Functional Outcome and Complications following Ileal Neobladder Reconstruction in Male Patients without Tumor Recurrence. More than 35 Years of Experience from a Single Center.

PURPOSE: There is a lack of data on true long-term functional outcome of orthotopic bladder substitution. The primary study objective was to report our 35-year clinical experience. MATERIALS AND METHODS: Since October 1985, 259 male patients from a large single center radical cystectomy series with complete followup of more than 60 months (median 121, range 60-267) without recurrence, irradiation or undiversion that might have affected the functional outcome, were included. RESULTS: Median age at radical cystectomy and at survey was 63 (range 23-81) and 75 (range 43-92) years, respectively. Overall 87% of patients voided spontaneously and residual-free. This rate decreased with increasing age at the time of surgery (less than 50 years old 94%, 70 years old or older 82%). Overall day/nighttime continence rates were 90%/82%. These rates decreased with increasing age at the time of surgery from 100%/88% to 87%/80%. The overall pad-free rate was 71%/47%. Bicarbonate use decreased from 51% (5 years) to 19% (25 years). Patients with a followup of more than 20 years had the lowest rate of residual urine and clean intermittent catheterization (0.0%) as well as use of more than 1 pad at daytime/nighttime (6.3%/12.5%) and mucus obstruction (0.0%). Serum creatinine showed only the age related increase. The surgical complication rate was 27% and correlated inversely with functional results (chi-squared 11.227, p <0.005), even when the younger age at the time of surgery (younger than 60 years) was related to higher rates of surgical complications (chi-squared 6.80, p <0.05). CONCLUSIONS: The ileal neobladder represents an excellent long-term option for urinary diversion with an acceptable complication rate.

Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14.

INTRODUCTION: Prostate cancer is the most frequent malignancy found to occur in Caucasian men, but its genetic basis remains elusive. A prostate cancer-susceptibility locus has been identified on chromosome 13q14. The tumour suppressor gene deleted in cancer cells 1 (DICE1/INTS6) is located within this interval on 13q14.3. MATERIALS AND METHODS: We performed mutation analysis of the DICE1/INTS6 gene in thirteen German prostate cancer families. RESULTS AND CONCLUSION: None of the patients harboured DICE1 mutations, and similar frequencies of the previously identified 13 bp deletion polymorphism in the DICE1 promoter were observed in the familial prostate cancer patients as compared with sporadic prostate cancer patients and controls. However, in one family with three affected brothers, the variations c.1215A>C (p.T405T) in exon 10 and c.2568A>G (p.S856S) in exon 17 were detected in a heterozygous pattern. In sporadic prostate cancer patients, variant c.2568A>G (p.S856S) was detected in 10/325 (3.08%) compared with 5/207 (2.42%) control samples (p > 0.05). We conclude that DICE1 appears to be involved in prostate cancer progression rather than in the initiation of prostate cancer.

Association of oncofetal protein expression with clinical outcomes in patients with urothelial carcinoma of the bladder.

PURPOSE: Oncofetal proteins are expressed in the developing embryo. Oncofetal protein expression correlates with the clinical outcome of nonmuscle invasive bladder urothelial carcinoma. IMP3, MAGE-A, glypican-3 and TPBG are oncofetal proteins that have not been well characterized in urothelial carcinoma of the bladder. MATERIALS AND METHODS: We investigated the expression of these 4 proteins and their association with clinical outcomes using tissue microarrays from 384 consecutive patients treated with radical cystectomy between 1988 and 2003 at 1 academic center. We stained for IMP3, MAGE-A, glypican-3 and TPBG. Univariable and multivariable Cox regression analyses were done to evaluate the association of oncofetal protein expression with disease recurrence and cancer specific mortality. RESULTS: IMP3, MAGE-A, glypican-3 and TPBG were expressed in 39.5%, 45%, 6% and 85% of urothelial bladder carcinomas, respectively. Expression was tumor specific and did not correlate with pathological features except for TPBG. At a median followup of 128 months 176 patients (46%) experienced disease recurrence, 175 (45.5%) had died of the disease and 96 (27.5%) had died of another cause. On univariable analysis IMP3 and MAGE-A expression was associated with an increased risk of disease recurrence (p <0.001 and 0.03) and cancer specific mortality (p = 0.004 and 0.03, respectively). On multivariable Cox regression analysis adjusted for the effects of standard clinicopathological features IMP3 and MAGE-A expression was independently associated with disease recurrence (p = 0.004, HR 1.55, 95% CI 1.15-2.11 and p = 0.02, HR 1.44, 95% CI 1.05-1.99, respectively) but not with cancer specific mortality. CONCLUSIONS: Oncofetal proteins are commonly and differentially expressed in urothelial carcinoma of the bladder compared to normal urothelium. IMP3 and MAGE-A expression was associated with disease recurrence and cancer specific mortality but glypican-3 and TPBG expression was not.

Frequent truncating mutations of STAG2 in bladder cancer.

Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer.

Loss of SPINK1 expression is associated with unfavorable outcomes in urothelial carcinoma of the bladder after radical cystectomy.

BACKGROUND: We assessed the association of serine protease inhibitor Kazal type I (SPINK1) expression with clinicopathologic outcomes in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC). MATERIALS AND METHODS: Tissue microarrays comprising 438 consecutive UCB patients treated with RC between 1988 and 2003 and 62 cases of normal urothelium controls were evaluated for SPINK1 protein expression by immunohistochemistry (IHC). Semiquantitative evaluation was performed by 2 pathologists blinded to clinical outcomes (loss of expression: <50% cells or intensity 0-2). RESULTS: In normal urothelium, SPINK1 expression was noted in umbrella cells of 32 of 62 controls (52%); 254 RC patients (57.9%) exhibited loss of SPINK1 expression. Loss of SPINK1 expression was significantly associated with higher pathologic stages (P = 0.002) and presence of lymph node metastasis (P = 0.04). At a median follow-up of 130 months (IQR: 98.4), loss of SPINK1 expression was associated with an increased risk of disease recurrence (P = 0.02) and cancer-specific mortality (P = 0.03). On multivariable analysis that adjusted for the effects of standard clinicopathologic parameters, SPINK1 was not an independent predictor of disease recurrence (P = 0.09) or cancer-specific mortality (P = 0.12). CONCLUSIONS: Over half of UCB patients treated with RC exhibit loss of SPINK1 expression. Loss of SPINK1 correlates with features of biologically aggressive UCB. Although SPINK1 expression did not have independent prognostic value in RC patients, it may serve as a biomarker for tumor staging and may be useful as an adjunct in clinical decision-making.

Protein kinase D2 is a crucial regulator of tumour cell-endothelial cell communication in gastrointestinal tumours.

BACKGROUND: Tumour angiogenesis is crucially dependent on the communication between the tumour and the associated endothelium. Protein kinase D (PKD) isoenzymes mediate vascular endothelial growth factor-A (VEGF-A) induced endothelial cell proliferation and migration and are also highly expressed in various tumours. AIM: To examine the role of PKDs for tumour proliferation and angiogenesis selectively in pancreatic and gastric tumours and in tumour-associated endothelium in vitro and in vivo. METHODS: PKD2 expression in human tumours was determined by immunohistochemistry. The effect of PKD2 depletion in endothelial cells by siRNAs was examined in sprouting assays, the chorioallantois model (CAM) and tumour xenografts. In murine endothelium in vivo PKD2 was knocked-down by splice switching oligonucleotides. Human PKD2 was depleted in xenografts by siRNAs and PKD2-miRs. PKD2 activation by hypoxia and its role for hypoxia-induced NR4/TR3- and VEGF-A promoter activity, expression and secretion was investigated in cell lines. RESULTS: PKD2 is expressed in gastrointestinal tumours and in the tumour-associated endothelium. Tumour growth and angiogenesis in the CAM and in tumour xenografts require PKD expression in endothelial cells. Conversely, hypoxia activates PKD2 in pancreatic cancer cells and PKD2 was identified as the major mediator of hypoxia-stimulated VEGF-A promoter activity, expression and secretion in tumour cells. PKD2 depletion in pancreatic tumours inhibited tumour-driven blood vessel formation and tumour growth in the CAM and in orthotopic pancreatic cancer xenografts. CONCLUSION: PKD2 regulates hypoxia-induced VEGF-A expression/secretion by tumour cells and VEGF-A stimulated blood vessel formation. PKD2 is a novel, essential mediator of tumour cell-endothelial cell communication and a promising therapeutic target to inhibit angiogenesis in gastrointestinal cancers.

Metronomic treatment with low-dose trofosfamide leads to a long-term remission in a patient with docetaxel-refractory advanced metastatic prostate cancer.

The treatment of metastatic prostate cancer patients refractory to androgen withdrawal and docetaxel therapy is currently discouraging and new therapeutic approaches are vastly needed. Here, we report a long-term remission over one year in a 68-year-old patient with metastatic docetaxel-refractory prostate cancer employing low-dose trofosfamide. The patient suffered from distant failure with several bone lesions and lymph node metastases depicted by a (11) C-Choline positron emission tomography/computerized tomography (PET/CT). After initiation of trofosfamide 100 mg taken orally once a day we observed a steadily decreasing PSA value from initial 46.6 down to 2.1 mug/L. The Choline-PET/CT was repeated after 10 months of continuous therapy and demonstrated a partial remission of the bone lesions and a regression of all involved lymph nodes but one. Taken together we found an astonishing and durable activity of the alkylating agent trofosfamide given in a metronomic fashion. We rate the side effects as low and state an excellent therapeutic ratio of this drug in our patient.

Prostate carcinoma: diffusion-weighted imaging as potential alternative to conventional MR and 11C-choline PET/CT for detection of bone metastases.

In a technical development study approved by the institutional ethics committee, the feasibility of fast diffusion-weighted imaging as a replacement for conventional magnetic resonance (MR) imaging sequences (short inversion time inversion recovery [STIR] and T1-weighted spin echo [SE]) and positron emission tomography (PET)/computed tomography (CT) in the detection of skeletal metastases from prostate cancer was evaluated. MR imaging and carbon 11 ((11)C) choline PET/CT data from 11 consecutive prostate cancer patients with bone metastases were analyzed. Diffusion-weighted imaging appears to be equal, if not superior, to STIR and T1-weighted SE sequences and equally as effective as (11)C-choline PET/CT in detection of bone metastases in these patients. Diffusion-weighted imaging should be considered for further evaluation and comparisons with PET/CT for comprehensive whole-body staging and restaging in prostate and other cancers.

Inhibition of glycogen synthase kinase-3 in androgen-responsive prostate cancer cell lines: are GSK inhibitors therapeutically useful?

The glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase widely expressed in mammalian tissues. Initially identified by its ability to modulate glycogen synthesis, GSK-3 turned out to be a multifunctional enzyme, able to phosphorylate many proteins, including members of the steroid receptor superfamily. Although GSK-3 was shown to phosphorylate the androgen receptor (AR), its effects on AR transcriptional activity remain controversial. Analysis of short hairpin RNA (shRNA)-mediated downmodulation of GSK-3 proteins in prostate cancer cells showed a reduction in AR transcriptional activity and AR protein levels. Pharmacological GSK-3 inhibitors such as the maleimide SB216763 or the aminopyrazole GSK inhibitor XIII inhibited AR-dependent reporter gene activity and AR expression in vitro. Analysis of androgen-induced nuclear translocation of the AR was performed in PC3 cells transfected with pAR-t1EosFP coding for EosAR, a green fluorescent AR fusion protein. When grown in presence of androgens, EosAR was predominantly nuclear. Incubation with SB216763 before and after androgen treatment almost completely reduced nuclear EosAR. In contrast, the thiazole-containing urea compound AR-A014418 increased rather than decreased AR-expression/function. Although not all GSK inhibitors affected AR-stability/function, our observations suggest a potential new therapeutic application for some of these compounds in prostate cancer.

11C-choline positron-emission tomography/computed tomography and transrectal ultrasonography for staging localized prostate cancer.

OBJECTIVE: To evaluate and compare the role of (11)C-choline positron emission tomography (PET) and transrectal ultrasonography (TRUS) in the preoperative staging of clinically localized prostate cancer. PATIENTS AND METHODS: Fifty-five consecutive patients with biopsy-confirmed prostate cancer had TRUS and (11)C-choline PET as a part of their clinical staging programme before radical retropubic prostatectomy (RP). The PET images were prospectively interpreted by a consensus decision of two nuclear medicine physicians and one radiologist with special expertise in the field. The TRUS was done by one experienced urologist. The criteria evaluated prospectively in each patient were extracapsular extension (ECE), seminal vesicle invasion (SVI) and bladder neck invasion (BNI). The results were compared with the histopathological findings after RP. RESULTS: At pathology, 32 patients were classified pT2, 16 as pT3a and three had pT3b lesions. In four patients the histopathological examination showed pT4 with BNI. The overall accuracy of PET in defining local tumour stage (pT2 and pT3a-4) was 70%; the overall accuracy by TRUS was 26%. PET was more sensitive than TRUS for detecting ECE (pT3a) and SVI (pT3b) in advanced stages, and in pT4 stages. The sensitivity and positive predictive value (PPV) (95% confidence interval) in stages pT3a-pT4 for PET were 36 (17-59)% and 73 (39-89)%. The sensitivity and PPV in stages pT3a-pT4 for TRUS were 14 (3-35)% and 100 (29-100)%. CONCLUSIONS: (11)C-choline PET and TRUS tended to understage prostate cancer. This series shows the current limited value of TRUS and PET for making treatment decisions in patients with clinically localized prostate cancer, especially if a nerve-sparing RP is considered. Treatment decisions should not be based on TRUS and (11)C-choline PET findings alone. In future studies, the combination of metabolic and anatomical information of PET and endorectal magnetic resonance imaging should be evaluated, as this might optimize the preoperative staging in prostate cancer.

Use of transrectal ultrasound-guided biopsy in the diagnosis of pelvic malignancies.

PURPOSE: To describe our experience with transrectal ultrasound (TRUS)-guided needle biopsy of pelvic malignancies. METHODS: Eleven patients with clinical suspecion of advanced malignant pelvic tumor were referred to our institution with a history of unsuccessful CT-guided biopsy, although a target lesion was demonstrated on pelvic CT or MRI. Cholin-PET and FDG-18-PET were also obtained individually in each patient. TRUS was performed using a commercially available three-dimensional scanner. Biopsies were performed with an 18G biopsy gun. In 9 of 11 patients, biopsy was successfully performed under analgesia, whereas general anesthesia was required in the other 2 patients. RESULTS: The lesions were identified with TRUS in all patients, and biopsies were taken successfully under TRUS guidance. In all patients, the harvested material was of excellent quality and was adequate for definitive pathological diagnosis. Pathological results included 6 nodal metastases from transitional cell carcinoma, 1 case of lymph node metastasis from prostate cancer, 1 paravesical recurrence of cervical cancer, 1 metastasis from cecal cancer, and 2 cases of paravesical metastasis of a gastric cancer. CONCLUSION: TRUS-guided biopsy is a useful technique for the diagnosis of pelvic malignancies. It is faster and less expensive than CT-guided biopsy, and in most cases sufficient material can be harvested for a definitive pathological diagnosis.

Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer.

BACKGROUND: It has been indicated that altered expression of the epidermal growth factor receptor (EGFR) promotes the invasive and metastatic potential of a variety of human malignancies. Therefore, the aim of the present study was to determine EGFR expression in clear cell renal cell carcinomas (RCC) to evaluate its prognostic relevance for the clinical course of the disease. MATERIALS AND METHODS: EGFR protein expression, detected by immunohistochemistry and tissue microarray analysis (TMA), was investigated in a cohort of 149 randomly selected patients subjected to tumor nephrectomy for RCC. RESULTS: The tumor cells preferably exhibited a homogeneous membrane-bound reactivity for EGFR; EGFR overexpression was detected in 70 (47%) of the primary tumor specimens, but in only 12 (9%) of the benign tissue samples (p<0.0001; Fisher's t-test). Tumor-associated EGFR staining was stratified into three groups: I: low staining score (n=75, 50%); II: intense expression (n=56, 38%); and III: strong overexpression (n = 18, 12%). Strong reactivity for EGFR was identified as predicting the patients' survival both during uni- and multivariate analysis (p=0.03). Interestingly, the overall survival of the intense expression group surpassed even the low expression group (p=0.023). CONCLUSION: The observation that primary RCC specimens exhibit EGFR at higher levels when compared with benign renal parenchyma indicates its role in tumor development and progression. The availability of more refined prognostic factors would assist decision making in terms of the value of more aggressive treatment options for prognostically defined subgroups of patients. Additionally, if overexpression of EGFR identifies RCC with a more aggressive biological behavior, the latter receptor might serve as a novel target for a more effective therapeutical approach to RCC.

Cystectomy and orthotopic ileal neobladder: the impact on female sexuality.

PURPOSE: January 1986 and September 2003 cystectomy and formation of an ileal neobladder were performed in 86 female patients. In this retrospective study we focused on the impact of orthotopic reconstruction on female sexuality. MATERIALS AND METHODS: To assess female sexuality the standardized self-reporting instrument female sexual function index was mailed to 44 patients who were 70 years or younger at cystectomy with a recurrence-free followup of greater than 1 year, no pelvic irradiation and no concomitant diseases impairing sexual functions. The questionnaire analyzes 6 domains (desire, arousal, lubrication, orgasm, satisfaction and pain) with 19 items. It was returned by 29 patients (65.9%) with a median age of 65.0 years. The indication for cystectomy was benign disease in 8 cases and malignancy in 21. RESULTS: Factors influencing female sexuality were age younger than 60 years, benign disease, partnership at surgery and current partnership. Clean intermittent catheterization, urinary stress incontinence and hormonal therapy did not affect the results. The 11 of 17 patients who remained sexually active after cystectomy even had slight improvement in all female sexual function items. Six patients ceased to be sexually active postoperatively due to erectile dysfunction or partner death. One patient with interstitial cystitis became sexually active following cystectomy due to the loss of pelvic pain. Another 12 patients remained sexually inactive postoperatively. CONCLUSIONS: All aspects of female sexuality may remain unchanged following cystectomy and ileal neobladder formation as long as sexual activity is not ceased due to other reasons. Even fertility can be preserved when the internal genitalia do not have to be removed.

Outcome in patients with seminal vesicle invasion after radical cystectomy.

PURPOSE: We evaluated the impact of seminal vesicle invasion by transitional cell carcinoma of the bladder in a large cystectomy series. MATERIALS AND METHODS: Between January 1985 and February 2002, 1,125 cystectomies were performed at our 2 institutions. In 68 male patients there was pathologically proved tumor extension to the perivesical fat, prostatic stroma and/or seminal vesicles, including group 1: 38 to the prostatic stroma alone, group 2-12 to the seminal vesicles alone, and group 3-18 to the seminal vesicles and prostatic stroma. Complete followup was available for all patients. Overall disease specific and progression-free survival rates were calculated using the Kaplan-Maier-Method. Survival rates were compared using the log rank test. RESULTS: The overall 5-year survival rate for all 68 patients was 23.1%. The 5-year disease specific survival rates were 41.1%, 0% and 0%, and the 5-year progression-free survival rates were 32.1%, 0% and 0% for groups 1 to 3, respectively. Survival was significantly decreased in patients with seminal vesicle infiltration with or without prostatic stromal infiltration compared with prostatic involvement alone. This difference was independent of lymph node status in groups 1 versus 2 and 3. CONCLUSIONS: Seminal vesicle invasion by bladder carcinoma has a significant impact on disease specific and progression-free survival compared with prostatic stromal involvement alone.

An innovative mobile lithotripter for extracorporeal shock wave lithotripsy and therapy.

INTRODUCTION: To assess the performance of a new mobile device for extracorporeal shock wave lithotripsy (ESWL) and therapy (ESWT). MATERIALS AND METHODS: 278 patients underwent 399 treatment for stone disease. 28 patients received 64 treatments for orthopaedic issues such as pseudarthrosis or enthesiopathies resistant to conservative treatment. RESULTS: During ESWL, minor pain symptoms were well resolved with analgesics intravenously. 45% of patients were stone-free and 50% had irrelevant fragments at the time of discharge. 66% of patients underwent a single treatment. Auxiliary measures after ESWL were necessary in 5%. After ESWT, pain symptoms of all patients were reduced on average to 5.2 points on a numerical rating scale from 1 to 10. Patients with bony nonunions produced callus if the bone scan before ESWT showed activity. No complication related to either form of treatment was observed. CONCLUSIONS: This innovative mobile lithotripter fulfils all expectations a user can have in an upt-to-date equipment: good disintegration, low side effects, easy handling, fast installation, dual imaging and suitability for ESWL and ESWT.