Enhanced expression of peroxisome proliferate-activated receptor gamma (PPAR-γ) in advanced prostate cancer.

BACKGROUND: Recent studies have underlined the role of nuclear receptors in the involvement of prostate cancer signalling pathways. PATIENTS AND METHODS: A total of 84 benign prostate hyperplasia (BPH), 84 low risk prostate cancer (LPC) and 64 advanced disease (APC) cases were sampled on a tissue microarray (TMA) and stained for retinoic acid receptor (RAR)-α, retionoid X receptor (RXR)-α, liver X receptor (LXR)-α, farnesoid X receptor (FXR) and proliferate-activated receptor gamma (PPAR)-γ and the (pro)-inflammatory molecules cyclooxygenase 2 (COX2), tumor necrosis factor (TNF)-α and inducible Nitric oxide synthase (iNOS) immunohistochemically. RESULTS: PPAR-γ expression in APC tissues was found to be significantly higher than that in LPC and BPH specimens (p<0.001). In contrast, RXR-a expression was significantly lower (p<0.001). COX2 staining demonstrated a trend towards overexpression in APC (p=0.025). No significant differences were found for RAR-α, iNOS and TNF-α expression. Staining of FXR and LXR was seen diffusely in the cytoplasm as well as in the nucleus, preventing sufficient evaluation by definition. CONCLUSION: This study provides the basis for applying PPAR-γ ligands clinically in treatment of APC.

Sonographic diagnosis of a posttraumatic arteriocavernosal fistula resulting in high-flow priapism.

We present a case of high-flow priapism due to perineal trauma and subsequent arteriocavernosal fistula, which was diagnosed by sonography. Selective arterial embolization led to complete detumescence without compromising the patient's erectile function. Color Doppler sonography is an appropriate diagnostic tool to diagnose arteriocavernosal fistula. Selective arterial embolization is a safe and effective therapeutic option.

Macroscopic sessile tumor architecture is a pathologic feature of biologically aggressive upper tract urothelial carcinoma.

OBJECTIVE: Macroscopic sessile tumor architecture was associated with adverse outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Before inclusion in daily clinical decision-making, the prognostic value of tumor architecture needs to be validated in an independent, external dataset. We tested whether macroscopic tumor architecture improves outcome prediction in an international cohort of patients. MATERIAL AND METHODS: We retrospectively studied 754 patients treated with RNU for UTUC without neoadjuvant chemotherapy at 9 centers located in Asia, Canada, and Europe. Tumor architecture was macroscopically categorized as either papillary or sessile. Univariable and multivariable Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. RESULTS: Macroscopic sessile architecture was present in 20% of the patients. Its prevalence increased with advancing pathologic stage and it was significantly associated with established features of biologically aggressive UTUC, such as tumor grade, lymph node metastasis, lymphovascular invasion, and concomitant CIS (all P values < 0.02). The median follow-up for patients who were alive at last follow-up was 40 months (IQR: 18-75 months, range: 1-271 months). Two-year RFS and CSS for tumors with papillary architecture were 85% and 90%, compared with 58% and 66% for those with macroscopic sessile architecture, respectively (P values < 0.0001). On multivariable Cox regression analyses, macroscopic sessile architecture was an independent predictor of both RFS (hazard ratio {HR}: 1.5; P = 0.036) and CSS (HR: 1.5; P = 0.03). CONCLUSION: We confirmed the independent prognostic value of macroscopic tumor architecture in a large, independent, multicenter UTUC cohort. It should be reported in every pathology report and included in post-RNU predictive models in order to refine current clinical decision making regarding follow-up protocol and adjuvant therapy.

Should we abstain from Gleason score 2-4 in the diagnosis of prostate cancer? Results of a German multicentre study.

PURPOSE: The present study analysed the loss of prognostic information related to the abandonment of Gleason score (GS) 2-4 by the International Society of Urological Pathology (ISUP-2005). METHODS: Within a 10-year period prior to the modification of GS, 856 patients (mean age 64.2 years) underwent radical prostatectomy (RP). The grade of agreement between GS in biopsy and definitive histology was calculated by Kappa statistics (κ). Univariable and multivariable influence of different preoperatively available parameters on disease-free survival (DFS) were assessed. The mean follow-up period was 39 months. RESULTS: Concordance between GS in biopsy versus RP samples was 58% (κ-value 0.354) and was improved by an increased number of biopsy cores. Undergrading in biopsy was present in 38% and not significantly enhanced by an extended time-period between biopsy and RP (threshold 90 d). PSA level, clinical tumour stage, fraction of positive cores (dichotomized at 34%), cases of RP per year and institution (dichotomized at 75), and GS independently influenced DFS. An upgrading to GS ≥ 7 was found in only 5.7% of patients presenting with GS 2-4 in the biopsy. Independent from definitive histology, patients with GS 2-4 had a significantly better prognosis compared to patients with a higher GS. CONCLUSIONS: The present study shows an independent prognostic impact of GS in biopsy samples classified according to the previous classification. The elimination of GS 2-4 by the ISUP 2005 results in a considerable loss of pretherapeutic prognostic information and therefore should be questioned in particular with regard to the increasing demand for active surveillance regimens.

Can vaccination or tyrosine kinase inhibitor therapy play a role in the adjuvant treatment of renal cell carcinoma?

Recurrence rates of approximately 35-65% after nephrectomy in patients with localized or locally advanced renal cell carcinoma clearly underline the need for adjuvant treatment modalities. Adjuvant treatment with cytokines, hormonal treatment and radiotherapy has not shown survival benefit. The only Phase III trial revealing significant prolongation of progression-free survival was published in 2004. In this trial, targeting the immune system using an autologous tumor-cell vaccine provided clinical efficacy, but as yet, no standard adjuvant therapeutic approach is available. Recent advances in understanding the molecular biology of renal cell carcinoma led to the development of several targeted agents showing antitumor efficacy and prolongation of progression-free survival in patients with metastatic kidney cancer, but to date, no data are available regarding their applicability and efficacy in the adjuvant setting. However, controlled trials applying these drugs in the adjuvant setting have already started and, hence, the question is raised as to whether there is still a role for vaccination immunotherapy in the era of targeted therapies. In this paper, results from current Phase III trials and other relevant studies regarding adjuvant treatment in renal cell carcinoma are reviewed with special interest on adjuvant vaccination therapies, particularly regarding future options of this therapeutic approach.

Novel electromagnetic lithotriptor for upper tract stones with and without a ureteral stent.

PURPOSE: We compared the treatment efficacy and safety of the novel Lithoskop electromagnetic extracorporeal shock wave lithotriptor for upper urinary tract stones with and without prior ureteral stent placement. MATERIALS AND METHODS: A total of 665 consecutive patients harboring single renal or ureteral stones underwent shock wave lithotripsy between August 2006 and July 2008. In 75 and 46 patients with renal and ureteral stones, respectively, stents were placed before the first shock wave lithotripsy session. Treatment outcome was assessed in relation to stent placement. All data were derived from a prospectively maintained database. RESULTS: The mean size of nonstented vs stented renal and ureteral stones was 8.6 vs 12.5 mm (p <0.0001) and 7.1 vs 7.3 mm (p = 0.6), respectively. The stone-free rate in nonstented vs stented renal and ureteral stone cases was 76.3% vs 77.3% and 91.4% vs 93.5%, respectively (each p >0.99). The total energy applied per stone was 110 +/- 83 vs 150 +/- 89 J (p <0.0001) and 183 +/- 131 vs 209 +/- 125 J (p = 0.1), respectively. Auxiliary measures were required after shock wave lithotripsy for renal and ureteral stones in 5.4% and 10.8% of nonstented, and in 1.3% and 4.3% of stented cases, respectively. No complications were detected in stented renal and ureteral stone cases compared to 2.9% and 6.9% in nonstented cases, respectively. CONCLUSIONS: A high success rate and a low complication rate were achieved in renal and ureteral stone cases with and without prior ureteral stent placement. Total energy needed to achieve a stone-free state did not differ between stented and nonstented ureteral cases, suggesting the absence of a significant influence of the stent. Overall stents decreased complications necessitating hospitalization and auxiliary invasive measures.

Does the current World Health Organization classification predict the outcome better in patients with noninvasive bladder cancer of early or regular onset?

OBJECTIVE: To compare the clinical outcome and prognostic power of the former and current World Health Organization (WHO) grading system in patients with early vs regular onset of noninvasive urothelial bladder cancer (UBC), as little is known of the natural history of early onset UBC and in how far it is reflected by histopathological grading and staging in guiding clinical decisions. PATIENTS AND METHODS: The medical records of 69 consecutive patients presenting with initial UBC of early onset (>or=45 years old, EO) and of 100 randomly chosen patients with regular onset (RO) were reviewed. There were no significant differences in gender distribution, risk factors or tumour stage. All histopathological specimens were re-staged and re-graded according to the former and current WHO grading. RESULTS: In all, 51 EO and 63 RO patients with tumours staged pTa and complete follow-up information were analysed. Recurrence-free survival (RFS) was prolonged in patients with EO. In EO neither the former nor the current WHO grading system was significantly related to RFS or to progression to muscle-invasive disease. In RO, while both WHO grading systems were significantly related to RFS, only the current WHO grading system was related to progression. CONCLUSION: While larger studies are needed, UBC in patients with EO and RO do not seem to differ in risk factors and oncological outcome. The current WHO classification reflects the outcome more accurately than the former classification in patients with RO. However, for EO no grading system has sufficient prognostic power and novel methods, i.e. molecular markers, need to be evaluated for clinical use.

Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach?

OBJECTIVES: We compared long-term outcome in patients with initial pT1G3 bladder cancer (BC) treated with early versus deferred cystectomy (CX) for recurrent pT1G3 or muscle-invasive BC after an initial bladder-sparing approach. The aim of this study was to compare survival rates and to analyse the influence of the recognised risk factors multifocality, tumour size, and carcinoma in situ (CIS) in initial transurethral resection of the bladder. METHODS: Between 1995 and 2005, a total of 105 patients were diagnosed with initial pT1G3 BC featuring>or=2 risk factors. Forty-five percent had multiple tumours, 73% tumours>3 cm in size, and 46% CIS. All patients were offered early CX. Fifty-one percent of patients opted for early and 49% underwent deferred CX for recurring BC. Risk factors were distributed evenly between the groups. RESULTS: Upstaging in the CX specimen was found in 30% of cases. No risk factor was related to upstaging. The 10-yr cancer-specific survival rate was 78% in early CX and 51% in deferred CX (p<0.01). No risk factor predicted cancer-related death in early CX. In survival analysis, CIS was related to a lower cancer-specific survival rate in deferred CX (p<0.001). CONCLUSIONS: Early as opposed to deferred CX seems to prolong the cancer-specific survival rate in high-risk pT1G3 BC. Patients with CIS should be considered for early CX owing to reduced cancer-specific survival in case of deferred CX.

A patient with testicular pseudolymphoma - a rare condition mimicking malignancy: a case report.

Three months following a right sided acute epididymitis a 62 year old patient presented with a painless right testicular swelling. Physical examination, scrotal ultrasound and operative exploration suggested malignancy. However, after inguinal orchiectomy a benign pseudolymphoma of the testis was revealed by pathological examination. A pseudolymphoma is a rare benign lesion which can only be distinguished from a malignant lymphoma by immuno-histochemistry and molecular-genetical investigation techniques.

Photodynamic diagnostics and noninvasive bladder cancer: is it cost-effective in long-term application? A Germany-based cost analysis.

OBJECTIVES: Noninvasive urothelial carcinoma of the bladder (UCB) causes an enormous economic burden to public health systems due to its life-long character and frequent recurrences. While white light (WL) cystoscopy is considered to be the gold standard for transurethral resection of the bladder, photodynamic diagnostic (PDD) has been shown to improve final outcome. Escalating healthcare costs warrant increased effectiveness in treating noninvasive UCB. No data based on assessment of costs have been published to date. METHODS: A series of 301 patients with noninvasive UCB were randomized prospectively to standard WL or PDD transurethral resections of the bladder. Intravesical adjuvant therapy was administered as reflected in the appropriate guidelines. Expenditures of subsequent procedures and PDD-associated costs were assessed. RESULTS: Median follow-up was 7.1 yr. Disease recurrence was found in 42% and 18% of WL and PDD patients, respectively (p=0.0003). In the WL group 2.0 and in the PDD group 0.8 transurethral resections of the bladder were noted per patient. In the WL group 1.0 and in the PDD group 0.3 recurring UCB occurred per patient, resulting in costs of 1750 euro per WL patient versus 420 euro per PDD patient in the follow-up period, respectively. Because a single expenditure of 135 euro was assessed for PDD, overall costs were significantly lower (by 1195 euro) in PDD patients. As the median follow-up was 7.1 yr, costs saved by PDD per patient per year were 168 euro. CONCLUSION: Our data suggest that PDD significantly cut costs related to recurring UCB. Further studies are needed from an economic point of view.

C-reactive Protein in Patients with Metastatic Clear Cell Renal Carcinoma: An Important Biomarker for Tumor-associated Inflammation.

Two consecutive multi-center phase II trials were designed to prove the hypothesis, whether therapeutic modeling of tumor-associated inflammatory processes could result in improved tumor response.Therapy in both trials consisted of low-dose capecitabine 1g/m2 twice daily p.o. for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily p.o., day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily p.o., day 1+. In study II low-dose IFN-alpha 4.5 MU sc. three times a week, week 1+, was added until disease progression.Eighteen, and 33 patients, respectively, with clear cell renal carcinoma and progressive disease were enrolled. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response after 4 weeks on treatment, p = 0.0005, in all 29 pts (100%) with elevated CRP levels. Median progression-free survival could be more than doubled from a median of 4.7 months (95% CI, 1.0 to 10.4) to 11.5 months (6.8 to 16.2) in study II, p = 0.00001. Median overall survival of population II was 26 months.Efficacious negative regulation of tumor-associated inflammation by transcription modulators may result in a steep increase of tumor response and survival.

Mitogen-activated protein kinase signaling is activated in prostate tumors but not mediated by B-RAF mutations.

OBJECTIVES: A dysregulated mitogen-activated protein kinase (MAPK) pathway plays an important role in various malignancies and is often mediated by mutations in several oncogenes (eg, RAF, RAS). B-RAF mutations, predominantly the specific V600E mutation and additional alterations in exons 11 and 15, were frequently detected in malignant melanomas, papillary thyroid tumors, and colorectal cancers with microsatellite instability (MSI). The present study investigated B-RAF mutations, MSI status, and activation of MAPK signaling in prostate tumors. METHODS: The V600E mutation of the B-RAF gene was analyzed using allele-specific polymerase chain reaction in 79 archival prostatic adenocarcinomas (pT1aG1 to pT3cG3, median Gleason score 6); exons 11 and 15 were sequenced. MSI status was determined using the National Cancer Institute consensus panel for hereditary nonpolyposis colorectal carcinoma (HNPCC) detection. Active MAPK signaling was investigated using immunohistochemistry for p44/ERK1 and p42/ERK2. RESULTS: No B-RAF mutations could be detected. Six of 79 tumors showed MSI positivity. Active MAPK signaling was detected in 51% of the analyzed tumors. No correlation was found between MAPK activity and histopathologic/clinical characteristics. CONCLUSION: The most frequent B-RAF gene alterations are not involved in prostate carcinogenesis. MSI is infrequent in prostate cancer and is not linked to B-RAF mutations. MAPK signaling is frequently activated in prostate tumors and might be suitable for a therapeutic approach.