[Photodynamic diagnostics in the urinary tract. Consensus paper of the Working Group for Oncology of the German Society for Urology]. / Photodynamische Diagnostik im Harntrakt. Konsensusempfehlungen des Arbeitskreises Onkologie der Deutschen Gesellschaft für Urologie.

Because of the frequency of occurrence and the long protracted course, bladder carcinoma is the most expensive solid tumor in terms of costs, from diagnosis to death of the patient. The most important cost factor within the total cost is the treatment of recurrent, non-muscle invasive bladder carcinoma. Photodynamic diagnosis (PDD) improves the early detection rate of non-muscle invasive bladder cancer, especially the detection of carcinoma in situ and severe dysplasia. PDD also reduces the number of residual tumors after TUR-B compared to white-light guided TUR-B and also the early recurrence rate although long-term outcome with hexylaminolaevulinic acid with regards to the general course of bladder cancer is still lacking. PDD has been used mainly for detection of bladder cancer and specifically carcinoma in situ in conjunction with diagnostic and therapeutic transurethral resection of the bladder. In 2006 hexylaminolaevulinic acid (HAL) was approved in the EU (EMEA) as a photosensitizer for the use in photodynamic diagnosis of the bladder. Several guidelines have incorporated PDD as optional form of diagnosis during endoscopy in proven or suspected bladder cancer, but no specific recommendations regarding indication and application of PDD exist. The German group of urologic oncology (AKO) invited urologists and biologists involved in the development of hexylaminolaevulinic acid as well its clinical use to participate in evaluating the data for HAL and its predecessor delta-aminolaevulinic acid (5-ALA). A consensus with regards to the indications, contraindications, technique, pre-clinical data, comparison of HAL and 5-ALA, current results, costs and follow-up was reached and are presented in this paper.

Tissue-specific transcription profiles of sex steroid biosynthesis enzymes and the androgen receptor.

17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 5alpha-reductase isoenzymes play a crucial role in the formation and metabolism of sex steroids. Not only the key androgens testosterone and dihydrotestosterone but also their precursors are potent activators of the androgen receptor and are, therefore, likely to act as determinants of male sexual differentiation and maturation in a differentially regulated way. The aim of the present study was to relatively quantify the expression of the mRNA of 17beta-HSD isoenzymes, namely, type 1, 2, 3, 4, 5, 7, and 10, together with the 5alpha-reductase type 1 and 2, and the androgen receptor in normal human males and females. RNA was isolated from peripheral blood cells of both sexes and from genital skin fibroblasts (GSFs) of two different localizations (foreskin and scrotal skin) obtained from phenotypically normal males. mRNA expression was semi-quantified by quantitative reverse-transcriptase polymerase chain reaction with the LightCycler Instrument (Roche). The examined enzymes show statistically significant differences in their transcription pattern between the blood and the GSF RNA samples. Within the GSF samples, there are also significant variations between the two examined localizations in the transcription of 17beta-HSD type 1, 2, 4, and 5 as well as for the androgen receptor. We found large interindividual variation of enzyme transcription patterns in all investigated tissues. In peripheral blood cells, no sex-specific differences were seen. We conclude that sex steroid enzymes are expressed not only in genital primary target tissues but also in peripheral blood. The expression in different target tissues may contribute to both the individual sexual and tissue-specific phenotype in humans.

[Intravesical cidofovir--instillation therapy for polyomavirus-associated hemorrhagic cystitis after bone marrow transplantation]. / Intravesikale Cidofovir--Instillationstherapie bei Polyomavirus-assoziierter hämorrhagischer Zystitis nach Knochenmarktransplantation.

Viral infections of the urogenital tract are a potential problem in patients taking immunosuppressive medication. We report a 14 year old male patient with hemorrhagic cystitis who had undergone bone marrow transplantation for the treatment of acute lymphoblastic leukemia. Attempts at coagulation as well as instillation treatment and continuous bladder irrigation were not sufficient to stop bleeding. Sequential to these procedures, local instillation with cidofovir into the bladder was started to treat a suspected infection with polyomavirus and the gross hematuria stopped within a few days.

[Is there an indication for neoadjuvant or adjuvant systemic therapy in renal cell cancer?]. / Gibt es eine Indikation zur neoadjuvanten oder adjuvanten Systemtherapie beim Nierenzellkarzinom?

Looking at the most frequent urological tumors kidney cancer has the worst prognosis. Primary therapy consists of operative tumor removal in most cases. A tumor cutoff between 4 and 5 cm represents the turn towards a significant risk for postoperative tumor relapse. In those patients neoadjuvant or adjuvant therapy would be indicated. However, no phase III trials on neoadjuvant therapy of kidney cancer have been published in the literature. In contrast, five phase III trials on adjuvant therapy of kidney cancer have been published. In four trials interferon-alpha and/or interleukin-2 were applied. None of these trials had a positive outcome. Moreover, adjuvant cytokine therapy was associated with significant side effects in 30% of patients. In the fifth trial an autologous tumor cell vaccine (Reniale) demonstrated an improvement of progression-free survival and overall survival. Also, there were less than 1% side effects. Results from active trials investigating a combination of interleukin-2, interferon-alpha and 5-FU, or a heat shock protein vaccine or an antibody are awaited soon. New trials are testing tyrosine kidney inhibitors such as sunitinib and sorafenib.

[Localized amyloidosis of the ureter]. / Lokalisierte Amyloidose des Harnleiters.

Localized amyloidosis of the ureter is a rare condition. Because of the difficulty in differentiating between localized amyloidosis and an obstruction due to other benign or malignant conditions of the urinary tract, in some cases even an unnecessary nephroureterectomy is performed. We describe a patient with obstructive amyloidosis of the right ureter. Diagnosis was confirmed by endoscopy with biopsies. The patient was treated successfully by partial ureterectomy and ureteroneocystostomy. No systemic involvement of other organs was detected and after a 2-year follow-up no local recurrence developed.

[Spontaneous hemorrhage of the adrenal gland during pregnancy]. / Spontane Nebennierenblutung während der Schwangerschaft.

INTRODUCTION: Spontaneous hemorrhage is a rare cause of masses in the adrenal gland and must be differentiated from hemorrhage caused by trauma, neoplasm or metastases. CASE REPORT: A 41-year-old pregnant woman presented with nausea and right flank pain. Under suspicion of a pyelonephritis she was referred to the urological department with a normal obstetric evaluation. Ultrasound revealed an inhomogeneous mass above the right kidney, which seemed to be an abscess. An MRI scan showed an adrenal hemorrhage, but a bleeding caused by a neoplasm was excluded by a post-partum MRI control only. Upon conservative therapy the clinical condition improved and the parameters of inflammation normalized. There was no evidence of a hormone-producing adrenal tumor, an adrenal insufficiency caused by the hemorrhage, or a coagulopathy. CONCLUSION: Spontaneous hemorrhage in the adrenal gland is a rare condition in pregnancy. The diagnosis is confirmed by MRI. If conservative treatment fails, adrenalectomy will be necessary. Adrenal function should be controlled during pregnancy and post-partum. Recurrent hemorrhage and a neoplasm must be excluded by a post-partum MRI.

[Focal dose escalation in the treatment of prostate cancer : Long-term results of HDR brachytherapy]. / Fokale Dosiseskalation in der Therapie des Prostatakarzinoms : Langzeitergebnisse der HDR-Brachytherapie.

BACKGROUND: We prospectively examined the effect and the safety of intensity-modulated HDR brachytherapy (IMBT) with focal dose escalation. MATERIALS AND METHODS: A total of 139 patients undergoing primary therapy for prostate cancer and 11 patients with recurrence were included. Data analysis focused on the following factors: date of primary diagnosis, Gleason score, initial prostate-specific antigen (PSA) value, PSA nadir, volume of the prostate in the transrectal ultrasound, biopsy of the prostate gland, androgen deprivation, chemotherapy, uroflowmetry, pre- and postoperative post-void residual urine (PVR), number of the needles in the prostate lobes and analysis of follow-up data. RESULTS: In the primary therapy group, 87.6 % of the patients had a PSA of 0-4 ng/ml at the time of follow-up, while in the recurrence group 81.8 % of patients were within this range. Overall, 55.8 % of patients in the primary group had a PSA nadir under 0.1 ng/ml, 37.2 % under 1 ng/ml, 5.8 % under 5 ng/ml and 1.2 % (1 patient) over 5 ng/ml. In the recurrence group, 100 % had a PSA nadir under 0.1 ng/dl. Fifty patients of the primary group reported grade 1 toxicity (Common Toxicity Criteria): 29 localized to the bladder and 21 to the rectum. Seventeen patients had grade 2 toxicity of the bladder and 1 patient had grade 3 toxicity of the bladder. Finally there was one grade 4 toxicity due to perforation of the sigmoid colon. In the recurrence group, 3 patients with grade 1 toxicity were observed (2 bladder and 1 bowl). Also 3 patients had grade 2 toxicity of the bladder, 1 patient had a grade 3 bladder toxicity and 1 patient had grade 4 toxicity due to bowl fistula. There were no grade 5 toxicities. CONCLUSION: The modifications of the "Kiel method" with focal dose escalation was proven as effective in locally advanced prostate carcinoma and in local recurrences of the disease with low level toxicity.

[Bone formation in the ureter. Osseous metaplasia of an obstructed ureter]. / Der Harnleiterknochen. Knöcherne Metaplasie eines obstruierten Harnleiters.

Bone formation outside the skeleton is well known. Yet, ossification within the urogenital tract is rare. The case of a patient with distal ureteral obstruction, hydronephrosis, and subsequent circular osseous metaplasia of the ureter is presented. Open transperitoneal right-sided nephrectomy with partial resection of the ureter was performed. Intraoperatively and in histopathologic examination circular bone formation adjacent to the ureteral wall was detected. There was no evidence of malignancy. Early animal experiments in the twentieth century showed that bone metaplasia may be induced by epithelium of the urinary tract under certain conditions such as ischemia, inflammation, necrosis, sclerosis, and trauma. Osseous metaplasia may therefore be considered a differential diagnosis of calcification of the upper urinary tract in the absence of urolithiasis.

[Noninvasive and invasive bladder cancer: diagnostics and treatment]. / Nichtinvasives und invasives Harnblasenkarzinom: Diagnostik und Therapie.

Therapy of superficial bladder tumors is transurethral resection (TUR), and in cases of pT1 or high-grade tumors a re-TUR is indicated. Patients with carcinoma in situ receive intravesical chemotherapy or BCG for at least 3 months. Persistent carcinoma in situ may be treated by radical cystectomy. With the provision of a functionally adequate urinary diversion, cystectomy represents an effective treatment for patients with muscle-invasive bladder cancer without metastatic spread. Regional lymph node metastases can be found in up to 15% of stage T1 disease and are present in 33% of stage T3/4 lesions. Thus, lymphadenectomy gains diagnostic and possibly also therapeutic importance. For selected patients, who cannot be treated by radical cystectomy, multimodal concepts aiming to preserve the bladder are discussed. After or prior to cystectomy systemic chemotherapy may become necessary for some patients to positively affect the course of the disease in cases of locally advanced or metastatic lesions.

[Penile skin necrosis after application of a ring and defect coverage by a skin mesh graft]. / Penishautnekrose nach Ringanlage und Defektdeckung mittels Spalthauttransplantation.

INTRODUCTION: Penile strangulations are rare and always need an individual emergency treatment. Functional impairment and loss of organ integrity are the most serious complications. CASE REPORT: A 43-year-old man came to our ambulance with a penile skin necrosis and a penile abscess. This was caused by a heating pipe that he had put on his penis six weeks ago. We first removed the pipe and performed a necrosectomy in a second step a skin mesh graft was applied. Six months later we observed a satisfactory cosmetic and good functional result. CONCLUSION: Even in serious penile injuries caused by strangulation a penectomy can be avoided by means of an individually planned emergency treatment.

[Postoperative polyuria after laparoscopic adrenalectomy for pheochromocytoma]. / Postoperative Polyurie nach laparoskopischer Adrenalektomie wegen Phäochromozytom.

Disturbances of osmoregulation leading to polyuria are well known complications after operations in the sella region. In contrast, increased urinary output following adrenalectomy is rare. We report a case of postoperative polyuria after laparoscopic adrenalectomy for pheochromocytoma with urine output up to 15 l per day. Treatment included careful monitoring of the patient and intravenous and oral replacement of fluids and electrolytes. In our case a normalisation of the urine output was observed after few days. A further treatment with vasopressin was not undertaken as the osmolality at all times was in normal range.

Optimizing syngeneic orthotopic murine bladder cancer (MB49).

The syngeneic orthotopic murine bladder cancer model MB49 is hampered by unreliable tumor implantation. We optimized this model by a simple modification of the standard implantation technique in three groups of mice. Fifty thousand (group I), 20,000 (group II), or 10,000 (group III) tumor cells were implanted into cauterized bladders by transurethral instillation, and dwell time was prolonged to 3 h. Tumor take, survival, and bladder weights were determined as outcome variables. To verify whether this modification maintained its sensitivity to topical immunotherapy, an initial tumor load of 100,000 MB49 cells was given, and mice were treated intravesically with Bacillus Calmette-Guérin or phosphate-buffered saline. The prolonged dwell time of tumor cells resulted in take rates of 100% in all three groups. Survival and bladder weights were significantly correlated with the number of instilled cells. Even with the highest tumor load, Bacillus Calmette-Guérin therapy improved survival and reduced bladder weights significantly, as compared to PBS. Thus, the modified model is highly reliable and maintains its susceptibility to topical immunotherapy.

Perforin-mediated lysis of tumor cells by Mycobacterium bovis Bacillus Calmette-Guérin-activated killer cells.

Immunotherapy with Bacillus Calmette-Guérin (BCG) is clinically established in the treatment of superficial bladder cancer. In our attempt to clarify the underlying immunological mechanism, we could previously show that stimulation of PBMC with BCG leads to the generation of cytotoxic BCG-activated killer (BAK) cells. Among others, these BAK cells as well as lymphokine-activated killer (LAK) cells have been suggested as possible effector cells during BCG therapy. To understand BCG-induced activation of effector lymphocytes more precisely, we investigated the lytic pathways of human BAK cells and compared BAK cell cytotoxicity with LAK cell cytotoxicity. Perforin and Fas ligand (FasL) are the major cytolytic molecules of cytotoxic lymphocytes. Our results demonstrate that BAK and LAK cells showed an increased expression of perforin and FasL as compared with unstimulated controls. Killing of T-24 bladder tumor as well as Jurkat cells by BAK and LAK cells was predominantly mediated via perforin as demonstrated by a drastically reduced lysis in the presence of concanamycin A and EGTA/MgCl2, respectively. In contrast, lysis (radioactive release assay) and membrane disintegration (Annexin V binding) of both targets by BAK and LAK cells could not be blocked with an inhibitory anti-FasL monoclonal antibody (NOK-1). Nevertheless, T-24 and Jurkat were susceptible to killing by recombinant soluble FasL and by Chinese hamster ovary cells expressing membrane-bound FasL. We conclude that cellular mediators of BCG effector mechanisms, such as BAK and LAK cells, kill their targets via perforin and independent of the FasL pathway. Because we also found increased numbers of perforin-expressing lymphocytes in patients after BCG therapy, our findings have potential clinical relevance because BCG therapy would not be impaired by FasL resistance of target cells, which recently has been described for some tumors.

[Combination treatment with antisense oligonucleotides and chemotherapy in vitro]. / Kombinationsbehandlung mit Antisense-Oligonukleotiden und Chemotherapeutika in vitro.

Oncological therapy strategies are increasingly concentrating on the causal, molecular changes involved in carcinogenesis. So called "smart drugs" such as antisense oligoneucleotide (AsON) can be used as specific inhibitors of individual genes. AsONs have shown their effectiveness in many studies. Clinical studies have demonstrated, however, that for many tumours the inhibition of a single gene is, due to multigenetic alteration, largely ineffective. The combination of AsONs with conventional chemotherapeutic agents is currently being investigated in phase III studies. In these studies, chemotherapeutic agents have been evaluated in cell culture together with AsON against the proliferation associated Ki-67 gene, as well as against the apoptosis associated bcl-2 gene via RT-PCR, immunochemistry and MTT cell viability assay. For both AsONs, significant target inhibition was achieved in cell culture with a high target gene expression. The prior treatment of tumour cells with bcl-2 AsON significantly increased the effectiveness of chemotherapy, while the combination of conventional chemotherapeutic agents with Ki-67 AsON showed no synergistic effects.

[Vaccine therapy of prostate cancer]. / Vakzinetherapie des Prostatakarzinoms.

Vaccine therapy of prostate cancer has been increasingly studied in trials over the past few years. The different vaccine techniques are quite variable and are predominantly used in patients with advanced hormone-refractory prostate cancer. In this review, vaccine techniques using tumor cells, dendritic cells or poxvirus are analyzed. For theses approaches phase-III trials are being planned, have been initiated or are already completed. Many trials demonstrate the efficacy with regard to endpoints such as stimulation of the immune system and/or biochemical response and/or clinical response. Recently, one vaccine approach using autologous dendritic cells demonstrated a statistically significant prolongation of overall survival compared to placebo in patients with hormone-refractory prostate cancer. Side effects of vaccination are generally mild. At present, there are trials are being planned or are already ongoing that combine vaccine with other treatment strategies or enroll patients with earlier disease stages.

[Ki-67 antisense therapy in murine renal cell carcinoma models]. / Ki-67 Antisense-Therapie in murinen Nierenzellkarzinom-Modellen.

PURPOSE: The Ki-67 antigen is only expressed in proliferating cells. Previously, it was shown that Ki-67 derived antisense oligonucleotides (asONs) specifically inhibit the proliferation of tumor cells and tumour growth in vitro and in subcutaneous bladder and prostate tumor models. We intended to evaluate the effects of this therapeutic concept in two renal cell carcinoma (RCC) models. MATERIAL AND METHODS: Human RCC cells (SK-RC 35) were initially transfected with FITC-labeled ONs and diffferent cationic lipids to analyze the transfection efficacy by flow cytometry (FACS). The potency of 14 different ONs sequences was compared by quantitative RT-PCR in vitro. For in vivo testing, ONs were administered to immunocompetent Balb/c mice bearing orthotopic RENCA tumors as well as to SCID mice bearing subcutaneous RCC SK-RC 35 xenografts. Tumor sizes and final tumor weights were documented. Additionally, several immunohistochemical staining procedures were performed. RESULTS: FACS analysis showed highly effective transfection conditions in vitro. Systemic administration of asONs significantly decreased the tumour growth in the RENCA model (p < 0.05) and in the SCID mouse model (p = 0.009). Immunohistochemical staining of tumor specimens revealed a marked down-regulation of target protein and a slight increase in apoptotic cells after antisense treatment while the microvessel count was not significantly altered. CONCLUSION: These results demonstrate that the Ki-67 antigen represents a suitable antiproliferative target and that asONs directed against this target are potent drugs that induce a significant inhibition of renal tumor growth in different mouse models.

Treatment of posttransplant hypertension by laparoscopic bilateral nephrectomy?

BACKGROUND: Hypertension is an important risk factor for the development of chronic graft failure and decreased graft and patient survival after renal transplantation. METHODS: Between September 1994 and August 1996, 14 patients underwent laparoscopic bilateral nephrectomy for treatment of drug-resistant hypertension after successful renal transplantation. Common causes of hypertension were largely excluded before bilateral nephrectomy. A scoring system was developed for comparison of different antihypertensive regimes. In this system, points were given according to type and dosage of each antihypertensive drug. RESULTS: At 6-month follow-up, all patients showed well-controlled blood pressure (median of mean arterial pressure: 104 vs. 130 mmHg preoperatively, P<0.001, n=14), and significantly fewer antihypertensive drugs were needed according to the scoring system (48.9+/-20.9 points vs. 105.9+/-23.5 points preoperatively, P<0.001, n=14). During laparoscopy, three conversions to open surgery were necessary. Postoperatively, four complications occurred. After laparoscopy, immunosuppression and other oral medication were given continuously. The hospital stay ranged between 3 and 6 days (median: 5 days). CONCLUSIONS: The results indicate that bilateral nephrectomy using the laparoscopic technique can be an effective alternative method for a selected group of patients with severe hypertension, which is unresponsive to conservative management after successful renal transplantation with regard to improving the long-term graft survival.

Technology evaluation: TG-1031, Transgene SA.

Tumor-associated antigens have considerable promise not only as diagnostic or prognostic markers but also as targets for active or passive immunotherapy. The epithelial mucin MUC1 is a transmembrane molecule which is expressed by most glandular epithelial cells. Transgene has developed VV-MUC1-IL-2 (TG-1031), an antigen-specific therapy, involving the tumor antigen MUC1 and the cytokine IL-2 combined with a vaccinia virus vector. Vaccinia virus vectors have been shown to stimulate a strong immune response to encoded antigens in vivo. This therapy has potential for the treatment of breast cancer, prostate cancer and other adenocarcinomas and is currently under investigation in phase I and II trials.

Technology evaluation: CN-706, Calydon Inc.

CN-706, an engineered adenovirus containing the prostate tissue-specific enhancer (PSE) gene is under development by Calydon as a potential treatment for prostate cancer. The company is collaborating with the Johns Hopkins Hospital, which has agreed to sponsor clinical trials [274956]. Phase I trials in patients with advanced and recurring prostate cancer began during 1998 at the Johns Hopkins Brady Urological Institute and the Oncology Center [283946], [296857], and the results of phase I/II trials were reported in 2000 [386879]. The US Patent Office issued three patents in October 1998 [301251] related to Calydon's technology for engineering viruses to replicate and kill prostate cancer cells [US-05648478], [US-05698443], [US-05783435]. In June 1999, Calydon was issued two further patents [US-05871726], [US-05830686], [327511].

Technology evaluation: Abarelix, Praecis pharmaceuticals.

Abarelix (PPI-149) is a luteinizing hormone-releasing hormone (LHRH) receptor antagonist under development by Praecis, Amgen and Sanofi-Synthelabo for the potential treatment of prostate cancer, breast cancer and hormone-related disorders [285672,328910]. Abarelix has entered phase III clinical trials for hormonally responsive prostate cancer [311887], and a sustained-release formulation is in a phase I/II clinical trial for endometriosis [317822]. In June 1997, Praecis entered into a collaboration with Sanofi-Synthelabo for the continued development and future marketing of Abarelix for the treatment of prostate cancer and other hormone-related disorders in Europe [248307]. In June 1998, Roche gained marketing rights in the US and elsewhere, under a joint development agreement [289677], which was later terminated. In March 1999, Amgen gained rights to develop Abarelix in the US, Canada, Australia, Asia and other secondary markets [317822]. Sanofi-Synthelabo expects to launch the compound in Europe in 2001 [345341,346302]. In March 1999, Merrill Lynch predicted sales in 2001 of US$75 million, with peak sales of up to US$400 million [336561]. In October 1999, Merrill Lynch predicted sales in 2003 of EUR 100 million [346209] and Lehman Brothers predicted sales of US$50 million in 2002 rising to a peak of US$150 million in 2010 [346267].