Michael Siegsmund

Association of the P-Glycoprotein Transporter MDR1C3435T Polymorphism with the Susceptibility to Renal Epithelial Tumors

Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the MDR1(C3435T) polymorphism drives expression and modulates disease risk. In an explorational case-control study, constitutional genotype frequencies were established at MDR1(C3435T) of 537 healthy control subjects and compared with those of 212 patients with renal epithelial tumors. There were 179 clear cell renal cell carcinoma (CCRCC) and 33 tumors collectively assigned as non-CCRCC. In a second study, genotypes of another 150 healthy control subjects and 50 patients with three non-CCRCC types (26 papillary RCC, 11 chromophobe RCC, and 13 renal oncocytic adenoma) were compared. PCR-restriction fragment length polymorphism-based analysis of constitutional DNA, and statistical analysis were applied. PGP expression was analyzed by quantitative immunohistochemistry. The explorational study showed a significant association between T allele frequency and the occurrence of tumors (P = 0.007). When tumors were histopathologically distinguished into frequent CCRCC and less frequent non-CCRCC, both patient groups contributed to this effect with a seemingly strong influence by the latter (P = 0.0419). The second study established the T allele as a risk factor especially for non-CCRCC (P = 0.0005) with the highest risk for homozygote TT allele carriers (P < 0.0001). Independently, MDR1(C3435T) genotype associated variations in PGP expression were shown in normal renal parenchyma with a 1.5-fold difference of median values (TT, 1.9; CC, 2.8; P = 0.0065). The data provide evidence for PGP to influence the susceptibility to develop renal epithelial tumors by virtue of its MDR1(C3435T) polymorphism and changes in expression. Especially T and TT carriers are at risk for developing non-CCRCC, i.e., papillary and chromophobe RCC as well as oncocytic adenomas.

PERCUTANEOUS NEPHROSTOMY VERSUS URETERAL STENTS FOR DIVERSION OF HYDRONEPHROSIS CAUSED BY STONES: A PROSPECTIVE, RANDOMIZED CLINICAL TRIAL

PURPOSE Urinary diversion with percutaneous nephrostomy or ureteral stent is indicated by symptoms, such as persistent colic, high temperature and uremia, of hydronephrosis caused by stones. We evaluate which of these 2 methods is superior concerning the course of procedure, relief of accompanying symptoms and quality of life in regard to patient age and sex. MATERIALS AND METHODS A total of 40 patients with stone induced hydronephrosis were randomized into either percutaneous nephrostomy or stent insertion groups. These patients were then evaluated by procedure (use of analgesics, x-ray exposure, success of insertion), relief of accompanying symptoms (duration of diversion, intravenous administration of antibiotics for high temperature) and quality of life (questionnaire immediately and 2 to 4 weeks postoperatively). RESULTS Two comparable groups of patients were formed, with an average age of 55 versus 49 years and a male-to-female ratio of 12:8 versus 9:11 for those who underwent percutaneous nephrostomy versus those who received a stent, respectively. Percutaneous nephrostomy was successfully completed in 100% of patients and stents were successful in 80%, with a 20% conversion to percutaneous nephrostomy. The x-ray exposure was shorter in the percutaneous nephrostomy group (p = 0.052). Administration of analgesics was more frequent in the stent group (p = 0.061). Percutaneous nephrostomy indwelling time was shorter (50% less than 2 weeks) than that of stents (25% less than 2 weeks, p = 0.043). Antibiotics were administered for greater than 5 days in 0% of patients who underwent percutaneous nephrostomy versus 64% in those with stents (p = 0.174). Reduction in quality of life was moderate but more pronounced in patients with stents compared to those who underwent percutaneous nephrostomy, and was more distinct in males and younger patients. The quality of life progressively improved in the course of diversion with percutaneous nephrostomy but deteriorated with stents. CONCLUSIONS Our results demonstrated that percutaneous nephrostomy is superior to ureteral stents for diversion of hydronephrosis caused by stones, especially in patients with a high temperature, as well as in males and juveniles.

Ketoconazole effectively reverses multidrug resistance in highly resistant KB cells

The antifungal agent ketoconazole was found to overcome resistance to vinblastine and doxorubicin in multidrug resistant KB-V1 cells in vitro. These cells are several hundred-fold more resistant than the parental cell line KB-3-1. Ketoconazole had little or no effect on the parental KB-3-1 cells. The concentrations used to overcome drug resistance in vitro have already been safely used in vivo for treatment of fungal infections and in the monotherapy of hormone independent prostate carcinomas to block adrenal androgen production. Because of a possible beneficial effect of a combination of ketoconazole and a chemotherapeutic drug in multidrug resistant cancers, we examined a panel of 11 prostate carcinoma tissues for the expression of the MDR1 gene by an RNA-PCR assay. MDR1 expression was detectable, albeit at low levels, in 8 of the 11 tumors, suggesting a possible role of this gene in the drug resistance of prostate carcinomas. Our data suggest that ketoconazole might be useful in overcoming multidrug resistance in concentrations that are achievable in humans.

Prognostic impact of lymphovascular invasion in radical prostatectomy specimens

To estimate the prognostic value of lymphovascular invasion (LVI) in patients with node‐negative prostate cancer treated by radical prostatectomy (RP).

Pseudomonas Exotoxin Conjugated to Monoclonal Antibody MRK16 Specifically Kills Multidrug Resistant Cells in Cultured Renal Carcinomas and In Mdr-Transgenic Mice

Using renal carcinoma and prostate carcinoma cell lines, we investigated the concept of targeting and killing multidrug resistant cells in urogenital cancers. Renal carcinoma lines HTB44, 45, 46, and 47 expressed a relatively low, but detectable level of multidrug resistance (MDR)1 mRNA as indicated by Northern blot analysis, whereas prostate lines LNCaP and DU145 were found to be MDR1-negative. Anti-P-glycoprotein monoclonal antibody MRK16 was conjugated to Pseudomonas exotoxin (PE) by a stable thioether bond. Treatment with MRK16-PE resulted in a dose-dependent killing of multidrug resistant renal carcinoma cells, while non-MDR expressing prostate carcinoma cells were not affected. Addition of excess MRK16 blocked the effect of MRK16-PE. Furthermore, MOPC-PE, a non-MDR associated monoclonal antibody control conjugate, did not target and kill multidrug resistant renal carcinoma cells. Having established that MRK16-PE was active against and specific for multidrug resistant cells in culture, we also tested bioactivity in MDR-transgenic mice, whose bone marrow cells express the human MDR1 gene at a level approximately equal to that found in many human cancers. Again, MRK16-PE killed multidrug resistant bone marrow cells with high efficiency in an intact animal, and killing was blocked by unconjugated MRK16.

Optimierter Einsatz der Strahlentherapie durch IMRT und Präzisionslokalisationsverfahren bei der Behandlung des fortgeschrittenen Prostatakarzinoms

ZusammenfassungMit der intensitätsmodulierten Strahlentherapie (IMRT) zusammen mit modernen, nichtinvasiven Lokalisationsverfahren steht eine Methodik zur Verfügung, mit der die konformale Bestrahlung des Prostatakarzinoms unter optimaler Schonung des Rektums potentiell verbessert werden kann.Diese Übersicht fasst einerseits die klinischen Erfordernisse an die Strahlentherapie beim fortgeschrittenen Prostatakarzinom und andererseits die neuen nichtinvasiven technischen Möglichkeiten zusammen, die helfen, diese Erfordernisse besser zu erfüllen. Zusammen mit der Diskussion der neuen biologischen Daten, die evtl. die Verkürzung der Radiotherapie ermöglichen, wurde versucht, diese Entwicklungen mit ihren theoretischen Vorteilen und eventuellen Problemen zu schildern, um diese Vorgänge über die Strahlentherapie hinaus transparent zu machen.AbstractIntensity modulated radiotherapy (IMRT) combined with recently developed noninvasive image-guided targeting techniques for tumor localization/repositioning provide a means to further improve on conformal radiotherapy of prostate cancer by optimally sparing the rectum. This refined approach may potentially improve treatment results for locally advanced prostate cancer while reducing side effects. This review summarizes the clinical requirements for effective prostate radiotherapy and describes the new technology that helps to better fulfil these requirements. These noninvasive developments, their potential benefit as well as their limitations, together with new data on fractionation sensitivity of prostate cancer that may lead to shortened overall treatment times may be of interest for all physicians treating patients with prostate cancer.

Radical cystectomy in the treatment of bladder cancer always in due time

INTRODUCTION The aim of this study was to examine how the survival rates for patients with muscle-invasive bladder carcinoma are influenced by the tumor stage at initial presentation. PATIENTS AND METHODS This study examined the clinical course of 452 patients who underwent radical cystectomy for bladder carcinoma from 1992 to 2004. The patients were divided into three groups according to the histological results of the initial and final transurethral tumor resection (TURB). In group 1 (n=114) patients who presented with a superficial bladder carcinoma which had a high likelihood of progressing underwent radical cystectomy. Group 2 included (n=92) patients who displayed a superficial tumor stage when they first presented and developed progressive muscle-invasive bladder carcinoma under conservative treatment. Group 3 (n=246) comprised patients who were already at the muscle-invasive tumor stage in the course of primary TURB. The histopathological characteristics of all transurethral tumor resections and radical cystectomy were recorded. Progression-free survival rates and overall survival rates in the three groups were then compared. RESULTS The average patient age at cystectomy was 64.3 (35-80) years, and the average follow-up period was 49 months. Progression-free survival and overall survival of all 452 patients were 56.1 and 53.6%, respectively, after 5 years. The best outcome was a progression-free 5-year survival rate of 78.4% with organ-confined, lymph node-negative tumors (n=213). This result was statistically significant (p<0.01) compared with the progression-free 5-year survival rate of 42.3% for non-organ-confined, lymph node-negative tumors (n=112). Lymph node-positive patients (n=127) achieved a progression-free 5-year survival rate of 29.0% regardless of the tumor infiltration. Group 1 patients achieved a progression-free survival rate of 71.3% and an overall survival rate of 69.1% after 5 years. Group 2 patients achieved a progression-free survival rate of 52.9% and an overall survival rate of 51.4% after 5 years. Group 3 patients achieved a progression-free survival and overall survival of 50.2% and 47.1%, respectively, after 5 years. There was no significant difference between groups 2 and 3 with regard to their progression-free or overall survival rates (p>0.45). However, both groups displayed significantly poorer progression-free and overall survival rates compared with group 1 (p<0.01). CONCLUSION Our results show that patients with superficial bladder carcinoma with tumor progression to muscle invasion do not have a better prognosis after radical cystectomy than patients presenting initially with muscle-invasive bladder carcinoma. Survival rates in this group can only be improved by singling out patients on the basis of risk factors at an earlier stage and carrying out cystectomy. Due to these results we must expect that waiting for a muscle invasion in patients with superficial bladder carcinoma with a high risk profile results in a significant impairment of prognosis.

Stellen wir die Indikation zur radikalen Zystektomie immer zeitgerecht

INTRODUCTION The aim of this study was to examine how the survival rates for patients with muscle-invasive bladder carcinoma are influenced by the tumor stage at initial presentation. PATIENTS AND METHODS This study examined the clinical course of 452 patients who underwent radical cystectomy for bladder carcinoma from 1992 to 2004. The patients were divided into three groups according to the histological results of the initial and final transurethral tumor resection (TURB). In group 1 (n=114) patients who presented with a superficial bladder carcinoma which had a high likelihood of progressing underwent radical cystectomy. Group 2 included (n=92) patients who displayed a superficial tumor stage when they first presented and developed progressive muscle-invasive bladder carcinoma under conservative treatment. Group 3 (n=246) comprised patients who were already at the muscle-invasive tumor stage in the course of primary TURB. The histopathological characteristics of all transurethral tumor resections and radical cystectomy were recorded. Progression-free survival rates and overall survival rates in the three groups were then compared. RESULTS The average patient age at cystectomy was 64.3 (35-80) years, and the average follow-up period was 49 months. Progression-free survival and overall survival of all 452 patients were 56.1 and 53.6%, respectively, after 5 years. The best outcome was a progression-free 5-year survival rate of 78.4% with organ-confined, lymph node-negative tumors (n=213). This result was statistically significant (p<0.01) compared with the progression-free 5-year survival rate of 42.3% for non-organ-confined, lymph node-negative tumors (n=112). Lymph node-positive patients (n=127) achieved a progression-free 5-year survival rate of 29.0% regardless of the tumor infiltration. Group 1 patients achieved a progression-free survival rate of 71.3% and an overall survival rate of 69.1% after 5 years. Group 2 patients achieved a progression-free survival rate of 52.9% and an overall survival rate of 51.4% after 5 years. Group 3 patients achieved a progression-free survival and overall survival of 50.2% and 47.1%, respectively, after 5 years. There was no significant difference between groups 2 and 3 with regard to their progression-free or overall survival rates (p>0.45). However, both groups displayed significantly poorer progression-free and overall survival rates compared with group 1 (p<0.01). CONCLUSION Our results show that patients with superficial bladder carcinoma with tumor progression to muscle invasion do not have a better prognosis after radical cystectomy than patients presenting initially with muscle-invasive bladder carcinoma. Survival rates in this group can only be improved by singling out patients on the basis of risk factors at an earlier stage and carrying out cystectomy. Due to these results we must expect that waiting for a muscle invasion in patients with superficial bladder carcinoma with a high risk profile results in a significant impairment of prognosis.

Stellen wir die Indikation zur radikalen Zystektomie immer zeitgerecht?@@@Radical cystectomy in the treatment of bladder cancer always in due time?

INTRODUCTION The aim of this study was to examine how the survival rates for patients with muscle-invasive bladder carcinoma are influenced by the tumor stage at initial presentation. PATIENTS AND METHODS This study examined the clinical course of 452 patients who underwent radical cystectomy for bladder carcinoma from 1992 to 2004. The patients were divided into three groups according to the histological results of the initial and final transurethral tumor resection (TURB). In group 1 (n=114) patients who presented with a superficial bladder carcinoma which had a high likelihood of progressing underwent radical cystectomy. Group 2 included (n=92) patients who displayed a superficial tumor stage when they first presented and developed progressive muscle-invasive bladder carcinoma under conservative treatment. Group 3 (n=246) comprised patients who were already at the muscle-invasive tumor stage in the course of primary TURB. The histopathological characteristics of all transurethral tumor resections and radical cystectomy were recorded. Progression-free survival rates and overall survival rates in the three groups were then compared. RESULTS The average patient age at cystectomy was 64.3 (35-80) years, and the average follow-up period was 49 months. Progression-free survival and overall survival of all 452 patients were 56.1 and 53.6%, respectively, after 5 years. The best outcome was a progression-free 5-year survival rate of 78.4% with organ-confined, lymph node-negative tumors (n=213). This result was statistically significant (p<0.01) compared with the progression-free 5-year survival rate of 42.3% for non-organ-confined, lymph node-negative tumors (n=112). Lymph node-positive patients (n=127) achieved a progression-free 5-year survival rate of 29.0% regardless of the tumor infiltration. Group 1 patients achieved a progression-free survival rate of 71.3% and an overall survival rate of 69.1% after 5 years. Group 2 patients achieved a progression-free survival rate of 52.9% and an overall survival rate of 51.4% after 5 years. Group 3 patients achieved a progression-free survival and overall survival of 50.2% and 47.1%, respectively, after 5 years. There was no significant difference between groups 2 and 3 with regard to their progression-free or overall survival rates (p>0.45). However, both groups displayed significantly poorer progression-free and overall survival rates compared with group 1 (p<0.01). CONCLUSION Our results show that patients with superficial bladder carcinoma with tumor progression to muscle invasion do not have a better prognosis after radical cystectomy than patients presenting initially with muscle-invasive bladder carcinoma. Survival rates in this group can only be improved by singling out patients on the basis of risk factors at an earlier stage and carrying out cystectomy. Due to these results we must expect that waiting for a muscle invasion in patients with superficial bladder carcinoma with a high risk profile results in a significant impairment of prognosis.

Früherkennung bei urologischen Tumoren

Bedauerlicherweise ist die wissenschaftliche Basis fur eine allgemeine Empfehlung zur Fruherkennung von urologischen Tumoren bislang unzureichend. Aus diesem Grund zogern die gesetzlichen Krankenkassen, entsprechende Fruherkennungsprogramme in ihren Leistungskata-12013 Fruherkennung bei urologischen Tumoren log aufzunehmen. Lediglich fur das Prostatakarzinom gibt es zunehmend Ergebnisse, die Fruherkennungsprogramme soziookonomisch sinnvoll erscheinen lassen.