I. Peters

Targeted therapy of urological tumours. Experimental field or established therapeutic approach

ZusammenfassungDer Einsatz der sog. „targeted“ Therapeutika verfolgt das Ziel, gegenüber der konventionellen Chemotherapie nicht allgemeine, im Wesentlichen in die zelluläre Replikation involvierte Mechanismen zu inhibieren, sondern auf molekularer Ebene gezielt die Aktivierung solcher Pathways oder Signaltranduktionswege zu beeinflussen, für die eine wesentliche Beteiligung an der Progression humaner Malignome angenommen wird. Während dieser Ansatz beispielsweise in der Behandlung des Nierenzellkarzinoms aufgrund der gegenüber Zytokin-basierten Therapieformen überlegenen klinischen Effektivität etabliert ist, stehen für andere urologische Malignome wie das Harnblasen- oder Prostatakarzinom lediglich rudimentäre Ergebnisse aus kleineren klinischen Serien zur Verfügung. Ziel der vorliegenden Arbeit ist es, den gegenwärtigen Stellenwert der Target-Therapie in der Behandlung verschiedener Tumorentitäten des urologischen Formenkreises zu beschreiben.AbstractUnlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.Unlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.

Die Target-Therapie urologischer Tumoren

ZusammenfassungDer Einsatz der sog. „targeted“ Therapeutika verfolgt das Ziel, gegenüber der konventionellen Chemotherapie nicht allgemeine, im Wesentlichen in die zelluläre Replikation involvierte Mechanismen zu inhibieren, sondern auf molekularer Ebene gezielt die Aktivierung solcher Pathways oder Signaltranduktionswege zu beeinflussen, für die eine wesentliche Beteiligung an der Progression humaner Malignome angenommen wird. Während dieser Ansatz beispielsweise in der Behandlung des Nierenzellkarzinoms aufgrund der gegenüber Zytokin-basierten Therapieformen überlegenen klinischen Effektivität etabliert ist, stehen für andere urologische Malignome wie das Harnblasen- oder Prostatakarzinom lediglich rudimentäre Ergebnisse aus kleineren klinischen Serien zur Verfügung. Ziel der vorliegenden Arbeit ist es, den gegenwärtigen Stellenwert der Target-Therapie in der Behandlung verschiedener Tumorentitäten des urologischen Formenkreises zu beschreiben.AbstractUnlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.Unlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.

C-reaktives Protein vor radikaler Zystektomie

BACKGROUND Numerous studies have shown a positive correlation between elevated C-reactive protein (CRP) and systemic spread of malignancies. The goal of the current study was to assess the predictive significance of preoperative CRP in patients undergoing radical cystectomy (RC). MATERIAL AND METHODS Preoperative CRP values were measured in 194 patients undergoing RC because of urothelial carcinoma between 1996 and 2005. Elevated CRP level was defined as ≥ 5 mg/l. RESULTS Preoperative increased CRP values were detected in 89 (45.9%) patients and these patients were more likely to have advanced tumor stages (pT3-4), positive resection margins and positive lymph nodes. Advanced urinary diversions were more common in patients with normal CRP values. In multivariate analysis, CRP was identified as an independent prognostic indicator for poor cancer-specific survival. CONCLUSION The results confirm previous reports that showed a prognostic significance of preoperative CRP elevation.

Die Methylierung des RASSF1A-Tumorsuppressorgenpromotors

Molecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.ZusammenfassungDer molekulare Zusammenhang zwischen bekannten Risikofaktoren wie Alter, Rauchen, Adipositas und der Entstehung urologischer Tumoren ist bisher unklar. Die Hypermethylierung von Promotor-CpG-Inseln ist mit einer unterdrückten Genaktivität assoziiert und wird häufig in Tumoren beobachtet. Die aberrierende Methylierung von Genpromotoren wurde aber auch in einer altersabhängigen Weise in normalen Geweben beobachtet und als Risikofaktor für die Karzinogenese vorgeschlagen.Wir beschreiben hier, dass das RASSF1A-Tumorsuppressorgen in normalem Nierengewebe eine altersabhängige Methylierung, die zusätzlich durch die Risikofaktoren Anthrakose und Adipositas beeinflusst wird, aufweist. Des Weiteren wurden für die RASSF1A-Promotormethylierung signifikant höhere Werte in peripheren Anteilen der Prostata im Vergleich zu der zentralen Zone erhalten.Erste Expressionsuntersuchungen weisen darauf hin, dass RASSF1A an frühen Ereignissen der Tumorentstehung beteiligt sein könnte. Im Zusammenhang mit weiteren, kürzlich in der Literatur beschriebenen Ergebnissen führt dies zu der Hypothese, dass die altersabhängige bzw. durch andere Lebensfaktoren beeinflusste Promotormethylierung spezifischer Gene zukünftig die Einschätzung des individuellen Tumorrisikos ermöglichen könnte.AbstractMolecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.

Methylation of the RASSF1A tumor suppressor gene promoter. Risk factor for carcinogenesis of urological tumors

Molecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.ZusammenfassungDer molekulare Zusammenhang zwischen bekannten Risikofaktoren wie Alter, Rauchen, Adipositas und der Entstehung urologischer Tumoren ist bisher unklar. Die Hypermethylierung von Promotor-CpG-Inseln ist mit einer unterdrückten Genaktivität assoziiert und wird häufig in Tumoren beobachtet. Die aberrierende Methylierung von Genpromotoren wurde aber auch in einer altersabhängigen Weise in normalen Geweben beobachtet und als Risikofaktor für die Karzinogenese vorgeschlagen.Wir beschreiben hier, dass das RASSF1A-Tumorsuppressorgen in normalem Nierengewebe eine altersabhängige Methylierung, die zusätzlich durch die Risikofaktoren Anthrakose und Adipositas beeinflusst wird, aufweist. Des Weiteren wurden für die RASSF1A-Promotormethylierung signifikant höhere Werte in peripheren Anteilen der Prostata im Vergleich zu der zentralen Zone erhalten.Erste Expressionsuntersuchungen weisen darauf hin, dass RASSF1A an frühen Ereignissen der Tumorentstehung beteiligt sein könnte. Im Zusammenhang mit weiteren, kürzlich in der Literatur beschriebenen Ergebnissen führt dies zu der Hypothese, dass die altersabhängige bzw. durch andere Lebensfaktoren beeinflusste Promotormethylierung spezifischer Gene zukünftig die Einschätzung des individuellen Tumorrisikos ermöglichen könnte.AbstractMolecular targets of known risk factors for the development of urological tumors, such as age, smoking, and adiposity, have not yet been elucidated. Hypermethylation of CpG islands in promoters can lead to silencing of gene expression and has frequently been detected in tumors. Age-dependent accumulation of methylation of gene promoters has been observed in various normal tissues and is discussed as a common risk factor for carcinogenesis.Here we describe the RASSF1A tumor suppressor gene as exhibiting an age-dependent promoter methylation in normal kidney tissue, which is additionally affected by the risk factors of anthracosis and adiposity. Furthermore, we found significantly increased methylation of the RASSF1A promoter when comparing peripheral versus central zone prostatic tissue samples.Preliminary expression analysis indicates that RASSF1A could be involved in early tumorigenesis. Our results support the hypothesis that age and other lifestyle-dependent factors may influence promoter methylation of specific genes, possibly serving as future individual tumor risk markers.

Systemic and surgical management of metastatic renal cell carcinoma

Several targeted therapies have become available for first-line (sunitinib, bevacizumab, pazopanib, temsirolimus) and second-line (sorafenib, pazopanib, everolimus) use in recent years. The superior outcomes achieved with these targeted agents have led to replacement of the formerly administered cytokines. New developments have raised the question of whether patients benefit from sequential therapies with tyrosine kinase inhibitors and/or whether combination regimes can improve clinical outcomes. This review gives an overview of the current therapeutic options for first- and second-line treatment in metastatic RCC as well as sequential and combination therapies. Adjuvant and neoadjuvant treatment options are being discussed. Furthermore, this review addresses surgical alternatives in the treatment of RCC.

Systemische und operative Therapie des metastasierten Nierenzellkarzinoms

Several targeted therapies have become available for first-line (sunitinib, bevacizumab, pazopanib, temsirolimus) and second-line (sorafenib, pazopanib, everolimus) use in recent years. The superior outcomes achieved with these targeted agents have led to replacement of the formerly administered cytokines. New developments have raised the question of whether patients benefit from sequential therapies with tyrosine kinase inhibitors and/or whether combination regimes can improve clinical outcomes. This review gives an overview of the current therapeutic options for first- and second-line treatment in metastatic RCC as well as sequential and combination therapies. Adjuvant and neoadjuvant treatment options are being discussed. Furthermore, this review addresses surgical alternatives in the treatment of RCC.

Nierenteilresektion bei cT1 Nierentumoren: Vergleich der konventionellen laparoskopischen Nierenteilresektion mit der LESS Nierenteilresektion in SITUS-Technik

BACKGROUND Partial nephrectomy is the treatment of choice for clinical stage 1 renal tumours. Open partial nephrectomy is the standard operative technique. The use of minimally-invasive strategies such as laparoscopic, robot-assisted partial nephrectomy or laparoendoscopic single site (LESS) partial nephrectomy has increased in recent years. PATIENTS/MATERIAL AND METHODS In this retrospective study, patients undergoing laparoscopic partial nephrectomy between December 2008 and November 2013 were evaluated. All patients presented with renal lesions suspicious for malignancy. Operations were performed as conventional laparoscopic transperitoneal partial nephrectomies (cLPN) or LESS partial nephrectomies (LESS-PN) in SITUS technique (single incision transumbilical surgery). The aim of the study was to compare perioperative outcome parameters such as duration of surgery, time of ischaemia, complications, need for transfusion, conversion rates, changes in renal function and duration of hospital stay in both groups. RESULTS A total of 85 laparoscopic partial nephrectomies were performed in this study (72 cLPN and 13 LESS-PN). The average tumour size was 2.68±1.47 cm (cLPN) vs. 2.46±1.11 cm (LESS-PN). The mean duration of surgery was 175.17±50.026 min (cLPN) and 185.77±35.991 min (LESS-PN). 45 (62.5%) operations (cLPN) vs. 10 (76.9%) (LESS-PN) were performed in zero-ischaemia technique. There were no significant differences in perioperative outcome parameters between both groups. Postoperative complication rates (Clavien-Dindo≥3) were 11.1% (cLPN) vs. 7.7% (LESS-PN). CONCLUSIONS LESS partial nephrectomy in SITUS technique is an attractive alternative to conventional laparoscopic and open partial nephrectomy.

Systemische und operative Therapie des metastasierten Nierenzellkarzinoms@@@Systemic and surgical management of metastatic renal cell carcinoma

Several targeted therapies have become available for first-line (sunitinib, bevacizumab, pazopanib, temsirolimus) and second-line (sorafenib, pazopanib, everolimus) use in recent years. The superior outcomes achieved with these targeted agents have led to replacement of the formerly administered cytokines. New developments have raised the question of whether patients benefit from sequential therapies with tyrosine kinase inhibitors and/or whether combination regimes can improve clinical outcomes. This review gives an overview of the current therapeutic options for first- and second-line treatment in metastatic RCC as well as sequential and combination therapies. Adjuvant and neoadjuvant treatment options are being discussed. Furthermore, this review addresses surgical alternatives in the treatment of RCC.

Die Target-Therapie urologischer Tumoren@@@Targeted therapy of urological tumours: Experimentierfeld oder etablierter therapeutischer Ansatz?@@@Experimental field or established therapeutic approach?

ZusammenfassungDer Einsatz der sog. „targeted“ Therapeutika verfolgt das Ziel, gegenüber der konventionellen Chemotherapie nicht allgemeine, im Wesentlichen in die zelluläre Replikation involvierte Mechanismen zu inhibieren, sondern auf molekularer Ebene gezielt die Aktivierung solcher Pathways oder Signaltranduktionswege zu beeinflussen, für die eine wesentliche Beteiligung an der Progression humaner Malignome angenommen wird. Während dieser Ansatz beispielsweise in der Behandlung des Nierenzellkarzinoms aufgrund der gegenüber Zytokin-basierten Therapieformen überlegenen klinischen Effektivität etabliert ist, stehen für andere urologische Malignome wie das Harnblasen- oder Prostatakarzinom lediglich rudimentäre Ergebnisse aus kleineren klinischen Serien zur Verfügung. Ziel der vorliegenden Arbeit ist es, den gegenwärtigen Stellenwert der Target-Therapie in der Behandlung verschiedener Tumorentitäten des urologischen Formenkreises zu beschreiben.AbstractUnlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.Unlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin.