Hans U. Schmelz

European Consensus Conference on Diagnosis and Treatment of Germ Cell Cancer: A Report of the Second Meeting of the European Germ Cell Cancer Consensus group (EGCCCG): Part I

OBJECTIVES The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

Diagnostic Value of Magnetic Resonance Imaging in Peyronie’s Disease—A Comparison Both with Palpation and Ultrasound in the Evaluation of Plaque Formation ☆

OBJECTIVE To compare the value of magnetic resonance imaging (MRI) with palpation and ultrasound in the evaluation of plaque formation in Peyronies disease. METHODS 57 patients underwent a standardized diagnostic procedure to evaluate plaque formation consisting of palpation and ultrasonography (7.5 MHz). MRI was performed during flaccidity and during erection induced by Prostaglandin E(1) including intravenous application of Gadolinium-diethylenetriaminepentaacetic acid (Gd-DPTA). RESULTS With all methods, 93 plaques have been detected in 57 patients. 85 plaques (91.4%) have been evaluated by palpation alone. Using ultrasound, 52 of these 93 plaques (55.9%) were detectable. This is equivalent to 61.1% of the palpable plaques. MRI confirmed 58 of the palpated plaques (68.2%) and exposed 8 primarily not palpable plaques at the penile basis. MRI revealed more palpable plaques than ultrasound, but this finding was not significant (p = 0.083). By means of sonography, calcification was evident in 14 plaques. MRI failed in revealing any calcification. After application of Gd-DPTA, 5 of 57 patients (9%) demonstrated contrast enhancement indicating local inflammation. None of these patients reported on penile pain. CONCLUSIONS Penile palpation in combination with ultrasound represents the method of choice to diagnose plaque formation in Peyronies disease. MRI provides better information on plaque formation at the penile basis. Calcification can only be proven by ultrasound, not by MRI. There may be additional information by MRI about local inflammation. A prospective study comparing the histological and MRI findings should be performed to answer the question, if pain is really associated with inflammation.

Prospective Analysis of Single Nucleotide Polymorphisms of the Transforming Growth Factor β-1 Gene in Peyronie’s Disease

PURPOSE The detection of increased expression of transforming growth factor beta-1 (TGF-beta1) in Peyronies disease plaques and the possibility of initiating a Peyronies disease-like condition by intratunical injection of a synthetic heptopeptide with TGF-beta-like activity in an animal model has provided evidence for the central role of this cytokine in the pathogenesis of this entity. Recently 2 defined single nucleotide polymorphisms in the coding region of the TGF-beta1 gene have been described that are associated with different levels of TGF-beta1 production. Based on these data we prospectively investigated the genetic association of distinct TGF-beta1 genotypes with Peyronies disease. MATERIALS AND METHODS DNA samples from 111 consecutive patients with idiopathic Peyronies disease and 100 controls were genotyped for the 2 defined dimorphic single nucleotide polymorphisms T869C and G915C in the coding region of the TGF-beta1 gene using allele specific polymerase chain reaction. RESULTS We found an increased frequency of the homozygous genotype of the single nucleotide polymorphism G915C in patients with Peyronies disease compared with healthy controls (89.2% versus 79%, p = 0.04). However, there were no significant differences in allele frequencies of the single nucleotide polymorphism T869C. CONCLUSIONS Experimental data from other investigators have shown that TGF-beta1 has an important role in the etiopathology of Peyronies disease. Our results indicate that the homozygous wild type of the G915C single nucleotide polymorphism in the coding region of the TGF-beta1 gene, which was recently associated with elevated TGF-beta1 production and pulmonary fibrosis, may influence the predisposition to Peyronies disease. However, it does not represent a major genetic risk factor.

Predicting metastasized seminoma using gene expression

Study Type – Prognosis (cohort)

German second-opinion network for testicular cancer: Sealing the leaky pipe between evidence and clinical practice

In 2006, the German Testicular Cancer Study Group initiated an extensive evidence-based national second-opinion network to improve the care of testicular cancer patients. The primary aims were to reflect the current state of testicular cancer treatment in Germany and to analyze the project’s effect on the quality of care delivered to testicular cancer patients. A freely available internet-based platform was developed for the exchange of data between the urologists seeking advice and the 31 second-opinion givers. After providing all data relevant to the primary treatment decision, urologists received a second opinion on their therapy plan within <48 h. Endpoints were congruence between the first and second opinion, conformity of applied therapy with the corresponding recommendation and progression-free survival rate of the introduced patients. Significance was determined by two-sided Pearson’s χ2 test. A total of 1,284 second-opinion requests were submitted from November 2006 to October 2011, and 926 of these cases were eligible for further analysis. A discrepancy was found between first and second opinion in 39.5% of the cases. Discrepant second opinions led to less extensive treatment in 28.1% and to more extensive treatment in 15.6%. Patients treated within the framework of the second-opinion project had an overall 2-year progression-free survival rate of 90.4%. Approximately every 6th second opinion led to a relevant change in therapy. Despite the lack of financial incentives, data from every 8th testicular cancer patient in Germany were submitted to second-opinion centers. Second-opinion centers can help to improve the implementation of evidence into clinical practice.

Intercomparison of apoptosis morphology with active DNA cleavage on single cells in vitro and on testis tumours

Apoptosis morphology (DNA condensation) and endonucleolytical DNA cleavage (TdT assay) were measured simultaneously on double fluorescence labelled cells employing confocal laser scanning and conventional immunofluorescence microscopy. In vitro experiments on irradiated HL‐60 cells revealed a high correspondence of non‐apoptotic (normal) cells without detectable DNA cleavage, versus apoptotic cells and apoptotic bodies showing DNA cleavage. Experiments performed on histological slides of testis tumours reflected a heterogeneous picture: non‐apoptotic (normal) cells, apoptotic cells, and apoptotic bodies appeared either with or without detectable DNA cleavage. These data allowed the characterization and quantitation of the grade of disturbance/heterogeneity of the apoptosis programme in vivo. Furthermore, the measured apoptotic index (AI) based on apoptosis morphology was lower than the AI assessed by DNA cleavage, in contrast to published work. Taken together, these methods represent a new approach and might be suitable for improved correlation with clinical parameters. In addition, the data presented confirm frequently published doubts regarding the ability of the TdT assay to detect apoptosis as defined by morphological criteria in tumours.

Giant Multilocular Cystadenoma of the Prostate: A Rare Differential Diagnosis of Benign Prostatic Hyperplasia

We report a case of giant multilocular cystadenoma of the prostate in a 43-year-old man. This is a rare benign entity of the prostate imitating symptoms of benign prostatic hyperplasia and originates from the prostate with extensive spread into the pelvis. Histologically, prostatic glands and cysts lined by cuboid to columnar epithelial cells with basally located nuclei are characteristic. Immunohistochemical staining is positive for prostate-specific antigen in the epithelial cells. Giant multilocular prostatic cystadenoma should be taken into account in the differential diagnosis in any case of a large cystic mass originating from the prostate.

APOPTOSIS IN HUMAN EMBRYONAL CELL CARCINOMA: PRELIMINARY RESULTS

Abstract Disorders in the regulation of apoptotic cell death may contribute to cancer. Furthermore, lymphocytes are supposed to play a role in counteracting tumorigenesis by inducing apoptosis in different human tumors. In this study, for the first time, tumor cell and lymphocyte apoptosis were investigated systematically in human embryonal cell carcinoma. DNA fragmentation and DNA condensation were measured simultaneously on double-fluorescence-labeled testis tumor sections using immunofluorescence microscopy. Different apoptotic indices (AIs), based either on biochemical (DNA fragmentation) or morphological criteria (DNA condensation) alone or on a combination of both, were determined in different histological regions in and around the tumor. Using morphological criteria alone, 40–75% of all apoptotic cells were not detected. Based on previous observations this finding might be related to subsets of apoptotic cells which induce the process of DNA condensation without activation of processes responsible for DNA fragmentation. Moreover, the AIs of tumor cells and lymphocytes were highest in the tumor region, compared with regions around the tumor and distant from it; these findings are discussed in the context of the Fas/FasL system.

A gene signature of primary tumor identifies metastasized seminoma

BACKGROUND The aim of this study was the prediction of metastatic status in seminoma based on examination of the primary tumor. METHODS Total RNA was isolated from metastasized seminoma (n = 10, T1N1-2M0), non-metastasized seminoma (n = 21, T1-3N0M0), and corresponding normal tissues. Pooled RNA from 10 biopsies of each tissue type was hybridized on whole genome microarrays for screening purposes. Ninety-two selected gene candidates were quantitatively examined using real-time quantitative polymerase chain reaction (RTQ-PCR). RESULTS Agreement in gene expression was 88% between the whole genome microarrays and RTQ-PCR. Metastasized seminoma showed 1,912 up-regulated and 2,179 down-regulated genes with ≥ 2-fold differences in gene expression compared non-metastasized seminoma. RTQ-PCR of selected genes showed that mean gene expression values were significantly reduced in metastasized compared with non-metastasized seminoma. The presence of metastases could be predicted based on an 85-gene expression signature by using logistic regression. Sensitivity and accuracy of the 10-fold cross-validation model were 77.8% and 84.2%, respectively. CONCLUSION A logistic regression model using an 85 gene expression signature allowed identification of metastasized seminoma from the primary tumor with a sensitivity of 77.8%.

Topical treatment of erectile dysfunction with prostaglandin E1 ethyl ester

Background: Prostaglandin E1 ethyl ester (PGE1‐EE) is a prodrug of prostaglandin E1 but with much improved transdermal penetration.