Ralph W. deVere White

Surgical Factors Influence Bladder Cancer Outcomes: A Cooperative Group Report

PURPOSE A randomized, cooperative group trial (Southwest Oncology Group 8710, Intergroup 0080) reported that neoadjuvant chemotherapy improved the survival of patients with locally advanced bladder cancer who were treated with radical cystectomy. We evaluated whether surgical factors from patients enrolled onto the study predicted bladder cancer outcomes. PATIENTS AND METHODS Surgical and tumor factors were recorded from surgical and pathologic reports from 268 patients with muscle-invasive bladder cancer who received radical cystectomy. Cystectomies were performed by 106 surgeons in 109 institutions. Half of the patients received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. Variables were tested in univariate and multivariate analyses for associations with postcystectomy survival (PCS) and local recurrence (LR) in all patients receiving cystectomy. RESULTS Five-year PCS and LR rates were 54% and 15%, respectively. A multivariate model adjusted for MVAC (P =.97), age (P =.03), pathologic stage (P =.0002), and node status (P =.04) showed that surgical variables associated with longer PCS were negative margins (v positive; hazard ratio [HR], 0.37; P =.0007), and > or = 10 nodes removed (v < 10; HR, 0.51; P =.0001). These associations did not differ by treatment arms (P >.21 for all tests of interactions between treatment and surgical variables). Predictors of LR in a multivariate model adjusted for MVAC (P =.16), pathologic stage (P =.02), and node status (P =.37) were positive margins (v negative; odds ratio [OR], 11.2; P =.0001) and fewer than 10 nodes removed (v > or = 10; OR, 5.1; P =.002). CONCLUSION Surgical factors influence bladder cancer outcomes after cystectomy, after adjustment for pathologic factors and neoadjuvant chemotherapy usage.

An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells

Although prostate cancer (CaP) is the most frequently diagnosed malignant tumor and the second leading cause of cancer deaths in American men, the mechanisms explaining the development and progression of CaP remain largely unknown. Recent studies have shown that some aberrantly expressed microRNAs (miRNAs) are involved in tumorigenesis. Although aberrant expression of certain miRNAs has been discovered in CaP, their function in this disease has not yet been defined. In this study, we found differential expression of miR-125b in androgen-dependent and independent CaP cells, as well as in benign and malignant prostate tissues. Furthermore, androgen signaling was able to up-regulate the expression of miR-125b. In addition, transfection of synthetic miR-125b stimulated androgen-independent growth of CaP cells and down-regulated the expression of Bak1. Our results suggest that miR-125b acts as an oncogene, contributing to the pathogenesis of CaP.

Serum prostate-specific antigen and prostate volume predict long-term changes in symptoms and flow rate: results of a four-year, randomized trial comparing finasteride versus placebo ☆

OBJECTIVES To determine whether baseline prostate-specific antigen (PSA), in addition to prostate volume, is associated with long-term changes in symptoms and urinary flow rate. METHODS Three thousand forty men with benign prostatic hyperplasia enrolled in the PLESS trial were randomly assigned to finasteride 5 mg or placebo for 4 years. Symptoms and flow rate were assessed every 4 months, and data were analyzed by dividing the patients into three groups by baseline PSA tertiles (0 to 1.3, 1.4 to 3.2, and 3.3 ng/mL or greater) and baseline prostate volume tertiles (14 to 41, 42 to 57, and 58 to 1 50 mL). RESULTS After the initial placebo effect, a slow deterioration in symptoms over time was observed in the placebo-treated men with a baseline PSA 1.4 ng/mL or greater. However, placebo-treated men in the lowest PSA tertile (less than 1.4 ng/mL) had sustained symptomatic improvement that was not seen in placebo-treated men in the higher tertiles (P<0.001). In all finasteride-treated groups, there was initial improvement followed by maintenance or continued symptom improvement over time (approximately 3 to 3.5 points by the end of 4 years). The differences in symptom score improvement between placebo and finasteride were marginal for men with baseline PSA levels less than 1.4 ng/mL (P = 0.128) but were highly significant for men with PSA levels 1.4 ng/mL or greater (P<0.001). Urinary flow rate results were similar to those observed for symptoms. Analysis of symptom and flow rate data by prostate volume tertiles in a 10% subset of men yielded similar results, namely a deterioration of symptoms and flow rate in the two higher tertiles treated with placebo (greater than 41 mL) and a sustained improvement in all three groups of finasteride-treated patients. CONCLUSIONS Baseline PSA and prostate volume are good predictors of long-term symptomatic and flow rate changes. Baseline PSA levels of 1.4 ng/mL or greater and enlarged prostate glands predict the best long-term response to finasteride compared with placebo.

Post-Prostatectomy incontinence and the Artificial Urinary Sphincter: A Long-Term Study of Patient Satisfaction and Criteria for Success

PURPOSE We investigated patient satisfaction with the artificial urinary sphincter and established criteria for a successful outcome by inquiring about patient perceived satisfaction, continence achieved and comparison with the surgeon office records. MATERIALS AND METHODS During 9 years 65 patients with post-prostatectomy incontinence underwent placement of the AMS800 artificial urinary sphincter. Review of charts and a telephone questionnaire were conducted to determine patient perceived satisfaction. RESULTS A total of 50 patients participated in the survey. Median followup was 23.4 months. Preoperative incontinence was severe. Of the patients 90% reported continuous leakage, and 70% wore an average of 6 diapers and 24% wore an average of 7.4 pads daily. The long-term complete continence rate was 20%. Of the patients with wetness 55% had leakage of a few drops daily and 22% had leakage of less than a teaspoon. Of all patients 50% had leakage daily, 24% had leakage 1 or more times a week and wore an average of 1.5 pads per day, and 6% reported changing clothes due to wetness. A total of 90% of the patients reported satisfaction with the artificial urinary sphincter and 96% stated that they would recommend or had recommended the artificial urinary sphincter to a friend. In retrospect, 92% of the patients would have the artificial urinary sphincter placed again, 90% of those undergoing revision reported no change in satisfaction and 14% reported improved sexual activity. CONCLUSIONS Patient satisfaction with the artificial urinary sphincter for post-prostatectomy incontinence is uniformly high. Although postoperative continence was not 100%, relative improvement in continence was the most significant factor affecting patient perceived outcome. Using these parameters criteria for a successful outcome can be established, and patient concerns regarding the artificial urinary sphincter can be dispelled.

Improved Detection of Recurrent Bladder Cancer Using the Bard BTA stat Test

OBJECTIVES To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

miR-125b promotes growth of prostate cancer xenograft tumor through targeting pro-apoptotic genes.

Increasing evidence demonstrates that aberrantly regulated microRNAs (miRNAs) contribute to the initiation and progression of human cancer. We previously have demonstrated that miR‐125b stimulated the growth of prostate cancer (CaP) cells. In this study, we further determined the influence of miR‐125b on the pathogenesis of CaP.

MicroRNA let-7c Suppresses Androgen Receptor Expression and Activity via Regulation of Myc Expression in Prostate Cancer Cells

Background: Let-7c is a microRNA down-regulated in prostate cancer. Results: Let-7c suppresses androgen receptor expression by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation and tumor growth. Conclusion: Let-7c suppresses androgen receptor expression. Significance: Our study demonstrates that let-7c plays an important role in regulation of androgen signaling and prostate cancer proliferation. Castration-resistant prostate cancer continues to rely on androgen receptor (AR) expression. AR plays a central role in the development of prostate cancer and progression to castration resistance during and after androgen deprivation therapy. Here, we identified miR-let-7c as a key regulator of expression of AR. miR-let-7c suppresses AR expression and activity in human prostate cancer cells by targeting its transcription via c-Myc. Suppression of AR by let-7c leads to decreased cell proliferation of human prostate cancer cells. Down-regulation of Let-7c in prostate cancer specimens is inversely correlated with AR expression, whereas the expression of Lin28 (a repressor of let-7) is correlated positively with AR expression. Our study demonstrates that the miRNA let-7c plays an important role in the regulation of androgen signaling in prostate cancer by down-regulating AR expression. These results suggest that reconstitution of miR-let-7c may aid in targeting enhanced and hypersensitive AR in advanced prostate cancer.

Fibroblast growth factor 2: its structure and property, paracrine function, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions

A growth factor extracted from prostatic tissue is called fibroblast growth factor 2 (FGF2), or basic FGF. It is synthesized mainly by stromal fibroblasts and functions in both an autocrine and paracrine fashion. When prostate cancer converts to an invasive phenotye from a dormant stage, the cancer cells respond to the extracellular FGF2 ligand through high-affinity FGFR2 IIIc receptor. Then, the cancer cells synthesize their own FGF2 to propagate their own growth. In addition, secreted FGF2, in conjunction with modified extracellular matrix (ECM), acts on the endothelial cells to promote tumor angiogenesis. The progression of prostate cancer is directly related to upregulated FGF2 gene expression and microvessel proliferation. The fact that FGF2 production and secretion will affect prostate cancer progression warrants a review of this growth factor. In the present review, FGF2 is explored in the context of structure and property, paracrine interactions, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions.

MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth.

Purpose Prostate cancer (PCa) is characterized by deregulated expression of several tumor suppressor or oncogenic miRNAs. The objective of this study was the identification and characterization of miR-let-7c as a potential tumor suppressor in PCa. Experimental Design Levels of expression of miR-let-7c were examined in human PCa cell lines and tissues using qRT-PCR and in situ hybridization. Let-7c was overexpressed or suppressed to assess the effects on the growth of human PCa cell lines. Lentiviral-mediated re-expression of let-7c was utilized to assess the effects on human PCa xenografts. Results We identified miR-let-7c as a potential tumor suppressor in PCa. Expression of let-7c is downregulated in castration-resistant prostate cancer (CRPC) cells. Overexpression of let-7c decreased while downregulation of let-7c increased cell proliferation, clonogenicity and anchorage-independent growth of PCa cells in vitro. Suppression of let-7c expression enhanced the ability of androgen-sensitive PCa cells to grow in androgen-deprived conditions in vitro. Reconstitution of Let-7c by lentiviral-mediated intratumoral delivery significantly reduced tumor burden in xenografts of human PCa cells. Furthermore, let-7c expression is downregulated in clinical PCa specimens compared to their matched benign tissues, while the expression of Lin28, a master regulator of let-7 miRNA processing, is upregulated in clinical PCa specimens. Conclusions These results demonstrate that microRNA let-7c is downregulated in PCa and functions as a tumor suppressor, and is a potential therapeutic target for PCa.

Cancerous miRNAs and their regulation

Although they account for only a very minor fraction of the expressed genome, microRNAs (miRNAs) are pivotal regulators of development and cellular homeostasis through their control of diverse cellular processes including proliferation, differentiation, apoptosis, survival, motility, and morphogenesis. Accordingly, several miRNAs have been functionally classified as proto-oncogenes or tumor suppressors and are aberrantly expressed in different cancer types. Deregulation (e.g., overexpression or loss of expression) of these so-called “cancerous” miRNAs can figure prominently in tumor initiation and progression by elaborating an inappropriate cellular program promoting uncontrolled proliferation, favoring survival, inhibiting differentiation, and/or promoting invasive behavior. These features would certainly promote tumor dissemination and persistence by favoring metastasis and therapy resistance. Cancerous miRNAs therefore represent attractive molecules for exploitation as biomarkers and therapeutic targets. In this review, we highlight recently characterized cancerous miRNAs and the mechanisms through which they contribute to the pathogenesis of human cancers. We also discuss the signal transduction pathways that regulate the expression of these miRNAs with particular attention to several essential transcription factors such as Myc, p53, and the androgen receptor.