Carsten-Henning Ohlmann

Fast-track rehabilitation after robot-assisted laparoscopic cystectomy accelerates postoperative recovery.

There is evidence from large abdominal surgeries and some open cystectomy series that multifactorial fast‐track regimens shorten postoperative convalescence without any effect on morbidity and mortality. Such a regimen is of particular interest in combination with minimally invasive techniques, as early patient recovery demands for more rapid nutrition and mobilisation schemes. The present study, in a single institution, reports on the design, application and results of a fast‐track protocol in patients undergoing robot‐assisted laparoscopic cystectomy. There was no evidence of a higher incidence of complications with the fast‐track regimen and postoperative recovery was faster.

da Vinci and Open Radical Prostatectomy: Comparison of Clinical Outcomes and Analysis of Insurance Costs

Purpose: To assess clinical outcomes and reimbursement costs of open and robotic-assisted radical prostatectomies in Germany. Methods: Perioperative data of 499 open (2003-2006) and 932 (2008-2010) robotic-assisted radical prostatectomies as well as longitudinal reimbursement costs of an anonymized health insurance research database from Germany containing data of patients who underwent robotic-assisted or open radical prostatectomy were retrospectively analysed in a single-centre study. Results: Significantly better outcomes after robotic-assisted vs. open prostatectomy were observed in regards to positive surgical margins (13.3 vs. 22.4%; p < 0.0001), intraoperative transfusions (0.1 vs. 2.6%; p < 0.0001), hospitalization (8.7 vs. 15.2 days; p < 0.0001) and duration of catheter (6.6 vs. 12.8 days; p < 0.0001). Operating time was significantly longer with robotic-assisted radical prostatectomy when compared to open surgery (184.4 vs. 128.0 min; p < 0.0001), while intraoperative complications showed a similar occurrence between both groups. Significant fewer postoperative complications were observed after robotic-assisted radical prostatectomy (26.5 vs. 42.5%; p < 0.0001) and rate of re-admission was lower for the robotic patients (13.6 vs. 19.4%; p = 0.0050). While insurance costs were higher in the 2 years before radical prostatectomy for the patients who underwent a robotic procedure (4,241.60 vs. 3,410.23 €; p = 0.202), additive costs of care of the year of surgery plus the 2 following years were less for the robotic cohort when compared to the costs incurred by the open group (21,673.71 vs. 24,512.37 €; p = 0.1676). Conclusions: The observed clinical advantages of robotic-assisted radical prostatectomy seem to result in reduced health insurance cost postoperatively when compared to open surgery. This should be taken into consideration regarding reimbursement and implementation of a clinically superior method.

Androgen deprivation for advanced prostate cancer

Androgen deprivation (ADT) by medical or surgical castration represents the standard therapeutic approach for managing prostate cancer (PCA) with systemic or locoregional metastases. Although ADT has been successfully used for more than 60 years, there are still major controversies with regard to the initiation (early versus delayed), type (complete versus monotherapy), and duration (continuous versus intermittent) of treatment. It is the purpose of this review to critically present the results of the various ADT options. Bilateral orchiectomy and subcutaneous application of luteinising hormone-releasing hormone (LHRH) analogues represent the guideline-recommended standard treatment for metastatic PCA, whereas estrogens are no longer recommended because of significant cardiovascular side effects despite comparable therapeutic efficacy. Antiandrogen monotherapy with bicalutamide is comparable to LHRH analogues in men with minimal tumour burden. However, survival rates are inferior in patients with extensive metastatic disease, in whom medical or surgical castration should be favoured. Complete ADT results in a median survival benefit of about 5% in men with low metastatic tumour burden, and it cannot be recommended for routine use. Early ADT is associated with a significant advantage in terms of symptom-free survival and prevention of metastasis-associated complications, but it does not result in a prolonged progression-free and overall survival when compared with delayed ADT. Despite encouraging results, intermittent ADT remains an experimental therapeutic approach that should be considered on an individual basis in carefully selected patients. Adjuvant ADT is still discussed controversially for men after radical prostatectomy, whereas it has become the standard approach in patients who undergo external beam radiation for locally advanced PCA.

Resection of metastases from prostate cancer

Surgical resection of a solitary or a limited number of metastases is a controversy in patients with prostate cancer that is increasingly being discussed. The improved accuracy of the detection of local or distant recurrences after primary treatment using modern imaging techniques including choline PET/CT led to an increased demand for salvage surgical procedures. Apart from the resection of synchronous metastases at the time of radical prostatectomy the oncological efficacy of a salvage lymphadenectomy or a salvage resection of visceral or osseous metastases remains to be proven. Here, the available data covering the different clinical scenarios for the resection of metastases in prostate cancer and recommendations of recently published guidelines are reviewed.

Improving the efficacy of targeted trials by multiple-marker analysis in castration-resistant prostate cancer

OBJECTIVES In order to improve the efficacy of targeted therapy trials, the expression profiles of several molecular markers that are potential candidates for targeted therapy were analyzed in patients with progressive castration-resistant prostate cancer. METHODS AND MATERIALS Paraffin-embedded samples of tumor tissue from 51 patients obtained from biopsies of metastases or remaining prostates were analyzed immunohistochemically for the expression of EGFR, PDGFRβ, Her-2/neu, c-Kit, and VEGF. Staining was analyzed according to the percentage of positively stained tumor cells and the intensity of staining. RESULTS According to the different cut-off values of 10%, 30%, 50%, or 70% for the percentage of positively stained cells, different rates of expression were found. Expression rates ranged from 30.6% to 61.2% for EGFR, from 34.7% to 57.1% for PDGFRβ, from 9.6% to 28.8% for Her-2/neu, from 12.5% to 22.4% for c-Kit, and from 51.1% to 74.5% for VEGF. Defining positive expression as ≥ 30% positively stained tumor cells, with an intensity of staining of ≥ 2+, resulted in positive expression of EGFR in 38.8%, PDGFRβ in 24.5%, Her-2/neu in 13.5%, c-Kit in 6.4%, and VEGF in 44.7% of the patients. CONCLUSIONS Our results demonstrate simultaneous expression of several markers in castration-resistant prostate cancer tissue. Translation of the results into modern, multi-arm clinical trial designs will improve the efficacy of recruiting and obtaining results, compared with multiple double-arm trials.

Androgendeprivation in der Therapie des Prostatakarzinoms

Androgen deprivation (ADT) by medical or surgical castration represents the standard therapeutic approach for managing prostate cancer (PCA) with systemic or locoregional metastases. Although ADT has been successfully used for more than 60 years, there are still major controversies with regard to the initiation (early versus delayed), type (complete versus monotherapy), and duration (continuous versus intermittent) of treatment. It is the purpose of this review to critically present the results of the various ADT options. Bilateral orchiectomy and subcutaneous application of luteinising hormone-releasing hormone (LHRH) analogues represent the guideline-recommended standard treatment for metastatic PCA, whereas estrogens are no longer recommended because of significant cardiovascular side effects despite comparable therapeutic efficacy. Antiandrogen monotherapy with bicalutamide is comparable to LHRH analogues in men with minimal tumour burden. However, survival rates are inferior in patients with extensive metastatic disease, in whom medical or surgical castration should be favoured. Complete ADT results in a median survival benefit of about 5% in men with low metastatic tumour burden, and it cannot be recommended for routine use. Early ADT is associated with a significant advantage in terms of symptom-free survival and prevention of metastasis-associated complications, but it does not result in a prolonged progression-free and overall survival when compared with delayed ADT. Despite encouraging results, intermittent ADT remains an experimental therapeutic approach that should be considered on an individual basis in carefully selected patients. Adjuvant ADT is still discussed controversially for men after radical prostatectomy, whereas it has become the standard approach in patients who undergo external beam radiation for locally advanced PCA.

Exosomes of invasive urothelial carcinoma cells are characterized by a specific miRNA expression signature

Muscle-invasive bladder cancer (MIBC) represents a highly aggressive tumor type compared to non-muscle-invasive tumors. MIBC is characterized by specific molecular alterations, which may also modulate extracellular tumorigenic effects. Tumor-associated exosomes, especially exosomal miRNAs, are important regulators in the interaction between tumor cells and tumor microenvironment by affecting tumor-promoting processes in target cells. It is important to analyze whether their exosomal patterns also reflect the specific molecular characteristics of MIBC. The aim of this study was to compare the miRNA expression in secreted exosomes from urinary bladder cancer cells (UBC) with different degrees of invasiveness. By electron microscopy, nanotracking analysis and western blot we proofed a high quality of isolated exosomes. Microarray analysis identified an invasion-associated signature of 15 miRNAs, which is significantly altered in exosomes of invasive UBC compared to non-invasive counterparts. Therefrom, 9 miRNAs are consistent differently expressed in both, invasive cells and their secreted exosomes. The remaining 6 exosome-specific miRNAs are only deregulated in exosomes but not in their parental cells. MiRNA alterations were verified by qPCR in cell culture and urinary exosomes. In conclusion, we showed that exosomes from invasive UBC cells are characterized by a specific miRNA signature. Further analyses have to clarify the functional relevance of exosomal miRNAs secreted by invasive bladder cancer cells for modification of the tumor microenvironment and their putative role as molecular markers in liquid biopsies.Muscle-invasive bladder cancer (MIBC) represents a highly aggressive tumor type compared to non-muscle-invasive tumors. MIBC is characterized by specific molecular alterations, which may also modulate extracellular tumorigenic effects. Tumor-associated exosomes, especially exosomal miRNAs, are important regulators in the interaction between tumor cells and tumor microenvironment by affecting tumor-promoting processes in target cells. It is important to analyze whether their exosomal patterns also reflect the specific molecular characteristics of MIBC. The aim of this study was to compare the miRNA expression in secreted exosomes from urinary bladder cancer cells (UBC) with different degrees of invasiveness. By electron microscopy, nanotracking analysis and western blot we proofed a high quality of isolated exosomes. Microarray analysis identified an invasion-associated signature of 15 miRNAs, which is significantly altered in exosomes of invasive UBC compared to non-invasive counterparts. Therefrom, 9 miRNAs are consistent differently expressed in both, invasive cells and their secreted exosomes. The remaining 6 exosome-specific miRNAs are only deregulated in exosomes but not in their parental cells. MiRNA alterations were verified by qPCR in cell culture and urinary exosomes. In conclusion, we showed that exosomes from invasive UBC cells are characterized by a specific miRNA signature. Further analyses have to clarify the functional relevance of exosomal miRNAs secreted by invasive bladder cancer cells for modification of the tumor microenvironment and their putative role as molecular markers in liquid biopsies.

Metastasenresektion beim Prostatakarzinom

Surgical resection of a solitary or a limited number of metastases is a controversy in patients with prostate cancer that is increasingly being discussed. The improved accuracy of the detection of local or distant recurrences after primary treatment using modern imaging techniques including choline PET/CT led to an increased demand for salvage surgical procedures. Apart from the resection of synchronous metastases at the time of radical prostatectomy the oncological efficacy of a salvage lymphadenectomy or a salvage resection of visceral or osseous metastases remains to be proven. Here, the available data covering the different clinical scenarios for the resection of metastases in prostate cancer and recommendations of recently published guidelines are reviewed.

Kidney transplantation from a deceased donor with anuric acute kidney injury caused by rhabdomyolysis.

Injury Caused by Rhabdomyolysis The kidney donor was a 21-year-old man (80kg, 180cm) with anoxic brain damage after cardiopulmonary resuscitation because of asystole, resulting from a suicidal medication overdose of baclofen (3750mg) and alcohol intoxication with 2g/L serum alcohol at admission. No other preexisting illness or regular medication intake was reported. Duration of cardiac arrest was not known; however, restoration of hemodynamic circulation by cardiopulmonary resuscitation was achieved within 8 min. An anuric, acute kidney injury (AKI) requiring dialysis was noted at admission. Anuria requiring continuous dialysis persisted during the hospital stay. Several features of the clinical course are of note: signs of a biochemically severe rhabdomyolysis developed with initial serum creatinine-kinase of 19,980 units/L, peaking at 140,200 units/L, and with a final value of 16,070 units/L. Serum bilirubin was elevated at admission (3.4mg/dL) with a subsequent increase to 18.8mg/dL at day 3. Antibiotic management with meropenem and vancomycin was initiated because of raised inflammatory markers despite a clinical focus not being identified. Finally, vasopressor therapy was required throughout the inpatient stay to maintain hemodynamic stability. Details on specific laboratory parameters from the donor are presented in Table 1. Donor brain death was confirmed 4 days after admission, with organ explantation performed the following day. Despite the young donor age, several transplant centers rejected the offered kidney before our acceptance. The corresponding right kidney could not be allocated and was finally submitted to histologic analysis where no pathologic findings were described. Excluding the heart, all other organs were considered for transplantation. The kidney recipient was a 48-yearold white female (67kg, 168cm), treated with hemodialysis for 18months because of an undefined collagenosis. A mismatch ratio recorded four mismatches (1Y1Y2). Cold ischemia time was 14hr 37min and warm ischemia time was 32min. A preimplantation biopsy was not considered because of the absence of risk factors for chronic damage. The transplant organ suffered from a delayed graft function, and dialysis was required on days 1 and 3 postoperatively. Graft biopsy was performed on day 8. Histologic analysis showed acute tubular necrosis and pathognomonic myoglobin deposition, consistent with ischemia and rhabdomyolysis. Although sufficient diuresis was established by day 4, a gradual decrease in serum creatinine was noted from day 10, reaching 1.92mg/dL at discharge (day 21). Creatinine stabilized below 0.92mg/dL after 1month, measuring 0.72mg/dL and glomerular filtration rate 87mL per min at the last control (day 523). A detailed course of creatinine is listed in Table 1. In the past, different strategies to expand the pool of donors for kidney transplantation have been described. The expanded criteria donor concept was proposed in the early 2000s, incorporating older donors with comorbidities, such as hypertension, diabetes, and renal dysfunction (1). As an ‘‘adequate’’ or ‘‘marginal’’ donor remains to be undefined, some centers now accept transplant organs with AKI reporting comparable graft outcomes to that of noninjured organs (2). Organ inclusion is justified by the potential reversal of renal damage in cases of AKI caused by: hypoxic-ischemic injury, nephrotoxic compound exposure, infection, or rhabdomyolysis. Such centers have reported successful renal transplantation and adequate graft function (3Y7). This is particularly true for cases with AKI caused by rhabdomyolysis (4, 7Y11). However, in literature, definition of rhabdomyolysis varied with reported resultant serum creatinine-kinase readings figures only moderately elevated in comparison to the current case (9Y12), and in contrast to our case, all these donors had urine output at donation (8Y11). The current case expands the acceptance criteria for the donor pool yet further. First, this case reports on a successful

Differential effects of ibandronate, docetaxel and farnesol treatment alone and in combination on the growth of prostate cancer cell lines

Abstract Ibandronate, one of the most potent bisphosphonates, has been shown to inhibit growth of various cancer cell lines. In contrast, little is known about the effects of ibandronate on prostate cancer cells. Therefore the aim of our study was to characterize the effects of ibandronate alone and in combination with docetaxel on the growth of prostate cancer cell lines and to identify the underlying signalling pathways. Material and methods. The prostate cancer cell lines LNCaP and PC-3 were treated with increasing concentrations of ibandronate and docetaxel alone and in combination. Viable cell number was measured after five days using a hemocytometer and the MTT-method. The effects of ibandronate were tentatively antagonized by addition of farnesyl-pyrophosphate (FPP) or farnesol (FOH). Results. Ibandronate inhibits growth of both prostate cancer cell lines in a dose dependent manner. In combination with docetaxel, synergistic effects are found as evidenced by a combination index (CI) of <1. Addition of FOH and FPP completely antagonized the growth inhibitory effects of ibandronate on both cell lines. Surprisingly, in combination with ibandronate and docetaxel, FOH further increased growth inhibition instead of antagonizing the growth inhibitory effects of ibandronate. Furthermore, FOH alone appeared to be a potent inhibitor of tumor cell growth. Discussion. Ibandronate effectively inhibits growth of prostate cancer cell lines via inhibition of the farnesyl-IPP-synthase and exhibits synergistic effects with docetaxel. In addition, FOH is a potent inhibitor of prostate cancer cell lines and may display an interesting treatment option for patients with CRPC.