[Is there an indication for adjuvant or neoadjuvant systemic chemotherapy in bladder cancer?]. / Gibt es eine Indikation für eine adjuvante oder neoadjuvante Systemtherapie beim Blasenkarzinom?

Two recent meta-analyses demonstrated a significant influence of adjuvant as well as neoadjuvant cisplatin-based chemotherapy regimens on survival of patients undergoing radical cystectomy for bladder cancer. Therefore, the introductory question can be answered with "yes". However, while providing the best evidence available to date on the subject, both analyses are based on clinical trials of dubious quality. Thus, the question today is not whether perioperative chemotherapy is advantageous in some patients undergoing radical cystectomy, but rather which subgroups will actually benefit from additional systemic treatment. Instead of a detailed literature overview, this article discusses potential advantages and disadvantages of perioperative chemotherapy and outlines basic principles for the design of future studies investigating both strategies in bladder cancer.

[Effect mechanism of intravesical BCG immunotherapy of superficial bladder cancer]. / Wirkmechanismen der intravesikalen BCG-Immuntherapie des oberflächlichen Harnblasenkarzinoms.

Immunotherapy for treatment of solid cancer mostly is an experimental treatment. In contrast, intravesical immunotherapy of superficial bladder cancer with bacille Calmette-Guérin (BCG) is clinically well established and accepted worldwide because of better results compared to topical chemotherapy. BCG is currently regarded as the most successful immunotherapy of cancer. Unfortunately the mechanism of action has not yet been fully clarified. This article gives an overview on the complex research on the mechanisms of actionhighly successful therapy.

[Expression of antimicrobial peptide MUC7 in kidneys with pyelonephritis]. / Die Expression des antimikrobiellen Peptids MUC7 in der Pyelonephritis.

BACKGROUND: Mucins are glycoproteins secreted by epithelial cells of various organ systems exerting multiple functions. MG2 as the protein transcript of the MUC7 gene has first been described as secreted by serous salivary glands in the oral cavity. We sought to explore changes of MUC7 expression in the kidney stimulated by bacterial infection of the upper urinary tract. METHODS: We investigated the gene expression of MUC7 by reverse transcriptase-polymerase chain reaction in voided urine specimens from 15 patients with acute pyelonephritis compared to 15 healthy volunteers. Furthermore, the gene and protein expression of MUC7 was studied in 15 renal tissue samples with chronic bacterial pyelonephritis versus 10 normal human kidney samples taken from tumor-bearing organs. RESULTS: MUC7 gene expression was detected in 5 of 15 voided urine samples of patients with pyelonephritis and in 2 samples from 15 healthy volunteers (Fisher's exact test p=0.39). MUC7 gene expression was detected in 7 of 15 tissue samples of kidneys with chronic pyelonephritis and in none of 10 normal renal tissue samples from tumor bearing organs (p=0.02). Immunohistochemical staining with the monoclonal antibody PANH3 revealed protein expression in 6 of the 15 tissue samples with chronic pyelonephritis, but not in normal tissue samples. CONCLUSION: Upregulated MUC7 expression in the urinary tract particularly in renal tubular epithelium can occur under inflammatory conditions. This indicates a putative role of MUC7 as an antimicrobial host defense molecule within the urogenital tract.

[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.

[Metastatic castration-resistant prostate cancer : Clinical data, new treatment options and therapy monitoring]. / Metastasiertes kastrationsresistentes Prostatakarzinom : Aktuelle Daten, neue Therapieoptionen und strukturiertes Therapiemonitoring.

Therapies currently available in Germany for metastatic castration-resistant prostate cancer (mCRPC) include docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223, all of which offer a potential survival benefit that adds up in their sequential application to a significant overall survival benefit. However, the optimal sequencing of these agents is still unclear. In the absence of evidence, treatment selection is based on the particular situation and on comorbid conditions of each individual patient. Furthermore, predictive markers to facilitate the selection of patients for a specific therapy or sequence of therapies remain an unmet need. However, with the recently discovered androgen receptor splice variant V7, which mediates (cross)resistance to or between abiraterone and enzalutamide, the first such marker has been identified. It is critical to monitor the response to treatments at prespecified intervals in order to optimize treatment sequencing so that the patient does not miss a valuable therapeutic window to receive alternative treatment that may prolong his life along with good symptom control and preservation of quality of life.

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.

[Metastatic castration-resistant prostate cancer: position paper for structured therapy monitoring]. / Metastasiertes kastrationsresistentes Prostatakarzinom: Positionspapier für ein strukturiertes Therapiemonitoring.

This position paper is intended to help to structure and to standardize therapy monitoring in patients with metastatic castration-resistant prostate cancer (mCRPC). With the treatment options available today, patients with metastatic disease can often maintain good quality of life and stable disease for several years. It is crucial that once a therapy becomes insufficiently effective that it be replaced in a timely manner by a new treatment option. From a prognostic point of view, it is important that patients receive as many as possible and in the ideal case all currently available treatment options.

Exploratory analysis of the visceral disease subgroup in a phase III study of abiraterone acetate in metastatic castration-resistant prostate cancer.

BACKGROUND: Visceral disease, non-nodal soft-tissue metastases predominantly involving the lung and liver, is a negative prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of COU-AA-301 assessed whether abiraterone acetate (AA) improved overall survival (OS) in mCRPC patients with visceral disease progressing post docetaxel. METHODS: In COU-AA-301, post-docetaxel mCRPC patients were randomized 2:1 to AA 1000 mg (n=797) or placebo (n=398) once daily, each with prednisone 5 mg b.i.d. The primary end point was OS; secondary end points included radiographic progression-free survival (rPFS), PSA response rate and objective response rate (ORR). Treatment effects in visceral disease (n=352) and non-visceral disease (n=843) subsets were examined using final data (775 OS events). RESULTS: AA plus prednisone produced similar absolute improvement in median OS in patients with (4.6 months) and without (4.8 months) visceral disease versus prednisone; hazard ratios (HRs) were 0.79 (95% confidence interval (CI): 0.60-1.05; P=0.102) and 0.69 (95% CI: 0.58-0.83; P<0.0001), respectively. Treatment with AA plus prednisone significantly and comparably improved secondary endpoint outcomes versus prednisone in both the subsets: the HRs for rPFS were 0.60 (95% CI: 0.46-0.78; P=0.0002) and 0.68 (95% CI: 0.58-0.80; P<0.0001) in visceral and non-visceral disease subsets, respectively. PSA response rates were 28% versus 7% in the visceral disease subsets and 30% versus 5% in the non-visceral disease subsets (both P<0.0001), and ORRs were 11% versus 0% (P=0.0058) and 19% versus 5% (P=0.0010), respectively. The incidence of grade 3/4 adverse events was similar between the subsets and between the treatment arms in each subset. Adverse events related to CYP17 blockade were increased in the AA arms and were similar in patients with or without visceral disease. CONCLUSIONS: AA plus prednisone provides significant clinical benefit, including improvements in OS and secondary end points, in post-docetaxel mCRPC patients with or without baseline visceral disease. The presence of visceral disease does not preclude clinical benefit from abiraterone.

[Value of intermittent androgen deprivation in the context of the current data situation]. / Stellenwert der intermittierenden Androgendeprivation im Kontext der aktuellen Datenlage.

Androgen deprivation therapy is an integral part of the treatment of advanced and progressive prostate cancer. Various prospective randomised trials have investigated whether or not temporary suspension of androgen deprivation might delay the emergence of castration resistant prostate cancer and concomitantly improve quality of life. Until now, no phase III trial has been able to prove that intermittent androgen deprivation might delay the development of castration resistant tumours. Data from previous trials, except for one study, did at least not show adverse effects on survival. Data on quality of life are inconsistent, showing a trend towards improved quality of life with IAD. German as well as European guidelines reflect IAD as an established constituent of day-to-day medical practice. This review is intended to provide a code of practice for an individualised treatment as based on recently published studies.

[Mistletoe extract for treatment of urological tumors]. / Mistelpräparate zur Behandlung urologischer Tumoren.

In Germany misteltoe extract is one of the most commonly used complementary therapeutic strategies in oncology. There are anthroposophical as well as phytotherapeutic concepts to explain the potential mechanism of action; however, the oncological and uro-oncological literature lacks definitive proof to support recommendations on which is the most effective drug, the optimal dose, a clear indication or its efficacy. Weighting the current data, potential side effects and contraindications, the application of mistletoe extract in daily uro-oncological practice requires careful consideration of the indications in the context of a detailed patient informed consent and request for this unique therapeutic modality.

[Extending the limits of lymphadenectomy during radical cystectomy: pitfalls in the interpretation of contemporary study results]. / Das Ausmass der Lymphadenektomie im Rahmen der radikalen Zystektomie: Fallstricke bei der Interpretation aktueller Studienergebnisse.

The optimal extent of lymphadenectomy performed during radical cystectomy for transitional cell carcinoma of the bladder is currently under intensive debate. Extending the limits of lymphadenectomy has been hypothesized to add further diagnostic and therapeutic benefit. However, our current knowledge is based exclusively on results from retrospective studies that are hampered by several statistical shortcomings. This article provides a critical analysis of the contemporary data on the subject and outlines typical statistical pitfalls that must be considered when interpreting such research results.

[Complete resection of urothelial cancer metastases with curative intent]. / Metastasenchirurgie in kurativer Absicht beim Urothelkarzinom.

BACKGROUND: Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS: Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS: The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION: The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.

[Nephron-sparing surgery]. / Organ erhaltende Nierentumorchirurgie.

Over the last two decades, nephron-sparing surgery has gained more and more importance. Initially it was done for imperative indications to preserve the remaining function of solitary kidneys. Today, because of favourable oncological results, elective nephron-sparing surgery is increasingly performed. According to the latest European Association of Urology guidelines on renal cell carcinoma, nephron-sparing surgery for tumours less than 4 cm with a healthy contralateral kidney is considered the standard therapeutic option because of excellent postoperative outcome and favourable oncological results. At major urological institutions, nephron-sparing surgery is even offered to patients with tumours larger than 4 cm (easy access, with partial resection deemed oncologically and technically feasible) for so-called extended elective indications. This review summarises the indications, perioperative management, various surgical approaches and techniques, and oncological results for nephron-sparing surgery, briefly highlighting data from our own institution.

Robot-assisted laparoscopic radical cystectomy: initial experience on 27 consecutive patients.

Recent reports have demonstrated that robot-assisted laparoscopic cystectomy is technically feasible. We report technical and functional results of a large series of patients undergoing laparoscopic cystectomy with the da Vinci surgical system (DVSS). A total of 27 patients (24 males) underwent laparoscopic radical cystectomy with the DVSS (intuitive surgical) between January 2004 and December 2005. Indications for cystectomy were muscle-invasive transitional cell carcinoma (TCC) or leiomyosarcoma of the urinary bladder (n = 24) and bladder shrinking following prior radiotherapy for TCC. A pelvic lymphadenectomy was a routine part of the procedure. Urinary diversions were ilieal conduits (n = 19) and ileal neobladders (n = 8). Mean operating time was 340 min (range 150-450) with a mean blood loss of 301 ml (range 50-550). The mean number of lymph nodes retrieved during lymphadenectomy was 23. Surgical margins were negative except in one case. After a mean follow-up of 10.2 months, two perioperative (anastomotic leakage, adhesions) and three postoperative complications (ileus, intestinal fistula, urinary tract obstruction) occurred. Six out of seven patients reported satisfying erectile function following nerve-sparing surgery. Day-time continence was completely restored after a mean 3.5 months in seven of eight patients. Robot-assisted laparoscopic cystectomy is a safe procedure. Satisfying functional and oncological short-term results can be achieved within acceptable operating time limits.

Spontaneous external drainage of renal abscess through persistent nephrostomy tract eleven years after percutaneous nephrolithotomy.

A unique case of spontaneous external drainage of a renal abscess through a persistent nephrostomy tract is reported in a patient with a history of two subsequent percutaneous nephrolithotomies 11 years earlier. Nephrostomy tracts can open up even after several years to provide an exit path for infected urine or renal abscess drainage.

[Computer-controlled infusion]. / Computergesteuerte Infusion.

For complex treatment regimens in the field of modern infusion therapy and for the administration of potent drugs (liquid management), a special microcomputer (Infucommand III) has been developed which makes it possible to control commercial infusion pumps via a standardized interface. By this means, infusion pumps can be combined with other medical instruments or further pumps to form an intelligent unit. Due to its small dimensions and few operating elements, the control device is easy to handle. A high safety standard has been achieved in routine operation, from the aspects of both hardware and software. Large memories (ROM and RAM) enable a large number of different user programs to be stored. In initial clinical trials the devices have already stood the test with regard to patient-controlled and EEG-controlled-anesthesia.

[Preoperative anxiolysis with lormetazepam. A model for measuring anxiety]. / Praeoperative Anxiolyse mit Lormetazepam. Ein Modell zur Angstmessung.

Lormetazepam significantly reduced anxiety during local anaesthesia when compared with a placebo control group. There were significantly fewer accompanying symptoms of spinal anaesthesia under lormetazepam than under placebo. This number fell in relation to the decrease in the patients' anxiety. Lormetazepam also proved to be significantly superior to placebo according to the physician's assessment of anxiety. There were no differences between the two groups with respect to side-effects. The results of the Erlanger Anxiety Scale--Situative (EAS-S) revealed: 1. Oral treatment with lormetazepam led to markedly lower anxiety values than treatment with placebo (p less than 0.1; t test, one-sided). - 2. Following additional, intravenous administration of lormetazepam an even greater difference between the two treatment groups became evident. - 3. The situative anxiety was lower under treatment with lormetazepam than with placebo, independent of the variables "sex", "trait anxiety" or "anxiety control mechanism" (dimension of sensitization-repression). - 4. Women attained higher actual anxiety values than did men. - 5. Patients with high basic anxiety expectedly attained higher situative anxiety scores than those with lower basic anxiety.

[A new formulation of etomidate in lipid emulsion--bioavailability and venous provocation]. / Eine neue Zubereitung von Etomidat in Lipidemulsion--Bioverfügbarkeit und Venenreizung.

In a prospective, randomized study of 16 volunteers, a new galenic formulation of the induction hypnotic etomidate in lipid emulsion was compared with the commercial form in propylene glycol (Hypnomidate). After 0.3 mg/kg etomidate plasma levels (HPLC) and hypnotic effects (visual EEG analysis) of both formulations were almost identical. Onset of action occurred after 41.6 s in the propylene glycol group (group I) and 35.6 s in the lipid emulsion group (group II). The hypnotic effect (greater than or equal to D0) lasted 7 min 20 s in group I and 6 min in group II. Plasma levels in group I decreased from 630 ng/ml after 2 min to 170 after 8 min and 37 after 130 min. With group II the plasma levels decreased from 770 ng/ml after 2 min to 150 after 8 min and 42 after 130 min (Fig. 1). In the propylene glycol experiment, 4 of 8 volunteers reported pain on injection. Within 7 days 4 persons developed phlebitis or thrombophlebitis. One showed signs of an allergic reaction (urticaria). With the new formulation of etomidate in lipid emulsion, neither venous sequelae nor allergic reactions were observed in any of the 8 volunteers (Table 2).

[Small bowel obturation ileus related to ingestion of a medical device]. / Dünndarmobturationsileus im Zusammenhang mit der Einnahme eines Medizinproduktes.

We report the case of a 50-year-old woman who was admitted to the hospital with an acute abdomen and underwent exploratory laparotomy. Intraoperatively, we suspected Crohn's disease of the ileocecal valve and decided to treat conservatively. However, in the further clinical course the patient became severely sick and developed a necrotizing ileocecal inflammation in combination with multiple perforations, 4-quadrants peritonitis and several other complications. Histopathology revealed an unspecific inflammation of the ileocecal valve. Furthermore, numerous little cellulose sponges were found in the resected intestinal segment. They were obstructing the lumen and were identical with the contents of an appetite suppressing medical device. A connection between the ingestion of this medical device and the penetrating inflammation of the ileocecal valve has to be suspected.