Urologic Oncology: Seminars and Original Investigations - Articles in Press

The ubiquitin-proteasome system in prostate cancer and its transition to castration resistance - Corrected Proof

Ioannis A. Voutsadakis, Christos N. Papandreou — 2010-06-28

Abstract: Prostate cancer is the most common carcinoma in the male population. In its initial stage, the disease is androgen-dependent and responds therapeutically to androgen deprivation treatment but it usually progresses after a few years to an androgen-independent phase that is refractory to hormonal manipulations. The proteasome is a multi-unit protease system that regulates the abundance and function of a significant number of cell proteins, and its inhibition results in cancer cell growth inhibition and apoptosis and is already exploited in the clinic with the use of proteasome inhibitor bortezomib in multiple myeloma. In order to be recognized by the proteasome, a target protein needs to be linked to a chain of the small protein ubiquitin. In this paper, we review the role of ubiquitin-proteasome system (UPS) in androgen receptor-dependent transcription as well as in the castration resistant stage of the disease, and we discuss therapeutic opportunities that UPS inhibition offers in prostate cancer.

Modified N-shaped ileal neobladder after radical cystectomy - Corrected Proof

2010-06-21

Abstract: Objective: We report on the feasibility and outcomes of the N-shaped pouch with an afferent tubular isoperistaltic segment as a new technique for creating a capacious, low pressure bladder substitute following radical cystectomy.Methods: Between April 2000 and April 2006, 42 patients (36 male, 6 female) with invasive bladder cancer were considered good candidates for orthotopic urinary diversion. All had radical cystectomy with bilateral pelvic lymphadenectomy and orthotopic bladder substitution by an ileal low pressure reservoir (N-shaped) with an afferent isoperistaltic tubular segment. Of the 42 patients, 36 (86%) had squamous cell carcinoma; 6 had transitional cell carcinoma. None of the patients had positive lymph nodes after pathologic examination of the specimen. The patients were available for a median follow-up period of 24.8 months. Follow-up included clinical and radiographic studies to determine functional and oncological outcomes.Results: Eleven patients (26.2%) had early complications during the period ≤ 3 months following surgery. Seven of these patients had complications such as wound infection, prolonged ileus, persistent urinary leakage, and deep venous thrombosis that were treated conservatively. One female patient developed a pouch-vaginal fistula that required repair. The remaining 3 patients had oncologic failures, 1 of which was isolated urethral recurrence. Late complications occurred in 15 patients (35.7%). These included pouch stones, outflow obstruction, mucus retention, and adhesive bowel obstruction. Daytime and night-time continence was achieved in 92% and 80% of the patients, respectively, and ureteroileal stricture was observed in 5%. The upper tracts remained unchanged or improved in nearly 95% of the patients.Conclusions: Ileal orthotopic bladder substitution (N-shaped) with an afferent ileal tubular segment offers good functional results with good preservation of the renal units. It is considered a safe and technically feasible surgical procedure.

Microvessel density as a prognostic factor in penile squamous cell carcinoma - Corrected Proof

2010-06-21

Abstract: Objective: To examine the potential effect of tumor-induced angiogenesis in squamous cell carcinoma of the penis as a possible prognostic factor.Patients and methods: Immunohistochemistry was preformed to detect microvessels in tumor samples of 64 patients with squamous cell carcinoma of the penis. We used a monoclonal mouse antibody directed against CD34 antigen. Only 61 (30 with and 31 without metastasis) patients had good staining properties and were included. After immunostaining, the entire tumor section was scanned microscopically at low power (×40) to identify hot spots within the tumor and at its periphery. Individual tumor microvessels were then counted under high power (×200) to obtain a vessel count in a defined area, and the mean of the 3 highest microvessel counts was taken as the microvessel density (MVD). Microvessel counting was performed using a computer-aided image analysis system. The nodal status was based on histopathologic examination or an uneventful follow-up ≥2 years.Results: The 5-year overall survival (OAS) was 75% and 30 % for those with high and low peritumoral MVD, respectively (log rank P = 0.01). No difference was noticed within the tumor with regard to high (5-year OAS of 65.03%) and low (5-year OAS of 60.56%) intratumoral MVD (log rank P = 0.99). The mean intratumoral MVD was 32.35 (3.16), 37.94 (3.35), and 62.66 (5.47) in T1, T2, and T3 respectively (ANOVA P = 0.0006), with increasing tendency. The mean peritumoral MVD was 55.91 (5.60), 56.8 (4.00), and 78.86 (8.71), respectively (P = 0.06). No correlation between MVD lymph node status and tumor grade was seen (P > 0.05).Conclusion: In our group of patients, a high peritumoral MVD was associated with a better 5-year OAS. However, for a reliable and reproducible assessment of tumor angiogenesis in penile squamous cell carcinoma, validation procedures and quality control protocols are mandatory.

Understanding the agreement of histology of familial testicular tumors - Corrected Proof

Hao Liu, Jan Sundquist, Kari Hemminki — 2010-05-20

A recent article, by Mai et al. reported clinicopathologic features of familial testicular germ cell tumors (TGCTs) collected in the auspices of the International Testicular Cancer Linkage Consortium (ITCLC) composed of more than 20 centers from 14 countries. The patients included 985 men with TGCTs from 461 families, of which 266 families with 2 cases had detailed histology information for both cases. The results indicated that there was no evidence of the concordance of the two main histologic types, seminoma and nonseminoma, of TGCTs within-family, the overall measure of concordance, κ was 0.15. No evidence of histologic concordance was observed among son–father pairs, fraternal pairs, cousins, or other kindred; the κ ranging from 0.16 to 0.38. These are agreeably modest κ values, but no P values were given. According to other types of epidemiologic studies, similar incidence trends in seminoma and nonseminoma have been suggested to imply sharing of etiologic factors between the histologic types .

The incidence and management of metachronous testicular germ cell tumors in patients with extragonadal germ cell tumors - Corrected Proof

2010-05-17

Abstract: Objectives: The optimal management of extragonadal germ cell tumor (EGGCT) and metachronous testicular germ cell tumor (MTGCT) has not been determined.Patients and methods: Fifty-one consecutive patients with EGGCT were identified. Testicular palpation or ultrasonography to rule out a primary testicular tumor was performed. Pretreatment testicular biopsies were not performed. The incidence and outcome of MTGCT, and the prognosis of EGGCT were evaluated.Results: Twenty-five and 26 patients, respectively, had mediastinal and retroperitoneal EGGCT. Fourteen and 37 patients, respectively, had seminoma and nonseminoma. Five patients developed MTGCT in patients with retroperitoneal EGGCT. The median interval from the primary treatment for EGGCT to MTGCT diagnosis was 64 months (range 15–120). The cumulative risk of developing MTGCT was 8.3% at 6 y. Five patients underwent an orchiectomy and have survived in the 16-months median follow-up period (range 4–30). Among the patients with seminomatous and nonseminomatous EGGCT, the 5-year survival rate was 84.6% and 78.3%, respectively. Among the patients with retroperitoneal and mediastinal nonseminomatous EGGCT, the 5-year survival rate was 94.7% and 58.8%, respectively.Conclusions: The prognosis of EGGCT without testicular biopsies was sufficient. EGGCT patients, especially retroperitoneal EGGCT, need long-term follow-up for MTGCT.

Osteoblasts can stimulate prostate cancer growth and transcriptionally down-regulate PSA expression in cell line models - Corrected Proof

2010-05-10

Abstract: Introduction: To investigate the effect of bone environment on cellular proliferation, mature prostate-specific antigen (PSA) production and secretion, and PSA transcriptional regulation of prostate cancer cells.Materials and methods: Androgen-independent C4-2 prostate cancer cells were co-cultured with various osteoblastic cells in a transwell system. Proliferation was measured via cell counting and MTT assay. Lactate and PSA were determined in the conditioned media (CM). Transcriptional activity of the full-length PSA promoter (6.1 kilobases) and of 3 deletion constructs was determined via luciferase reporter assay upon exposure to CM from various osteoblastic cell lines.Results: Osteoblastic bone cells and CM, but not control cells (fibroblast) or CM, reproducibly stimulated the proliferation of C4-2 cells. The co-culture system, PSA production by C4-2 cells transiently decreased when in co-culture with osteoblastic, but not with control cells. After abundant prostate cell proliferation, the secreted PSA levels rose exponentially. Addition of CM from osteoblastic cells, but not control cells, consistently decreased (about 3-fold) the transcriptional activity of the PSA promoter in C4-2 cells. Deletion construct analysis of the PSA promoter revealed that the transcriptional down-regulation is dually controlled by elements close to the TATA and upstream androgen responsive (AREIII) components.Conclusions: The osteoblastic environment stimulates prostate cancer cell proliferation but reduces PSA production initially. The mechanism of PSA down-regulation is transcriptional, most likely in response to soluble factors present in the osteoblastic bone stromal cell CM. Transcriptional down-regulation appears to be mediated by elements near both the TATA box and the AREIII component.

Discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy - Corrected Proof

2010-05-10

Abstract: Objectives: In muscle invasive bladder cancer (MIBC), careful clinical staging is essential for patient counseling and decision-making. Bimanual palpation (BP) is an integral part and guideline advice of clinical staging. Until now, however, the value of BP has never been studied. With this study, we aim to determine the accuracy of clinical staging through BP.Methods: Detailed clinical data were collected from a population-based series of 1,409 patients with MIBC, diagnosed between 1989 and 2005, in the region of the Comprehensive Cancer Centre East in The Netherlands. Selected were all patients who underwent BP (n = 738). Preoperative tumor-stage (cT-stage) determined through BP was compared with post-cystectomy pT-stage. Contingency tables were made to determine the correlation between cT-stage and pT-stage.Results: In 18 of 142 patients in whom BP showed an organ-confined tumor, the tumor was unresectable (pT4) at the time of surgery. Four out of 9 patients who had a suspected T4 tumor on BP but who underwent cystectomy anyway appeared to have operable tumors at cystectomy. In 87 patients (57.6%), accurate staging through BP was observed. In 17 patients (11.3%), clinical overstaging was found, and in 47 patients, (31.1%) clinical understaging.Conclusions: Frequently, pT-stage after cystectomy does not correlate with preoperative cT-stage based on BP. Discrepancy was observed in 42% of the patients: in 11%, clinical overstaging and in 31%, clinical understaging. Based on these data, some caution is suggested when interpreting the outcome of BP. Prospective data is needed for a more formal evaluation of the staging accuracy of BP.

Testicular sparing surgery for small masses - Corrected Proof

2010-05-10

Abstract: Objectives: To determine the proportion of benign testicular lesions among candidates for testicular sparing surgery (TSS) and to assess the safety and efficacy of this procedure.Methods and Materials: Sixteen patients underwent surgical exploration for testicular tumors with TSS intent in our center. Surgery was performed via an inguinal approach with temporary cord occlusion and frozen section (FS) analysis of the lesions. Benign findings allowed for TSS, whereas cancer prompted total orchiectomy.Results: The lesions measured 8–25 mm in the largest diameter. Eleven of the 16 lesions were benign (69%) and TSS was accomplished in these cases. Complete concordance was observed between the results of FS and permanent sections. Of the 5 patients with cancer, 3 had pure seminoma, and embryonal carcinoma and teratoma were found in 1 patient, each. Surveillance was applied in 4 of these patients, and chemotherapy was used in the patient with embryonal carcinoma. With an average follow-up duration of 48 months, all are alive and free of disease. All 11 patients in whom TSS was accomplished had an uneventful postoperative course, and with an average follow-up duration of 28 months, 9 have normal scrotal physical examination and ultrasound, whereas 2 patients were lost to follow-up.Conclusions: Sixty-nine percent of testicular lesions under 25 mm are benign. TSS is safe and effective in patients with small benign lesions. Cancer is reliably detected by FS, and testicular exploration is not associated with local or distant recurrence in any of our patients.

Carboplatin plus paclitaxel therapy after docetaxel in men with metastatic castrate resistant prostate cancer - Corrected Proof

2010-05-10

Abstract: Objectives: Docetaxel is considered first-line chemotherapy for patients with metastatic castrate resistant prostate cancer (CRPC). Carboplatin and paclitaxel have demonstrated activity in CRPC but published data are limited regarding use after docetaxel.Methods: A retrospective, bi-institutional review was conducted of patients with advanced CRPC treated with carboplatin plus paclitaxel after docetaxel. Therapy was evaluated for tolerability, response, and survival. Endpoints used modified Prostate Cancer Working Group 2 criteria.Results: Twenty-five patients were identified from February 2000 to March 2008. Median pretreatment PSA was 130.2 ng/ml [range 0.1–2100]. Sites of metastases included bone (88%), lymph nodes (52%), pelvis (32%), lung (28%), and liver (20%). A median 4.5 cycles of docetaxel [range 1–22] were given with a median progression-free survival (PFS) of 12 weeks [range 2–68]. Eighty-eight percent of patients (22/25) were docetaxel-refractory at the initiation of therapy with carboplatin (AUC 4–6) day 1 plus paclitaxel 60–80 mg/m2 days 1, 8, and 21 recycled every 28 days. Patients received a median of 3.5 cycles [range 1–8] of carboplatin/paclitaxel with a median PFS of 12 weeks [range 2–35]. Sixty-four percent of patients (16/25) achieved ≥30% reduction in PSA with a median overall survival of 42 weeks [95% CI 30.6–53.5 weeks]. Grade 3 or 4 adverse hematologic events occurred in 11/25 (44%) patients, with no neutropenic fever or grade 3/4 non-hematologic toxicity.Conclusion: Carboplatin/paclitaxel chemotherapy following docetaxel in metastatic CRPC is well tolerated with favorable PSA response rates and survival. This combination is a viable option after progression on docetaxel-based therapy.

Concomitant carcinoma in situ is a feature of aggressive disease in patients with organ confined urothelial carcinoma following radical nephroureterectomy - Corrected Proof

2010-05-10

Abstract: Objective: Carcinoma in situ (CIS) is associated with increased risk of progression when found with high-grade non-muscle-invasive bladder cancer, yet its impact is less clear in the upper urinary tract. In the current study, we evaluated the impact of concomitant CIS on recurrence-free survival and cancer-specific survival following radical nephroureterectomy for upper tract urothelial carcinoma (UTUC).Materials and methods: A multi-institutional retrospective cohort of 1,387 patients undergoing radical nephroureterectomy was identified. Concomitant CIS was defined as the presence of CIS in association with another pathologic stage; patients with CIS alone were excluded from the analysis. The presence of concomitant CIS served as the exposure variable with disease recurrence and cancer-specific mortality as the outcomes. Organ-confined disease was defined as AJCC/UICC stage II or lower.Results: Concomitant CIS was identified in 371 of 1,387 (26.7%) patients and was significantly more common in patients with a previous bladder cancer history, high grade, and high stage tumors. In a multivariable analysis, concomitant CIS was a predictor of disease recurrence (HR = 1.25, P = 0.04) and cancer specific mortality (HR = 1.34, P = 0.05) for patients with organ-confined UTUC, but not in the entire cohort. Other prognostic variables, such as grade, stage, lymphovascular invasion, and lymph node status, were associated with poorer overall and recurrence-free survival for all patients.Conclusion: The presence of concomitant CIS in patients with organ-confined UTUC is associated with a higher risk of recurrent disease and cancer-specific mortality. This information may be useful in refining surveillance protocols and in more appropriate selection of patients for adjuvant chemotherapy.

T1 bladder cancer: Advocating early cystectomy to improve oncologic control - Corrected Proof

Jeffrey S. Montgomery, Alon Z. Weizer, James E. Montie — 2010-05-10

Treating bladder cancer is challenging. Even with efforts to promote early detection and close surveillance, nearly 50% of patients undergoing cystectomy die of metastatic disease . This alarming rate has remained relatively unchanged despite advances in bladder cancer detection, staging, use of intravesical therapy, and surgical technique. T1 bladder cancer accounts for up to 45% of superficial bladder tumors and more than 90% of these tumors are high grade . Of these, 30% progress to muscle-invasive disease within 5 years of diagnosis when treated with transurethral resection (TUR) alone. Although traditionally referred to as superficial disease, T1 bladder cancer is unique compared with Ta and carcinoma in situ (CIS). T1 disease either develops or inherently possesses the genetic capability to invade the bladder wall, penetrating the basement membrane into the lamina propria and often the associated muscularis mucosa, with the risk of tumor progression and metastasis if not effectively eliminated.

Expression profile of E-cadherin and N-cadherin in non-muscle-invasive bladder cancer as a novel predictor of intravesical recurrence following transurethral resection - Corrected Proof

2010-05-10

Abstract: The objective of this study was to investigate the impact of the expression profile of E-cadherin and N-cadherin in newly diagnosed non-muscle-invasive bladder cancer (NMIBC) on the probability of intravesical recurrence in patients undergoing transurethral resection (TUR). This study included 115 consecutive patients diagnosed as having NMIBC following TUR. Expression levels of E-cadherin and N-cadherin in TUR specimens from these patients were measured by immunohistochemical staining. In this series, intravesical recurrence occurred in 35 of 115 patients (30.4%). Immunohistochemical study showed that positive expression of E-cadherin and N-cadherin were noted in 62 (53.9%) and 48 (41.7%) specimens, respectively. Intravesical recurrence was detected in only 7 of 62 patients (11.3%) with positive E-cadherin expression, while 33 of 48 patients (68.8%) with positive N-cadherin expression developed intravesical recurrence. When patients were divided into 4 groups according to the positivities of E-cadherin and N-cadherin expression, intravesical recurrence was detected in 27 of 30 patients (90.0%) with negative E-cadherin as well as positive N-cadherin expression, and the intravesical recurrence-free survival of this group was significantly poorer than those of the remaining 3 groups. Furthermore, negative E-cadherin as well as positive N-cadherin expression was identified as the most powerful independent predictor for intravesical recurrence following TUR on multivariate analysis. These findings suggest that the loss of E-cadherin and gain of N-cadherin expression in on NMIBC appeared to be significantly associated with postoperative recurrence; therefore, the switch from E-cadherin to N-cadherin expression might be involved in the mechanism underlying intravesical recurrence of on NMIBC.

Defining sexual function after radical retropubic prostatectomy - Corrected Proof

Moira E. Dwyer, Ajay Nehra — 2010-05-10

While the prevalence of erectile dysfunction (ED) as a direct sequela of radical retropubic prostatectomy (RRP) is universally recognized, statistics regarding the frequency of ED following RRP are widely disparate . As Wang aptly remarked in a 2007 review, “currently published clinical studies produce poorly interpretable and inconsistent determinations of erection outcome following the treatment of clinically localized prostate cancer” . Unfortunately, this fact hinders the ability of the urologist not only to counsel patients, but also to optimize postoperative therapies and, consequently, maximize patient recovery of sexual function. Such an environment requires urologic oncologists and urologists with an expertise in sexual medicine to establish an integrated approach to the pre- and postoperative evaluation, diagnosis, and management of patients undergoing pelvic surgery that is based on a common understanding of sexual function in the post-prostatectomy patient. Developing clear definitions for sexual function in this population would subsequently lay the groundwork for universal standards of both counseling and treatment of patients undergoing pelvic surgery.

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma - Corrected Proof

2010-05-10

Abstract: Objective: To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib.Patients and methods: We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables.Results: Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤1 year was found. There was a shorter OS for patients ≥60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period.Conclusions: Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.

Significance of focal proliferative atrophy lesions in prostate biopsy cores that test negative for prostate carcinoma - Corrected Proof

2010-05-10

Abstract: Objectives: To evaluate the prevalence and short-term follow-up of focal proliferative atrophy lesions, either with or without the presence of inflammation (PIA/PA), and its correlation with the PSA levels, focusing on the prostate biopsy cores that test negative for prostate adenocarcinoma (PCa).Methods: Five hundred fifty consecutive patients who had undergone a transrectal ultrasound-guided transperineal prostate biopsy were evaluated retrospectively for the presence and follow-up of focal proliferative atrophy lesions. PIA/PA were defined according to De Marzo. The prevalence of atrophy in PCa and negative biopsy cores was compared by means of χ2. After logarithmic transformations of the PSA values, t-test and ANOVA were applied for the comparison of the means. Incidence of newly diagnosed PCa during follow-up (mean 33.7 months) in patients with or without focal proliferative atrophy was compared by means of χ2.Results: A focal atrophic lesion resulted in 161/339 negative biopsies. PIA was observed in 93/161 patients (57.8%), while PA was observed in the remaining 68/161 (42.2%). Among the negative biopsy cases, the difference in PSA values were not statistically significant according to the presence or absence of atrophy (P = 0.120). The group of negative biopsies with PIA was similar in terms of PSA characteristics with the benign (PA P = 0.738; non-atrophy P = 0.342), and cancer subgroups (P = 0.094); 245/339 (72.3%) patients were successfully followed-up. Biopsy was repeated in 24/71 (33.8%) patients with PIA, in 14/50 (28%) with PA and in 27/124 (21.7%) with no atrophy lesions at initial biopsy. The incidence of newly diagnosed PCa in the 3 groups was not statistically different (χ2, P = 0.81).Conclusions: Focal proliferative atrophy lesions are a common finding in biopsy specimens negative for PCa. Patients with negative biopsy associated with PIA presented similar PSA characteristics as patients with biopsy-proven PCa. However, the incidence of PCa at short-term follow-up did not differ significantly between patients with PIA, PA, or no atrophic lesions at initial biopsy. Based on our findings, early repeat biopsy does not seem to be necessary after an initial diagnosis of PIA/PA, although a longer follow-up is mandatory for definitive conclusions.

Tumor cytoreduction results in better response to androgen ablation—a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer - Corrected Proof

2010-05-10

Abstract: Objectives: To investigate the oncologic influence of transurethral resection of the prostate (TURP) as a cytoreductive surgery in metastatic hormone sensitive prostate cancer (mHSPC), in the setting of continuous complete androgen blockade (CAB).Materials and methods: Medical histories of 146 consecutive Chinese males with newly diagnosed mHSPC, registered in our institution in 2006 and 2007, were reviewed. All of these patients received CAB as initial systematic therapy. Demographics and cancer control outcomes from 39 mHSPC patients who underwent TURP for a relief of bladder outlet obstruction were compared with those of the other 107 who received CAB only when they were still hormone-sensitive. Median follow-up was 15 months (3 to 27 months).Results: Age at diagnosis, baseline PSA, and biopsy Gleason score were comparable between the 2 groups. Patients who underwent a TURP had lower PSA nadir (median 0.15 ng/ml vs. 0.82 ng/ml, P = 0.015) and longer time to PSA nadir (11.2 months vs. 6.4 months, P < 0.001). More patients in the non-TURP group developed hormone refractory prostate cancer (P = 0.007). The TURP group had a tendency towards longer disease-specific survival and overall survival (24.4 months vs. 24.1 months and 24.4 months vs. 22.9 months, respectively), though this did not reach statistical significance.Conclusions: TURP resulted in a better and more prolonged response to hormone therapy in mHSPC, with a trend towards positive influence in disease specific survival and overall survival. To date, our preliminary report is the first study regarding long-term survival of cytoreductive surgery in mHSPC, and further investigations are warranted.

Role of fluorescence in situ hybridization in bladder cancer surveillance of patients with negative cytology - Corrected Proof

2010-05-10

Abstract: Objectives: The clinical utility of urine markers in urothelial cancer (UC) surveillance is not established. We previously evaluated the use of fluorescence in situ hybridization (FISH) in managing patients with atypical cytology at risk for UC. This study evaluates its role in patients with negative cytology with a history of UC.Materials and methods: Between June 2007 and January 2009, every patient with a history of UC who underwent cystoscopy and cytology with UroVysion test were identified. A comprehensive chart review was performed on each patient with negative cytology.Results: The population comprised 142 patients undergoing cancer surveillance; 111 patients with negative cystoscopy, 19 with equivocal cystoscopy, and 12 with positive cystoscopy. In patients with negative cystoscopy, there was cancer in only 1 of 111 patients. UroVysion could detect the only patient with UC with sensitivity of 100% and had a negative predictive value (NPV) of 100%. In patients with equivocal cystoscopy, it detected 2 tumors that would be missed by cytology. There were 4 false negative results (sensitivity 33.3% and NPV 66.7%). In patients with obvious lesion on cystoscopy, there were 9 false negative results (sensitivity 10% and NPV 18.2%).Conclusions: Few patients with negative cystoscopy and negative cytology have cancer. Patients with equivocal and positive cystoscopy and negative cytology frequently have cancer and the UroVysion FISH assay was not helpful in these cases. The cost-effectiveness of the FISH assay needs to be assessed prior to widespread use in patients with negative cytology.

Experimental orthotopic prostate tumor in nude mice: Techniques for local cell inoculation and three-dimensional ultrasound monitoring☆ - Corrected Proof

2010-05-10

Abstract: Objectives: Orthotopic prostate cancer models are of great importance for cancer research. Orthotopic models in mice have been described previously. However, these studies lack a detailed methodological description and fail to define standards for local cell inoculation. Herein, we studied the effect of different protocols on tumor growth and report for the first time the use of high resolution ultrasound for monitoring of tumor growth.Materials and methods: Orthotopic inoculation of DU 145 MN1 prostate cancer cells was performed in 30 nude mice varying (1) the amount of cells (5 × 105 vs. 5 × 104), (2) the number of puncture sites, and (3) the addition of matrigel. Surgical complications such as recoil of cells through the injection canal and rupture of the prostatic capsule were monitored. Animals were tracked by ultrasound imaging after 4, 5, and 6 weeks. Autopsy and histology confirmed local tumor growth.Results: A take rate of 27/30 (90%) was observed. Growth of orthotopic prostate tumors was increased after inoculation of a large amount of cells under the capsule of 1 dorsal prostate lobe, but inoculation of small amounts of cells still induced local tumors. Noninvasive ultrasound examination allowed to identify orthotopic tumor formation and to monitor tumor growth in vivo. Addition of matrigel did not accelerate tumor growth. Complications like recoil (6.8%) or rupture of the prostate capsule (1.4%) were rare.Conclusions: Inoculation of DU 145 MN1 cells under the prostate capsule with a defined procedure results in very high take rates. Ultrasound screening is feasible to repetitively monitor tumor growth.

The role of radical cystectomy in patients with clinical T4b bladder cancer - Corrected Proof

2010-04-26

Abstract: Objectives: Patients with clinical T4b bladder cancer (extension to pelvic wall and/or adjacent organs other than prostate, vagina, or uterus) are commonly considered unresectable. We hypothesized that select patients might achieve durable benefit from multiagent chemotherapy and extirpative surgery.Methods: We identified patients with clinical T4bN0 bladder cancer from our IRB-approved database of patients undergoing radical cystectomy (n = 1,194). Relevant demographic, clinical, and pathologic data were compiled. Overall (OS), disease-specific (DSS), and recurrence-free survival (RFS) were analyzed by Kaplan-Meier estimation. Cox proportional hazards regression modeling was used to evaluate the influence of several potential prognostic factors.Results: Twenty-three patients (16 male) with a median age of 65 years met study criteria. Chemotherapy was administered preoperatively to 19 (83%) and postoperatively to 8 (35%) patients. Eight patients died of disease and 1 of other causes. The 1-, 2-, and 5-year DSS was 91% (95% C.I. 70%–98%), 66% (95% C.I. 42%–83%), and 60% (95% C.I. 34%–78%), respectively. Eight of 17 patients with pT2-4 tumors succumbed to disease compared with none of 6 who were ≤pT1 (P = 0.04). Other predictors of decreased DSS included positive surgical margins (HR = 5.34, 95% C.I. 1.25–22.83) and presence of pathologic nodal metastasis (HR = 29.33, 95% C.I. 3.13–275.19). Variant histology was more common in this cohort than in the overall cystectomy database (43% vs. 11%).Conclusions: Long-term survival can be achieved in a proportion of patients with cT4b bladder cancer undergoing chemotherapy and extirpative surgery. Careful selection of patients and meticulous surgical technique to avoid positive margins are critical.

An update on targeted therapy in metastatic renal cell carcinoma - Corrected Proof

2010-04-26

Abstract: An improved understanding of the biological pathways deregulated in renal cell carcinoma has led to the development of various targeted agents, changing dramatically the therapeutic options for this disease. However, despite numerous opinions and guidelines, the optimal treatment still remains uncertain. In this review, we analyze the most recent published reports regarding the agents sunitinib, bevacizumab, sorafenib, temsirolimus, and everolimus. Moreover, we assess the novel targeted drugs pazopanib and axitinib. In addition, given the likely lack of cross-resistance between these targeting agents, we discuss sequential and combination targeted therapy in metastatic renal cell carcinoma, analyzing the most recent data.

Surveillance Epidemiology and End Results (SEER) program and population-based research in urologic oncology: An overview - Corrected Proof

Emil Scosyrev, James Messing, Katia Noyes, Peter Veazie, Edward Messing — 2010-04-05

Abstract: The Surveillance, Epidemiology, and End Results (SEER) program is a commonly used data source in cancer research. This article provides an introduction to the SEER database, describes important data items available from SEER on the most commonly diagnosed urologic malignancies (prostate, bladder, and kidney cancers), and reviews limitations of SEER data for urologic oncology research.

Outcome prediction for prostate cancer detection rate with artificial neural network (ANN) in daily routine - Corrected Proof

2010-04-05

Abstract: Background: We evaluated the use of the artificial neural network (ANN) program “ProstataClass” of the Department of Urology and the Institute of Medical Informatics at the Charité-Universitätsmedizin Berlin in daily routine to increase prostate cancer (CaP) detection rate and to reduce unnecessary biopsies.Materials and methods: From May 2005 to April 2007, a total of 204 patients were included in the study. The Beckman Access PSA assay was used, and pretreatment prostate specific antigen (PSA) was measured prior to digital rectal examination (DRE) and 12 core systematic transrectal ultrasound (TRUS) guided biopsies. The individual ANN predictions were generated with the use of the ANN application for the Beckman Access PSA and free PSA assays, which relies on age, PSA, percent free prostate specific antigen (%fPSA), prostate volume, and DRE. Diagnostic validity of total prostate specific antigen (tPSA), %fPSA, and the ANN was evaluated by ROC curve analysis.Results: PSA and %fPSA ranged from 4.01 to 9.91 ng/ml (median: 6.65) and 5% to 48% (median: 15%), respectively. Of all men, 46 (22.5%) demonstrated suspicious DRE findings. Total prostate volume ranged from 7.1 to 119.2 cc (median: 35). Overall, 71 (34.8%) CaP were detected. Of men with suspicious DRE, 28 (60.9%) had CaP on initial biopsy. The ANN was 78% accurate in the original report. The AUC of ROC curve analysis was 0.51 for PSA, 0.66 for %PSA, and 0.72 for the ANN-Output, respectively.Conclusions: Our results in this independent cohort show that ANN is a very helpful parameter in daily routine to increase the CaP detection rate and reduce unnecessary biopsies.

Significant activity of single agent vinorelbine against small-cell cancer of the bladder as second line chemotherapy: A case series and review of the literature - Corrected Proof

2010-04-05

Abstract: Small-cell carcinoma of the urinary bladder is an extremely uncommon form of urologic malignancy, accounting for less that 1% of new cases of bladder cancer. It is an aggressive malignancy which, like its pulmonary counterpart, tends to spread with distant metastases. This malignancy is generally chemotherapy and radiotherapy sensitive. Metastatic disease is typically treated with regimens active against small-cell carcinoma of the lung, such as cisplatin and etoposide. There are no data regarding second-line treatment of this cancer. We report our experience in 3 patients using the second generation vinca alkaloid, vinorelbine, in refractory metastatic small-cell carcinoma of the bladder. These 3 patients had extensive prior therapy but all 3 responded to weekly vinorelbine, with a complete response (CR) in 1, near CR in the second, and partial response in the third. Of note, the patient who sustained a CR has remained without disease and with excellent quality of life for nearly 4 years since starting vinorelbine. Indeed, the therapy was very well tolerated in all 3 patients with grade 2 cytopenia being the only toxicity. We conclude that vinorelbine is well tolerated and has activity in this case series in the second-line treatment of metastatic small-cell carcinoma of the bladder.

mTOR pathway inhibition in renal cell carcinoma - Corrected Proof

2010-03-08

Abstract: Renal cell carcinoma therapy has changed in a very significant way in the last few years. Up to 5 new agents have been developed, improving the results previously achieved with cytokine therapy. Bevacizumab, sorafenib, sunitinib, temsirolimus, and everolimus are now part of the therapeutic arsenal for this illness. Particularly, this has been the first tumoral type in which inhibition of mammalian target of rapamycin (mTOR) has proved its efficacy in phase III trials, either as first-line therapy for poor prognosis patients (temsirolimus, CCI-779) or as second-line therapy after failure of tyrosine-kinase inhibitors (everolimus, RAD001). In this paper, we review the basis for mTOR inhibition in RCC, and discuss the results of the trials involving temsirolimus and everolimus for the treatment of this disease.

Rictor-dependent AKT activation and inhibition of urothelial carcinoma by rapamycin - Corrected Proof

2010-03-08

Abstract: Objective: We previously reported a very high cumulative incidence of urothelial carcinoma in Taiwanese kidney transplant recipients. Rapamycin, the inhibitor of mTOR Complex 1, provides alternative immunosuppressive therapy after kidney transplantation with less neoplastic potential. We examined the in vivo and in vitro effects of rapamycin on urothelial carcinoma.Materials and methods: The rat model of urothelial carcinoma was induced by 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in Fischer F344 rats. The anti-tumor effect of rapamycin was assessed grossly, microscopically, and by Western blot analysis. The mechanism of rapamycin's attenuation of urothelial carcinoma was also evaluated by T24 cells.Results: Rapamycin significantly reduced urinary bladder tumor growth in the rat model of 0.05% BBN-induced urothelial carcinoma (P < 0.001). The blood trough levels of rapamycin were correlated with the occurrence of urothelial carcinoma. In vitro, rapamycin also inhibited the cell proliferation, migration, and invasion, as well as the protein expression of vascular endothelial growth factor-A of T24 urothelial carcinoma cells, whereas rapamycin did not induce significant apoptosis in T24 cells. Rapamycin decreased the expression of phospho-mTOR, phospho-S6K, cyclin D1, and VEGF-A. Rapamycin also activated AKT in T24 cells in the rat model of urothelial carcinoma. The rapamycin-associated activation of AKT was inhibited by rictor siRNA, but not raptor siRNA.Conclusions: This study provides in vitro and in vivo evidence that rapamycin may inhibit the development of urothelial carcinoma. The present findings also suggest rictor-dependent AKT activation as a consequence of mTORC1 inhibition.

Subepithelial growth patterns in urothelial carcinoma—frequency and prognostic significance - Corrected Proof

2010-03-08

Abstract: Purpose: Most urothelial carcinomas are exophytic, but some tumors exhibit subepithelial components, either in the form of endophytic growth pattern (EGP) or as von Brunn's nests involvement (VBNI). The purpose of this study was to investigate the frequency, inter-relations and clinical significance of these forms of subepithelial neoplasia in urothelial carcinoma.Patients and methods: Between June 1995 and December 2007, 760 patients (mean age of 67.5 years) underwent transurethral resection of bladder tumors in our institution, including 478, 157, and 112 patients with stage Ta, T1, and ≥T2 disease, respectively. Isolated or concomitant Tis were present in 137 (18%) patients. Median postoperative follow-up period was 53 months.Results: EGP was found in 86 cases (11.3%) and VBNI in 30 (3.9%) patients. Both forms of subepithelial growth were significantly more common in higher stage and grade tumors and were associated with each other. Multivariate analysis showed that EGP is an independent prognostic factor of stage progression (HR 4.6, P < 0.0001) and disease specific mortality (HR 2.6, P = 0.001) but not of tumor recurrence (HR 1.2, P = 0.51). VBNI was found an independent prognostic factor of tumor progression (HR 5.1, P < 0.0001), but neither of tumor recurrence nor disease specific mortality.Conclusions: Subepithelial growth is not an uncommon in bladder cancer. It is more frequent in high-grade and high-stage tumors. The findings of this study suggest that subepithelial growth carries a higher risk for stage progression (EGP and VBNI) and mortality (EGP), but not tumor recurrence.

C-reactive protein as an adverse prognostic marker for men with castration-resistant prostate cancer (CRPC): Confirmatory results - Corrected Proof

2010-03-08

Abstract: We previously reported that higher serum concentrations of C-reactive protein (CRP) are associated with shorter survival in men with castration-resistant prostate cancer (CRPC). To confirm this finding in an independent data set, we used 119 CRPC patients enrolled in 6 phase II clinical trials and examined the relationship of CRP, alkaline phosphatase, hemoglobin, age, ECOG PS, and prostate specific antigen (PSA) with survival. Median follow-up was 19.7 months (0.9–98.5 months), and 89% have died. After analyzing the form of the risk function using the generalized additive model method, univariate and multivariate Cox proportional hazard models were used to assess associations between baseline individual categorical and continuous variables. Quartiles of CRP were: 0–1.0, 1.1–4.9, 5.0–17.0, and 17.1–311 mg/L. In a Cox multivariate model, log2 (CRP) (HR 1.106, P = 0.013) as well as hemoglobin and alkaline phosphatase were independently associated with survival, confirming that higher CRP is associated with shorter survival in CRPC. Since CRP is a marker of inflammation, this finding suggests that inflammation may play an important role in the natural history of advanced prostate cancer. CRP is a readily measurable biomarker that has the potential to improve prognostic models and should be validated in a prospective clinical trial.

Robot-assisted radical cystectomy: An expert panel review of the current status and future direction - Corrected Proof

2010-03-08

Abstract: Objective: At the 9th Annual Meeting of the Society of Urologic Oncology (SUO), an expert panel discussed the current status of robot-assisted radical cystectomy (RARC).Materials and methods: The presentations were derived from: (1) review of published literature, unpublished addendums, and SUO abstracts, (2) initial abstract data of pooled results of 528 patients from the International Robot-Assisted Cystectomy Consortium (IRCC), and (3) an internet-based survey of the SUO membership (n = 54) on training and practice patterns related to RARC.Results: Using pathologic assessment of surgical margins as a surrogate for cancer control, the results are favorable with organ confined disease, with select expert series showing no positive margins and the IRCC group reporting 4%. In non-organ-confined disease, select expert series also show no positive margins, while for the IRCC group it was 15%. The median lymph node yield in all series is 12–19 with 5%–33% positive. The S-model robot is preferred for an extended node dissection to the aortic bifurcation. In experienced hands, estimated blood loss is <500 cc, and hospital discharge by postoperative d 4–5. Complications appear similar to open and decrease with experience. In one study comparing RARC to open, pain scales were similar but morphine use was consistently lower for RARC. The technique is most often applied to the bladder and lymph nodes only with a mini-laparotomy for the diversion; technical considerations for female patients were described. The membership surveys showed that 37% of respondents have attempted RARC, but < 20% received robot console training during fellowship. The greatest area of concern was the adequacy of the lymph node dissection in the higher regions—common iliac to peri-caval/aortic.Conclusions: Initial reports of RARC demonstrate feasibility of technique, early oncologic outcomes, and learning curve experiences. Surgeons learning RARC should select patients without clinical evidence of locally advanced disease, and consider a second look open node dissection. Experienced surgeons have demonstrated the possibility of reduced blood loss, opiate requirement, and hospital stay. Moving forward, an international consortium has been organized to address the unmet needs of prospective comparisons with long-term oncologic outcomes, standardized complication reporting, and quality of life.

Reliability of the 34βE12, keratin 5/6, p63, bcl-2, and AMACR in the diagnosis of prostate carcinoma - Corrected Proof

Cetin Boran, Engin Kandirali, Fahri Yilmaz, Erdinc Serin, Mesut Akyol — 2010-03-02

Abstract: Objective: In this study, we aimed to investigate which basal cell marker should be used with α-methylacyl coenzyme A racemase (AMACR) to increase diagnostic accuracy in the diagnosis of prostate carcinoma.Materials and methods: A total of 98 cases of prostate biopsy, comprising 65 cases with prostate adenocarcinoma and 33 cases without adenocarcinoma, were included in this study. Prostate-specific antigen (PSA) serum levels before biopsies were obtained. The number of cores with malignant glands and Gleason scores for each case were determined. Paraffin sections were stained immunohistochemically with 34βE12, keratin 5/6, p63, bcl-2, and AMACR.Results: According to staining pattern, extensiveness, and intensity of basal cell markers in benign glands, 34βE12 gave the best results. As negative markers for prostate adenocarcinoma, the best markers were p63 and 34βE12. According to the AUC values in ROC curves for both extensiveness and intensity, the arrangement from the best to the worst was 34βE12, p63, bcl-2, and keratin 5/6. The 34βE12 had the best sensitivity and specificity values (95% and 98%, respectively). Staining extensiveness and intensity of keratin 5/6 in malignant glands, and those of bcl-2 in benign glands had statistically significant positive correlation with serum PSA levels. Even though AMACR is a negative marker for benignity, some of the benign glands also had positive immune reaction with AMACR. However, AMACR positivity was usually focal and weak. Nevertheless, intensively stained subjects were also present. No correlation was present between AMACR and basal cell markers.Conclusions: As a result, we suggest that keratin 5/6 and bcl-2 should not be used to identify benign glands in prostate biopsy since they show high positivity in malignant glands and high negativity in benign glands. 34βE12 should be the first choice as a basal cell marker. p63 can be used together with 34βE12, but it may not give additional diagnostic information. When we evaluated the correlation of basal cell markers, we did not find any complementary staining results among basal cell markers. Our study showed that 34βE12 is the most appropriate negative marker to combine with AMACR as a positive marker for the diagnosis of prostate adenocarcinoma.

Impact of radiofrequency ablation on PBMC subpopulation in patients with renal cell carcinoma - Corrected Proof

2010-03-02

Abstract: Purpose: With the development of diagnostic techniques, renal cell carcinoma (RCC) is currently diagnosed in earlier stages, allowing the introduction of less invasive techniques in its management. One of the most promising new treatment methods is based on the utilization of high temperature created by radiofrequency current circulating around the needle probe introduced into the tumor. Besides the direct destruction of the cancer tissue, the treatment may induce immunologic reaction to tumor antigens released from destroyed tumor cell. This paper describes changes observed in the peripheral blood lymphocyte population after radiofrequency ablation (RFA) of RCC.Methods: Blood was tested before, and 2, 4, and 6 weeks after the RFA in 6 patients with RCC for the proportions and numbers of CD3+, CD3+HLA-DR+, CD3+CD4+, CD3+CD8+, and CD56+CD16+ cells. The blood was stained with fluorochrome-conjugated monoclonal antibodies and percentages of cells expressing various markers were determined by flow cytometry.Results: In all patients, the changes were most pronounced 2 weeks after the procedure. The proportion of CD4+ and CD8+ lymphocytes were changed. In 1 patient, an increase in both CD4+ and CD8+ cells was observed. In 5 out of 6 patients, the proportion of activated (DR+) cells was increased over the whole follow-up period with the highest values in the second week after RFA. The percentage of the CD56+CD16+ was decreased in most of the patients.Conclusions: Our study confirms that in the majority of patients, RFA of the renal tumors causes significant changes in the proportion of the peripheral immune cells. We suggest that the results presented in this article shows the necessity for further studies.

Nerve-sparing robotic prostatectomy in preoperatively high-risk patients is safe and efficacious - Corrected Proof

2010-03-02

Abstract: Objective: Given the higher likelihood of extraprostatic extension in high-risk patients, many urologists will sacrifice the neurovascular bundles in such patients in an attempt to decrease the risk of positive surgical margins. In contrast, we frequently perform nerve-sparing in high-risk patients. We analyzed our outcomes in patients with preoperatively high-risk prostate cancer according to the D'Amico risk group classification, and stratified by nerve-sparing status.Materials and methods: An institutional database of 1,503 robotic-assisted laparoscopic prostatectomies (RALP) was queried for patients presenting with PSA > 20 ng/ml, Gleason 8 or higher on biopsy, or clinical stage T2c or higher. Interfascial nerve-sparing was performed whenever oncologically feasible. Validated questionnaires were used to assess baseline and postoperative functional outcomes.Results: Adequate follow-up was available in 123 high-risk patients. Mean serum PSA was 10.8. Bilateral, unilateral, and non-nerve-sparing was performed on 58%, 15%, and 27%, respectively. On final histopathology, 42% were organ confined; 55 patients had extraprostatic extension, and 35 had seminal vesicle invasion. Positive surgical margins occurred in 31%: 15% focal and 16% extensive. Favorable pathologic outcomes (organ-confined and negative surgical margins) were observed in 40%. Biochemical recurrence occurred in 20%. Nerve-sparing was associated with more favorable pathologic features, possibly due to selection bias. When controlling for adverse pathologic features, nerve-sparing was not associated with higher rates of positive surgical margins or biochemical recurrence. At a median follow-up of 13 months, 78% were continent and 56% were potent. The “trifecta” of continence, potency, and freedom from recurrence was achieved in 28 patients (23%).Conclusions: Nerve-sparing robotic-assisted laparoscopic prostatectomy can be safely performed in patients with preoperatively high risk prostate cancer. Histopathologic and short-term oncologic outcomes at 13-month median follow-up are comparable to those in open surgical series from similar cohorts.

Prospective comparison of PSA kinetics following two different prostate cancer brachytherapy planning methods: Preoperative and real-time intraoperative dosimetry planning - Corrected Proof

Haim Matzkin, Juza Chen, Amira Stenger, Rubi Agai, Nicola J. Mabjeesh — 2010-03-02

Abstract: Objectives: Preoperative planning (PP) and intraoperative planning (IoP) are established 125I-brachytherapy techniques for the treatment of localized prostate cancer. We prospectively compared the effects of each method on reducing PSA levels.Materials and methods: One hundred eighty patients treated with brachytherapy as monotherapy without neoadjuvant androgen deprivation therapy or external beam radiation using PP (75) or IoP (105) methodologies and with ≥5 years of follow-up were included in the study. CT-based dosimetry was calculated 1 month postoperatively. PSA was obtained every 3 months for the first year and semiannually thereafter. Available PSA and dosimetric data from both groups were analyzed and compared.Results: At 5 years after brachytherapy, the probability of having a nadir PSA value < 0.5 ng/ml was 90% in the IoP group compared with 60% in the PP group (P < 0.0001). The rate of PSA decline was 3-fold faster in the IoP group than in the PP group. Dosimetry results highly favored the IoP method: mean V100 (%) and D90 (Gy) were 95 and 180 vs. 60 and 81 (P < 0.001), respectively.Conclusions: Our initial finding of highly superior postimplant CT dosimetry calculations of the IoP method are now substantiated by the biochemical favorable results (PSA kinetics) of this method.

Impact of the expression of Aurora-A, p53, and Mib-1 on the prognosis of urothelial carcinomas of the upper urinary tract - Corrected Proof

2010-03-02

Abstract: Objectives: To investigate whether overexpression of p53, MIB-1, and Aurora-A on protein level played a role in the relapse of urothelial carcinomas of the upper urinary tract (UC-UUT).Materials and methods: The following data from the files of 42 patients treated for UC-UUT were collated: age, prior history of cancer, tumor stage and grade, and disease progression. Immunohistochemistry (IHC) for p53, MIB-1, and Aurora-A was performed on tissue microarray sections from tumor tissue.Results: Patients aged 46 to 100 years (mean 70.6 years). Overall, 23 (54%) patients died from progression of UT-UCC. The surgical stage was significantly associated with MIB-1 and Aurora-A overexpression (P = 0.004 for each). Univariate analysis showed that relapse was significantly associated with ureteral localization (P = 0.02), the presence of vascular invasion (VI) (P = 0.003), high grade (P = 0.04), high stage UT-UCCs (P = 0.02), and p53 (P = 0.01), Aurora-A (P = 0.01), and MIB-1 overexpression (P = 0.02). In multivariate analysis, relapse was associated with high grade (P = 0.04), high stage (P = 0.04), VI (P < 0.0001, respectively), and p53 (P = 0.04) and Aurora-A (P = 0.02) overexpression but not with MIB-1 overexpression (P = 0.06). In addition, expressions of p53, MIB-1, and Aurora-A were significantly associated with presence of VI (P = 0.008, P = 0.001, and P = 0.003, respectively).Conclusion: Aurora-A and p53 are important factors in UC-UUT development and might be useful as independent factors for predicting clinical outcome and presence of VI. Aurora-A seems to influence the development of VI and tumor aggressiveness via a mechanism not clearly elucidated yet.

111-In-capromab pendetide imaging using hybrid-γ camera-computer tomography technology is not reliable in detecting seminal vesicle invasion in patients with prostate cancer - Corrected Proof

2010-03-02

Abstract: Objectives: In this study, we evaluate the diagnostic utility of a hybrid γ-camera-computer tomography (SPECT-CT) indium-111 (111-In)-capromab pendetide scan in detecting seminal vesicle invasion (SVI) in select patients evaluated for primary surgical treatment of prostate cancer (CaP).Methods and materials: We retrospectively analyzed a prospective database of patients who underwent preoperative SPECT-CT imaging with 111-In-capromab-pendetide as part of a staging evaluation who were subsequently treated with radical surgery in our center. Only patients with clinically localized disease were included. We calculated diagnostic properties of the hybrid scan in detecting SVI compared with final pathology. Regression analyses were performed, including scan and preoperative variables to predict SVI.Results: We retrieved 50 medical records matching our criteria. Median patient age was 61 years (range 45–74). Most patients had a clinical T1c CaP and biopsy Gleason score of 7 or higher. On final pathology, SVI was found in 12 (24%) specimens and radiotracer signal in the seminal vesicle region was reported in 15 (30%) imaging studies. Hybrid SPECT-CT imaging had a sensitivity of 25%, specificity of 61.9%, positive and negative predictive values of 20% and 74.3%, respectively, for detecting SVI. SPECT-CT results did not contribute significantly to SVI prediction on univariate (P = 0.627) or multivariate (P = 0.754) analyses.Conclusions: SPECT-CT imaging with 111-In-capromab-pendetide is not reliable in detecting or excluding SVI in this select cohort. High rates of positive radiotracer signals from healthy seminal vesicles raise concerns regarding pharmacologic properties of this radiotracer molecule.

Primary vs. post-chemotherapy retroperitoneal lymph node dissection (RPLND) in patients with presence of teratoma at orchiectomy - Corrected Proof

Stephen B. Williams, Ravi Kacker, Graeme S. Steele, Jerome P. Richie — 2010-03-02

Abstract: Objective: The presence of teratoma in the primary orchiectomy specimen creates controversies for subsequent management. Although predominant teratoma is less likely to metastasize, teratoma in the retroperitoneum may be less amenable to chemotherapy. In order to elucidate the issues about teratoma in the primary tumor, we reviewed differences between primary retroperitoneal lymph node dissection (P-RPLND) vs. post-chemotherapy RPLND (PC-RPLND) in patients with teratoma at orchiectomy.Materials and methods: Patients who had undergone RPLND at our institution from 2001 to 2008 were identified, and clinical charts reviewed. Eighty-three patients with teratoma at orchiectomy were identified and perioperative data were obtained.Results: Of the 83 patients with teratoma at orchiectomy who underwent RPLND, 44 (53%) and 39 (47%) underwent primary and PC-RPLND, respectively. Median follow-up was 1.4 years. Of the 83 patients with primary teratoma at orchiectomy, there were 7 (8%) patients with pure teratoma and 76 (92%) patients with mixed histology. Of the patients with mixed histology, 72 (87%) patients had embryonal carcinoma and 36 (43%) had LVI. There were 19 (43%) positive lymph nodes for P-RPLND, of which 13 (30%) contained teratoma. For the PC-RPLND group, 30 (77%) of lymph nodes were positive, of which 28 (72%) contained teratoma. There were 3 (4%) recurrences overall, all of which recurred in the PC-RPLND group. There were 11 (13%) perioperative complications total. There were no deaths in either group.Conclusions: Patients with teratoma at orchiectomy were associated with other high risk features and are at significant risk for metastatic disease. Patients with post-chemotherapy retroperitoneal findings are at significant risk for viable GCT and/or teratoma and should undergo PC-RPLND.

Renal oncocytoma—are there sufficient grounds to consider surveillance following prenephrectomy histologic diagnosis - Corrected Proof

2010-02-22

Abstract: Introduction: Oncocytoma is a benign neoplasm of the kidney and comprises about 12% of all renal masses. A definitive preoperative diagnosis of oncocytoma is currently technically not feasible and its practical implication is controversial.Objectives: To analyze the current status of preoperative diagnostic tools for oncocytoma, study the different occurrences of oncocytoma-renal cell carcinoma (RCC) coexistence, including the phenomenon of true hybrid tumors, and investigate the rare reports on the natural history of unresected oncocytoma.Materials and methods: A PubMed search was performed using the following key word: oncocytoma, renal cell carcinoma, natural history, electron microscopy, and cytogenetics. Medline articles and abstracts prior to August 2009 were reviewed.Results and conclusions: At the moment, preoperative renal mass biopsy is the only way for prenephrectomy histologic diagnosis of oncocytoma. However, it is expected that some of these biopsies, although suggestive for oncocytoma, will suspect chromophobe RCC. In all the English literature, the number of true ipsilateral synchronous hybrid oncocytoma-RCC tumors is extremely low in comparison with the “pure” oncocytomas being resected worldwide. There is almost no data on the natural history of oncocytoma.

Squamous cell carcinoma of the penis: Predicting nodal metastases by histologic grade, pattern of invasion and clinical examination - Corrected Proof

2010-01-08

Abstract: With a diagnosis of squamous cell carcinoma of the penis, there is still a significant need to define the tumor criteria that allow the disease to be stratified according to the risk of developing lymph node metastases.The histopathology of the primary tumor in 72 consecutive patients with resected squamous cell carcinoma of the penis was reviewed for this study. Tumor tissue was reviewed for (1) histologic grade, (2) invasion pattern, (3) tumor stage, (4) proportion of poorly differentiated tumor cells, (5) invasion depth, (6) proportion of tumor necrosis, (7) angioinvasion, (8) histologic classification, (9) number of lesions, (10) growth pattern, (11) number of mitoses, (12) degree of keratinization, and (13) clinical groin status.It was found that the presence of inguinal lymph node metastases correlated in descending order of frequency with grade G2/G3, clinically positive groin status, reticular invasion, stage pT2/T3, >50% poorly differentiated tumor cells, depth of invasion, and comedolike tumor necrosis. These results revealed that the risk of inguinal lymph node metastasis in penile carcinoma can be predicted on the basis of 3 major factors: histologic grade, pattern of invasion, and clinical groin status.

Prostate-specific antigen: An evolving role in diagnosis, monitoring, and treatment evaluation in prostate cancer - Corrected Proof

Heather Payne, Philip Cornford — 2010-01-08

Abstract: Prostate specific antigen (PSA) was introduced as a prostate cancer screening tool more than 20 years ago. However, there is continuing debate regarding its utility in screening for prostate cancer. Mass screening is costly, may result in the diagnosis and treatment of prostate cancers that never become clinically significant, and the evidence of a subsequent reduction in mortality is inconclusive. In addition to its role in screening, PSA is also used to monitor the progression of the disease, both localized and metastatic. Although the evidence is contradictory, PSA is still an important tool for monitoring patient progression following treatment of definitive localized prostate cancer. However, its use in monitoring castrate-resistant prostate cancer (CRPC) is more controversial, particularly in the context of novel targeted treatments, which may have little impact on PSA levels. These issues highlight the urgent need to identify prostate cancer biomarkers that will improve early disease detection, increase accuracy of diagnosis, determine the aggressiveness of disease, and monitor treatment efficacy, particularly in late-stage disease. This review discusses the key issues associated with the use of PSA as an early screening tool for prostate cancer, as a prognostic marker to measure disease progression in both early- and late-stage prostate cancer, and as a surrogate endpoint in clinical trials with new agents.

Patterns of enlarged lymph nodes in patients with metastatic renal cell carcinoma - Corrected Proof

2010-01-07

Abstract: Objective: We reviewed the imaging studies of patients with known metastatic renal cell carcinoma (RCC) in order to more accurately assess where retroperitoneal lymphadenopathy occurs.Methods: The database of patients with metastatic RCC was reviewed and 101 patients were found from 2002 to 2006. Each patient's CT scans were then reviewed. Twenty-seven retroperitoneal sections were defined for each patient, with 3 positions in each of the x-, y-, and z-axis. Lymph nodes greater than 1 cm were then counted for each section.Results: Of the 101 patients, 31, of whom 28 qualified, were found to have retroperitoneal lymphadenopathy of a least 1 cm or greater. Two-thirds of nodes (87 out of 124) exhibited a suprahilar, intra-aortocaval, and retro-aortocaval trend of lymph node enlargement. Three patients (11%) had isolated infrahilar nodes, while 8 patients (29%) exhibited a skip lesion pattern by imaging criteria. Only 4 patients (14%) were noted to have lymph nodes that were confined to the ipsilateral (paraaortic or paracaval) nodes in the perihilar and infrahilar region, which would be readily accessible during renal surgery.Conclusions: Lymphatic drainage in RCC is ill-defined, likely due to multiple lymphatic outflow channels. However, after a review of retroperitoneal lymphadenopathy imaging in patients with known metastatic RCC, there does seem to be a cephalad, posterior, and medial drainage pattern.

Biopsy accuracy in identifying unilateral prostate cancer depends on prostate weight - Corrected Proof

2010-01-07

Abstract: Objective: To evaluate the association between prostate weight and the diagnostic performance of routine biopsy schemes in detecting unilateral prostate cancer (PCa) that may be amenable to focal therapy.Methods and Materials: Retrospective analysis of patients undergoing radical prostatectomy at Duke University Medical Center from 1990 to 2007. The cohort was dichotomized according to prostate weight (≤40 and >40 g) and further divided by biopsy scheme: 6–9 (sextant) and 10–20 cores (extended). Diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values were calculated within each prostate weight group and compared between biopsy schemes.Results: A total of 859 patients were included in the study. Patients with prostates >40 g were generally older and had higher PSA levels (P < 0.0001 and P = 0.036, respectively). Unilateral disease was more common in prostates >40 g both on biopsy (69% vs. 60%, P = 0.009) and on final pathology (21% vs. 14%, P = 0.017) despite larger total tumor volume (6.1 vs. 4.8 cc, P < 0.001). Low grade PCa was also more common in larger glands (P = 0.003). Overall, extended biopsy schemes performed better than sextant but the benefit was statistically significant only in prostates >40 g.Conclusions: Despite having higher tumor volumes, men with prostate weight >40 g were more likely to have unilateral PCa than those with smaller prostates. In prostates >40 g, increasing the number of cores harvested at biopsy increased the diagnostic performance for detecting cancer laterality. Therefore, our results suggest that the benefit of more extensive tissue sampling may be higher in larger prostates compared with smaller ones when selecting candidates for prostate hemiablation.

Orthotopic bladder substitution following radical cystectomy in women: Comparative study between sigmoid and ileal neobladders - Corrected Proof

2010-01-07

Abstract: The objective of this study was to retrospectively compare the clinical outcomes of sigmoid and ileal neobladders (NBs) created in women. This study included 18 and 14 women who underwent orthotopic NB reconstruction using sigmoid and ileal segment, respectively, after radical cystectomy, and postoperative clinical outcomes between the sigmoid and ileal NB groups (SNBG and INBG) were compared. Eighteen early and 7 late complications occurred in 12 and 6 women, respectively; however, there was no significant difference in the incidence of complications between SNBG and INBG. The proportion of patients who could void spontaneously in SNBG (94.4%) was significantly greater than that in INBG (64.3%), while there was no significant difference in continent status between these 2 groups. Despite the lack of significant differences in maximal flow rate and voided volume, post-void residual in SNBG (15.7 ml) was significantly smaller than that in INBG (62.0 ml). SF-36 survey for postoperative quality of life (QOL) did not show any significant differences in 7 of the 8 scores between the 32 women with NB and an age-matched control population; however, 3 of the 8 scores in SNBG were significantly superior to those in INBG. During the observation period of this study, urethral recurrence did not occur in any woman, and there was no significant difference in cancer-specific survival between the 2 groups. These findings suggest that it might be preferable to create sigmoid rather than ileal NB in women following radical cystectomy considering the favorable voiding function and QOL in SNBG.

Does preoperative symptom classification impact prognosis in patients with clinically localized upper-tract urothelial carcinoma managed by radical nephroureterectomy? - Corrected Proof

2010-01-07

Abstract: Objectives: To evaluate if preoperative symptom classification could refine prediction of outcomes for patients with clinically localized upper-tract urothelial carcinoma (UTUC) managed by radical nephroureterectomy (RNU).Methods: Data on 654 patients with localized UTUC who underwent RNU were reviewed. Preoperative symptoms were classified as incidental (S1), local (S2), and systemic (S3). Clinical and pathologic data were compared between the cohorts. Kaplan-Meier analyses and Cox proportional hazard modeling were used to determine recurrence-free and cancer-specific survival amongst the symptom cohorts.Results: Symptom classification was S1 in 213 (33%) patients, S2 in 402 (61%), and S3 in 39 (6%). S3 symptoms were associated with advanced pathology, including higher stage, grade, and lymph node (LN) positivity. Five and 10-year recurrence-free and cancer-specific survival estimates were similar for patients with S1 and S2 symptoms (P = 0.75 and 0.58, respectively), but was worse for patients with S3 symptoms (P < 0.001 for both). On multivariate analysis adjusting for final pathologic stage, grade, and LN status, S3 symptoms were not an independent predictor of recurrence (HR 1.44, P = 0.19) or death due to disease (HR 1.66, P = 0.07). Addition of symptom classification, however, increased the accuracy of a model consisting of stage, grade, and LNs for prediction of recurrence-free and cancer-specific survival by 1.4% and 1.3%, respectively (P < 0.001 for both).Conclusions: Local symptoms do not confer worse prognosis compared with patients with incidentally detected UTUC. However, systemic symptoms are associated with worse outcomes despite apparently effective RNU. Patients with systemic symptoms may harbor micrometastatic disease and could potentially benefit from a more rigorous metastatic evaluation or perioperative chemotherapy regimens.

Neoadjuvant docetaxel/estramustine prior to radical prostatectomy or external beam radiotherapy in high risk localized prostate cancer: A phase II trial - Corrected Proof

2009-12-21

Abstract: Background: Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation.Patients and methods: Patients (n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation.Results: All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%.Conclusions: Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.

Osteopontin overexpression predicts poor prognosis of upper urinary tract urothelial carcinoma - Corrected Proof

2009-12-21

Abstract: Objectives: Studies indicate overexpression of osteopontin (OPN) promotes carcinogenesis, progression and metastasis of multiple human malignancies. However, the function of OPN in urothelial carcinoma (UC) of the upper urinary tract has not been investigated. This study evaluates the clinical significance of OPN expression in upper urinary tract UC.Materials and methods: One hundred and ten cases (median age = 64, range = 24–84 years) of renal pelvic or ureter UC were retrospectively reviewed in this study. OPN expression were evaluated by immunohistochemistry staining on paraffin-embedded section of the tumor and scored by two qualified pathologists.Results: High OPN expression was found in 54 (49.1%) of the cancer specimens. OPN expression was not significantly correlated with tumor T stage (P = 0.761), N stage (P = 0.339) or grade (P = 0.349). However, OPN expression was differently expressed by gender (P = 0.012) and cancer location (P = 0.026). OPN expression did not correlate with bladder recurrence-free (P = 0.661) or extra-bladder recurrence-free (P = 0.787) survival, but high OPN expression was a significant predictor for cancer-specific survival (P = 0.014).Conclusion: Our findings indicated that higher OPN expression is a potential biomarker to predict patient survival. Further study is necessary to investigate the role of OPN in the carcinogenesis of upper urinary tract UC.

Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: A prospective single-center study - Corrected Proof

2009-12-21

Abstract: Background: The extent of lymph node involvement is the most relevant prognostic factor in patients with penile cancer.Objective: To prospectively analyze the diagnostic accuracy of 18F-FDG-PET/CT-scan in the assessment of inguinal lymph node involvement in patients with invasive penile carcinoma.Patients and methods: Thirty-five patients with invasive penile carcinoma were staged prospectively by 18F-FDG-PET/CT-scan, and blindly evaluated by 2 nuclear medicine physicians. In total, lymph node involvement was assessed in 70 inguinal groins. Reference standard was either histology or clinical follow-up with a minimum of 31 months (mean: 48.4 months; range: 31–68 months).Results: 18-FDG-PET/CT showed a sensitivity of 88.2% and a specificity of 98.1%. Positive predictive value (PPV) was 93.8%, while negative predictive value (NPV) was 96.3%. In two groins, metastasis of 5 and 7 mm were missed by PET/CT scan.Conclusion: 18F-FDG-PET/CT is a promising staging tool in assessing the inguinal lymph node involvement of patients with penile carcinoma. Integration of PET/CT scanning into preoperative staging algorithms may avoid surgical staging in selected patients.

Acute toxicity of image-guided hypofractionated radiotherapy for prostate cancer: Nonrandomized comparison with conventional fractionation - Corrected Proof

2009-12-14

Abstract: Objectives: To compare acute toxicity of prostate cancer image-guided hypofractionated radiotherapy (hypo-IGRT) with conventional fractionation without image-guidance (non-IGRT). To test the hypothesis that the potentially injurious effect of hypofractionation can be counterbalanced by the reduced irradiated normal tissue volume using IGRT approach.Materials and methods: One hundred seventy-nine cT1-T2N0M0 prostate cancer patients were treated within the prospective study with 70.2 Gy/26 fractions (equivalent to 84 Gy/42 fractions, α/β 1.5 Gy) using IGRT (transabdominal ultrasound, ExacTrac X-Ray system, or cone-beam computer tomography). Their prospectively collected data were compared with data of 174 patients treated to 80 Gy/40 fractions with non-IGRT. The difference between hypo-IGRT and non-IGRT cohorts included fractionation (hypofractionation vs. conventional fractionation), margins (hypo-IGRT margins: 7 mm and 3 mm, for all but posterior margins; respectively; non-IGRT margins: 10 and 5 mm, for all but posterior margins, respectively), and use of image-guidance or not. Multivariate analysis was performed to define the tumor-, patient-, and treatment-related predictors for acute toxicity.Results: All patients completed the prescribed radiotherapy course. Acute toxicity in the hypo-IGRT cohort included rectal (G1: 29.1%; G2: 11.2%; G3: 1.1%) and urinary events (G1: 33.5%; G2: 39.1%; G3: 5%). Acute toxicity in the non-IGRT patients included rectal (G1: 16.1%; G2: 6.3%) and urinary events (G1: 36.2%; G2: 20.7%; G3: 0.6%). In 1 hypo-IGRT and 2 non-IGRT patients, radiotherapy was temporarily interrupted due to acute toxicity. The incidence of mild (G1-2) rectal and bladder complications was significantly higher for hypo-IGRT (P = 0.0014 and P < 0.0001, respectively). Multivariate analysis showed that hypo-IGRT (P = 0.001) and higher PSA (P = 0.046) are correlated with higher acute urinary toxicity. No independent factor was identified for acute rectal toxicity. No significant impact of IGRT system on acute toxicity was observed.Conclusions: The acute toxicity rates were low and similar in both study groups with some increase in mild acute urinary injury in the hypo-IGRT patients (most probably due to the under-reporting in the retrospectively analyzed non-IGRT cohort). The higher incidence of acute bowel reactions observed in hypo-IGRT group was not significant in the multivariate analysis. Further investigation is warranted in order to exclude the bias due to the nonrandomized character of the study.

The presence of circulating tumor cells does not predict extravesical disease in bladder cancer patients prior to radical cystectomy - Corrected Proof

2009-12-14

Abstract: Objective: Due to imprecise clinical staging, the finding of extravesical and node-positive disease at the time of radical cystectomy (RC) for patients with clinically localized bladder cancer is not uncommon. Circulating tumor cells (CTCs) have been shown to be present in the peripheral blood of patients with metastatic urothelial carcinoma. The object of this study was to evaluate the ability of CTCs to predict extravesical disease in bladder cancer patients prior to RC.Materials and methods: Peripheral blood samples from 43 patients with bladder cancer were evaluated using the CellSearch (Veridex, LLC, Raritan, NJ) CTC assay prior to RC. The sensitivity, specificity, and positive predictive value (PPV) of CTC status in predicting extravesical disease was calculated. Receiver operating characteristic (ROC) curves were generated to quantify the ability of CTCs to predict extravesical and node-positive disease.Results: CTCs were detected in 9 (21%) patients prior to RC. The sensitivity, specificity, and PPV of CTC status in predicting extravesical disease were 27%, 88% and 78%, respectively. The accuracy of CTC status in predicting extravesical (≥pT3 or node-positive) disease for the entire cohort was 0.576. In a model incorporating preoperative hydronephrosis, CTC status did not improve the predictive accuracy for extravesical disease (0.576 vs. 0.585, P = 0.915).Conclusion: CTCs were detected in low numbers in a small percentage (21%) of patients prior to undergoing RC at our institution. CTC status was not a robust predictor of extravesical or node-positive disease in this cohort. CTC status is not likely to be a clinically useful parameter for directing therapeutic decisions in patients with ≤cT2 bladder cancer.

Conditionally replicating adenovirus therapy utilizing bone sialoprotein promoter (Ad-BSP-E1a) in an in vivo study of treating androgen-independent intraosseous prostate cancer - Corrected Proof

2009-12-07

Abstract: Background: Adenoviral based gene therapy has been used in clinical trials in control of advanced prostate cancer. In this study, a promising conditionally replicating adenovirus (CRAd) driven by a tissue specific bone sialoprotein promoter in controlling prostate cancer both in vitro and in vivo is demonstrated.Methods: C4-2B, an androgen-independent prostate cancer cell line, was treated with PBS, Ad-BSP-TK, or the Ad-BSP-E1a in vitro, and in subcutaneous and intraosseous xenographs. Cell proliferation, PSA level in condition medium, tumor volume, and/or serum PSA were followed.Results: The growth of C4-2B and the PSA production was dramatically suppressed by Ad-BSP-E1a at very low dosage (0.3 MOI) compared with PBS and Ad-BSP-TK treatment in vitro. In the subcutaneous model, the tumor volume was significantly lower statistically in the Ad-BSP-E1a treated group than the Ad-BSP-TK control group (P = 0.02). In the intraosseous model, the mice treated in the Ad-BSP-E1a treatment group demonstrated a significant lower PSA compared to that in the control group (P < 0.01) at week 8 and week 16 post-treatment.Conclusions: The CRAd Ad-BSP-E1a revealed potential in treating prostate cancer in this model system. Using viral or none-viral mediated gene therapy to treat prostate carcinoma continues to be a potential avenue to treat afflicted men with prostate cancer.

Renal cell carcinoma with caval involvement: Contemporary strategies of surgical treatment - Corrected Proof

2009-12-07

Abstract: Objectives: We retrospectively evaluated the outcome of the surgical treatment of patients with renal cell carcinoma (RCC) and extensive inferior vena cava (IVC) involvement. Our aim was to investigate if a particular surgical technique could reduce morbidity and complications associated with this condition.Materials and methods: From 1996 to 2007, 22 patients with RCC and extensive IVC involvement underwent radical surgical treatment with the intention to avoid, whenever possible, sternotomy and cardiopulmonary bypass. The level of the tumor thrombus was I (<2 cm above the renal vein) in 2 patients, II (below the intrahepatic vena cava) in 9 patients, III (intrahepatic vena cava below the diaphragm) in 7 patients, and IV (atrial) in 4 patients. Extracorporeal vascular bypass was used for 4 patients with level IV and for 2 patients with level III tumor thrombi, with hypothermic circulatory arrest in 2 patients. Extensive liver mobilization techniques were adopted in 16 patients. Overall and cancer-specific survival (CSS) were analyzed based on tumor extent (N0M0, N+M+), pathologic stage (pT3b, pT3c, pT4), thrombus level, and caval wall infiltration.Results: Two patients died within 1 month of surgery and the remaining 20 patients have a mean follow-up of 32.2 months (range 6–90): 8 are alive (overall survival 40%), but 2 with disease (CSS 30%). A total of 10 severe complications developed in 8 patients (36%). Both overall and CSS were significantly associated with tumor stage (Log-rank P = 0.0237 and 0.0465), presence of nodal or systemic metastases (Log-rank P = 0.0835 and 0.0669; Wilcoxon's test P = 0.0407 and 0.0411), and caval wall infiltration (Log-rank P = 0.0200 and 0.0418).Conclusions: Despite the low overall survival, related to the high percentage of nodal and systemic metastases, aggressive surgical management with resection of synchronous metastatic disease for symptom palliation and cytoreduction, followed by immunotherapy is justified in this setting. A transabdominal approach to RCC and IVC involvement, even in patients with level III thrombus, can provide the surgeon with an exposure similar to thoracoabdominal incisions without the complications associated with thoracotomy.

Phase I trial with a combination of docetaxel and 153Sm-lexidronam in patients with castration-resistant metastatic prostate cancer - Corrected Proof

2009-12-07

Abstract: Background: This study was designed to evaluate toxicity and preliminary efficacy of 2 cycles of concomitant standard dose/schedule of 153Sm-lexidronam plus Q 3 weeks schedule escalating doses of docetaxel in metastatic castration-resistant prostate cancer (mCRPC).Methods: mCRPC patients with progressive bone metastases were treated in 4 cohorts. Docetaxel doses were escalated from 50, 50, 0 mg/m2 (on days 1, 22, 43, per 12-week cycle) to 75, 75, 75 mg/m2. 153Sm-lexidronam was administered on days 2 (Q 12 weeks) at dose of 1 mCi/kg/cycle (maximum of 2 cycles).Results: Thirteen patients received an average of 3.6 doses of docetaxel (range, 2–6 doses, median 4) and 1.5 doses of 153Sm-lexidronam (range, 1–2, median 2). Toxicity was primarily hematologic. There were total 35 episodes grade 3/4 neutropenia with a median 7 (range 7–14) days to recovery to ≤grade 1. One dose limiting grade 3 thrombocytopenia occurred on cohorts 3 and 4. Eight of 13 (62%) patients had PSA > 50% decrease as best response during the treatment. Median time to bone disease progression was 5.2 months (range 91 days–10 months+); 6/13 (46%) patients had stable/improved bone scans at 6 months and 6/6 (100%) symptomatic patients had improvement in pain.Conclusions: Concurrent 6-month administration of 4 doses (75 mg/m2) of standard Q 3 weeks schedule of docetaxel with 2 Q 3 months infusions of 1 mCi/Kg 153Sm-lexidronam is feasible with reversible bone marrow suppression, and deserves further testing in mCRPC patients with extensive bone metastasis.