Dirk G. Engehausen

De novo malignancies in renal transplant recipients: experience at a single center with 1882 transplant patients over 39 yr.

Cancers complicating organ allografts are a major cause of morbidity and mortality after renal transplantation. Different registries have described an overall three to eightfold increase in cancer risk compared with the general population. This retrospective study investigated the incidence and outcome of de novo malignancies following kidney transplantation in a single German kidney transplantation center.

The value of extended transurethral resection of bladder tumour (TURBT) in the treatment of bladder cancer.

Study Type – Therapy (case series)

Combined-modality treatment and organ preservation in bladder cancer: Do molecular markers predict outcome?

Purpose:In invasive bladder cancer, several groups have reported the value of organ preservation by a combined-treatment approach, including transurethral resection (TUR-BT) and radiochemotherapy (RCT). As more experience is acquired with this organ- sparing treatment, patient selection needs to be optimized. Clinical factors are limited in their potential to identify patients most likely to respond to RCT, thus, additional molecular markers for predicting treatment response of individual lesions are sorely needed.Patients and Methods:The apoptotic index (AI) and Ki-67 index were evaluated by immunohistochemistry on pretreatment biopsies of 134 patients treated for bladder cancer by TUR-BT and RCT. Expression of each marker as well as clinicopathologic factors were then correlated with initial response, local control and cancer-specific survival with preserved bladder in univariate and multivariate analysis.Results:The median AI for all patients was 1.5% (range 0.2–7.4%). The percentage of Ki-67-positive cells in the tumors ranged from 0.2% to 85% with a median of 14.2%. A significant correlation was found for AI and tumor differentiation (G1/2: AI = 1.3% vs. G3/4: AI = 1.6%; p = 0.01). A complete response at restaging TUR-BT was achieved in 76% of patients. Factors predictive of complete response included T-category (p < 0.0001), resection status (p = 0.02), lymphovascular invasion (p = 0.01), and Ki-67 index (p = 0.02). For local control, AI (p = 0.04) and Ki-67 index (p = 0.05) as well as T-category (p = 0.005), R-status (p = 0.05), and lymphatic vessel invasion (p = 0.05) reached statistical significance. Out of the molecular markers only high Ki-67 levels were associated to cause-specific survival with preserved bladder. On multivariate analysis, T-category was the strongest independent factor for initial response, local control and cancer-specific survival with preserved bladder.Conclusion:The indices of pretreatment apoptosis and Ki-67 predict a favorable outcome in bladder cancer patients treated with TUR-BT and RCT. Molecular markers may help to select patients for an organ-sparing approach.Hintergrund:Mehrere Arbeitsgruppen konnten zeigen, dass eine multimodale organerhaltende Behandlung des invasiven Blasenkarzinoms unter Einsatz der transurethralen Resektion (TUR-BT) und anschließender Radiochemotherapie (RCT) zu Therapieergebnissen führt, die denen der primären Zystektomie gleichwertig sind. Je mehr Erfahrungen mit dieser Therapiestrategie gewonnen werden, umso genauer sollte die Patientenauswahl erfolgen. Das Potential klinischer Faktoren, Patienten zu identifizieren, die von einer RCT profitieren, ist limitiert. Prädiktive molekulare Marker sind hier dringend notwendig.Patienten und Methodik:Der Apoptoseindex (AI) und der Ki-67-Index wurden an prätherapeutischen Biopsien von 134 Patienten, die mittels TUR-BT und RCT behandelt wurden, immunhistochemisch bestimmt. Die Expression beider Marker sowie klinische Faktoren wurden anschließend mit der initialen Ansprechrate, der lokalen Kontrolle und dem krankheitsspezifischen Überleben mit intakter Blase univariat und multivariat korreliert.Ergebnisse:Der Median des AI aller Patienten betrug 1,5% (Spanne: 0,2-7,4%). Der Prozentsatz Ki-67-positiver Tumorzellen reichte von 0,2% bis 85% bei einem Median von 14,2%. Eine signifikante Korrelation zeigte sich zwischen AI und Tumordifferenzierung (G1/2: AI = 1,3% vs. G3/4: AI 1,6%; p = 0,01). Ein komplettes Ansprechen wurde bei 76% der Patienten zum Zeitpunkt der „Restaging“-TUR-BT erreicht. Prädiktive Faktoren für das komplette Ansprechen waren die T-Kategorie (p < 0,0001), der Resektionsstatus (p = 0,02), die Lymphgefäßinvasion (p = 0,01) und der Ki-67-Index (p = 0,02). In Bezug auf die lokale Kontrolle erreichten der AI (p = 0,04) und der Ki-67-Index (p = 0,05) sowie die T-Kategorie (p = 0,005), der Resektionsstatus (p = 0,05) und die Lymphgefäßinvasion (p = 0,05) statistische Signifikanz. Von den molekularen Markern war nur der Ki-67-Index mit dem krankheitsspezifischen Überleben mit erhaltener Blase korreliert. Die T-Kategorie war der stärkste unabhängige prognostische Faktor für alle drei Endpunkte in der multivariaten Analyse.Schlussfolgerung:Die Indizes für die prätherapeutische Apoptose und Ki-67 prädizieren einen günstigen Verlauf nach TUR-BT und RCT. Molekulare Marker können bei der Selektion von Patienten für ein organerhaltendes Therapieverfahren hilfreich sein.

Magnetic resonance image-guided biopsies with a high detection rate of prostate cancer.

Aim. To explore the potential of transrectal magnetic resonance image- (MRI-) guided biopsies of the prostate in a patient cohort with prior negative ultrasound guided biopsies. Patients and Methods. Ninety-six men with suspected prostate cancer underwent MRI-guided prostate biopsies under real-time imaging control in supine position. Results. Adenocarcinoma of the prostate was detected in 39 of 96 patients. For individual core biopsies, MRI yielded a sensitivity of 93.0% and a specificity of 94.4%. When stratifying patients according to the free-to-total prostate-specific antigen (PSA) ratio, the prostate cancer discovery rate was significantly higher in the group with ratios less than 0.15 (57.1%). Conclusion. MRI-guided biopsy of the prostate is a diagnostic option for patients with suspected prostate cancer and a history of repeatedly negative transrectal ultrasound-guided biopsies. Combined with the free-to-total PSA ratio, it is a highly effective method for detecting prostate cancer.

Combined-Modality Treatment and Organ Preservation in Bladder Cancer

Purpose:In invasive bladder cancer, several groups have reported the value of organ preservation by a combined-treatment approach, including transurethral resection (TUR-BT) and radiochemotherapy (RCT). As more experience is acquired with this organ- sparing treatment, patient selection needs to be optimized. Clinical factors are limited in their potential to identify patients most likely to respond to RCT, thus, additional molecular markers for predicting treatment response of individual lesions are sorely needed.Patients and Methods:The apoptotic index (AI) and Ki-67 index were evaluated by immunohistochemistry on pretreatment biopsies of 134 patients treated for bladder cancer by TUR-BT and RCT. Expression of each marker as well as clinicopathologic factors were then correlated with initial response, local control and cancer-specific survival with preserved bladder in univariate and multivariate analysis.Results:The median AI for all patients was 1.5% (range 0.2–7.4%). The percentage of Ki-67-positive cells in the tumors ranged from 0.2% to 85% with a median of 14.2%. A significant correlation was found for AI and tumor differentiation (G1/2: AI = 1.3% vs. G3/4: AI = 1.6%; p = 0.01). A complete response at restaging TUR-BT was achieved in 76% of patients. Factors predictive of complete response included T-category (p < 0.0001), resection status (p = 0.02), lymphovascular invasion (p = 0.01), and Ki-67 index (p = 0.02). For local control, AI (p = 0.04) and Ki-67 index (p = 0.05) as well as T-category (p = 0.005), R-status (p = 0.05), and lymphatic vessel invasion (p = 0.05) reached statistical significance. Out of the molecular markers only high Ki-67 levels were associated to cause-specific survival with preserved bladder. On multivariate analysis, T-category was the strongest independent factor for initial response, local control and cancer-specific survival with preserved bladder.Conclusion:The indices of pretreatment apoptosis and Ki-67 predict a favorable outcome in bladder cancer patients treated with TUR-BT and RCT. Molecular markers may help to select patients for an organ-sparing approach.Hintergrund:Mehrere Arbeitsgruppen konnten zeigen, dass eine multimodale organerhaltende Behandlung des invasiven Blasenkarzinoms unter Einsatz der transurethralen Resektion (TUR-BT) und anschließender Radiochemotherapie (RCT) zu Therapieergebnissen führt, die denen der primären Zystektomie gleichwertig sind. Je mehr Erfahrungen mit dieser Therapiestrategie gewonnen werden, umso genauer sollte die Patientenauswahl erfolgen. Das Potential klinischer Faktoren, Patienten zu identifizieren, die von einer RCT profitieren, ist limitiert. Prädiktive molekulare Marker sind hier dringend notwendig.Patienten und Methodik:Der Apoptoseindex (AI) und der Ki-67-Index wurden an prätherapeutischen Biopsien von 134 Patienten, die mittels TUR-BT und RCT behandelt wurden, immunhistochemisch bestimmt. Die Expression beider Marker sowie klinische Faktoren wurden anschließend mit der initialen Ansprechrate, der lokalen Kontrolle und dem krankheitsspezifischen Überleben mit intakter Blase univariat und multivariat korreliert.Ergebnisse:Der Median des AI aller Patienten betrug 1,5% (Spanne: 0,2-7,4%). Der Prozentsatz Ki-67-positiver Tumorzellen reichte von 0,2% bis 85% bei einem Median von 14,2%. Eine signifikante Korrelation zeigte sich zwischen AI und Tumordifferenzierung (G1/2: AI = 1,3% vs. G3/4: AI 1,6%; p = 0,01). Ein komplettes Ansprechen wurde bei 76% der Patienten zum Zeitpunkt der „Restaging“-TUR-BT erreicht. Prädiktive Faktoren für das komplette Ansprechen waren die T-Kategorie (p < 0,0001), der Resektionsstatus (p = 0,02), die Lymphgefäßinvasion (p = 0,01) und der Ki-67-Index (p = 0,02). In Bezug auf die lokale Kontrolle erreichten der AI (p = 0,04) und der Ki-67-Index (p = 0,05) sowie die T-Kategorie (p = 0,005), der Resektionsstatus (p = 0,05) und die Lymphgefäßinvasion (p = 0,05) statistische Signifikanz. Von den molekularen Markern war nur der Ki-67-Index mit dem krankheitsspezifischen Überleben mit erhaltener Blase korreliert. Die T-Kategorie war der stärkste unabhängige prognostische Faktor für alle drei Endpunkte in der multivariaten Analyse.Schlussfolgerung:Die Indizes für die prätherapeutische Apoptose und Ki-67 prädizieren einen günstigen Verlauf nach TUR-BT und RCT. Molekulare Marker können bei der Selektion von Patienten für ein organerhaltendes Therapieverfahren hilfreich sein.

Clinical decisions for treatment of different staged bladder cancer based on multitarget fluorescence in situ hybridization assays

Non-invasive methods for detecting genetic alterations of bladder cancer are increasingly becoming the focus of attention as diagnostic tools. The fluorescence in situ hybridization we performed to detect genetic alterations of chromosomes 3, 7, 9p21, and 17 (UroVysion Test) showed very high sensitivity, higher even than cytology, in detecting bladder tumors of varying differentiation (pTa-pT4). The use of this test in everyday clinical urology can be a very useful decision aid in treating problem cases. A pT1G3 bladder carcinoma in the presence of multichromosomal alterations should be treated as a muscle-invasive pT2 tumor. Other superficial bladder tumors (pTaGI-III, pT1GI-II) with negative histopathology in follow-up and positive FISH analysis with the UroVysion Test should have bladder mapping performed again. Although FISH analysis is currently the most sensitive marker for bladder tumors, the elaborate handling, the cost of the DNA probes and the laboratory equipment required, limit the use of this method in the urologist’s everyday routine.

Pretreatment proliferation and local control in bladder cancer after radiotherapy with or without concurrent chemotherapy.

Purpose:To investigate whether the addition of chemotherapy to radiotherapy (RT) is beneficial particularly in bladder tumors that possess the capacity for rapid proliferation.Patients and Methods:The Ki-67 index was evaluated by immunohistochemistry on pretreatment biopsies from 136 patients treated by transurethral tumor resection (TURBT) and RT (n = 50) or platin-based radiochemotherapy (RCT; n = 86). Ki-67 expression was correlated with response to RT/RCT and long-term local control rates. The median follow-up was 43 months.Results:The percentage of Ki-67-positive cells ranged from 1.5% to 89%. Complete response (CR) was observed in 100/131 patients (76%, five without restaging TURBT). A statistically significant association between high Ki-67 index (≥ median) and CR was noted for patients receiving RCT (93% vs. 66% for Ki-67 < median; p = 0.001), but not for patients treated with RT alone (p = 0.12). Long-term local control was 39% for patients treated with RT, and 44% for patients after RCT (p = 0.49). Patients with high Ki-67 index did significantly better when subjected to combined RCT (55% vs. 33% with low Ki-67 index; p = 0.006), whereas no difference between high and low Ki-67 status was observed in the RT group (39% each; p = 0.57). On multivariate analysis, Ki-67 status was an independent predictor for local failure in the RCT group (risk ratio, 0.43; p = 0.007). Disease-specific survival was significantly better after RCT (62%) as compared with RT (42%; p = 0.03), however, the Ki-67 index was not related to this endpoint.Conclusion:Rapid proliferation is associated with improved local control, if patients are treated with concurrent RCT. The cytostatic effect of concurrent chemotherapy may effectively inhibit repopulation during fractionated RT.Ziel:Untersuchung der Frage, ob eine simultane Radiochemotherapie (RCT) besonders bei Harnblasenkarzinomen mit hoher Proliferationsrate zu günstigen Ergebnissen führt.Patienten und Methodik:Der Ki-67-Index wurde immunhistochemisch an prätherapeutischen Biopsien von 136 Patienten untersucht, die nach transurethraler Tumorresektion (TURBT) mittels Bestrahlung (RT; n = 50) oder cisplatinbasierter RCT (n = 86) behandelt wurden. Die Ki-67-Expression wurde mit dem Tumoransprechen nach RT/RCT und mit der lokalen Kontrollrate korreliert. Die mediane Nachbeobachtungszeit betrug 43 Monate.Ergebnisse:Der Prozentsatz Ki-67-positiver Zellen lag zwischen 1,5% und 89%. Eine Vollremission (CR) wurde bei 100/131 Patienten erreicht (76%, fünf Patienten erhielten keine Restaging-TURBT). Eine statistisch signifikante Assoziation zwischen hohem Ki-67-Index (≥ Median) und CR bestand für Patienten, die eine RCT erhielten (93% vs. 66% für Ki-67 < Median; p = 0,001), aber nicht für Patienten mit alleiniger RT (p = 0,12). Eine langfristige lokale Kontrolle konnte bei 39% der mit RT und bei 44% der mit RCT behandelten Patienten erreicht werden (p = 0,49). Bei Patienten mit hohem Ki-67 war die lokale Kontrolle signifikant besser, wenn sie eine RCT erhielten (55% vs. 33% mit niedrigem Ki-67-Index; p = 0,006), wohingegen in der Gruppe der ausschließlich bestrahlten Patienten kein Unterschied in der lokalen Kontrolle zwischen Tumoren mit hohem und niedrigem Ki-67-Status beobachtet wurde (39% für beide Gruppen; p = 0,57). In der multivariaten Analysis war der Ki-67-Status ein unabhängiger Prädiktor für die lokale Kontrolle in der RCT-Gruppe (relatives Risiko 0,43; p = 0,007). Das krankheitsspezifische Überleben war nach RCT (62%) signifikant besser als nach RT (42%; p = 0,03). Der Ki-67-Index war mit diesem Endpunkt nicht assoziiert.Schlussfolgerung:Eine hohe Proliferationsrate ist mit einer verbesserten lokalen Kontrolle verbunden, wenn Patienten eine simultane RCT erhalten. Der zytostatische Effekt der simultanen Chemotherapie wirkt möglicherweise der Tumorzellrepopulierung während fraktionierter RT entgegen.

Dynamic Tissue Perfusion Measurement: A New Tool for Characterizing Renal Perfusion in Renal Cell Carcinoma Patients

Introduction: Renal cell carcinoma (RCC) is characterized by intense angiogenesis with hyperexpression of proangiogenic factors. This study explored the potential of dynamic tissue perfusion measurement (DTPM) to detect differences in tissue perfusion between kidneys with RCC and corresponding healthy kidneys. Patients and Methods: 30 patients with unilateral, histologically confirmed RCC underwent DTPM by color Doppler ultrasound. Before scheduled surgery, Doppler ultrasound data were acquired from four transverse areas of the affected kidney and the contralateral healthy kidney. Doppler ultrasound data were recorded over a 10-second period and characteristic tissue perfusion parameters were determined. Results: The kidneys with RCC displayed characteristic changes in perfusion parameters. A significant increase in signal intensity and a significant decrease in flow resistance were noted. A combination of several DTPM parameters was used to distinguish correctly between kidneys bearing RCC or healthy kidneys with up to 75% accuracy. There was no association between the perfusion parameters and the pathological characteristics of the respective tumors. Conclusions: DTPM is a promising tool for the evaluation of whole-organ tissue perfusion. This study demonstrates the feasibility of performing DTPM measurements in kidneys bearing RCC lesions. In tumors that are characterized by extensive neovascularization, this method has the potential to be a valuable diagnostic tool.

Bladder cancer - the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register clinicaltrials.gov

BackgroundUro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade.MethodsWe searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95% confidence intervals, and a p value <0.05 was considered statistically significant.ResultsThe number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85% of these studies are focusing on prostatic (45%) and kidney neoplasms (40%), whereas only 11% were registered for bladder cancers.ConclusionsWhile the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported.

Clinical Course of Plasmacytoid Urothelial Carcinoma of the Upper Urinary Tract: A Case Report

Plasmacytoid urothelial carcinoma of the bladder represents a rare and aggressive variant of urothelial carcinoma, which is usually diagnosed at an advanced pathologic stage. Until now, no reports exist on this rare tumor type in the upper urinary tract. Herein, we present the first report on the clinical course of a metastatic plasmacytoid urothelial carcinoma of the renal pelvis and show its unfavorable outcome despite multimodal therapy.