Kirk Wojno

Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo.

The identification of novel tumor-interactive chemokines and the associated insights into the molecular and cellular basis of tumor-microenvironment interactions have continued to stimulate the development of targeted cancer therapeutics. Recently, we have identified monocyte chemoattractant protein 1 (MCP-1; CCL2) as a prominent regulator of prostate cancer growth and metastasis. Using neutralizing antibodies to human CCL2 (CNTO888) and the mouse homologue CCL2/JE (C1142), we show that treatment with anti-CCL2/JE antibody (2 mg/kg, twice weekly i.p.) attenuated PC-3Luc-mediated overall tumor burden in our in vivo model of prostate cancer metastasis by 96% at 5 weeks postintracardiac injection. Anti-CCL2 inhibition was not as effective as docetaxel (40 mg/kg, every week for 3 weeks) as a single agent, but inhibition of CCL2 in combination with docetaxel significantly reduced overall tumor burden compared with docetaxel alone, and induced tumor regression relative to initial tumor burden. These data suggest an interaction between tumor-derived chemokines and host-derived chemokines acting in cooperation to promote tumor cell survival, proliferation, and metastasis.

Relationship and significance of greatest percentage of tumor and perineural invasion on needle biopsy in prostatic adenocarcinoma.

Serum prostate-specific antigen (PSA) levels and the biopsy Gleason sum are used along with clinical staging to predict prostatectomy pathology results for men with localized prostate cancer. The additional predictive value of perineural invasion (PNI) in pretreatment prostate needle biopsies for evaluating tumor stage in this setting is controversial. The current study evaluates the independent predictive value of PNI for tumor staging in a cohort of 632 men who underwent radical retropubic prostatectomies for clinically localized adenocarcinoma of the prostate between the years 1994 and 1998. None of these men received hormonal or radiation therapy before surgery. In addition to the Gleason sum, biopsy results contained detailed information regarding tumor burden: 1) total number of biopsy cores involved by adenocarcinoma, 2) greatest percentage of any single biopsy involved by prostate carcinoma (GPC), and 3) total percentage of cancer added over all cores (TPC). The presence or absence of any PNI was recorded. Pretreatment factors were analyzed in a univariate and multivariate fashion to determine their predictive value using the TNM tumor stage (pT2 vs pT3) and the modified tumor staging system, which includes surgical margin status (pT2 vs pT3 or positive surgical margin) as end points. Univariate analysis revealed a significant association between pT3 disease and several preoperative factors including age, Gleason sum, serum PSA, digital rectal examination, PNI, GPC, TPC, and the total number of positive cores (p <0.01). Multivariate analysis indicated that serum PSA, Gleason sum, age, and GPC contributed significantly to predicting pT3 disease with odds ratios of 2.7 (95% CI, 1.7-4.3), 2.3 (95% CI, 1.7-3.1), 1.7 (95% CI, 1.1-2.7), and 1.7 (95% CI, 1.4-2.1) respectively. PNI was significant in multivariate analysis only when GPC and TPC were not considered, due to a significant interaction between GPC and PNI (p <0.0001, Wilcoxons rank sum test). These predictive factors showed a similar relationship to adverse pathology when an alternative definition of adverse pathology was used that included positive surgical margins (pT3 or any positive margin). In the interaction between GPC and PNI, GPC was more significant than PNI in predicting pT3 disease. However, PNI added additional information when adverse pathology was defined more broadly as pT3 or any positive margin.

BK Virus as a Cofactor in the Etiology of Prostate Cancer in Its Early Stages

ABSTRACT Prostate cancer has been projected to cause almost 10% of all male cancer deaths in the United States in 2007. The incidence of mutations in the tumor suppressor genes Rb1 and p53, especially in the early stages of the disease, is low compared to those for other cancers. This has led to the hypothesis that a human virus such as BK virus (BKV), which establishes a persistent subclinical infection in the urinary tract and encodes oncoproteins that interfere with these tumor suppressor pathways, is involved. Previously, we detected BKV DNA in the epithelial cells of benign and proliferative inflammatory atrophy ducts of cancerous prostate specimens. In the present report, we demonstrate that BKV is present at a much lower frequency in noncancerous prostates. Additionally, in normal prostates, T-antigen (TAg) expression is observed only in specimens harboring proliferative inflammatory atrophy and prostatic intraepithelial neoplasia. We further demonstrate that the p53 gene from atrophic cells expressing TAg is wild type, whereas tumor cells expressing detectable nuclear p53 contain a mix of wild-type and mutant p53 genes, suggesting that TAg may inactivate p53 in the atrophic cells. Our results point toward a role for BKV in early prostate cancer progression.

Cystic Renal Masses: A Reevaluation of the Usefulness of the Bosniak Classification System

RATIONALE AND OBJECTIVES We evaluated the utility of the Bosniak system for classifying cystic renal masses on computed tomography (CT) scans. METHODS The CT scans of 20 patients with 24 cystic renal masses that were subsequently surgically removed or biopsied were reviewed retrospectively. Masses were categorized using the Bosniak system and were correlated with the pathology results. RESULTS The final pathology results of the cystic renal masses were as follows: Seven of seven category I lesions were benign, one of five category II lesions was benign, zero of four category III lesions were benign, and zero of six category IV lesions were benign. Neither of two unclassifiable cystic lesions were benign. The average enhancement of lesions in categories II, III, and IV was 6.3, 2.3, and 27.6 Hounsfield units (H), respectively. The two uncategorizable lesions had a mean enhancement of 26.8 H. CONCLUSION The results of our study serve to underscore some limitations of the Bosniak classification system because most of our category II and all of our category III lesions were malignant, suggesting that minimally complex cystic renal masses may contain malignant cells. Contrast enhancement of less than 10 H was demonstrated in lesions in categories II and III.

Histotripsy of the Prostate: Dose Effects in a Chronic Canine Model

OBJECTIVES To develop the technique of histotripsy ultrasound therapy as a noninvasive treatment for benign prostatic hyperplasia and to examine the histotripsy dose-tissue response effect over time to provide an insight for treatment optimization. We have previously demonstrated the feasibility of prostate histotripsy fractionation in a canine model. METHODS Various doses of histotripsy were applied transabdominally to the prostates of 20 canine subjects. Treated prostates were then harvested at interval time points from 0 to 28 days and assessed for histologic treatment response. RESULTS The lowest dose applied was found to produce only scattered cellular disruption and necrosis, whereas higher doses produced more significant regions of tissue effect that resulted in sufficient fractionation of tissue so the material could be voided with urination. Urethral tissue was more resistant to the lower histotripsy doses than was parenchymal tissue. Treatment of the urethra at the lowest doses appeared to heal, with minimal long-term sequelae. CONCLUSIONS Histotripsy was effective at fractionating parenchymal and urethral tissue in the prostate, in the presence of a sufficient dose. Further development of this technique could lead to a noninvasive method for debulking the prostate to relieve symptoms associated with benign prostatic hyperplasia.

Body Composition and Serum Prostate-Specific Antigen: Review and Findings from Flint Men’s Health Study

Recent studies have suggested that obesity is associated with lower serum prostate-specific antigen levels, perhaps influencing the recommendation for prostate biopsy and potentially explaining part of the observed poorer prognosis among obese men. African-American men have the greatest rates of prostate cancer and are more likely to die of the disease, making early detection a priority in this group. We present findings from the Flint Mens Health Study, a study of African-American men, that are consistent with most studies suggesting that overweight men have prostate-specific antigen levels that are 0.15 to 0.30 ng/mL lower than those who are not overweight. We have coupled our results with a systematic review of publications in this area.

Is residual neurovascular tissue on prostatectomy specimens associated with surgeon intent at nerve-sparing and postoperative quality of life measures?

OBJECTIVES Preservation of periprostatic neurovascular tissue at the time of radical prostatectomy has been correlated with subsequent erectile function and urinary continence. We evaluated whether the amount of neurovascular tissue identified on prostatectomy specimens correlated with surgeons intention of nerve-sparing and/or predicted quality of life outcomes. MATERIALS AND METHODS Radical prostatectomy specimens from 60 patients were evaluated by 2 pathologists for residual neurovascular bundle tissue. Reviewable pathology was available for 17, 19, and 19 patients with bilateral, unilateral, and non-nerve-sparing radical prostatectomy, respectively. The patients completed the Expanded Prostate Cancer Index Composite, a validated quality of life questionnaire. Differences between neurovascular tissue thickness, surgeons intent at nerve-sparing, and quality of life among patients in each group were analyzed using standard statistical software. RESULTS Neurovascular tissue thickness identified on radical prostatectomy specimens did not correlate with surgeons intent at performing a nerve-sparing procedure, nor was it found to be predictive of postoperative quality of life. Surgeons intent at neurovascular preservation, however, was associated with improved sexual and urinary function scores at 1 year (both P < 0.05). CONCLUSIONS Surgeon intent, regardless of the amount of neurovascular tissue identified on radical prostatectomy specimen, is predictive of postoperative sexual-related and urinary quality of life. This suggests that factors other than the amount of neurovascular tissue spared contribute to postoperative sexual and urinary function.

TRANSITIONAL CELL CARCINOMA IN SITU OF THE SEMINAL VESICLES: 8 CASES WITH DISCUSSION OF PATHOGENESIS, AND CLINICAL AND BIOLOGICAL IMPLICATIONS

PURPOSE Mucosal migration of transitional cell carcinoma in situ is a potential mechanism for multifocal lower tract disease. MATERIALS AND METHODS The clinical course and pathological studies of 8 cases of carcinoma in situ are reviewed in detail. RESULTS The pattern of disease of carcinoma in situ of seminal vesicle provides circumstantial evidence for mucosal migration of cancer from a bladder or prostatic urethral origin. CONCLUSIONS A monoclonal origin of bladder cancer combined with mucosal spread of carcinoma in situ suggests that incomplete destruction of carcinoma in situ may adversely affect long-term results by permitting extension into the distal ureters, prostatic duct or seminal vesicles. Protracted intravesical treatment of carcinoma in situ without complete elimination of the disease allows the natural history of mucosal spread to become evident.

The Clinical and Economic Implications of Specimen Provenance Complications in Diagnostic Prostate Biopsies

PURPOSE Inaccurate diagnoses of prostate cancer can result from transposition or contamination of patient biopsy specimens, which are known as specimen provenance complications. We assessed the clinical and economic burden of specimen provenance complications in prostate biopsies in the United States. MATERIALS AND METHODS We performed a comprehensive, systematic review of the literature to approximate the effect of specimen provenance complications on direct medical costs, patient QALYs and medicolegal costs. Data were extracted from published studies on specimen provenance complications rates, prostate cancer treatment efficacy, treatment cost, litigation/settlement costs after false diagnoses of prostate biopsies and patient quality of life. Sensitivity analysis was done to identify factors that most influenced the outcomes and assess the robustness of the findings. RESULTS Of the estimated 806,251 primary and secondary prostate biopsies performed annually in the United States 20,322 specimen provenance complications were projected to result in 4,570 clinically meaningful false diagnoses and an expected loss of 634 QALYs. The total burden of specimen provenance complications was projected to exceed

PD28-03 CORRELATION BETWEEN A GENOMICS TEST AND ADVERSE PATHOLOGY AFTER RADICAL PROSTATECTOMY AMONG ACTIVE SURVEILLANCE CANDIDATES

879.9 million or