Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression.

Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3ß1 and α6ß1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151(free)) correlates clinically with tumor progression and metastasis. Clustering CD151(free) through its integrin-binding domain promotes accumulation in areas of cell-cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151(free) clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151(free) in prostate cancer correlates with poor patient outcome. When CD151(free) is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151(free) as an independent predictor of survival. Moreover, the detection of CD151(free) can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151(free) with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression.

Perineural invasion and TRUS findings are complementary in predicting prostate cancer biology.

INTRODUCTION: Clinical variables with more accuracy to predict biologically insignificant prostate cancer are needed. We evaluated the combination of transrectal ultrasound-guided biopsy of the prostate (TRUSBx) pathologic and radiologic findings in their ability to predict the biologic potential of each prostate cancer. MATERIALS AND METHODS: A total of 1043 consecutive patients who underwent TRUSBx were reviewed. Using pathologic criteria, patients with prostate cancer (n = 529) and those treated with radical prostatectomy (RP) (n = 147) were grouped as: "insignificant" (Gleason score ≤ 6, prostate-specific antigen (PSA) density ≤ 0.15 ng/ml, tumor in ≤ 50% of any single core, and < 33% positive cores) and "significant" prostate cancer. TRUSBx imaging and pathology results were compared with the RP specimen to identify factors predictive of "insignificant" prostate cancer. RESULTS: TRUSBx pathology results demonstrated perineural invasion in 36.4% of "significant" versus 5.4% of "insignificant" prostate cancers (p < 0.01) and pathologic invasion of periprostatic tissue in 7% of significant versus 0% of insignificant prostate cancers (p < 0.01). TRUS findings concerning for neoplasia were associated with significant tumors (p < 0.01). Multivariable analysis demonstrated perineural invasion in the biopsy specimen (p = 0.03), PSA density (p = 0.02) and maximum tumor volume of any core (p = 0.02) were independently predictive of a significant prostate cancer. CONCLUSIONS: TRUS findings concerning for measurable tumor and perineural invasion in TRUSBx specimens appear to be complementary to Epstein's pathologic criteria and should be considered to aid in the determination whether a prostate cancer is organ-confined and more likely to be biologically insignificant.

Multifocality rather than tumor location is a prognostic factor in upper tract urothelial carcinoma.

OBJECTIVES: Whether a patient has urothelial carcinoma located within the renal pelvis or ureter remains a controversial prognostic indicator in clinical urology. We wished to evaluate whether tumor location is associated with recurrence in patients undergoing nephroureterectomy for upper tract urothelial cancer in a large volume patient cohort. SUBJECTS AND METHODS: We created a retrospective database of patients from 7 academic centers throughout Canada who underwent nephroureterectomy for upper tract urothelial carcinoma. Patient demographics as well as pathologic and surgical factors were analyzed to evaluate any statistical association between tumor location and overall survival, disease-free survival, and disease-specific survival. RESULTS: A total of 1,029 patients had data available for analysis with a mean follow up of 3.2 years. Kaplan Meier 5-year disease-free survivals (DFS) were 46%, 37%, and 19% for renal pelvis tumors, ureteric tumors, and multifocal tumors respectively. There was no association between the location of the tumor and the DFS, however, disease involving both the ureter and renal pelvis was associated with lower DFS and overall survival (OS) (P < 0.001). CONCLUSIONS: Tumor location does not appear to have any influence on the risk of recurrence of disease following nephroureterectomy in this large patient cohort. However, multifocal tumors involving both the ureter and renal pelvis had a significantly worse prognosis and should be considered for more aggressive management.

Extended followup oncologic outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (T2c-T3b).

PURPOSE: We assessed and compared the survival outcomes between cryoablation and external beam radiation therapy in patients with locally advanced prostate cancer (cT2c-cT3b). MATERIALS AND METHODS: Patients with locally advanced prostate cancer, recruited from 1999 to 2002, were randomized to primary cryoablation or external beam radiotherapy. All patients received neoadjuvant hormonal therapy for 3 months before and 3 months after the procedures. Patients underwent followup transrectal ultrasound guided biopsy (at 3, 6, 12, 18 and 24 months for cryoablation, and at 18 and 24 months for external beam radiotherapy) and as clinically indicated thereafter. Biochemical failure was based on the Phoenix criterion (prostate specific antigen nadir +2 ng/dl). RESULTS: A total of 62 patients completed the trial. Median followup was 105.2 months (SD ±35.8). Accrual was limited due to newer data favoring longer neoadjuvant hormonal therapy and higher external beam radiotherapy dose for locally advanced prostate cancer. There was a greater reduction in prostate volume in the cryoablation group after intervention (-54% vs -34%, p ≤0.01). Disease specific survival and overall survival were comparable between the groups. However, the 8-year biochemical disease-free survival rate was significantly lower in the cryoablation group (17.4% vs 59.1%) (p = 0.01). CONCLUSIONS: This randomized trial with median followup approaching 9 years showed that cryoablation was inferior in attaining biochemical disease-free survival in patients with locally advanced prostate cancer (cT2c-T3). Cryoablation may be more suited for less bulky prostate cancer. Longer duration neoadjuvant hormonal therapy or a multimodal approach may provide optimal biochemical disease-free survival in this patient population.

Ghrelin receptor as a novel imaging target for prostatic neoplasms.

BACKGROUND: Ghrelin is a natural growth hormone secretagogue (GHS) that is co-expressed with its receptor GHSR in human prostate cancer (PCa) cells. Imaging probes that target receptors for ghrelin may delineate PCas from benign disease. The specificity of a novel ghrelin-imaging probe for PCa over normal tissue or benign disease was assessed. METHODS: A fluorescein-bearing ghrelin analogue was synthesized (fluorescein-ghrelin(1-18)), and its application for imaging was evaluated in a panel of PCa cell lines and human prostate tissue. Prostate core biopsy samples were collected from fresh surgery specimens of 13 patients undergoing radical prostatectomy. Ghrelin probe signal was detected and quantified in each sample using a hapten amplification technique and associated with pathological features. RESULTS: The ghrelin probe was taken up by GHSR-expressing LNCaP and PC-3 cells, and not in BPH cells that express low levels of GHSR. Binding was blocked by competition with excess unlabeled probe. The ghrelin probe signal was 4.7 times higher in PCa compared to benign hyperplasia tissue (P = 0.0027) and normal tissue (P = 0.0093). Furthermore, while the ghrelin probe signal was 1.9-fold higher in PIN compared to benign hyperplasia (P = 0.0022) and normal tissue (P = 0.0047), there was no significant difference in the signal of benign hyperplasia compared to normal tissue. CONCLUSION: The imaging probe fluorescein-ghrelin(1-18) is specific for PCa, and did not associate significantly with benign hyperplasia or normal prostate tissue. This data suggests that ghrelin analogues may be useful as molecular imaging probes for prostatic neoplasms in both localized and metastatic disease.

How long can patients with renal cell carcinoma wait for surgery without compromising pathological outcomes?

INTRODUCTION: Surgical wait times have been shown to be of significance in other malignancies, but limited studies exist in renal cell cancer (RCC). We analyzed surgical waiting time for RCC patients to see if there was an adverse impact on pathological characteristics. METHODS: Our centre triages RCC patients on the basis of perceived tumour risk. The waiting time for surgery is adjusted stage for stage: clinical T1 at 90 days, T2 at 40 days, T3 and T4 at 30 days. We retrospectively reviewed the charts of 354 patients who underwent surgery for RCC. Patients were assessed for pathological upstaging, positive lymph nodes, tumour recurrence and tumour size within each stage. Analysis was performed, using surgical waiting time as a categorical variable, to test for associations with disease recurrence or adverse pathological characteristics. RESULTS: The median time from the first consultation to surgery was 41 days and the mean follow-up was 26.6 months. Waiting time stage for stage was: clinical T1 at 57.12 days, clinical T2 at 36.8 days, clinical T3 and T4 at 30.32 days. On multivariate analysis, pathological tumour size was associated with progression, whereas no significant association was found between waiting time and upstaging. Higher stage tumours, sarcomatoid pathology and clinical evidence of progression were associated with shorter waiting times for early interventions. CONCLUSIONS: There was no statistically significant evidence for upstaging or progression during the waiting period for our group of patients. The data reinforce previous studies reporting a "safe" period of active surveillance in T1 RCC without affecting their final pathological outcome.

Cumulative summation graphs are a useful tool for monitoring positive surgical margin rates in robot-assisted radical prostatectomy.

OBJECTIVE: • To explore the usefulness of cumulative summation (CUSUM) graphs for monitoring positive surgical margin (PSM) rates during a surgeon's transition from open to robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: • Data were prospectively collected from patients undergoing RARP by a single surgeon. • Preoperatively all patients were either low or moderate risk under the D'Amico classification system. • A CUSUM graph was charted retrospectively to analyse the PSM rate in patients undergoing RARP for pathological stage T2 (pT2) disease. • Acceptable and unacceptable PSM rates were set at 10% and 15% respectively. RESULTS: • From a cohort of 226 patients, 158 patients with pT2 disease were selected. The mean (range) age of these patients was 59.2 (39-73) years, the median (range) Gleason score was 6 (4-9), the mean (range) PSA was 6.43 (0.52-17.5) ng/mL and the mean (range) prostate volume was 44 (18-120) cm(3). In all, 21 patients had PSMs (13%). • CUSUM graphs were produced and clearly demonstrated the change in PSM rate over time. CONCLUSION: • CUSUM graphs are a novel and useful visual representation of the learning curve for surgeons. • PSM rates in patients with pT2 disease are a good outcome to monitor using CUSUM graphs as they are binary and lack the confounding factors associated with other outcomes such as continence and erectile dysfunction. • We advocate the use of CUSUM graphs as a method of quality assurance with the introduction of a robotics programme.

Disease-free survival following salvage cryotherapy for biopsy-proven radio-recurrent prostate cancer.

BACKGROUND: The optimum treatment of prostate cancer recurrence following radiation therapy (RT) remains controversial due to the lack of long-term data. OBJECTIVE: Our aim was to review the survival of patients who underwent salvage cryotherapy to the prostate gland for biopsy-proven recurrent prostate cancer and establish prognostic indicators. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was performed on all patients undergoing salvage cryotherapy at an academic urology unit for biopsy-proven locally recurrent prostate cancer after RT from 1995 to 2004. Patients' preoperative, perioperative, and postoperative data were reviewed and recorded. INTERVENTION: Two freeze-thaw cycles of transperineal cryotherapy were performed under transrectal ultrasound guidance by a single surgeon. MEASUREMENTS: The primary outcome was survival. Secondary outcomes were disease-free survival (DFS), metastasis-free survival, and progression to androgen-deprivation therapy. RESULTS AND LIMITATIONS: Of 187 patients, 176 had records available for follow-up (follow-up rate: 94%). Mean follow-up was 7.46 yr (range: 1-14 yr). Fifty-two patients were followed for >10 yr. DFS at 10 yr was 39%. Risk factors for recurrence were presalvage prostate-specific antigen (PSA), preradiation, and presalvage Gleason score. A PSA nadir >1.0 ng/dl was highly predictive of early recurrence. CONCLUSIONS: Salvage cryotherapy led to an acceptable 10-yr DFS. Presalvage PSA and Gleason score were the best predictors of disease recurrence. A PSA nadir >1 ng/dl following cryotherapy indicated a poor prognosis, and recurrence of disease was universal in these patients.

Immunotherapy for metastatic prostate cancer: where are we at with sipuleucel-T?

IMPORTANCE OF THE FIELD: Prostate cancer is the leading malignancy in North American men and despite improvements in treatments 20 - 30% of patients will relapse. Immunotherapy using activated mononuclear cells is a way to harness the body's adaptive immune response to fight metastatic prostate cancer. AREAS COVERED IN THIS REVIEW: In 2005, at least 10 therapeutic cancer vaccines, designed to confer active, specific immunotherapy against tumor-associated antigens, were in clinical trials. These covered potential fields of immunological strategy to overcome castration-resistant prostate cancer. WHAT THE READER WILL GAIN: A literature review was performed using the search terms sipuleucel-T, Provenge and APC8015 or APC-8015, and restricted to English language articles from 2000 to 2010. The immunological design and development of sipuleucel-T are summarized. The efficacy and safety of sipuleucel-T are discussed based on current data from clinical trials. Ongoing clinical trials involving sipuleucel-T are summarized. TAKE HOME MESSAGE: Efficacy and safety with sipuleucel-T has been demonstrated in Phase I/II trials. The latest data from a Phase III trial shows that sipuleucel-T has met the primary endpoint of survival benefit. Further work is needed to understand the mechanisms behind cancer vaccine failure and elucidate the population for whom this vaccine will be suitable.

Cost analysis of two follow-up strategies for localized kidney cancer: a Canadian cohort comparison.

INTRODUCTION: The cost of surveillance strategies in patients after radical nephrectomy for localized primary renal cell carcinoma (RCC) has not been evaluated. We compared the costs of 2 different surveillance strategies, the new Canadian Urological Association (CUA) guidelines and the old strategy implemented in our institution. METHODS: Seventy-five patients who underwent radical nephrectomy for primary non-metastatic renal cancer were retrospectively reviewed. The direct cost of surveillance was determined and compared with the theoretical cost which would have been accrued using the CUA guidelines. RESULTS: Our mean follow-up was 31.1 (SD ± 20.4) months. The overall and disease-free survival endpoints were 87.7% and 85.2%, respectively. Total medical costs were higher for our old institutional surveillance strategy than the CUA guidelines ($181 861 vs. $135 054). For the complete follow-up of 75 patients, a cost-savings of $46 806 could have been achieved following the CUA guidelines (p = 0.002). Of recurrences, 7 of 8 were detected by routine screening, only 1 recurrence was identified by symptoms. The cost per recurrence detected in our old protocol was $9 812.92. The increased cost of our institution was due to more visits with basic testing, symptomatic investigation, and follow-up of imaging tests. The median percent cost attributable to these extra tests was 15% (range 0 to 59). CONCLUSION: Based on our results, we endorse the new CUA surveillance strategy in RCC follow-up as appropriate and cost effective in comparison with previous follow-up strategies used at our institution.

Histological changes in the human prostate after radiotherapy and salvage high intensity focused ultrasound.

The histological changes (both macroscopic and microscopic) in the prostate following the combination of external beam radiotherapy and salvage high intensity focused ultrasound (HIFU) have not been previously described. This article describes the case of a 65-year-old male who presented with recurrent localized prostate cancer after undergoing external beam radiotherapy for low-risk prostate cancer. He was treated with salvage HIFU, and 4 weeks later presented with symptoms and signs consistent with a prostatorectal fistula. During a period of conservative management, his serum prostate-specific antigen levels started rising after having reached a nadir. A radical cystoprostatectomy and repair of fistula were performed after conservative management failed. Histological changes of dense fibrosis were noted in the region where the prostate should have been located. A literature review of the histological findings in the prostate after HIFU is discussed in this article, as well as the available evidence for the management of patients with local failure after the combination of external beam radiotherapy and salvage HIFU.

Primary mucinous cystadenocarcinoma of the pelvic retroperitoneum in a male.

Primary mucinous cystadenocarcinoma of the retroperitoneum is an extremely rare malignancy with only 2 male patients reported in the literature. We describe an unusual case presenting as a pelvic mass in a male with previous pan-proctocolectomy and end ileostomy for Crohn's disease and review the available literature.

High-intensity focused ultrasound: where are we and where to from here?

High-intensity focused ultrasound (HIFU) has evolved significantly from early work treating cerebral lesions. The ability to treat deep soft-tissue lesions without damaging superficial structures led to it being used for prostate cancer treatment both in the primary and salvage setting. Primary HIFU treatment for prostate cancer leads to 5-year disease free survival rates of up to 70-80% in selected patients with little morbidity; however, comparative studies with established treatment modalities are lacking. Salvage treatment with HIFU leads to significantly more morbidity than primary treatment yet the morbidity appears the same or less than other salvage treatments following external-beam radiation treatment. We believe that with the development of more advanced imaging techniques combined with multimodality prostate imaging that HIFU's future lies in focal treatment of prostate cancer.

Three-dimensional imaging clarifies the process of tracheoesophageal separation in the rat.

BACKGROUND/PURPOSE: The process of tracheoesophageal separation during early development of the foregut has been disputed and has led to difficulties explaining how congenital abnormalities of the trachea and esophagus might occur. This study clarifies the embryogenesis of tracheoesophageal separation by using sequential 3-dimensional imaging at crucial stages of foregut development. METHODS: Timed pregnant Sprague Dawley rats were killed at days 11, 11.5, 12, 12.5, and 13. The embryos were harvested, histologically sectioned, and stained with H&E. Digitized photographs were taken of sequential serial transverse sections and their tracings layered in a 3-dimensional rendering program before being "skinned" to produce a 3-dimensional object. RESULTS: The first respiratory structures to develop are the bronchi on day 11.5. They are evident first as bulges on the ventrolateral wall of the foregut approximately two thirds of the way between the lowest pharyngeal pouch and the level of the hepatic diverticulum and pancreatic buds. Lateral grooves dorsal to the respiratory bud on the lateral walls extend cranially. On day 12 the lateral bulges have developed into the 2 main bronchi, although the trachea is yet to separate from the foregut. On days 12.5 to 13 the trachea progressively elongates, and by day 13 tracheoesophageal separation is complete. CONCLUSIONS: After the main bronchi have developed, the trachea forms when the ventral component of the foregut is "cut" away from the dorsal component. There is an area of apoptosis at the point of tracheoesophageal separation, and, as the embryo grows, this causes the separation point to stay at a constant distance from the pharynx. Meanwhile, the trachea and esophagus distal to it increase dramatically in length. The area immediately caudal to the initial point of tracheoesophageal separation ultimately forms the stomach.