[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.

[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.

[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.

[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.

[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.

[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.

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.

[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.

[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.

[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.

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.

[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.

Killing of Fas ligand-resistant renal carcioma cells by interleukin-2- and BCG-activated effector cells.

Activated cytolytic effector cells like lymphokine-activated killer (LAK) and the recently described bacillus-Calmette-Guerin-activated killer (BAK) cells are thought to mediate antitumor effects against metastatic renal cell carcinoma (RCC) and superficial bladder cancer respectively. Perforin and Fas ligand (FasL) have been described as the major lytic principles in cellular cytotoxicity. Using a radioactive-release assay and specific inhibitors, we investigated the molecular mechanisms used by LAK and BAK cells in the lysis of renal carcinoma cells. In addition, we evaluated the susceptibility of RCC cells to FasL-mediated cytotoxicity. LAK and BAK cells effectively lysed the renal cancer cell line SK-RC-35 upon cell-cell contact. Both effector cell populations were shown to produce perforin and FasL as determined by reverse transcriptase/polymerase chain reaction (RT-PCR). Using fluorescence-activated cell sorting analyses and RT-PCR, we detected a marked Fas receptor (Fas, CD95) expression on RCC cells. However, RCC cells were shown to be resistant to killing by recombinant FasL and lysis by BAK and LAK cells was not inhibited in the presence of anti-FasL antibody. In contrast, the cytotoxicity exerted by LAK and BAK cells was drastically reduced in the presence of the Ca2+-chelating agent EGTA as well as concanamycin A, a specific inhibitor of perforin-mediated lysis. These results demonstrate that cytolysis of FasL-resistant RCC cells by activated immune cells is mediated via perforin. Our findings give further insights into the molecular mechanisms involved in the elimination of RCC by cytotoxic lymphocytes activated with biological response modifiers.

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.

[The effect of propofol-ketamine anesthesia on hemodynamics and analgesia in comparison with propofol-fentanyl]. / Einfluss einer Propofol-Ketamin-Narkose auf Kreislaufverhalten und Analgesie im Vergleich mit Propofol-Fentanyl.

Propofol (Diprivan), a modern intravenous hypnotic, produces a reduction in both cardiac index (CI) and mean arterial pressure (MAP). Ketamine (Ketanest), a potent analgesic, in contrast, causes an increase in MAP and CI. The aim of the present study was to investigate whether the combination of propofol and ketamine can give better hemodynamic stability during the induction and maintenance of general anesthesia than propofol used with fentanyl, whose cardiodepressant actions may cumulate. METHODS. For induction of general anesthesia 10 patients (ASA I and II) each received 3-5 boluses of propofol (0.5 mg.kg-1 during 35 s until predetermined level of anesthesia was reached (stage D2/E0 according to [20]) followed by a continuous propofol infusion (0.120 mg.kg-1.min). Fentanyl 0.1 mg was administered to each patient in group A for induction of anesthesia and again if evident pain was present. In group B ketamine was given following a pharmacokinetic model based on computer-simulated calculation. After an initial bolus of 38 mg injected within 2 min further doses of 42 mg, 35 mg, 32 mg and 28 mg ketamine were administered over 30 min at a time. Signs of evident pain were treated by means of supplementary doses of 0.5 mg.kg-1. RESULTS. In both groups a moderate drop of MAP was observed after the induction of general anesthesia. Two patients in each group showed a distinct decrease in MAP (-32%). The heart rate dropped slightly (-9%) in group A, but did not change in group B. Following intubation the MAP rose by less in group A (+8%) than in group B (+21%). After the beginning of the operation the group treated with propofol/fentanyl showed major hemodynamic changes; in particular, bradycardia with less than 40 bpm was observed in more patients than in the propofol/ketamine group. Postoperatively, fewer patients in group B required rescue doses of analgesics (1 of 10) than these in group A (7 of 10), though vigilance was better in group B. DISCUSSION. The dose of ketamine administered during the induction of general anesthesia may have been not high enough to neutralize the cardiodepressant effect of propofol. But during the maintenance of anesthesia there was in fact better hemodynamic stability in group B than in group A as a result of the neutralization of opposing actions. Fentanyl even intensified the fall in MAP after propofol. Patients in group B showed better vigilance as well as better pain relief postoperatively. The population of the fentanyl group was obviously more deeply sedated and analgesia was still inadequate. In our study general intravenous anesthesia with propofol and ketamine offered the advantages of better analgesia, a higher state of vigilance and the absence of respiratory depression during the postoperative phase compared with the combination of propofol and fentanyl.

[Etomidate using a new solubilizer. Experimental clinical studies on venous tolerance and bioavailability]. / Etomidat mit einem neuen Lösungsvermittler. Klinisch-experimentelle Untersuchungen zur Venenverträglichkeit und Bioverfügbarkeit.

Pain following intravenous injection as well as thrombophlebitis are substantial side effects of etomidate that have been reported from the first clinical study (1972-1973) onwards. Investigations of our own and by Gran et al. have pointed out that injectable etomidate with intralipid as a solvent removes side effects without impairing the good hypnotic action. The idea of using a lipid emulsion as a solvent was presented a few years later, inducing two further studies. METHOD. Both pharmacodynamic (continuous EEG registration) and pharmacokinetic [determination (HPLC) of plasma levels of the active substance] investigations were carried out on volunteers. At random 16 volunteers received etomidate in propylene glycol or etomidate in lipid emulsion for general anesthesia. A dose of 0.3 mg kg-1 was given over 60 s. In a clinical study 100 patients were divided into two independent groups of 50 each. They received either the commercially available etomidate in 35% propylene glycol (group I) or the new formulation containing 20 mg etomidate in 10 ml of a lipid-emulsion (Lipofundin MCT 20%) (group II). A dose of 0.3 mg kg-1 etomidate was given. RESULTS. There was a higher concentration of etomidate for 8 min after injection in lipid emulsion compared with etomidate in propylene glycol. The plasma concentration of etomidate (200 ng/ml) correlates with C2 corresponding to the light sleep stage after etomidate in propylene glycol, but with D0 according to the deep sleep stage after etomidate in lipid emulsion. At lower plasma concentrations, the hypnotic action of etomidate in propylene glycol is stronger than the effect of the lipid emulsion. This result means that it is possible that a part of the etomidate remains in the lipid particles. In the clinical study the anesthetic induction time was nearly identical in both groups; blood pressure and heart rate were stable. Following etomidate in propylene glycol, 36% of the patients complained of a painful injection. On the first postoperative day, 9 of 47 patients showed signs of phlebitis and three others thrombosis. On the 7th day a venous reaction was evident in 22% of these patients; 2 patients had developed phlebitis, 5 thrombosis and 4 thrombophlebitis. After etomidate in lipid emulsion, there were no signs of local irritation. The same results have been obtained in the study with volunteers. CONCLUSION. Two unpleasant side effects of etomidate, pain on injection and postoperative thrombophlebitis, were abolished by the solvent "lipid emulsion".