[Radionuclide therapy for the treatment of skeletal metastases of urological malignancies: a forgotten therapy?]. / Radionuklidtherapie bei Knochenmetastasen urologischer Tumoren: Eine vergessene Therapie?

Many patients suffering from urological or non-urological malignancies develop bone metastases. One symptom often found is severe skeletal pain which siginificantly lowers the quality of life. Further symptoms are pathological fractures, spinal cord compression and hypercalcemia. The systemic radiopharmaceutical therapy represents an important systemic treatment option, in addition to chemotherapy, hormone therapy, external beam radiation, bisphosphonates and analgesics. The radionuclide therapy is rarely used and often used in a later phase of disease, mainly known for the bone pain palliation. This review article should help remind physicians to use this interesting therapy. It focuses on the common radionuclides Strontium-89-chloride, Samarium-153-EDTMP (ethylene-diamine-tetra-methylene-phosphonate) and Rhenium-186-HEDP (hydroxyethylidene-diphosphonate), their physical characteristics and differences, contraindications of the therapy like spinal cord compression and side effects. Additionally, potential tumoricidal activity and improvement of survival are discussed when using the radionuclides repetitively or in combination. The European and German guidelines are included. Furthermore, the combination of radionuclides and bisphosphonates or chemotherapy are briefly discussed, based on available clinical studies. Additionally, alpharadin (radium-223 chloride) is discussed, an experimental radiopharmaceutical under clinical evaluation, which emits alpha-radiation. In phase III clinical trials, it was shown to significantly increase the median overall survival in patients with bone metastases from advanced prostate cancer.

Gene-expression signature of adhesion/growth-regulatory tissue lectins (galectins) in transitional cell cancer and its prognostic relevance.

AIMS: Lectins, and especially galectins, appear to be important in malignancy-associated processes. The aim was to analyse comprehensively the presence of galectins in urothelial tumours. METHODS AND RESULTS: Non-cross-reactive antibodies against seven family members from the three subgroups (prototype: galectin-1, -2 and -7; chimera type: galectin-3; tandem-repeat type: galectin-4, -8 and -9) were used. Gene expression was monitored in specimens of normal urothelium, fresh tumour tissue and cell lines by real-time polymerase chain reaction (PCR). The presence and evidence of tumour-associated up-regulation were shown for galectin-1 and -3. This was less clear-cut for galectin-4 and -8. Galectin-7 was expressed in all cell lines; galectin-2 and -9 were detected at comparatively low levels. Galectin-2, -3 and -8 up-regulation was observed in superficial tumours, but not in muscle-invasive tumours (P < 0.05). Immunoreactivity correlated with tumour grading for galectin-1, -2 and -8, and disease-dependent mortality correlated with galectin-2 and -8 expression. Binding sites were visualized using labelled galectins. CONCLUSIONS: The results demonstrate a complex expression pattern of the galectin network in urothelial carcinomas. Galectin-1, -2, -3 and -8 are both potential disease markers and also possible targets for bladder cancer therapy.

[The role of perineal ultrasound compared to lateral cysturethrogram in urogynecological evaluations]. / Die Perinealsonographie im Vergleich zum lateralen Zysturethrogramm bei der Inkontinenzdiagnostik der Frau.

PURPOSE: The aim of this study was to evaluate prospectively whether perineal ultrasound is comparable to the lateral cysturethrogram in the evaluation of incontinent women. PATIENTS AND METHODS: Following urodynamic investigations, a lateral cysturethrogram and perineal ultrasound (5 MHz probe, bladder filling 300 mL) were performed in 98 incontinent women. In women with detrusor overactivity and consecutively reduced bladder capacity, ultrasound was performed at maximum capacity. To evaluate differences between perineal ultrasound and the cysturethrogram, the difference between bladder neck and lower border of symphysis and the retrovesicle angle beta were determined at rest and during the Valsalva manoeuvre. RESULTS: Using perineal ultrasound, the differences between bladder neck and symphysis could be determined at rest and during the Valsalva manoeuvre in all patients. The determination of the retrovesical angle beta was possible in all patients at rest and in 89 of the 98 women during the Valsalva manoeuvre. The lateral cysturethrogram enabled the determination of difference between bladder neck and symphysis and the retrovesicle angle beta at rest in 81 of 98 women. During the Valsalva manoeuvre, the difference between bladder neck and symphysis and retrovesicle angle beta could be determined in 72 of the 98 women. In the 26 remaining women, the determination was impossible due to severe adiposity or cystoceles of the second or third degree. CONCLUSIONS: Perineal ultrasound provides comparable data to the lateral cysturethrogram. In patients with adiposity, perineal ultrasound seems to be superior. Within the routine evaluation of women suffering from incontinence, the lateral cysturethrogram can be replaced by perineal ultrasound without any limitations of the diagnostic value.

[Georg Kelling (1866-1945): the man who introduced modern laparoscopy into medicine]. / Georg Kelling (1866-1945): Der Erfinder der modernen Laparoskopie.

On 23 September 1901, Georg Kelling (1866-1945) from Dresden performed a celioscopy with a Nitze cystoscope on a dog in Hamburg. This was the beginning of the era of laparoscopy.His doctoral thesis already reflected his early interest in the anatomy and physiology of the gastrointestinal tract. This experience, together with his knowledge on air insufflation of the abdomen, enabled him to be the first to develop the procedure he named "celioscopy." During this pioneer time of laparoscopy, he developed various basic principles that are still valid today and demonstrated astonishingly visionary skills. Although his pioneering achievements have hardly been acknowledged to this day, modern laparoscopy has confirmed Kelling's visions and scientific work in almost all aspects. His name and achievements have most definitely earned a place in the history of endoscopy.

Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers as a possible medical treatment of the overactive bladder and urge incontinence.

Urinary incontinence affects millions of people worldwide and also represents a social problem. People of all ages suffer from urinary incontinence. The disease is found in about 30% of women aged 30 to 60 years. There are different types of incontinence. Urge incontinence is the most often pharmacologically treated type. The mainly used substances belong to the class of antimuscarinic drugs. Their use is limited by several side effects. Furthermore, in some patients anticholinergic medication is ineffective and antimuscarinics used as single medication do not lead to a sufficient therapeutic effect. Other possible pharmacological substances for treatment of overactive bladder (detrusor instability) associated with urge and urge incontinence are the selective beta-adrenoceptor-agonists which are mainly responsible for the adrenergic mediated relaxation. It depends on the species, which beta-adrenoceptor-subtype (the beta2- and/or beta3-adrenoceptor) mainly mediates the relaxation. Non selective beta-adrenoceptor-agonists exhibit serious cardiovascular side effects like tachycardia or decrease of blood pressure by stimulating beta1- and beta2-adrenoceptors. These side effects should be decreased when using selective agonists. Additionally, substances whose targets are membrane channels of muscle cells could be interesting for treatment of overactive bladder. This group includes L-type calcium antagonists and potassium channel openers of ATP-sensitive potassium channels or BK channels. Especially the local use of the pharmacologically very potent calcium antagonists could be an interesting therapeutic approach, since systemic cardiovascular side effects were avoided. After chronic oral treatment with different calcium antagonists effects on the detrusor muscle were reduced or could not be detected, possibly due to an upregulation of 1,4-dihydropyridine-sensitive potassium channels. A very interesting approach is the use of potassium channel openers said to be selective for the urinary bladder. If there is a selectivity for the detrusor muscle, cardiovascular side effects were reduced. Possibly, the local use is a useful application form. Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers are pharmacological approaches, which are not yet available for clinical use.

Protein profiling of bladder cancer using the 2D-PAGE and SELDI-TOF-MS technique.

Protein profiling is a promising tool for tumor characterization and the detection of tumor markers in bladder cancer. Techniques for 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and surface-enhanced laser desorption/ionization with time-of-flight mass spectrometry (SELDI-TOF-MS) have improved; both were evaluated using bladder tumor tissue. Normal urothelium and pTa G2, pT1 G3, and >or=pT3 G3 tissues were obtained from the operating room and, after macrodissection, subjected to 2D-PAGE and to SELDI-TOF-MS ProteinChip. 2D-PAGE gels expressed significantly different protein patterns for pTa G2 and pT3 G3 tumors. pT1 G3 tumors showed expression profiles similar to those of the invasive tumors, with upregulation of galectin 3, gelsolin, villin 2, moesin, and annexin 6. Similarly, distinct protein peaks were detected for superficial and muscle-invasive urothelial cancers by SELDI-TOF-MS. Six of seven superficial pTa G2 tumors showed an intense peak at 6.7 and 10.1 kD, while invasive carcinomas showed an intense peak near 9.5 kD. No disturbing influence of surrounding tissue on the results was detected. It was shown that both techniques (2D-PAGE and ProteinChip) work well, and especially ProteinChip analysis seems promising for clinical application.

Relaxant effects of beta-adrenergic agonists on porcine and human detrusor muscle.

AIM: Relaxant effects of different beta-adrenoceptor agonists on porcine and human detrusor were examined. Thus, the beta-adrenoceptor subtype mainly responsible for relaxation in the detrusor muscle of pigs was characterized. Additionally, different effects of several beta-agonists in both species were shown. METHODS: Experiments were performed on muscle strips of porcine and human detrusor suspended in a tissue bath. The relaxant effects of the non-selective beta-agonist isoprenaline, the selective beta2-agonists procaterol, salbutamol and the selective beta3-agonists BRL 37344, CL 316 243 and CGP 12177 on potassium-induced contraction were investigated. The inhibitory effect of different substances on the maximum contraction and the rank order of potency for endogenous catecholamines was determined in pigs. Furthermore, concentration-relaxation curves were performed for pigs and humans. RESULTS: Pigs: In the pre-treatment experiments isoprenaline and procaterol showed similar effects. The concentration-response experiments showed that the maximum relaxation induced by procaterol and salbutamol was more than 90%, not significantly different from isoprenaline, whereas the maximum relaxations of CL 316 243, BRL 37344 and CGP 12177 amounted to 68, 70 or 30%, respectively. Rank order of potencies was isoprenaline > or = adrenaline > noradrenaline. Humans: Isoprenaline, procaterol, salbutamol and CL 316 243 showed a maximum relaxation of 80, 41, 24 and 35% and pD2 values of 6.24, 5.65, 5.48 and 5.55, respectively. CONCLUSION: Beta2-receptors play a main functional role in mediating relaxation of porcine detrusor. Selective beta2- and beta3-agonists similarly relax the human detrusor. Effects were smaller compared with the pig.

[Current diagnostics and therapy of the overactive bladder and urge incontinence]. / Aktuelle Diagnostik und Therapie bei Harnblasenhyperaktivität und Dranginkontinenz.

Urinary incontinence affects millions of people worldwide and also represents a social problem. Costs of urinary incontinence and overactive bladder are very high. Urge incontinence is the involuntary loss of urine associated with a strong desire or urge to urinate. There are two types of urge incontinence: One is associated with involuntary detrusor contractions leading to a loss of urine, the other is characterized by a hypersensitive bladder in which micturition reflexes are induced due to an increased afferent activity. It is important to distinguish between an idiopathic type of urge incontinence and a symptomatic type possibly caused by infections, tumours, bladder stones or foreign bodies. Diagnostics is based on a careful medical history, clinical examination and urodynamic evaluation. The use of a voiding diary is necessary. Current agents for drug therapy rely upon their anticholinergic properties. Their use is limited by side effects such as blurred vision, dizziness, constipation and dryness of the mouth. Additionally, patients refractory to anticholinergic medication can be treated by endoscopic direct injection of botulinum toxin into the detrusor muscle. These patients can also be treated by intravesical application of vanilloid derivatives in the bladder leading to a desensitization of bladder sensory fibers. In some cases of refractory urge incontinence, electrical neuromodulation is effective. Other pharmacological approaches could be selective b-adrenoceptor agonists, calcium antagonists and potassium channel openers, but these substances are not yet available for clinical use.

[Early instillation in superficial bladder carcinoma. Current status]. / Die Frühinstillation des Harnblasenkarzinoms. Eine Standortbestimmung.

The high recurrence rate in superficial bladder cancer (>70%) is caused by the adhesion of free floating tumor cells during transurethral treatment, by incomplete resections, and by overlooked and new tumors. Frequent follow-ups and reoperations are necessary. A single immediate instillation after TUR shows positive effects in reducing recurrence rates and is therefore recommended in the European Guidelines from 2001. The amount, concentration, instillation time, and substances have not yet been standardized. By analyzing the literature we found many different techniques of early instillation therapy. Different substances, concentrations, varying instillation times, and application times make a comparison of these studies very difficult. Further studies are needed to standardize early postoperative instillation therapy.