R. Küfer

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.

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.

CHORIOALLANTOIC MEMBRANE ASSAY: VASCULARIZED 3-DIMENSIONAL CELL CULTURE SYSTEM FOR HUMAN PROSTATE CANCER CELLS AS AN ANIMAL SUBSTITUTE MODEL

PURPOSE Chorioallantoic membranes have been used as a reliable biomedical assay system for many years. Chicken eggs in the early phase of breeding are between in vitro and in vivo systems but may provide an immunodeficient, vascularized test environment. We tested this model as an in vivo system for prostate cancer research. MATERIALS AND METHODS Single cell suspensions of LNCaP, PC-3 and Tsu-Pr1 human prostatic cancer cell lines as well as 2 immortalized normal human prostate epithelial cell lines were inoculated on the chorioallantoic membrane of fertilized chicken eggs on day 5 or 6 of breeding. Tumor growth and viability of the embryo was evaluated by stereo microscopy. At day 10 the membranes were removed and embedded in paraffin. Cell morphology was assessed after hematoxylin and eosin staining. Cellular expression of cytokeratin, prostate specific antigen and androgen receptor as well as apoptosis induction was confirmed by immunohistochemistry. RESULTS Three days after tumor cell inoculation on the extraembryonic vascular system of the chorioallantoic membrane cell growth and formation of 3-dimensional tumors became apparent in 100% of inoculated membranes. Strong neo-angiogenesis was detected next to the established tumors and tumor cells invading the stroma of the chorioallantoic membrane. Cytokeratin expression as well as prostate specific antigen and androgen receptor in LNCaP cells confirmed the human prostate tumor origin. Assessment of quantitative in vivo apoptosis induction in LNCaP cells after intravenous injection of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate confirmed the model as a versatile in vivo system. CONCLUSIONS The well vascularized chorioallantoic membrane of bred chicken eggs is a suitable system for early in vivo cancer research. Reliable growth of prostate cancer cell lines is feasible and allows the evaluation of proliferation and apoptosis induction after intravascular or topic application of anticancer drugs. Exploitation of this assay enables a substantial reduction in or substitution for subsequent animal experiments.

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.

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

To evaluate and compare the role of 11C‐choline positron emission tomography (PET) and transrectal ultrasonography (TRUS) in the preoperative staging of clinically localized prostate cancer.

New-Generation Lithotripters for Treatment of Patients with Implantable Cardioverter Defibrillator: Experimental Approach and Review of Literature

PURPOSE The influence of shockwaves applied during extracorporeal shockwave lithotripsy on the function of implantable cardioverter defibrillators was evaluated. Mechanical influences as well as proper electrical function were tested in an experimental approach. MATERIALS AND METHODS Two implantable defibrillators (Ventak Mini 1743 and AVII 1821) were exposed to the shockwaves of a new-generation lithotripter. Each of the antidysrhythmic devices was tested at several distances from and within the focus of the lithotripter. All studies were performed with maximum energy and the number of shockwaves used for stone treatment. The devices were connected to an ECG simulator, and continuous recording of a surface ECG, a shock ECG, and marker channel was performed. RESULTS No macroscopic and microscopic mechanical damage was observed. The detection function of the implantable defibrillators was not altered by any electromagnetic artifacts even when brought into the focus of the shockwaves. All induced ventricular dysrhythmias were terminated properly regarding artifact sensing. However, after defibrillation, the pacing function of the Ventak Mini cardioverter defibrillator, which was programmed into the demand mode, failed. In this case, there was no post-shock pacing in the period of post-defibrillation asystole. The failure was caused by artifact oversensing. CONCLUSION In patients with implanted cardiac devices undergoing treatment with a new-generation lithotripter, deactivation of the defibrillator is not mandatory. For safety reasons, continuous ECG recording is recommended. To avoid pacing failure by artifact oversensing, the shockwaves should be applied in a R-wave synchronous mode.

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.

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.

Testosteronsubstitution und Prostatakarzinom

Hypogonadism is highly prevalent in the elderly and in men with prostate cancer. Symptoms of hypogonadism, such as depression, lack of libido, and decreased bone mineral density, can significantly impair quality of life. In addition, testosterone plays an important role in erectile preservation and in growth and function of the cavernosal and penile nerves. There are compelling data showing that testosterone replacement therapy (TRT) does not increase the risk of prostate cancer. The literature (four published studies) concerning men treated with TRT after definitive therapy for prostate cancer reports only one biochemical recurrence. Based on these data, physicians cannot really justify withholding TRT from symptomatic patients after they have been successful treated for prostate cancer. This review gives the practising urologist an overview of the latest literature and useful advice on this controversial topic.

[Klippel-Trénaunay syndrome. A rare cause of recurrent macrohematuria: case report].

ZusammenfassungEin 37-jähriger Mann mit Klippel-Trenaunay-Syndrom stellt sich mit einer ausgeprägten schmerzlosen Makrohämaturie in unserer Klinik vor. Ein MRT ergab Blutgefäße mit ausgedehntem Durchmesser in der Blasenwand. Eine diagnostische Bildgebung ist in diesem Fall unverzichtbar, um sich über das genaue Ausmaß der Läsion ein Bild zu verschaffen, da die intraoperativ gefundene Blutungsquelle häufig nur die „Spitze des Eisberges“ sein kann. Die Laserkoagulation ist bei Versagen konservativer Maßnahmen die Therapie der Wahl.AbstractA 37-year-old man with Klippel-Trénaunay syndrome presented with an episode of painless severe gross hematuria. Magnetic resonance imaging (MRI) revealed vessels of significant diameter in the bladder wall. Diagnostic imaging is mandatory in order to be aware of the extent of the lesion as the bleeding identified intraoperatively may only be the “tip of the iceberg.” If conservative means fail, laser coagulation should be the treatment of choice.