Urologic Oncology: Seminars and Original Investigations - Articles in Press

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.

An update on Society of Urologic Oncology fellowship programs - Corrected Proof

Christopher L. Amling — 2010-03-02

Society of Urologic Oncology (SUO) fellowship programs provide a unique educational opportunity for advanced education in urologic oncology. To provide guidelines for educational program content, the SUO Fellowship Committee began to certify fellowship programs in 2000. Since then and particularly over the last several years, there have been a growing number of fellowships seeking SUO certification. This expansion and the recognized variability in program content have led to a need for development of program requirements and a core curriculum. The inconsistent and unmonitored process of fellow application and selection has also prompted interest in a fellowship matching program. In this article, the current status of SUO-certified fellowships will be reviewed and the goals for development of program requirements, a core curriculum, and a fellowship matching program will be set forth.

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.

Surgical management of locally recurrent renal cell carcinoma post-renal cryoablation: Importance of stringent selection criteria - Corrected Proof

Philippe E. Spiess — 2010-03-02

Over the past decade, significant advances have been made in the treatment options for small renal masses (SRM), including percutaneous/laparoscopic ablative procedures (radiofrequency ablation, cryoablation), laparoscopic (pure or robotic assisted) partial nephrectomy, and active surveillance (for the very select patient with multiple co-morbidities and a stable, small renal lesion). Each of these treatment alternatives has its inherent merits and drawbacks. For the most part, the major limitation of the renal ablative procedures has been their limited long-term data, necessitating regular surveillance imaging (with possible requirement for percutaneous biopsy) post-ablation, as well as the slightly higher recurrence rate compared with the gold standard treatment for SRM, which remains partial nephrectomy. However, one important consideration not emphasized in the scientific literature is that this treatment modality should only be offered to a select subset of patients, namely those with masses that are postero-lateral, less than 2.5 cm in largest greatest diameter, and are not situated within the region of the renal hilum . Recently, I have managed 2 patients with locally recurrent renal cell carcinoma post-laparoscopic renal cryoablation. Both patients had renal biopsies at the time of the renal cryoablative procedure confirming the histologic diagnosis of renal cell carcinoma (clear cell type). One patient had a 4.3 cm left mid-pole exophytic renal mass at presentation, whereas the second patient had a 2.8 cm right renal hilar mass. Both patients were treated at 2 separate outside facilities and were felt to be completely ablated with “real time” intra-operative ultrasound. On surveillance imaging at 3 and 6 months, both patients had persistently enhancing renal lesions, which were subsequently biopsied percutaneously and confirmed to represent locally recurrent/persistent renal cell carcinoma (). In fact, the patient presenting with the left renal tumor developed a subsequent 2.5 cm left adrenal nodule in addition to his renal mass, which had increased in size to 5.8 cm. Both patients were thereafter referred to my care for surgical management of locally recurrent renal cell cancer. Both patients underwent complete metastatic evaluations, which were negative. These patients were thereafter scheduled for open radical nephrectomy. As highlighted by Nguyen et al. , surgical management of locally recurrent renal cell carcinoma following ablative type procedures can be quite challenging in regards to the extensive fibrosis and obliteration of anatomical surgical planes. Both surgical cases were characterized by very dense scar tissue throughout the surgical field, with the kidneys being adherent to adjacent structures (bowel mesentery, spleen/pancreas on the left, and liver on the right side). Nevertheless, both patients had an uneventful intra- and postoperative course. They were discharged home at 5 and 7 days following surgery with no attributable complications. Both pathology reports confirmed the presence of viable renal cell carcinoma, with the patient presenting with the left renal mass having a left adrenal metastasis. At this point, both patients are without evidence of disease at 3 and 5 months follow-up.

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.

Prostate cancer screening and mortality: Comparison of recent randomized controlled clinical trials - Corrected Proof

Badar M. Mian — 2010-01-25

Screening and early detection of prostate cancer through the use of prostate specific antigen (PSA) is probably one of the most controversial subjects in urology, if not in all of medicine. Despite 20 years of PSA testing for prostate cancer detection, the true benefits and/or risks of early detection and active treatment have not been fully understood. Prostate cancer is associated with a heterogeneous biological behavior and often has a long preclinical phase. PSA screening introduces a relatively long lead time and length time bias, which confounds the attempts to measure its true impact on prostate cancer related mortality. In the absence of level I evidence, much of the data used to support (and oppose) prostate cancer screening comes from observational studies. The results of 2 randomized controlled trials, which were initiated nearly 15 years ago, had been awaited with great anticipation. The effects of screening on mortality in both trials were published recently and, surprisingly, the results of these 2 trials were contradictory. The trials differ from each other in many respects, including study design, follow-up, and patient population. Here, we discuss the extent to which the differences amongst these trials may be responsible for the contradictory results of screening for prostate cancer.

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.

Testing for urinary hyaluronate improves detection and grading of transitional cell carcinoma - Corrected Proof

2009-12-07

Abstract: Objective: The purpose of this study is to establish a method for the diagnosis and grading of transitional cell carcinoma (TCC), which is responsible for 90% of bladder tumors, using a recently developed ultrasensitive assay for the measurement of hyaluronan (HA).Materials and methods: Urine samples were collected prior to surgery (cystoscopy, transurethral resection for bladder cancer (TURBT), and cystectomy) in 350 patients. After the procedure, pathologic examination revealed that 160 patients had TCC. HA was measured directly in the urine by a noncompetitive enzyme-linked immunosorbent assay (ELISA)-like fluorometric assay. Using the receiver operator characteristic curve (ROC), t-test, Dunn test, Kruskal-Wallis test, and Mann-Whitney test, we evaluated the differences between groups (those with TCC vs. those without TCC).Results: By analyzing the ROC curve, we chose a urinary HA cutoff value of 13.0 μg/l for indicating risk of TCC. Using the value this of 13.0 μg/l, we found that this test had an overall sensitivity of 82.3% and an overall specificity of 81.2%. The positive predictive value of this assay was 78.9%, the negative predictive negative value was 84.2%, and the predictive accuracy was 81.7%. Logistic regression analysis revealed that every 1 μg/l increase in HA increased a patient's likelihood of having TCC by 3.9%. The sensitivity of this test to detect superficial tumors was 76.6%, whereas its sensitivity for detecting invasive tumors was 94.6%. The urinary HA excretion of patients with TCC, classified according to the TNM staging system and the World Health Organization (WHO) grading system, were compared, and a significant difference was observed between the HA levels of patients with superficial tumors compared with invasive tumors (P = 0.005) as well as between patients with low- vs. high-grade carcinomas (P < 0.001). Patients with urinary HA levels >35 μg/l had a 4.63 times increased risk of having an aggressive, invasive, high grade tumor (P = 0.005).Conclusions: Our results support the postulate that urinary HA may be used as a tumor marker to aid in the diagnosis and grading of TCC. Additionally, more invasive tumors produce and release more HA in urine than superficial tumors, thus higher HA levels indicate more aggressive disease.

An adult Xp11.2 translocation renal carcinoma showing response to treatment with sunitinib - Corrected Proof

2009-12-07

Abstract: A rare variant of renal cell carcinoma (RCC) with a translocation involving Xp11.2 has become increasingly recognized as a separate entity in the 2004 World Health Organization (WHO) kidney carcinoma classification. These tumors predominantly affect children and young adults and tend to present with advanced stage disease. Although reported to be indolent in children, adult cases run a more aggressive course. Little is known about their natural history, prognosis and response to therapy.We report a case of Xp11 translocation renal cancer in a 33-year-old male patient who presented with widespread rapidly progressive metastatic disease involving extensive intra-thoracic lymph nodes, supra-clavicular, retroperitoneal lymph nodes, lung nodules, and peritoneal mass.He had failed to respond to treatment with high dose interleukin 2, but showed a significant clinical response to treatment with the multikinase inhibitor sunitinib. CT scan performed after 3 cycles (18 weeks) of therapy revealed more than 65% reduction of measurable disease by response evaluation criteria in solid tumors (RECIST) criteria, resolution of other assessable lesions, and a clinical benefit that lasted for over 13 months. But unfortunately, this was subsequently followed by a rapidly progressive course.The well-recognized clinical efficacy of multikinase inhibitors such as sunitinib and sorafenib is based on the outcomes in patients with clear cell histology. There is limited data on efficacy in non-clear cell RCC, but activity in translocation RCC has not been reported. To our knowledge, this is the first documented case of Xp11 translocation carcinoma to have demonstrated an objective durable response to sunitinib. It remains unclear how resistance to sunitinib develops, but the results to date support further evaluation of sunitinib in cases of translocation RCC.

Postoperative nomogram for invasive bladder cancer: Does it really work? A multicenter cohort study - Corrected Proof

2009-12-04

Abstract: Objectives: Nomograms are statistical models designed to maximize predictive accuracy. We have tested the statistical correlation between the predictions of International Bladder Cancer Nomogram Consortium and the clinical outcomes in a multicenter Italian cohort of patients treated with radical cystectomy (RC) and pelvic lymph-nodes dissection.Methods and materials: Two hundred four patients who underwent RC were selected for multiple variable and then enrolled in the study. Patients were tested by the “online tool” based on the nomogram, then stratified and risk grouped for 5-year predicted disease-free survival (pDFS): low risk (67%–100%), intermediate risk (34%–66%), and high risk group (0%–33%). Receiving operating characteristic curve (ROC) quantified the area under curve (AUC) as predictive accuracy. Actual overall survival (aOS) and actual disease-free survival (aDFS) were calculated with Kaplan-Meyer analysis. Median of pDFS was compared with 5-year aDFS.Results: AUC was 0.69 (P < 0.001). The aOS is 50% (95% confidence interval (95% CI, −7.68/+8.23) at 5-years after RC, the aDFS is 65.5% (95% CI, −7.56/+8.98).The 5-year aDFS is 75.3% (−8.82/+12.53) in low risk group; 67.3% (−12/+16.4) in intermediate risk group; 28.3% (−20/+17.2) in high risk group. The 5-year aDFS was well calculated by the nomogram but in all groups the nomogram slightly underestimated the prediction. In intermediate risk group, 5-year aDFS overscored both the nomogram pDFS and the pDFS range of this group (34%–66%). In all patients investigated, the pDFS was 65%, a value close to the 5-year aDFS found (65.6%).Conclusion: Statistical correlation between postoperative nomogram prediction and the clinical reality was observed.

Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaïve castration-resistant prostate cancer - Corrected Proof

2009-12-04

Abstract: Background: Azacitidine is a hypomethylating agent that activates genes repressed by promoter methylation. Preclinically, demethylating agents reverse resistance of prostate cancer to androgen ablation. A phase II trial evaluated azacitidine for men with castration-resistant prostate cancer (CRPC) progressing on combined androgen blockade (CAB).Methods: Chemonaïve patients with CRPC on CAB and PSA-doubling time (DT) < 3 months were eligible. The primary endpoint was prolongation of PSA-DT to ≥3 months. Correlation of biologic activity (fetal hemoglobin, plasma DNA LINE-1 methylation) with prolongation of PSA-DT was tested. CAB was continued and azacitidine 75 mg/m2 was administered subcutaneously on days 1–5 of each 28-day cycle up to 12 cycles or until clinical progression/intolerable toxicities.Results: Thirty-six patients were enrolled, 80.6% had metastatic disease, and 34 were evaluable. A PSA-DT ≥ 3 months was attained in 19 patients (55.8%). Overall median PSA-DT was significantly prolonged compared to baseline (2.8 vs. 1.5 months, P < 0.01). Fourteen patients had some PSA decline during therapy and 1 patient had a ≥30% decline compared with baseline. The median clinical progression-free survival was 12.4 weeks. Grade 3 toxicities included fatigue (12%), and neutropenia (6%), with 4 patients discontinuing due to toxicities. A trend in decreasing plasma DNA LINE-1 methylation was seen with longer treatment duration (P = 0.06), which significantly correlated with prolongation of PSA-DT (P = 0.02).Conclusions: Azacitidine favorably modulates PSA kinetics in chemonaïve CRPC that correlates with decreasing plasma DNA LINE-1 methylation. Given the excellent tolerability, further development of azacitidine for CRPC may be warranted, with exploration of combination regimens.

A gene signature of primary tumor identifies metastasized seminoma - Corrected Proof

2009-11-30

Abstract: Background: The aim of this study was the prediction of metastatic status in seminoma based on examination of the primary tumor.Methods: Total RNA was isolated from metastasized seminoma (n = 10, T1N1-2M0), non-metastasized seminoma (n = 21, T1-3N0M0), and corresponding normal tissues. Pooled RNA from 10 biopsies of each tissue type was hybridized on whole genome microarrays for screening purposes. Ninety-two selected gene candidates were quantitatively examined using real-time quantitative polymerase chain reaction (RTQ-PCR).Results: Agreement in gene expression was 88% between the whole genome microarrays and RTQ-PCR. Metastasized seminoma showed 1,912 up-regulated and 2,179 down-regulated genes with ≥2-fold differences in gene expression compared non-metastasized seminoma. RTQ-PCR of selected genes showed that mean gene expression values were significantly reduced in metastasized compared with non-metastasized seminoma. The presence of metastases could be predicted based on an 85-gene expression signature by using logistic regression. Sensitivity and accuracy of the 10-fold cross-validation model were 77.8% and 84.2%, respectively.Conclusion: A logistic regression model using an 85 gene expression signature allowed identification of metastasized seminoma from the primary tumor with a sensitivity of 77.8%.

Intermediate-differentiated invasive (pT1 G2) penile cancer—oncological outcome and follow-up - Corrected Proof

2009-11-30

Abstract: Objectives and aims: Due to the low prevalence of penile cancer, little evidence exists on the metastatic potential and the ideal treatment strategies in intermediate-differentiated invasive (pT1 G2) penile cancer. The current study aimed to analyze the oncologic outcome of patients with penile carcinoma with long-term follow-up in a single-center study.Patients and methods: In this retrospective study, 38 patients with histologically proven T1 G2 squamous cell carcinoma of the penis were included. Only the ‘classic’ subtype was analyzed. Treatment of the primary tumor was Nd:YAG laser-therapy, excision, or partial amputation. Follow-up was performed according to EAU guidelines (2004).Results: Mean follow-up was 78.1 months (range: 9–285 months). Local recurrence was seen in 12 patients (31.6%), but was not correlated with disease related death (P = 0.7944). Rate of local recurrence was not dependent on treatment modality (P = 0.3481); 13 patients died, accounting for a disease related survival rate of 81.6% during observation period. Positive lymph nodes were seen in 28.9% of patients and were significantly correlated with disease related death (P = 0.00004). Clinically enlarged inguinal lymph nodes were not correlated with histologically confirmed positive lymph nodes (P = 0.5785).Conclusions: For patients with T1 G2 penile cancer, organ preserving therapy appears to be a suitable treatment option. In our series, nearly one third of patients developed inguinal lymph node metastases, which highlights the potential benefit of surgical staging. Larger prospective multicenter studies are needed to define the best treatment strategy for intermediate-differentiated invasive penile cancer.

A MicroRNA expression profile defining the invasive bladder tumor phenotype - Corrected Proof

2009-11-30

Abstract: Objective: The purpose of this study was to identify microRNA (miRNA) involved in the transition between the noninvasive and invasive urothelial carcinoma of the bladder (UCB) phenotype.Methods: Differential expression of miRNA was identified in a microarray format between noninvasive and invasive UCB cell lines and confirmed using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) within this cell panel. Normalization of qRT-PCR with miR-222 was established from the microarray data and validated within a panel of 57 UCB tumors (26 noninvasive lesions (Ta/G1) and 31 invasive lesions (T2-T4). Pre-miR constructs were transfected into appropriate UCB cell lines to establish a change in invasive potential.Results: Differential expression of miRNAs was identified from microarray analysis and included reduced expression associated with miR-30b, miR-31, miR-141, miR-200a, miR-200b, miR-200c, miR-205, miR-21 in invasive lesions and elevated miR-99a in noninvasive UCB lesions. Reduced invasion potential was recorded in UM-UC-3, following pre-miR transfection, in all UCB cell lines with the exception of UM-UC-3/miR-30b transfectants. Our results identify a panel of miRNA modulated and expressed in invasive UCB tumors and demonstrates a role for them in the invasive phenotype.Conclusions: The diagnostic test, based on the three most discriminatory miRNAs in our panel (miR-200c, miR-141, and miR-30b), showed a sensitivity of 100% and a specificity of 96.2%. Such a panel of miRNAs has the potential to identify invasive bladder tumors misclassified in pathologic assessment of bladder biopsy specimens.

Obesity does not correlate with adverse pathologic findings on transperineal template-guided mapping biopsy of the prostate - Corrected Proof

2009-11-30

Abstract: Background: Obesity has correlated with adverse pathologic features on prostate biopsy and may predispose to a higher rate of prostate cancer-related death after radical prostatectomy. In this study, we examine the potential relationship between body mass index (BMI) and histopathologic findings on transperineal template-guided mapping biopsy of the prostate (TTMB).Methods: From January 2005 to January 2008, 244 consecutive patients underwent TTMB using an anatomic-based technique. The criteria for TTMB included previously negative transrectal ultrasound (TRUS) biopsy with persistently elevated PSA and/or diagnosis of ASAP, or HG-PIN. The study population was divided into 4 different BMI cohorts (BMI < 25, BMI 25–29.9, BMI 30–34.9, and BMI ≥ 35 kg/m2). Biopsy findings were compared between the various BMI cohorts using one-way analysis of variance (ANOVA) and the χ2 test.Results: Pre-TTMB clinical parameters, including PSA and prostate volume, were not significantly different between the various BMI cohorts. On average, the study population had undergone 1.7 TRUS biopsies before TTMB. Of the 244 study patients, 112 (45.9%), were diagnosed with prostate adenocarcinoma on TTMB. There was no difference in the rate of cancer detection between the different BMI cohorts. Among patients diagnosed with prostate cancer, BMI did not correlate with Gleason score or percent of positive biopsy cores. When the geography of biopsy-positive cores was analyzed, there were no statistically significant differences in cancer location among the different BMI groups.Conclusions: In this study, obesity did not predispose toward higher Gleason score, larger cancer volume, or geographic cancer distribution on repeat biopsy with TTMB.

Significance of P-glycoprotein, P53, and survivin expression in renal cell carcinoma - Corrected Proof

Firat Baytekin, Burcin Tuna, Ugur Mungan, Guven Aslan, Kutsal Yorukoglu — 2009-11-30

Abstract: Objectives: This study addresses the relationship between cell cycle control protein p53, apoptosis inhibitor gene survivin, and chemotherapy resistance protein P-glycoprotein (P-gp) expression, and their prognostic impact in renal cell carcinoma (RCC).Methods: A group consisting of 104 patients with RCC was included from a predefined period of time. The median follow-up was 46 months. Tumor stage was defined according to the 2002 Tumor-Node-Metastasis staging system, and Fuhrman nuclear grading was used. Expression of p53, survivin, and P-gp was assessed on immunohistochemically stained slides of the representative blocks of the tumors.Results: A significant relationship was found between survival and histologic subtype (P = 0.001), tumor stage (P = 0.011), and tumor grade (P < 0.001). Although there was inverse correlation between p53 expression and stage (P = 0.014) and grade (P = 0.04), no correlation was observed with the histopathologic type or survival. There was no correlation between survivin expression and histologic subtype, stage, or survival, but there was a significant inverse correlation between survivin expression and tumor grade (P = 0.018). No significant correlation was found between any parameters tested, and P-gp expression.Conclusions: Survivin, P-gp, and p53 expression do not play a role in prognosis of RCC. Our results suggest that survivin expression may be positively regulated by mutant p53 in RCC, and this expression may have an impact on resistance to chemotherapy in RCC.

The multi-disciplinary management of high-risk prostate cancer - Corrected Proof

2009-11-30

Abstract: Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying and treating those men with localized cancer who are at a higher risk of dying from their disease. We discuss the risk stratification of patients in order to better identify those patients at higher risk of progression. A comprehensive review of the literature was then performed reviewing the roles of surgery, radiotherapy, hormone therapy, and chemotherapy, as well as combinations of these modalities, in treating these challenging patients. An integrated approach combining local and systemic therapies can be beneficial in the management of high-risk localized prostate cancer. The choice of therapy or combination of therapies is dependant upon many considerations, including patient preference and quality of life aspects. It is becoming clearer that the addition of hormonal therapies or chemotherapies to established therapies, such as radiotherapy or surgery, will have significant benefits. As evidence accumulates regarding the efficacy of these new regimens, our hope is that the challenge of optimizing the management of high-risk prostate cancer will be delivered. However, many important questions remain unresolved regarding the optimal type, combination, timing of therapy, and duration of therapy. Such questions will only be answered with large, well-designed prospective clinical trials.

Improving the efficacy of targeted trials by multiple-marker analysis in castration-resistant prostate cancer - Corrected Proof

2009-11-30

Abstract: Objectives: In order to improve the efficacy of targeted therapy trials, the expression profiles of several molecular markers that are potential candidates for targeted therapy were analyzed in patients with progressive castration-resistant prostate cancer.Methods and materials: Paraffin-embedded samples of tumor tissue from 51 patients obtained from biopsies of metastases or remaining prostates were analyzed immunohistochemically for the expression of EGFR, PDGFRβ, Her-2/neu, c-Kit, and VEGF. Staining was analyzed according to the percentage of positively stained tumor cells and the intensity of staining.Results: According to the different cut-off values of 10%, 30%, 50%, or 70% for the percentage of positively stained cells, different rates of expression were found. Expression rates ranged from 30.6% to 61.2% for EGFR, from 34.7% to 57.1% for PDGFRβ, from 9.6% to 28.8% for Her-2/neu, from 12.5% to 22.4% for c-Kit, and from 51.1% to 74.5% for VEGF. Defining positive expression as ≥30% positively stained tumor cells, with an intensity of staining of ≥2+, resulted in positive expression of EGFR in 38.8%, PDGFRβ in 24.5%, Her-2/neu in 13.5%, c-Kit in 6.4%, and VEGF in 44.7% of the patients.Conclusions: Our results demonstrate simultaneous expression of several markers in castration-resistant prostate cancer tissue. Translation of the results into modern, multi-arm clinical trial designs will improve the efficacy of recruiting and obtaining results, compared with multiple double-arm trials.

GREB1 tissue expression is associated with organ-confined prostate cancer - Corrected Proof

2009-11-30

Abstract: Objective: By reason of its heterogeneous behavior, it is difficult to determine the prognosis of many prostate cancer cases. Patients with the same clinicopathologic conditions may present varying clinical findings and rates of progression. We determined the role of new genes as potential molecular markers for prostate cancer prognosis.Materials and methods: We performed a microarray analysis of two pools of patients with prostate cancer divided according to their clinicopathologic characteristics. After that, we validated these results by testing the genes with most different expressions between the two pools using the quantitative real time polymerase chain reaction method. We analyzed gene expression in 33 patients with localized prostate cancer according to prostate specific antigen (PSA), pathologic stage, Gleason score, and biochemical recurrence. For statistical analysis we used the Mann-Whitney Test.Results: The microarray analysis revealed that 4,147 genes presented a different expression between the two pools. Among them, 3 genes, TMEFF2, GREB1, and TH1L, were at least 13-times overexpressed, and 1 gene, IGH3, which was at least 5times under-expressed in pool 1 (good prognosis) compared with pool 2 (bad prognosis), were selected for analysis. After the validation tests, GREB1 was significantly more overexpressed among patients with stage T2 compared with T3 (P = 0.020). The expressions of other 3 genes did not present significant differences according to the clinicopathological variables.Conclusions: Tissue expression of GREB1 is associated with organ-confined prostate cancer and may constitute a gene associated with a favorable prognosis.

Urothelial dysplasia and inflammation induced by Schistosoma haematobium total antigen instillation in mice normal urothelium - Corrected Proof

2009-11-30

Abstract: Objectives: Squamous cell carcinoma of the urinary bladder has been associated with Schistosoma haematobium infection in many parts of Africa. The epidemiologic association is based on case control studies and on the close correlation of urinary bladder cancer incidence with prevalence of S. haematobium infection within different geographic areas. A parasite-tumor linkage is further suggested by the predominance of squamous cell (as opposed to transitional cell) morphology of bladder carcinomas seen in S. haematobium-endemic areas. The cellular mechanisms linking S. haematobium infection with cancer formation are not yet defined. In the present study, we hypothesized that the parasite antigens might induce alterations in urothelium.Materials and methods: We investigated the effects of S. haematobium total antigen in CD-1 mice normal bladders after intravesical administration of the parasite antigens. The bladders were analyzed histopathologically 20 and 40 weeks after treatment.Results: Intravesical instillation of S. haematobium total antigens induces the development of urothelial dysplasia and inflammation.Conclusions: In our work, we demonstrate for the first time that S. haematobium antigens are the direct cause of alterations in urothelium.

Fluorescence-guided laser therapy for penile carcinoma and precancerous lesions: Long-term follow-up - Corrected Proof

2009-11-30

Abstract: Objectives and aims: Laser therapy for penile carcinoma is commonly used despite high recurrence rates of up to 48%. The aim of our study was to investigate the long-term recurrence rate of patients treated by fluorescence-guided laser therapy for penile carcinoma and its impact on oncologic outcome.Patients and methods: Between 1999 and 2005, a total of 26 patients with premalignant carcinoma in situ (Tis) (n = 11) or invasive penile carcinoma (n = 15) were treated by fluorescence-guided laser therapy in our center. The mean follow-up was 71.1 months (range 41–104 months). Recurrence rate, time to recurrence, and impact on survival was investigated for Tis patients and penile carcinoma patients separately.Results: No patient died tumor-associated recurrence during follow-up. No local progression of T stage was observed in patients with Tis tumor. In the group with invasive penile cancer, there were 4 (15.4%) local recurrences. However, 3 of them occurred after more than 3 years and, therefore, are more likely to be considered as “de novo” carcinoma. No intra- or perioperative side effects of photodynamic diagnosis (PDD) were observed.Conclusions: Local recurrence rate of laser therapy can be reduced by fluorescence guidance without impairing cosmetic or functional results. The necessary equipment is available in many centers that perform PDD for urothelial bladder cancer. PDD, therefore, can be considered to be cost-effective and easy to perform. Prospective multi-center studies to directly compare recurrence rates between white light and fluorescence-guided laser therapy for penile carcinoma are required.

The orthotopic Fischer/AY-27 rat bladder urothelial cell carcinoma model to test the efficacy of different apaziquone formulations - Corrected Proof

2009-11-30

Abstract: Objectives: Apaziquone used intravesically showed significant activity in phase I and II marker lesion studies in non-muscle-invasive bladder cancer. The objective of this study was to assess antitumor activity and safety of 3 different formulations of intravesical apaziquone in an orthotopic rat bladder cancer model.Materials and methods: Female Fischer F344 rats were instilled with 1.5 × 106 AY-27 urothelial cell carcinoma cells and divided in 3 treatment groups (n = 10) and 1 placebo group (n = 6). Intravesical treatment was administered for 1 hour on days 2 and 5. Rats were treated with apaziquone in the formulation used in phase I/II clinical trials (group 1); apaziquone with an altered buffering capacity being used in phase III clinical trials (group 2), and apaziquone as in group 2, but without propylene glycol in the diluent (group 3). On days 5 and 14, the bladder wall was inspected by cystoscopy and evaluated for macroscopic tumor growth. After sacrificing the rats (day 14), cystectomy was performed and the bladders were investigated.Results: There were no signs of any toxicity due to the study drug. On histopathologic examination of the bladders 0, 1, and 2 tumors per group were found in group 1, 2, and 3, respectively. In the placebo-treated group, 60% of animals developed tumor, which is comparable to untreated animals.Conclusions: Apaziquone showed an excellent antitumor activity. The effectiveness of apaziquone in this orthotopic rat bladder tumor model corroborates the clinical observations and implies the validity of this model.

Antiproliferative and apoptosis inducing effects of indirubin-3′-monoxime in renal cell cancer cells - Corrected Proof

2009-11-30

Abstract: Objectives: Indirubin-3′-monoxime, which is a selective and potent inhibitor of cyclin-dependent kinases (CDKs) has shown preclinical activity in several human cancer cells. This study investigated if indirubin-3′-monoxime can induce apoptosis and tumor cell death in 3 human (A498, CAKI-1, CAKI-2) and 1 murine renal cell cancer (RENCA) cell line.Methods: The growth inhibitory and apoptosis induction properties were evaluated by EZ4U, a cytotoxic assay and by flow cytometry of annexin-V/PI staining during treatment with doses ranging from 5.0 to 15.0 μM indirubin-3′-monoxime over 72 hours. To further establish the underlying molecular targets of indirubin-3′-monoxime, survivin, a major anti-apoptotic protein was additionally determined by intracellular flow cytometry.Results: Our results show that indirubin-3′-monoxime induces growth arrest and apoptosis in all renal cell cancer (RCC) cell lines. All RCC lines expressed survivin. However, a clear correlation between apoptosis induction and expression of survivin was not found.Conclusions: As treatment of metastatic renal cell cancer (mRCC) remains a challenge, and the need for continuing assessment of novel agents in the treatment of this disease is mandatory. Indirubin-3′-monoxime seems to be a candidate for further evaluation.

Immunohistochemistry for the differential diagnosis of renal tumors with oncocytic features - Corrected Proof

M. Jesus Fernández-Aceñero, Alicia Cazorla, F. Manzarbeitia — 2009-11-20

Abstract: Objective: Histologic analysis of renal tumors usually enables accurate diagnosis, but some tumors may show overlapping histopathologic features, which makes classification difficult. Diagnosis can be extremely challenging in tumors showing oncocytic change, mainly for oncocytomas, chromophobe carcinoma, papillary carcinomas with eosinophilic cells (type 2), and conventional renal cell carcinomas with eosinophilic oncocytic-like cells. The purpose of the present study is to analyze whether the patterns of immunohistochemical expression can help differential diagnosis of these tumors.Material and methods: A thorough review of the files of the Department of Surgical Pathology, Fundación Jiménez Díaz, Madrid, Spain has retrieved 308 records of renal cell carcinomas in the last 12 years, with 15 renal oncocytomas (RO), 28 papillary carcinomas (PRCC), and 13 chromophobe carcinomas (CHRCC). We have performed immunohistochemistry on representative paraffin blocks from 9 oncocytomas, 11 chromophobe carcinomas, 10 papillary carcinomas, and 11 conventional cell carcinomas with oncocytic cells, from which we had suitable material. The immunohistochemical panel included CD117, α-methylacyl-coenzyme A racemase, CD10, p53, progesterone receptors, and cytokeratins 7 and 20.Results: Our results show a considerable overlap between immunohistochemical expression in these tumors. Although immunohistochemistry can be helpful in some difficult cases, no markers allow a clear-cut distinction between these tumors, and diagnosis must still rely on morphologic features and histochemical techniques, as well as on molecular techniques when available.

Expression of glutathione-S-transferases isoenzymes and P53 in exfoliated human bladder cancer cells - Corrected Proof

2009-11-20

Abstract: Objectives: This study investigates the usefulness of glutathione-S-transferases (GST) isoenzymes and p53 immunostaining as a marker of malignancy in urinary cytology, and evaluates their potential effect in increasing diagnostic accuracy in a series of urine cytologic samples. They are also correlated with cytopathology diagnosis and histopathologic diagnosis.Materials and methods: In this study, the slides from 124 bladder carcinoma patients prepared by the cytocentrifugation method were observed. The cytomorphologic properties of these cancer cells were determined. Moreover, the immunocytochemical distributions of GST alpha (GSTA), pi (GSTP), mu (GSTM4), theta (GSTT1) isoenzymes and p53 protein were studied for the patients.Results: The urothelial cancer cells had small cytoplasm and rough nuclear membrane. The chromatin granules were heterogeneously distributed in each malignant cell's nucleus. There was a pleomorphism of the malignant cells' nuclei. According to immunocytopathologic observations, the urothelial cancer cells had stronger staining intensity than the benign cells had in 48% of cases for GSTA, 46% of cases for GSTP, 38% of cases for GSTM4, and 42% of cases for GSTT1. For all papillary cases, the malignant cells were stained negative, while the benign cells were positive. For 83% of patients, the malignant cells were stained positive for p53. There was a significant difference in GSTA (P = 0.006), GSTT1 (P = 0.004), GSTP (P = 0.000) and p53 (P = 0.000) expressions for benign cells whereas, a non-statistical difference in the malignant cells for GSTA, GSTT1, GSTP, GSTM4, and p53 expressions (P > 0.05).Conclusions: GST isoenzymes and p53 immunostaining were not found to be markers of malignancy in urinary cytology.

Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States - Corrected Proof

Scott M. Gilbert, Yong-fang Kuo, Vahakn B. Shahinian — 2009-11-20

Abstract: Purpose: Androgen deprivation therapy (ADT) for prostate cancer increased substantially through the 1990s, but more recent national trends regarding incident and prevalent use have been incompletely characterized.Methods: Linked Surveillance, Epidemiology, and End Results (SEER)–Medicare data were used to study patterns of ADT utilization. Prevalence of ADT in the male Medicare population was estimated by examining a cohort of prostate cancer patients and a 5% noncancer control population, from 1991 to 2005. ADT use across different indications was examined for men with incident cancers from 2000 to 2002. Nested logit models were used to examine determinants of ADT use in men with lower risk prostate cancer not treated definitively by surgery or radiation.Results: Prevalent ADT use increased through the 1990s, peaked in 2000 at 3.17% of all male Medicare beneficiaries, subsequently stabilized, then dropped in 2005 to 2.92%. Between 2000 and 2002, use in incident prostate cancer was stable, with 44.8% use in all cases, 15% of cases as an adjuvant with radiation, and 14% as a primary therapy. In the nested logit model, predictors of ADT use in a lower risk setting were older age, higher stage and grade, and elevated prostate-specific antigen levels.Conclusions: Following a period of rapid expansion during the 1990s, incident and prevalent use of ADT has leveled, and may be starting to decline. Further research is needed to monitor how reductions in reimbursement for GnRH agonists will affect appropriate use of ADT as well as use in settings where its benefits may be marginal.

Oncologic control obtained after radical prostatectomy in men with a pathological Gleason score ≥ 8: A single-center experience - Corrected Proof

2009-11-20

Abstract: Objective: To assess the oncologic control afforded by radical prostatectomy (RP) in high-risk prostate cancers with a Gleason score ≥ 8.Materials and methods: We performed a retrospective review of prostate cancer patients who underwent RP between 1995 and 2005 for prostate cancer and who had a pathologic Gleason score ≥ 8. Biochemical recurrence was defined as a single rise in PSA levels over 0.2 ng/ml after surgery.Results: Overall, 64 patients were included and followed for a median time of 84.3 months. The mean age was 63 ± 5.2 years. The mean preoperative PSA was 11.9 ± 7.3 ng/ml (1.9–31), and 29 patients (46%) had a PSA > 10 ng/ml. The biopsy Gleason score was ≤7 for 49 patients (76.6%). After pathologic analysis, there were 25 (39%) stage pT2, 37 (58%) stage pT3, and 2 (3%) stage pT4 patients. Nine patients had lymph node involvement (14%). The surgical margins were positive in 25 patients (39%). In 51 patients, (80%) the Gleason score was underestimated by biopsies: 40 patients with a definitive score of Gleason 8 had a Gleason score of 6 or 7 on biopsies, while 11 patients with a Gleason score of 9 initially, had a Gleason score of 7 or 8. Twenty-seven patients underwent adjuvant treatment: external radiation therapy (n = 19), HRT (n = 3), or both (n = 5). During follow-up, 41 patients (64%) presented with a biochemical recurrence, and 11 (17%) died. The PSA-free survival rate at five year was 44%.Conclusion: RP remains a possible therapeutic option in certain cases of the high-risk cohort of patients with a Gleason score ≥ 8. However, patients should be warned that surgery might only be the first step of a multi-modal treatment approach. The modalities of adjuvant treatments and the right schedule to deliver it following RP still need to be defined.