patients diagnosed with stage A2 prostate cancer have a high probability of disease progression. Several studies have reported that morphometrically determined nuclear shape descriptors provided accurate separation of these patients that was superior to Gleason grading methods. To evaluate critically the usefulness of nuclear morphometry for prediction of prognosis we developed a system, The Hopkins Morphometry System, that calculated and compared 15 different shape descriptors that were analyzed by 17 different statistical tests. We tested this system on 18 untreated patients with stage A2 prostate cancer with an average followup of 10.5 years (range 5 to 18 years). For each patient 17 statistical analyses of the 15 shape descriptors (255 total) were evaluated and 50 analyses (50 of 255, 19.6%), including average nuclear roundness factor, provided significant separation (p less than 0.01) of the patients on the basis of outcome, whereas the Gleason score (p equals 0.076) did not. The best separation (p less than 0.01) was provided by the lower quartile analysis of the ellipticity shape descriptor. (J. Urol., 142:1254-1258, 1989)

The role of the androgen receptor in the development and progression of prostatic carcinoma has not been defined. The development of androgen receptor antibodies has provided new opportunities for direct immunohistochemical analysis. We compared the androgen receptor staining characteristics of fresh human prostatic carcinoma with benign prostatic hyperplasia (BPH) using an avidinbiotin complex method. Cancer and BPH obtained from the same radical retropubic prostatectomy specimen in 10 prostate cancer patients (68.5 ± 7.3 years old standard deviation) and BPH from 10 noncancer patients (71.5 ± 7.7 years old) were incubated with AR52, a rabbit polyclonal antibody against a synthetic androgen receptor peptide. Nuclei within each section were graded for intensity of androgen receptor staining (0—absent, 1—weak, 2—moderate or 3—strong) and the percentage (0 to 100%) of nuclei sampled staining at each of these intensity levels was determined. A total intensity score (0 to 300) was the summation of the products of each intensity score (0 to 3) and their corresponding percentages. Cancer sections (166 ± 69) stained less intensely and more heterogeneously than BPH in cancer patients (246 ± 41, Student’s t test p <0.05) and noncancer patients (225 ± 39, p <0.05). The decreased intensity and greater heterogeneity of androgen receptor staining in cancer tissue may implicate a quantitative or functional difference in androgen receptor between prostatic carcinoma and BPH.

We evaluated the optimal means of prevention and treatment of urinary tract infections in 46 patients with an intermittently catheterized neurogenic bladder. Suppression with nightly 160 mg. trimethoprim and 800 mg. sulfamethoxazole compared to placebo showed no difference in the rate of symptomatic or total urinary tract infections. Symptomatic urinary tract infections occurred at the same rate whether routine asymptomatic infections were treated or not. Three-day antibiotic treatment of urinary tract infections showed no decrease in the frequency of symptomatic or total urinary tract infections compared to 10-day therapy. The frequency of post-treatment urinary tract infection persistence, relapse and cure was identical in both groups. Suppressive antibiotics, treatment of asymptomatic urinary tract infections and full course antibiotic therapy offered no advantage over placebo, treatment of symptomatic urinary tract infection only and short course therapy in the management of urinary tract infection in patients with an intermittently catheterized neurogenic bladder.

We determined if immunohistochemical expression of the epidermal growth factor receptor and cathepsin D in the primary tumor was of prognostic value in clinically localized prostate cancer after radical prostatectomy.

Clinically localized renal cell carcinoma is cured by radical nephrectomy in 47% [stage T3a (II)] to 65% [stage T1, T2 (I)] of the patients. Local recurrence and metastatic disease probably result from undetectable microscopic metastases present at operation. Chemotherapy and immunotherapy may improve cure rates if administered adjuvantly. The outcome of individual patients who share surgical stage cannot be predicted reliably by tumor histology, pathological grading and/or nuclear deoxyribonucleic acid analysis.

Many grading systems for prostatic carcinoma exist; however, none allows pathologists to predict accurately the prognosis of individual patients. The Dunning R-3327 prostatic adenocarcinoma model consist of sublines of known metastatic potential which were indistinguishable until recently. A visual grading system of cancer cell motility distinguished the metastatic potentials of Dunning sublines maintained in vitro and was validated prospectively. We used this grading system to assess the metastatic potential of cells harvested directly from in vivo Dunning tumors. We graded the motility of cells from three Dunning sublines of low (<10%) (G, ATI, AT2) and three sublines of high (>90%) AT3, MAT-LyLu, PAT2) metastatic potential. Cells obtained from primary tumors were studied by time lapse videomicroscopy after passages 1, 3 and 5 in vivo and in vitro. Membrane ruffling, pseudopodal extension and cellular translation were graded 0-10. Serial analysis of mean and heterogeneity (coefficient of variation) of membrane ruffling, pseudopodal extension and cellular translation demonstrated that subline motility grades were assessed adequately by a sample of 10 cells. Motility did not depend upon whether cells were maintained in vitro or in vivo; however, motility increased with successive passages in four of six sublines. In 60 cells harvested directly from the fifth in vivo passage, three sublines of low metastatic potential were distinguished from three sublines of high metastatic potential (Student’s ttest, p <0.01). Individual cells from the sublines were identified correctly as high or low metastatic in 83, 78 and 70% of cases by membrane ruffling, pseudopodal extension and cellular translation respectively, and logistic regression analysis failed to improve classification accuracy. A visual grading system of cancer cell motility described the metastatic potential of in vivo neoplasms in the Dunning model and may warrant testing in human prostatic cancer.

Eleven patients with persistent urge incontinence and frequent side effects on oral anticholinergic agents were treated with oxybutynin chloride administered intravesically. Five mg. tablets were dissolved in saline, and the solution was instilled twice daily and retained for 30 minutes. One patient was unable to retain the medication because of severe detrusor hyperreflexia and was eliminated from the study. The remaining 10 patients all reported subjective improvement following treatment and all became totally continent. No side effects were observed. In these 10 patients mean bladder capacity increased from 224 to 360ml. (p less than 0.01) and mean maximum filling pressure decreased from 33 to 24cm. water (p equals 0.17). Two additional patients with continent ileocecal urinary diversions were treated with topical oxybutynin chloride instilled directly into the intestinal reservoir. Both patients reported improved comfort with filling and 1 demonstrated a decrease in uninhibited contractions. These encouraging results suggest that treatment with topical oxybutynin chloride is an effective alternative in patients with voiding dysfunction who either are unresponsive to or have intolerable side effects on oral medications.

We report a case of resection of a unilateral adrenal pseudocyst that precipitated life-threatening adrenal insufficiency. The patient had extremis unresponsive to pressor agents in the immediate postoperative period. Hydrocortisone administration produced temporary resolution and a cosyntropin-stimulation test confirmed adrenal insufficiency. Because of the presence of an adrenal mass, the preoperative evaluation included a formal endocrinological evaluation. Thus, we were able to document the occurrence of acute postoperative primary adrenal insufficiency.

We describe 2 patients with unrecognized acquired immunodeficiency syndrome who presented with acute urological conditions. One patient had inapparent obstructive anuric renal failure and the other had a testicular mass. The etiology in each case was large cell lymphoma. Recognition of the acquired immunodeficiency syndrome by urologists requires an awareness of its many unusual presentations. (J. Urol., 138: 627–629, 1987)

Many grading systems for prostatic carcinoma exist; however, none allows pathologists to accurately predict the prognosis of individual patients. Examination of deadfixed histological sections of malignancies may not be the best way to predict the biological behavior of livingdynamic tumors. We have developed a grading system that reproducibly characterized the motility of living cancer cells. In the Dunning R3327 rat prostatic adenocarcinoma model, three sublines of high metastatic potential (>90%) were distinguished from four sublines of low metastatic potential (<10%). Individual cells from these sublines were correctly identified as high or low metastatic in 96% of cases by grading membrane ruffling, pseudopodal extension, and vectoral translation.

A total of 53 consecutive patients who were candidates for surgical treatment of prostatic cancer underwent preoperative evaluation of the lymph node status by computerized tomography scanning and/or lymphangiography combined with skinny needle aspiration biopsy of any abnormal lymph nodes. In 7 of 14 patients (50 per cent) ultimately found to have stage D1 disease lymphatic metastases were confirmed histologically with needle biopsy alone, thus, obviating the need for pelvic lymph node dissection. Over-all sensitivity, specificity and accuracy rates were 50, 100 and 91.4 per cent, respectively, for computerized tomography scanning with biopsy and 53.8, 100 and 84.1 per cent, respectively, for lymphangiography with biopsy. Computerized tomography scanning and lymphangiography with aspiration biopsy are cost-effective means to identify approximately 50 per cent of the patients who ultimately have lymphatic metastases.