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Summary. About 20% of patients with erectile dysfunction do not react to intracavernous pharmacological treatment (SKAT) because of a cavernous leak. The first attempt to treat venous insufficiency goes back as far as the beginning of the century. Ligature and resection of the superficial and deep veins of the penis (DPVL) were performed in 122 patients (nonresponders to SKAT with a maintenance flow of less than 40 ml min−1). Twenty-four patients suffered from primary dysfunction and 98 from secondary dysfunction. The average age of the patients was 49 years, and the average duration of the preoperative erectile dysfunction 4.4 years. Postoperative follow-up was carried out for 70 months. In 98% of the patients, cavernosography revealed a dorsal leak. Twenty-six per cent had ectopic veins, 38% a leakage through the crural veins and 24% a glandular or spongiosal shunt. After the 70-month follow-up, only 14% of the 122 patients were able to achieve an adequate spontaneous erection and 19% also responded to SKAT. Depending upon the time elapsed since the operation, the rate of spontaneous reaction was reduced. It was found that younger patients with a short history of erectile dysfunction, no arterial cofactor, a maintenance flow of less than 100 ml min−1 and a severe dorsal leakage from a DPVL were the most likely to benefit from this procedure. Since degeneration of smooth muscle cells of the cavernosa is in most patients the cause of the venous leakage, penis vein surgery is to be regarded as symptomatic treatment.

Zusammenfassung Carnitin im Spermaplasma als Parameter fur die Nebenhodenfunktion Carnitin kann als ein Reprasentant des Sekretes gelten, das uber den Ductus deferens dem Ejakulat zufliest. Uber 94% des freien Carnitin stammen aus dem Nebenhoden. Die Haufigkeitsverteilung des Carnitingehaltes im Sperma bei Normalpersonen und Azoospermien wird dargelegt; die Korrelation mit den konventionellen Spermiogramm-Parametern wird besprochen. Bei verschiedenen andrologischen Krankheitsbildern wird auch unter besonderer Berucksichtigung von Vasoresektionen und Klinefelter-Syndromen die Wertigkeit der Carnitinbestimmung untersucht. Anhand von zwei kasuistischen Beispielen wird dargelegt, wie man aufgrund gleichzeitiger Bestimmung von Fruktose, Citrat und Carnitin einen hohen Samenwegsverschlus diagnostizieren kann. Split-Ejakulatuntersuchungen bestatiten, das das freie Carnitin nicht aus den Blaschendrusen stammt, sondern uber den Ductus deferens dem Sperma zufliest.

Objective To reduce the incidence of postoperative palpable induration after treating congenital penile curvature, using a modified corporoplasty technique. Patients and methods In a retrospective unrandomized clinical trial, 105 patients with a congenital penile angulation of >30° and for whom coitus was therefore difficult or impossible, underwent surgical correction. Of the 105 patients, 55 underwent the Nesbit–Kelâmi technique, whereby a diamond-shaped section of the tunica albuginea is excised and the defect closed with an interrupted suture. The remaining 50 patients underwent the modified corporoplasty, the edges of the tunica albuginea being brought together with a continuous, blood-tight, intratunical suture, and the end knots buried. Results The early results ( 6 months) also showed that these patients developed fewer palpable indurations (16% vs 44%). Conclusion The modified corporoplasty reduced the incidence of postoperative haematoma and late complications (e.g. palpable indurations) after the surgical correction of congenital penile curvature.

Background Although cancer of the prostate is one of the most commonly diagnosed cancers in men, no curative treatment currently exists after its progression beyond resectable boundaries. Therefore, new agents for targeted treatment strategies are needed. Cross-linking of tumor antigens with T-cell associated antigens by bispecific monoclonal antibodies have been shown to increase antigen-specific cytotoxicity in T-cells. Since the prostate-specific membrane antigen (PSMA) represents an excellent tumor target, immunotherapy with bispecific diabodies could be a promising novel treatment option for prostate cancer. Methods A heterodimeric diabody specific for human PSMA and the T-cell antigen CD3 was constructed from the DNA of anti-CD3 and anti-PSMA single chain Fv fragments (scFv). It was expressed in E. coli using a vector containing a bicistronic operon for co-secretion of the hybrid scFv VHCD3-VLPSMA and VHPSMA-VLCD3. The resulting PSMAxCD3 diabody was purified from the periplasmic extract by immobilized metal affinity chromatography (IMAC). The binding properties were tested on PSMA-expressing prostate cancer cells and PSMA-negative cell lines as well as on Jurkat cells by flow cytometry. For in vitro functional analysis, a cell viability test (WST) was used. For in vivo evaluation the diabody was applied together with human peripheral blood lymphocytes (PBL) in a C4-2 xenograft-SCID mouse model. Results By Blue Native gel electrophoresis, it could be shown that the PSMAxCD3 diabody is mainly a tetramer. Specific binding both to CD3-expressing Jurkat cells and PSMA-expressing C4-2 cells was shown by flow cytometry. In vitro, the diabody proved to be a potent agent for retargeting PBL to lyze C4-2 prostate cancer cells. Treatment of SCID mice inoculated with C4-2 tumor xenografts with the diabody and PBL efficiently inhibited tumor growth. Conclusions The PSMAxCD3 diabody bears the potential for facilitating immunotherapy of prostate cancer and for the elimination of minimal residual disease.

BACKGROUND Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo. METHODS The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts. RESULTS In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC50 value = 220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected. CONCLUSIONS A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer. Prostate 68: 129–138, 2008. © 2007 Wiley-Liss, Inc.

// Marta Michalska 1 , Susanne Schultze-Seemann 1 , Lioudmila Bogatyreva 2 , Dieter Hauschke 2 , Ulrich Wetterauer 1 , Philipp Wolf 1 1 Department of Urology, Medical Center, University of Freiburg, Freiburg, Germany 2 Institute for Medical Biometry and Statistics, Medical Center, University of Freiburg, Freiburg, Germany Correspondence to: Philipp Wolf, e-mail: philipp.wolf@uniklinik-freiburg.de Keywords: prostate cancer, PSMA, immunotoxin, docetaxel, chemotherapy Received: November 26, 2015 Accepted: February 23, 2016 Published: March 9, 2016 ABSTRACT Docetaxel (DOC) is used for the first-line treatment of castration resistant prostate cancer (CPRC). However, the therapeutic effects are limited, only about one half of patients respond to the therapy and severe side effects possibly lead to discontinuation of treatment. Therefore, actual research is focused on the development of new DOC-based combination treatments. In this study we investigated the antitumor effects of a recombinant immunotoxin targeting the prostate specific membrane antigen (PSMA) in combination with DOC in vitro and in vivo . The immunotoxin consists of an anti-PSMA single chain antibody fragment (scFv) as binding and a truncated form of Pseudomonas aeruginosa Exotoxin A (PE40) as toxin domain. The immunotoxin induced apoptosis and specifically reduced the viability of androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cells. A synergistic cytotoxic activity was observed in combination with DOC with IC 50 values in the low picomolar or even femtomolar range. Moreover, combination treatment resulted in an enhanced antitumor activity in a C4-2 SCID mouse xenograft model. This highlights the immunotoxin as a promising therapeutic agent for a future DOC-based combination therapy of CPRC.

To compare task performances of novices and experts using advanced high-definition 3D versus 2D optical systems in a surgical simulator model. Fifty medical students (novices in laparoscopy) were randomly assigned to perform five standardized tasks adopted from the Fundamentals of Laparoscopic Surgery (FLS) curriculum in either a 2D or 3D laparoscopy simulator system. In addition, eight experts performed the same tasks. Task performances were evaluated using a validated scoring system of the SAGES/FLS program. Participants were asked to rate 16 items in a questionnaire. Overall task performance of novices was significantly better using stereoscopic visualization. Superiority of performances in 3D reached a level of significance for tasks peg transfer and precision cutting. No significant differences were noted in performances of experts when using either 2D or 3D. Overall performances of experts compared to novices were better in both 2D and 3D. Scorings in the questionnaires showed a tendency toward lower scores in the group of novices using 3D. Stereoscopic imaging significantly improves performance of laparoscopic phantom tasks of novices. The current study confirms earlier data based on a large number of participants and a standardized task and scoring system. Participants felt more confident and comfortable when using a 3D laparoscopic system. However, the question remains open whether these findings translate into faster and safer operations in a clinical setting.

Purpose: Adjuvant intravesical immunotherapy with bacillus Calmette-Guerin (BCG) for noninvasive superficial bladder cancer has been shown to decrease tumor recurrence significantly. However, serious local and systemic side effects of this treatment have promoted the use of other immunoactive substances, which to date have failed to show efficacy equal to that of BCG immunotherapy. Materials and Methods: In the current phase I/II clinical trial an aqueous mistletoe extract standardized to mistletoe lectin was administered intravesically to 30 patients with superficial urothelial bladder carcinoma. About 4 weeks after transurethral resection each patient received 6 instillations at weekly intervals of 50 ml extract with mistletoe lectin concentrations between 10 and 5,000 ng/ml, which was retained in the bladder for 2 hours. Three patients per group received a dose, which was then doubled in the next group. Clinical followup consisted of examinations with cystoscopy, cytology and random biopsies. To detect cytokines and tumor necrosis factor-p75 receptor venous blood and urine samples were taken before instillation, and 2, 6 and 24 hours thereafter. Results: The tolerability of intravesically administered mistletoe extract was good at all applied concentrations. None of the patients had local or systemic side effects according to WHO classification 1–4. Within the 12-month observation time study patients with pTa G2 and pT1 G2 tumors showed a recurrence rate of 33%, comparable to that in a local historical control group of patients with equal stage and grade who were treated with adjuvant BCG. Comparison of urine cytokine levels before instillation, and 2, 6 and 24 hours thereafter brought about no significant alterations in all measured cytokines. Conclusions: From these results it is concluded that standardized mistletoe extract could be a potential alternative adjuvant therapy for superficial bladder cancer. Nevertheless, the optimal intravesical treatment regimen has yet to be defined.

To evaluate the viability and biocompatibility of a novel, patented bioadhesive system for intrarenal embedding and retrieval of residual fragments after endoscopic lithotripsy. Complete stone clearance via active removal of residual fragments (RF) after intracorporeal laser lithotripsy may be time-consuming and fail in many cases. Therefore, the novel adhesive has been developed and evaluated for the first time in an in vivo pig model in the present work. Four female domestic pigs underwent flexible ureteroscopy (RIRS) or percutaneous nephrolithotomy (PNL) under general anesthesia (8 kidneys, 4 × RIRS, 4 × PNL) evaluating the bioadhesive system. Interventions: RIRS without adhesive system (sham procedure, kidney I); 3 × RIRS using the bioadhesive system (kidneys II–IV); and 4 × PNL using the bioadhesive system (V–VIII). We endoscopically inserted standardized human stone probes followed by comminution using Ho:YAG lithotripsy. The bioadhesive (kidney II–VIII) was then applied and the adhesive-stone fragment complex extracted. After nephrectomy, all kidneys were evaluated by two independent, blinded pathologists. Endpoints were the procedure’s safety and adhesive system’s biocompatibility. We observed no substantial toxic effects. We were able to embed and remove 80–90% of fragments. However, because of the pig’s hampering pyelocaliceal anatomy, a quantified, proportional assessment of the embedded fragments was compromised. For the first time, we demonstrated the proven feasibility and safety of this novel bioadhesive system for embedding and endoscopically removing small RF in conjunction with a lack of organ toxicity in vivo.

Sildenafil is the oral phosphodiesterase-5 inhibitor that revolutionized treatment for erectile dysfunction. We investigated a potential association of the G protein beta 3 subunit (GNB3) C825T polymorphism, a determinant of intracellular signal transduction, with the drug response to sildenafil in patients with erectile dysfunction.In 113 men with erectile dysfunction and 111 healthy male controls genotype status of the GNB3 C825T polymorphism was determined by polymerase chain reaction and restriction analysis. Patients with erectile dysfunction received sildenafil at a dose of 25 to 100 mg. according to the individual erectile response. Drug response was measured by interviewing the patient according to the erection scale of 0 to 5.The GNB3 genotype distribution of patients with erectile dysfunction exactly matched that of healthy controls. Analysis of the response to sildenafil revealed a significant association of C825T allele status with the erectile response to sildenafil. In the group with TT genotype we observed a 90.9% response but only a 50.9% and 48.9% response in patients with the CC and TC genotype, respectively. The odds ratio for a positive erectile response was 10.0 (95% CI 1.2 to 81.1) for patients with the TT versus the TC/CC genotype (p = 0.01).The response to sildenafil is significantly associated with GNB3 C825T genotype status in patients with erectile dysfunction.

BackgroundTo use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder.MethodsA combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin.ResultsWe selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (pConclusionsThis is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.

Obwohl die Induratio penis plastica bereits seit Jahrhunderten bekannt ist, sind bis heute Ursachen und auslosende Faktoren nicht eindeutig identifiziert. Daher sind viele der gebrauchlichen Therapieansatze empirisch und nicht wissenschaftlich belegt. Auch ohne Behandlung kommt es in bis zu einem Viertel der Falle zu einer spontanen Ruckbildung der Befunde. In der initialen Therapie werden eine Vielzahl von Medikamenten oral oder intralasional eingesetzt, ohne dass es hierfur uberzeugende Daten aus randomisierten, prospektiven klinischen Studien gibt. Daneben sind als weitere Behandlungsmoglichkeiten eine perkutane Hochvolt-Bestrahlung oder eine extrakorporale Stoswellentherapie der Induration beschrieben. Schlieslich stehen bei deutlicher Peniskurvatur und funktioneller Beeintrachtigung der Sexualfunktion eine Reihe operativer Masnahmen zur symptomatischen Behandlung,d.h.Begradigung des Penis, zur Verfugung.Die Implantation eines hydraulischen Penisimplantats wird bei starker Peniskurvatur und gleichzeitiger erektiler Dysfunktion favorisiert.

BackgroundTransurethral resection of the prostate (TURP) is considered the gold standard for male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). However, TURP may lead to sexual dysfunction and incontinence, and has a long recovery period. Prostatic urethral lift (PUL) is a treatment option that may overcome these limitations.ObjectiveTo compare PUL to TURP with regard to LUTS improvement, recovery, worsening of erectile and ejaculatory function, continence and safety (BPH6).Design, setting, and participantsProspective, randomized, controlled trial at 10 European centers involving 80 men with BPH LUTS.InterventionPUL or TURP.Outcome measurements and statistical analysisThe BPH6 responder endpoint assesses symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation, and safety. Noninferiority was evaluated using a one-sided lower 95% confidence limit for the difference between PUL and TURP performance.Results and limitationsPreservation of ejaculation and quality of recovery were superior with PUL (p

Latest publications state equal efficacy of a recently introduced new percutaneous technique ("ultra-mini PCNL", UMP) and flexible ureteroscopy (fURS) in the treatment of medium-size urinary stones. Today we face challenges concerning cost-effectiveness and reduction of in-hospital length of stay. In this retrospective study, we compare clinical outcome parameters and costs of treatment (endoscopes and disposables) of both techniques.Thirty patients treated by UMP at two tertiary university centres were matched to 30 fURS patients from previously recorded databases. Data analysis included operating time, length of stay, stone-free rates (SFR), complications (Clavien II), ancillary procedures (presurgical ureteral stenting, secondary ureteral stenting or placement of a nephrostomy tube, secondary procedures) and costs for disposable materials and instruments (endoscopes, as calculated per procedure).We found no significant differences in operating times (UMP vs. fURS: 121/102 min), hospital length of stay (2.3/2.0 days), SFR (84/87 %) and complications (7/7 %). Costs for disposable materials and endoscopes were 656 euro (UMP) and 1,160 euro (fURS) per procedure.UMP and fURS are both safe and effective in the treatment of medium-size urinary stones. Costs for endoscopes and disposable materials are significantly lower in UMP.

BACKGROUND The presence of lymphocytic infiltration in prostate carcinomas has been shown to have prognostic relevance. However, it is not yet clear if this infiltrate represents a tumor-specific activated cell population or not. Therefore, the aim of the present study was to characterize the activation status of freshly isolated tumor infiltrating lymphocytes (TIL) from prostate carcinomas (PCa) and benign hyperplasia (BPH) with respect to the mRNA expression of cytokines and apoptotic factors. METHODS TIL were isolated from mechanically disaggregated tumor material by gradient centrifugation. The cells of the interphase were depleted from epithelial cells with anti-human epithelial antigen magnetic beads and then CD3+- lymphocytes were selected with magnetic beads against this determinant. In these pure lymphocyte preparations the mRNA expression of IL-1, IL-10, IFN-γ, TNF-α, Fas and Fas ligand was determined by using a semiquantitative RT-PCR. Contamination with tumor cells was excluded by a PCR for PSA and PSMA. RESULTS The CD3+-TIL from 21 patients with PCa and 20 patients with BPH expressed significantly higher levels of IL-10- and Fas ligand-mRNA compared to the autologous CD3+- PBL, whereas the expression of IL-1-, TNF-α- and Fas-mRNA was not different in either cell population. In contrast, the mRNA levels of IFN-γ were significantly higher only in the CD3+-TIL from the carcinomas but not from the BPH compared to autologous CD3+-PBL. CONCLUSIONS Since high levels of IFN-γ have been reported to be produced by specifically lytic lymphocytes, our results suggest the presence of specifically activated TIL in the prostate carcinomas but not in the BPH, whereas inflammatory activated TIL are present both in the carcinomas and the BPH. Prostate 45:1–7, 2000. © 2000 Wiley-Liss, Inc.

The aim of the present study was to elucidate whether only local, or also systemic immunomodulatory effects may be induced by intravesical BCG therapy of superficial urinary bladder cancer.A total of 37 patients with stages Ta to T1b superficial transitional cell bladder carcinomas received 6 weekly BCG instillations after transurethral resection of the tumor. In a first group of 19 patients blood was taken before each BCG instillation and 6 weeks after the last one. In a second group of 18 patients blood and urine was taken before and 2, 6, and 24 hours after each BCG instillation. In the mitogen-stimulated whole blood cell cultures and in the urine samples the levels of the cytokines IL-1beta, IL-2, IL-10, TNF-alpha and IFN-gamma were determined by enzymoimmunological tests. Additionally, in all plasma and urine samples the levels of TNF-p75-receptor (TNF-p75-R) were measured.Comparison of ex vivo leukocyte cytokine production in the blood cell cultures of the patients of group I revealed no significant change in the levels of the cytokines. In contrast, TNF-p75-R plasma levels increased significantly during the experimental time of 12 weeks (por =0.01). In the blood cell cultures of the group II patients a different daytime variation of cytokine production was seen, compared to the 19 healthy controls. After BCG instillation the normal peak cytokine production in the evening was suppressed. A significant rise in plasma TNF-p-75-R levels was measured 24 hours after BCG instillation (por =0.05). In the urine of these patients significantly higher levels of all measured cytokines and TNF-p75-R were observed 6 to 24 hours after the instillation.The results suggest that besides the well known local immune activation, BCG instillation also leads to a modulation of peripheral immune mechanisms.

Since the first child was born after in-vitro fertilization in 1978, different techniques of ovarian stimulation, oocyte retrieval and embryo culture have improved significantly. The development of microinjection techniques was a mile stone in reproductive medicine. Even in cases of severe impairment of semen quality, using the Intracytoplasmic Sperm Injection (ICSI), pregnancy rates of approximately 20 % per treatment cycle can be achieved. However for using artificial reproductive techniques (ART) the female age is a major limiting factor as well as the development of premature ovarian failure (POF). Crucial for the male is the question whether or not sperm cells can be retrieved. Today an interdisciplinary approach is recommended to take care of the afflicted couple in order to address the complex problem of infertility. There is evidence that children born after microinjection techniques bare a higher risk for chromosomal aberrations compared to the normal population. However rates of major malformations seem to be identical in both groups. An evaluation of the potential risks and efforts and an extensive counseling of the infertile couple has to be taken before initiating invasive ART.

Disorders of sexual function are a frequent sequel to the surgical treatment of tumors in men. Operations involving the abdominal cavity, the retroperitoneal space and the true pelvis can damage the nerve and blood supply of the sexual organs, and this may cause dysfunction of the mechanisms of erection and ejaculation. Since it is often a matter of sexually active patients at the reproductive stage of their lives, the prevention of these secondary effects of tumor therapy takes on a special significance. Impairment of the erection mechanism or disturbances of ejaculation may follow the operative, radiological or medical treatment of a variety of tumors. They are a frequent consequence of the treatment of carcinoma of the bladder, prostate, testes, colon or rectum, and are particularly to be feared after radical operations that can damage the integrity of the nerves and vessels of the pelvis and lumbar region, since these are necessary for the physiological function of the sex organs. Today, with a thorough understanding of the neuroanatomy and with modern surgical techniques, these effects are avoidable in a high percentage of cases. If, however, effective treatment of the neoplasm requires such a radical operation that damage to these nerve pathways cannot be avoided, the consequent reduction of the sexual activity and fertility of patients in this age group can seriously impair the quality of their lives. Even so, there are many therapeutic procedures available which make it possible to treat disturbances both of the erection mechanism and of ejaculation in almost all cases.

Purpose: Renal cell carcinoma occurs as a sporadic tumor but may be part of the autosomal dominant von Hippel-Lindau disease, characterized by retinal and central nervous system hemangioblastoma, pheochromocytoma, pancreatic cysts and renal cell carcinoma. We determine the prevalence of von Hippel- Lindau disease in a series of unselected renal cell carcinoma cases by molecular genetic analysis, and compare sporadic to von Hippel-Lindau renal cell carcinoma with respect to morphology and biology. Materials and Methods: We established registers comprising 63 subjects with von Hippel-Lindau renal cell carcinoma, belonging to 30 distinct families (register A), and 460 unselected patients operated on for renal cell carcinoma in an 11-year period (register B). Molecular genetic analysis of the von Hippel-Lindau gene was performed for living patients of register A, repreSenting 80% of von Hippel- Lindau families, and register B, 62% living patients, to identify von Hippel- Lindau germline mutations. In addition, register B was evaluated by a questionnaire (95% response) for familial occurrence of von Hippel-Lindau disease. Results: The prevalence of von Hippel-Lindau renal cell carcinoma was 1.6% in 189 consenting unselected renal cell carcinoma patients. Risk factors for occult germline von Hippel-Lindau gene mutations in register B included familial renal cell carcinoma in 3 of 3 patients (100%), multifocal or bilateral renal cell carcinoma in 1 of 10 (10%) and age younger than 50 years at diagnosis in 1 of 33 (3%). Compared to sporadic von Hippel-Lindau renal cell carcinoma was characterized by an occurrence 25 years earlier, association with renal cysts, multifocal and bilateral tumors, cystic organization and low grade histology, and a better 10-year survival (p

Die Ejakulatanalyse stellt eine der wichtigsten Untersuchungen zur Erfassung des mannlichen Fertilitatsstatus dar. Durch die makroskopische und mikroskopische Bewertung und durch Anwendung biochemischer Nachweisverfahren zur Charakterisierung der Zusammensetzung des Seminalplasmas last sich eine Klassifikation der Ejakulatqualitat vornehmen. Es gibt verschiedene Klassifikationssysteme, die sich vor allem durch die unterschiedliche Beurteilung der Spermienmorphologie unterscheiden. Am gebrauchlichsten sind die von der Weltgesundheitsorganisation empfohlenen Richtlinien zur Analyse des menschlichen Ejakulats und der Spermien/Zervixschleim-Interaktion (WHO 1992). Mit Hilfe spezieller Funktionstests lassen sich Partialfunktionen der Spermien erfassen, allerdings ist die prognostische Aussagekraft dieser Testverfahren begrenzt. Trotz groser Bemuhungen um eine standardisierte Untersuchungstechnik kommt es durch unvermeidbare subjektive Einflusfaktoren zu einer z. T. ausgepragten Befundvariabilitat zwischen verschiedenen andrologischen Laboratorien. Die Problem der internen und externen Qualitatskontrolle im andrologischen Labor ist bisher nur unzureichend gelost.

Trotz der Entwicklung neuer assistierter reproduktionsmedizinischer Techniken darf auf eine umfassende andrologische Untersuchung nicht verzichtet werden, um dem infertilen Paar eine optimale Therapie anbieten zu konnen. Neben einer detaillierten Anamneseerhebung ist die korperliche Untersuchung des Mannes in einer ungewollt kinderlos gebliebenen Partnerschaft die Basis fur alle weiteren diagnostischen und therapeutischen Masnahmen. Der Ultraschall ist heute bei der urologisch-andrologischen Untersuchung so bedeutend geworden, das er die „dritte Hand“ des Untersuchers genannt wird. Alle Genitalorgane – Hoden, Nebenhoden, Prostata, Blaschendrusen und Penis – sind sonographisch hervorragend abzubilden und krankhafte Veranderungen mit einer hohen Treffsicherheit zu diagnostizieren.

Ejaculatory duct obstructions are diagnosed in approximately 5% of azoospermic men and can be treated by transurethral resection (TURED) or incision of the ducts. Eight patients with azoospermia and ejaculatory duct obstructions were treated by TURED after clinical examination, semen analysis, biochemical analysis of seminal plasma, endocrine analysis, transrectal ultrasonography and testicular biopsy. In 3/3 cases of cystic and in 3/5 cases of non-cystic obstruction. TURED of the stenosis was possible. During a follow-up of 12 months there was an increase in semen volume and sperm count in 3/3 and 3/5 patients, respectively. No pregnancy was achieved during the period up to 12 months. Clinical symptoms such as haemospermia and pain disappeared in all cases. In our cases and another 98 cases of ejaculatory duct obstructions documented in the literature, men of semen quality improved in 38-60% with a pregnancy rate of men 22-31% after TURED. We conclude that there is a correlation between the aetiology of ejaculatory duct obstructions and success rate of TURED.

As a decreased production of Th1 cytokines by stimulated peripheral blood leukocytes has recently been shown in patients with various carcinomas, the present study was performed to determine whether these patients also exhibit a Th1/Th2 imbalance compared to healthy controls. We measured the production of the Th1 cytokines IL-2 and IFN-gamma as well as the Th2 cytokines IL-4, IL-6 and IL-10 in mitogen-stimulated peripheral blood mononuclear cell (PBMC) cultures of patients with urinary bladder carcinomas (n = 47), prostate carcinomas (n = 111) and renal cell carcinomas (n = 67) as compared to 40 age-matched healthy controls. In the PBMC cultures of the tumor patients, the levels of the Th1 cytokines IL-2 and IFN-gamma were lower as compared to the controls. For IFN-gamma, the differences were highly significant and in the patients with renal cell carcinomas it could be shown that the values decreased with increasing tumor mass. In contrast, the levels of the Th2 cytokines IL-4, IL-6 and IL-10 were comparable in the PBMC cultures of tumor patients and controls. From these results, it is concluded that there is only a malfunction in Th1 cells but no switch from a Th1 type to a Th2 type cytokine profile in the PBMCs of cancer patients.

Objectives: Stricture of the vesico-urethral anastomosis is a well-known complication after radical prostatectomy. Dilatation, stricture incision or resection have been proposed for

To evaluate the Single-Incision Transumbilical Surgery (SITUS) technique as compared to an established laparoendoscopic single-site surgery (LESS) technique (Single-Port Laparoscopic Surgery, SPLS) and conventional laparoscopy (CLS) in a surgical simulator model. Sixty-three medical students without previous laparoscopic experience were randomly assigned to one of the three groups (SITUS, SPLS and CLS). Subjects were asked to perform five standardized tasks of increasing difficulty adopted from the Fundamentals of Laparoscopic Surgery curriculum. Statistical evaluation included task completion times and accuracy. Overall performances of all tasks (except precision cutting) were significantly faster and of higher accuracy in the CLS and SITUS groups than in the SPLS group (p = 0.004 to p

The international guidelines on urolithiasis state that the percutaneous approach is superior for kidney stones ≥20 mm. Nevertheless, several groups have reported high stone-free rates (SFRs) with low morbidity for ureteroscopic treatment of calculi >15 mm. We hereby describe a new technique including the combined use of semirigid and flexible ureteroscopy via a large ureteral access sheath (UAS). The proposed technique includes (a) preoperative ureteral stenting, (b) use of a large lumen UAS (14/16F, 35 cm), (c) use of a semirigid ureteroscope, (d) holmium laser lithotripsy, (e) passive and (f) active fragment extraction, and finally, the removal of caliceal stones (g) using a flexible scope. We conducted a prospective outcome analysis for 38 patients treated at two tertiary university centers. Perioperative data were as follows: median cumulative stone size 24.5 mm (20–60), median operating time 95 min (50–205), post-operative ureteral stenting (2–35 days) in 33 patients (86.8 %), Clavien complications 2 and 3 in 7.9 %, primary SFR 63.2 %, and overall computed tomography (CT) controlled SFR after 3 months 81.8 % (including staged procedures). No late complications were observed. The combined use of semirigid ureteroscopy and an UAS further develops the endoscopic treatment of kidney stones. This is the first series of this kind that confirms high SFRs by CT. The approach has significant advantages: Superior irrigation and outflow enhance both vision and stone clearance, and multiple ureteral passages without putting the ureter at injury risk. These encouraging results make this modality an appealing alternative to percutaneous nephrolithotomy.

Traditionally, pathology reports have been textual, with a high degree of variability. In part, they miss some of the information needed, e.g. for therapy decisions. To meet all requirements, it would be helpful to have a tool providing reminders of the necessary data and facilitating the transfer of these data into a pathology information system (PIS). Here, we describe a TNM-adapted toolset including a PIS-integrated structured template that contributes to improving pathology reports of prostatectomy specimens.All prostatectomy reports between January 2002 and August 2010 (n = 1049) were classified into descriptive reports (DRs) (n = 411), structured reports (SRs) arranged according to tumour spread, lymph node status, and surgical margin status (n = 333), and template-based synoptic reports (TBSRs) (n = 305). The report types were compared with regard to the content of 11 organ-specific essential data (ED) items crucial for exact TNM classification, therapy decisions, or prognostication. All 11 ED items were included in 2.7% of DRs, 43.5% of SRs and 97.2% of TBSRs, with a statistically highly significant difference (P 0.001).SRs, and particularly TBSRs, are advantageous as compared with DRs regarding the content of ED and the clarity of the data layout. The use of TBSRs leads to a reduction in failed data transfer and therefore to an increase in the quality of pathology reports.

The goal of the present study was to test the (177)Lu-labelled anti-PSMA monoclonal antibody 3/F11 ((177)Lu-DOTA-3/F11) as a new radioimmunotherapeutic agent in a prostate cancer SCID mouse xenograft model.The mAb 3/F11 was (177)Lu labelled using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as chelating agent. DOTA-3/F11 was tested for cell binding and serum immunoreactivity by flow cytometry. The biodistribution and the therapeutic efficacy of (177)Lu-DOTA-3/F11 in mice bearing PSMA-positive C4-2 prostate cancer xenografts were evaluated.3/F11 and DOTA-3/F11 showed high and specific cell binding and similar serum half-lives of approximately seven days. Biodistribution studies revealed an increasing tumour uptake of (177)Lu DOTA-3/F11 over time with maximum tumour-to-muscle and tumour-to-blood ratios after 72 h. A single dose of 1 MBq (177)Lu-DOTA-3/F11 inhibited tumour growth and prolonged survival.This study indicated that (177)Lu-DOTA-3/F11 may be a suitable radioimmunotherapeutic agent for the treatment of prostate cancer.

From February 1987 to September 1991, 122 men with erectile impotence and confirmed cavernosal venous leakage underwent penile venous surgery. After a postoperative follow-up of 36 months, only 18.8% of the patients had satisfactory erections without further therapy. Another 32.5% postoperatively converted to responders to intracavernous injection therapy with vasoactive drugs. Therefore, a total of 51.3% benefitted from the operation. Dynamic pharmacocavernography proved to be the most important examination in terms of establishing indication and prognosis. According to our results, there are two basically different forms of cavernosal venous leakage with different postoperative outcomes: primary and secondary corporeal incompetence. In many cases, an arterial cofactor was determined.

In this study, different variants of the anti-PSMA single-chain antibody fragment (scFv) D7 were cloned, varying in linker type, position of hexahistidine tags and VH-VL orientation. From these scFv, Pseudomonas exotoxin A-based immunotoxins were constructed and their biological activities against prostate cancer cells were compared.Binding of the constructs to PSMA-expressing prostate cancer cells was determined by flow cytometry. ADP-ribosyltransferase activity was analysed and cytotoxicity was measured with WST-1 assays.Different linker types did not influence the characteristics of the scFv or immunotoxins. The addition of an N-terminal hexahistidine-tag, however, resulted in decreased expression, binding and cytotoxicity. scFv in VH-VL orientation showed the highest expression and binding, whereas immunotoxins in VL-VH orientation exhibited the best binding and cytotoxicity.The present study showed how structure influences the characteristics of scFv and immunotoxins. It is therefore suggested that for each individual construct the optimal structure has to be determined separately.

Numerous efforts exist for developing primary prostate cancer cultures for studying the biology of this tumor entity and for evaluation of the effectiveness of novel therapies. However, there is doubt if cultures that represent the fully differentiated phenotype can be established. The aim of the present study was to characterize primary outgrowing prostate epithelial cells due to their basal or luminal characteristics and their potential for serving as androgen-responsible model. From fresh prostate cancer radical prostatectomy specimens, pieces of approximately 2-4 mm diameter were placed on top of transwell culture chambers, which were coated with matrigel and cultured in prostate epithelial selection medium with 10% fetal calf serum. The monolayer of outgrowing cells was incubated with a physiological concentration of 1 nM dihydrotestosterone (DHT). One group was additionally cultivated without DHT and another group was treated with the 5-alpha-reductase-inbitors MK-368 and MK-905. From the monolayer of the outgrowing cells, RNA was isolated and the expression of androgen receptor (AR), prostate-specific antigen (PSA), Kallikrein 2 (KlK2), prostate-specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA), cytokeratin (CK)5, and CK18 was determined by realtime quantitative PCR. The outgrowing cells from the prostate cancer tissue pieces could be characterized as epithelial cells with basal and transit amplifying characteristics as shown by co-expression of CK5 and CK18. In all cultures, a very low expression of the luminal cell marker genes AR, PSA and KLK2 was measured. The levels of PSCA were clearly higher with a broad variation. Upon cultivation without DHT or treatment with alpha-reductase inhibitors no regulation of AR, PSA and KlK2 was found. Due to the co-expression of basal and luminal marker genes, primary prostate cancer cultures can be charaterized as models of transit amplifying cells of the prostatic epithelium. They do not represent the differentiated secretory androgen-responsive cell phenotype.

The prostate specific membrane antigen (PSMA) represents an attractive antigen for antibody-based diagnostic and therapeutic intervention in prostate cancer, since it is highly restricted to the prostate and overexpressed in all tumor stages. The present work describes the in vitro characterization of the three anti-PSMA monoclonal antibodies (mAbs) 3/A12, 3/E7, and 3/F11 in comparison to the mAb J591.The mAbs were tested for saturation and competitive binding on C4-2 prostate cancer cells by flow cytometry. Immunohistochemical staining was conducted on frozen prostate normal and cancer tissues as well as on lymph node metastases. Similarly, potential crossreactivities were tested on a broad panel of human normal tissues.The anti-PSMA mAbs showed a strong binding to C4-2 cells with mean half-maximal saturation concentrations of about 14 nM for 3/A12, 17 nM for 3/E7, 9 nM for 3/F11, and 16 nM for J591. Competitive binding studies revealed that our three mAbs bind to different extracellular PSMA epitopes. The mAbs showed comparable staining of epithelial cells for all tested normal and tumorous prostate tissues. Extraprostatic staining was observed on secretory cells of the salivary glands and on the brush border of the duodenal columnar epithelium. J591 additionally showed positive staining of the normal breast epithelium.Due to their specific binding characteristics, the anti-PSMA mAbs 3/A12, 3/E7, and 3/F11 show great promise for diagnostic and therapeutic applications in prostate cancer.

Introduction: Androgen deprivation is the preferred treatment for disseminated prostate cancer. However, it mostly leads to the development of incurable androgen-independent disease. The aim of the present study was to compare gene expression changes that occur after treatment with either the antiandrogen bicalutamide or the 5-α-reductase inhibitors finasteride (MK906) and MK386. Materials and Methods: LNCaP cells of low passages were treated with MK906 and MK386 at 5 µM each or with bicalutamide at 10 µM for 48 h. In these cultures we analyzed the expression of 22,500 transcripts on the Affymetrix Human U133+ 2.0 GeneChip platform. Gene expression was verified by real-time quantitative Taqman PCR. Results: Our studies revealed 312 differentially regulated genes upon bicalutamide treatment and 68 differentially regulated genes upon treatment with the 5-α-reductase inhibitors. There were 35 genes equally regulated by both drugs. This subset of genes included those with the highest fold change in both treatment groups. In the subset KlK2, TMPRSS2, TRGC2, PMEPA1 and TM4SF1 were downregulated, whereas EGR1, DDC and OPRK1 were upregulated. Conclusions: A cohort of interesting genes that are differentially expressed after androgen withdrawal could be found in this study. Investigation into these genes could contribute to a better understanding of antiandrogen treatment and development of androgen-independent prostate cancer.

Recently, we have described a bispecific PSMA x CD3 diabody with one binding site for the T-cell antigen receptor (TCR-CD3) and another for the Prostate Specific Membrane Antigen (PSMA). It effectively eliminates human prostate cancer cells by redirecting T-lymphocytes in vitro and in vivo. Here, we show that activation of the T-cells and killing of the tumor cells, only occurred when the T-cells were coincubated with PSMA-positive tumor cells and the PSMA x CD3 diabody. Both CD4+ and CD8+ human T-lymphocytes were activated. Surprisingly, they were equally potent in their cytotoxic activity, proliferation, and up-regulation of activation markers. Both, CD4+, and CD8+ T-cells mainly used the perforin-granzyme- based pathway and to a somewhat lesser extent the FasL pathway to lyse tumor cells. When Jurkat T-cells were stimulated with the diabody alone, the TCR-CD3 was not triggered. In contrast, when the diabody was clustered with a secondary antibody the TCR-CD3 was stimulated as detected by Ca(2+)-influx and Erk, IkappaB, and linker of activated T-cell phosphorylation. Clustering of the diabody could also be achieved by the dimeric PSMA antigen expressed on tumor cells. Thus, although the diabody binds to all T-cells, only those in contact with PSMA-expressing cancer cells are activated. In conclusion, the PSMA x CD3 diabody is suitable for a controlled polyclonal T-cell therapy of prostate cancer.

A functional study was done to examine a possible role of calcitonin-gene-related peptide in human penile erection and its possible therapeutic applications for patients with erectile dysfunction. In the determination of an effective dosage, 5 ng. (2 patients), 50 ng. (2 patients), 500 ng. (4 patients), 5 micrograms (4 patients) and 25 micrograms (7 patients) were injected intracavernously, and pulse and blood pressure were monitored. Arterial inflow was measured by Doppler sonography, smooth muscle relaxation was determined by the analysis of cavernous electrical activity and cavernous outflow occlusion was recorded by cavernosometry. In 12 patients the erectile response of prostaglandin E1 was compared to the response of an equal (6 patients) or decreased dose of prostaglandin E1 combined with an equal weight of calcitonin-gene-related peptide. In 14 patients the erectile response to the combination of calcitonin-gene-related peptide and prostaglandin E1 was compared to the response of prostaglandin E1 alone, and with a combination of 15 mg./ml. papaverine and 0.5 mg./ml. phentolamine. Calcitonin-gene-related peptide induced an increase in the penile arterial inflow, cavernous smooth muscle relaxation and cavernous outflow occlusion. Histochemical results indicated nerve fibers positive for calcitonin-gene-related peptide within the cavernous bodies. A dose-dependent erectile response to calcitonin-gene-related peptide was observed at doses of 500 ng. to 25 micrograms. Systemic side effects were first observed at a dose of 25 micrograms in 2 of 7 patients. The combination of calcitonin-gene-related peptide and prostaglandin E1 was more effective in inducing a full erection than either prostaglandin E1 alone or the combination of papaverine and phentolamine. Pain was reported in 4% of the patients who received the combination of calcitonin-gene-related peptide and prostaglandin E1, whereas 42% of those who received prostaglandin E1 alone reported pain. Our results suggest that calcitonin-gene-related peptide may be a possible neurotransmitter for penile erection. A combination of calcitonin-gene-related peptide and prostaglandin E1 seems to be an effective alternative combination in the treatment of impotence.

Background: Muscarinic receptor antagonists are the standard of care for patients with overactive bladder (OAB). However, they can increase heart rate, and this can be disadvantageous in patients with coronary heart disease (CHD) or congestive heart failure (CHF). Comedications frequently used in the treatment of cardiovascular disease can further increase the risk for elevation of heart rate. Objective: As such high-risk patients have not been well represented in most randomized trials of muscarinic receptor antagonists, we investigated whether the muscarinic receptor antagonist solifenacin alters heart rate or has other cardiovascular adverse effects during routine use in OAB patients. The study evaluated these effects both in the overall group and in pre-defined risk groups. The overall tolerability and safety of solifenacin were also explored. Methods: This open-label, post-marketing surveillance study was specifically designed to evaluate the cardiovascular safety of solifenacin 5–10 mg once daily during a 12-week treatment course without specific inclusion or exclusion criteria but with systematic documentation of heart rate-relevant co-morbidities and comedications. The study was conducted in 4450 patients with OAB under the care of office-based urologists. The primary outcome measurement was heart rate. Secondary outcome measures were blood pressure and overall adverse events, which were systematically recorded before, during (after 1 week) and at study end; in many cases, an ECG was also conducted. Results: CHD, previous myocardial infarction or CHF were reported by 11.9%, 1.6% and 7.0% of patients, respectively, and >60% were receiving at least one comedication. An ECG was conducted prior to solifenacin treatment in 915 patients and revealed abnormalities in 17.3%. At study end, 72.4% and 19.1% of patients were taking solifenacin 5 mg and 10 mg, respectively. No clinically relevant alterations in mean heart rate (75.2 ± 8.2 beats/min pre-treatment vs 74.5 ± 7.6 beats/min at study end) or mean blood pressure (137/82 mmHg pretreatment vs 134/81 mmHg at study end) were observed. In the subgroup of patients who underwent ECG both before and during treatment, no increase in the prevalence of pathological findings was noted. Adverse effects were rare (affecting 4.8% of patients), and treatment discontinuations due to adverse effects occurred in only 1.4% of patients. Among various possible cofactors, only age >80 years and the presence of comedications significantly affected adverse event incidence. Conclusion: In real-life conditions, i.e. with inclusion of large numbers of patients with cardiovascular co-morbidities and taking comedications, therapeuti-cally effective doses of solifenacin did not increase heart rate or blood pressure.

This chapter will introduce the APS used in the case studies from AspenTech, i2 Technologies, Oracle and SAP: aspenONE, Six.One, EnterpriseOne, and Advanced Planner and Optimizer (APO). As these tools regularly consist of a multitude of software modules and special add-ons, only a brief survey without claiming completeness can be given. Furthermore, different lines of business can use different modules of an APS. It is also possible to use an APS only partially, e. g. without modules for scheduling or only using modules for demand planning and demand fulfillment. For each individual case the composition of modules has to be evaluated and selected (see Chap. 16).