Clinical characteristics, treatment patterns and relapse in patients with clinical stage IS testicular cancer.

PURPOSE: Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. METHODS: Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher's exact and Chi-square test. RESULTS: Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. CONCLUSION: Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Discriminating metastasised from non-metastasised seminoma based on transcriptional changes in primary tumours using NGS.

BACKGROUND: We aimed to better discriminate (occult) metastasised from non-metastasised seminoma based on transcriptional changes of small RNAs in the primary tumour. METHODS: Total RNAs including small RNAs were isolated from five testicular tumours of each, lymphogenic, occult and non-metastasised patients. Next-generation sequencing (SOLID, Life Technologies) was used to examine transcriptional changes. Small RNAs showing ⩾50 reads and a significant ⩾2-fold difference using non-metastasised tumours as the reference group were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines. RESULTS: On average, 1.3 × 10(7), 1.4 × 10(7) and 1.7 × 10(7) small RNA reads were detectable in non-metastasised, occult and lymphogenic metastasised seminoma, respectively, of which 30-32% remained after trimming. Between 59 and 68% represented annotated reads and between 8.6 and 11% were annotated small RNA tags. Of them, 137 small RNAs showed>50 reads and a two-fold difference to the reference. In univariate analysis, 32-38 small RNAs significantly discriminated lymphogenic/occult from non-metastasised seminoma, and among these different comparisons, it were the same small RNAs in 51-88%. Many combinations of two of these small RNAs allowed a complete discrimination of metastasised from non-metastasised seminoma irrespective of the metastasis subtype. CONCLUSIONS: Metastasised and non-metastasised seminoma can be completely discriminated with a combination of two small RNAs.

[Value of targeted treatment for testicular cancer: from molecular approaches to clinical possibilities]. / Der Stellenwert der Targeted-Therapie beim Hodentumor: Von molekularen Ansätzen zu klinischen Möglichkeiten.

Due to the introduction of tyrosine kinase-inhibitors in the treatment of metastatic renal cell cancer, targeted therapy raises hopes for other urological tumors as well. Even if excellent cure rates, achieved by standardization of diagnosis und therapy, have made testicular cancer a curable disease, up to 6% of young patients still die from tumors refractory to therapy. The quality of life of patients in advanced stages needing aggressive treatment should be improved by new therapies with reduced side effects. The role of tyrosine kinase inhibitors and angiogenesis inhibitors as well as intervention in the cell cycle and induction of apoptosis are discussed.

[Sclerosing Sertoli cell tumor of the testis: a rare tumor. Case report and review of the literature on the subtypes of Sertoli-cell tumor]. / Sklerosierender Sertoli-Zell-Tumor des Hodens - ein seltener Tumor : Fallvorstellung und Literaturübersicht über die Subtypen des Sertoli-Zell-Tumors.

Sertoli cell tumors of the testis are extremely rare (0.4-1.5% of all testicular neoplasms) and have a heterogeneous pathology. Histopathologically classic, large cell calcifying and sclerosing subtypes are differentiated.Up to now, 14 cases of sclerosing Sertoli cell tumor are known. This article presents a new case and compares the three subtypes. The subtypes differ in particular in age of onset, malignant potential, prognosis, and therapy. While no cases of sclerosing Sertoli cell tumor with a malignant course have been reported, both other subtypes have been found to be potentially malignant. In the case of malignancy the prognosis is very poor, and it is difficult to select the best treatment because there is so little experience with this type of tumor. Once the diagnosis of a Sertoli cell tumor has been confirmed, exact determination of the histological subtype is essential to allow appropriate risk-adapted therapy. The various histological subtypes are presented with the clinical features, prognosis and treatment of each.

Metanephric adenoma of the kidney: case report and review of the literature.

Metanephric adenoma is a rare tumor of the kidney. So far metanephric adenomas were considered to be benign, slowly growing and non-metastasizing tumors with an excellent prognosis. Only recently two cases of metastasized metanephric adenomas were published. Therefore, diagnostic work up, therapy and follow up of this tumor have to be reassessed. We report the case of a 42 year old male with metanephric adenoma. Current literature concerning metanephric adenoma is reviewed.

Apoptosis in non-tumorous adult human testis tissue. Comparison of so-called 'normal' testis tissues.

INTRODUCTION: Apoptosis seems to play an important role in tumorigenesis, prognosis and therapy of testicular tumors. To understand its biological significance, it is important to quantify the amount of apoptosis and to compare the rate of apoptosis to that of a normal, unaffected reference tissue. Usually tissue from the unaffected site of the testis in patients with testicular cancer or testis tissue from patients who underwent surgical castration due to prostate cancer is used as the reference tissue. However it is not known, if both tissues are equivocal with respect to their apoptotic index. The purpose of the study was to compare the two most often used reference tissues for the quantification of apoptosis in testicular tissues with regard to their apoptotic index. MATERIALS AND METHODS: The apoptotic indices of both tissues were compared, using two standard apoptosis detection methods, i.e. in situ end labeling and a morphological approach. RESULTS: The apoptotic index in testis tissue from patients who were surgically castrated for anti-hormonal treatment of prostate cancer was shown to be significantly higher than the apoptotic index of tumor free but tumor-associated testicular tissue of testis cancer patients. There was a strong relationship between the apoptotic index and the age of the patients. CONCLUSION: Although there might be genetic changes in the tumor-associated testicular tissue influencing the apoptotic index, it seems advisable to use tumor-associated tissue rather than testis tissue of patients with prostate cancer as the reference tissue, due to the significant age dependence of the apoptotic index.

Gene expression profiling in seminoma and nonseminoma.

PURPOSE: Gene expression profiles of seminoma were compared with nonseminoma to get insights into tumorigenesis. MATERIALS AND METHODS: Eleven testicular tumor biopsies (five pure seminoma, six nonseminoma; pT1N0M0 to pT2N2M1) and biopsies from unaffected sites were analyzed once per patient using a macroarray (1,176 genes). On the same patients, six genes were validated using real-time quantitative (RTQ) polymerase chain reaction (PCR). Additionally, in a separate cohort of 19 patients, 24 genes selected from the macroarray were measured using RTQ-PCR. RESULTS: (1) The agreement in gene expression was 94% between the two methods and two different patient cohorts. (2) Two features in gene expression were independent of the tumor entity: Most changes of gene expression occurred in five functional groups like "cell cycle" and "apoptosis." Genes within these groups were almost similarly (> 80%) up- or downregulated. (3) Nonseminoma were characterized by downregulated genes (75%), but in seminoma, upregulated genes (64%) prevailed. Furthermore, 64.4% of those genes that were differentially expressed in both tumor entities were usually upregulated in seminoma but downregulated in nonseminoma. A reverse pattern was found in 24.4% of such genes. Eleven percent of these genes showed a similar up- or downregulation in gene expression in both tumor entities. CONCLUSION: Seminoma in this preliminary study can be differentiated from nonseminoma due to almost opposing gene expression profiles (89% of the significantly differentially expressed genes) and are in line with the histological discrimination of both tumor entities. Underlying mechanisms and implications regarding the origin and tumor progression of both entities are discussed.

Significance of apoptosis in metastasizing testis tumors.

Testis tumors of embryonal origin (ten metastasized, six non-metastasized) and 17 mixed testis cell carcinomas (eight metastasized, nine non-metastasized) were examined. A triple immunofluorescence microscopic labeling procedure allowed the simultaneous detection of two features of apoptosis, namely morphological changes in the nucleus (DNA condensation visualized by DAPI staining) and the process of DNA fragmentation (TdT-assay) in tumor cells as well as T-cells (recognized by their CD45RO epitope). Both methods for apoptosis detection showed similar apoptotic indices (AI) only in 2.6% of all tumors. Most tumors (81.6%) showed more cells with DNA fragments than condensed chromatin, but in a number of cases (10.5%) the opposite pattern was found. These data add to the few published in vivo examinations of apoptosis using different methods and help to explain differences in the judgment of apoptosis significance for tumor prognosis. With regard to tumorigenesis, non-metastasized testis tumors were characterized by higher AIs of tumor cells and T-cells compared with metastasized tumors, which could be interpreted as a characteristic of tumors in an earlier stage of their development into an apoptosis-resistant phenotype. For the first time, in metastasized tumors a 5 to 25-fold increase of the T-cell's AIs over the corresponding AIs of tumor cells was shown. This suggests a successful counterattack of tumor cells, thus supporting the process of metastasis. However, only ten out of 33 tumors revealed these AI changes, which again highlights that tumor biology cannot be predicted by a single parametric approach. It remains to be seen whether these characteristics might be suitable for a reliable prediction of metastasis.

Epithelioid sarcoma of the penis--a rare differential diagnosis of Peyronie's disease.

We report on a case of penile epithelioid sarcoma in a 29-year-old man presenting with a dorsal penile plaque that primarily was misdiagnosed as Peyronie's disease. Although the initial clinical findings of these two different entities appear similar, the consequence for the patient is severe. The only way of differentiating these disorders are histological findings. The principal microscopic characteristics of epithelioid sarcoma are the distinctive nodular arrangement, central degeneration and necrosis of the tumor cells with epithelioid appearance and eosinophilia. Immunohistochemical data (cytokeratin, epithelial membrane antigen, vimentin, CD 34, desmin) confirm the diagnosis. We conclude that in cases with slightest doubts on the diagnosis of Peyronie's disease, especially in younger men suffering from a fast-growing penile induration, a bioptic clarification of the entity should be performed to exclude a high malignant disease that can be only treated as far as it is localized by radical surgery.

Apoptosis in human embryonal cell carcinoma: preliminary results.

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.

Modified approach for apoptosis detection reveals changes in apoptotic processes in the seminoma-associated tissue.

Apoptosis morphology (DNA condensation) and internucleosomal DNA cleavage (TdT assay) were measured simultaneously on double fluorescence labeled testis tumor sections, employing conventional immunofluorescence microscopy. Six different apoptosis indices (Al) were determined based either solely on morphological or biochemical criteria, or on a combination of both processes. Measurements were performed in metastasized and non-metastasized seminoma, and in histological regions located distantly and associated with the tumor. Preliminary results on 19 histologies revealed that up to 66% of apoptotic cells were not detected, depending on the method used for apoptosis detection. Besides, no changes of solely morphologically defined Al was found in the different histological regions. By contrast, significant changes (p < 0.0004) in the different histological regions were detected when measuring Als, e.g., defined by DNA fragmentation occurring without DNA condensation in apoptotic cells. Those changes were not detected in metastasized seminoma. These data, for the first time allow a comparison of two widely used approaches for apoptosis detection. Furthermore, the results revealed differences in apoptotic processes in tissue associated with non-metastasized seminoma detectable by a modified evaluated TdT assay but not by morphological changes, although this TdT method fails to show the total amount fo apoptotic cells.

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.

Role of intracellular Ca2+ stores in smooth muscle of human penile erectile tissue.

OBJECTIVE: In human erectile tissue smooth muscle contraction and detumescence are highly dependent on an increase in cytosolic [Ca2+]. The Ca2+ influx can be derived from the extracellular space or from intracellular sarcoplasmic stores. The role of both pathways was evaluated in an organ bath study on human cavernosal strips. PATIENTS AND METHODS: The tissue was obtained from 12 patients with chronic erectile dysfunction. The effects of Ca2+-free solution, ryanodine, caffeine and of nifedipine on electrically and adrenergically induced contractions were evaluated. RESULTS: Following an incubation period of 10 min in Ca2+-free solution the electrically induced contraction was reduced to 20%, whereas the contraction induced by phenylephrine (PE) was only reduced to 64 +/- 6% (mean +/- SEM). Ryanodine inhibited the PE-contraction to 30 +/- 6% and the additional application of caffeine or nifedipine further reduced the contraction to 11% and 8%. CONCLUSION: The results give evidence for a role of intracellular Ca2+-stores in human cavernosal tissue. Whether the more marked effect of ryanodine in tissue from patients with erectile failure in comparison with similar experiments in rabbit cavernosal tissue might be a sign of an increased cavernosal contractility in these patients remains to be shown in future experiments with normal erectile tissue.

[Recurrent pneumothorax after surgical resection treatment]. / Pneumothoraxrezidiv nach chirurgischer Resektionsbehandlung.

Between 1984 and 1994, 27 men and 4 women with primary spontaneous pneumothorax were treated surgically by excision of the bullae, without pleurectomy. The purpose of the present study was to establish by computed tomography (CT) of the lung whether the excision permanently eliminated the cause of pneumothorax. The median follow-up was 72 (21-127) months. There were two patients with recurrences (6.4%) who were operated on again. Sixteen of 31 patients had new blebs in the apex of the lung as documented by postoperative CT. The study indicates that simple excision of the bullous area cannot prevent the recurrence of blebs.