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Abstract: With a diagnosis of squamous cell carcinoma of the penis, there is still a significant need to define the tumor criteria that allow the disease to be stratified according to the risk of developing lymph node metastases. The histopathology of the primary tumor in 72 consecutive patients with resected squamous cell carcinoma of the penis was reviewed for this study. Tumor tissue was reviewed for (1) histologic grade, (2) invasion pattern, (3) tumor stage, (4) proportion of poorly differentiated tumor cells, (5) invasion depth, (6) proportion of tumor necrosis, (7) angioinvasion, (8) histologic classification, (9) number of lesions, (10) growth pattern, (11) number of mitoses, (12) degree of keratinization, and (13) clinical groin status. It was found that the presence of inguinal lymph node metastases correlated in descending order of frequency with grade G2/G3, clinically positive groin status, reticular invasion, stage pT2/T3, >50% poorly differentiated tumor cells, depth of invasion, and comedolike tumor necrosis. These results revealed that the risk of inguinal lymph node metastasis in penile carcinoma can be predicted on the basis of 3 major factors: histologic grade, pattern of invasion, and clinical groin status. [Copyright &y& Elsevier]

The aim of this study was to validate recently proposed modifications to the current TNM classification of penile squamous cell carcinoma (PSCC) by using data from four German urological centers. We identified 89 patients treated for histologically confirmed PSCC between 1996 and 2008 and reclassified them according to the proposed TNM staging revisions. The proposed changes restricted T2 to tumoral invasion of the corpus spongiosum, whereas invasion of the corpus cavernosum was considered as T3. No changes were made to T1 and T4. Furthermore, N1 was limited to unilateral and N2 to bilateral inguinal lymph node involvement regardless of their number. Pelvic lymph node involvement and fixed lymph node were considered as N3 tumors. The range of follow up after initial treatment was 1-142 months (mean 38). Node-negative cases following the current classification were 65.2% (30/46), 48.5% (16/33) and 87.5% (7/8) for T1, T2 and T3, respectively. According to the proposed classification, N0 cases were markedly reduced in the T3 group (55.5%, 10/18) and relatively changed in the T2 group (56.5%, 13/23). T4 patients had no negative disease status. The 3-year disease-specific survival (DSS) rates for the proposed categories were 85.4%, 71.6% and 62.4% for T1, T2 and T3, respectively. For the current categories, the 3-year DSS rates were 85.4%, 66.9% and 100% for T1, T2 and T3, respectively. The 3-year DSS of the current N categories was 78.7%, 51% and 13.3% for N1, N2 and N3, respectively. According to the newly proposed categories, the 3-year DSS was 70%, 50% and 13.3% for N1, N2 and N3, respectively. Tumor and nodal staging of the newly proposed TNM classification show a more distinctive survival compared to the current one. However, a multi-institutional validation is still required to further corroborate the proposed modifications. [ABSTRACT FROM AUTHOR]

Overweight/obesity is known to increase the risk of developing renal cell carcinoma (RCC). However, data on the prognostic impact of overweight in RCC is still conflicting. We assessed whether different body mass index (BMI) levels at the time of surgery had an effect on the long-term prognosis of RCC patients. We evaluated 771 patients, with complete information about their BMI, who had undergone renal surgery for RCC between 1990 and 2005 at the authors’ institution; the mean follow-up was 5.48 years. Underweight, normal weight, pre-obesity, and obesity were diagnosed in 4 (0.5%), 239 (31%), 356 (46.2%), and 172 (22.3%) RCC patients, respectively. Overweight (BMI >25) was significantly associated with younger age ( P = 0.004) and positive nodal status ( P = 0.04) but not with tumor stage, grade, visceral metastasis, gender, histological subtype, or tumor-related symptoms. Overweight patients had a significantly lower risk of cancer-related death; their median 5-year tumor-specific survival rate was 80% as opposed to 72% for patients with a BMI below 25 ( P = 0.003). Interestingly, subgroup analysis revealed that the positive association between overweight and survival was even more pronounced in organ-confined ( P < 0.001) RCC, but no correlation was observed in advanced disease ( P = 0.23). We were able to identify overweight as an independent prognostic marker of improved tumor-specific survival in patients with organ-confined RCC. Basic research is required to resolve the dilemma of why, if a higher BMI predisposes to RCC, it concurrently prolongs survival after patients have undergone (partial) nephrectomy. [ABSTRACT FROM AUTHOR]

Objectives: Current data on the prognostic impact of urinary collecting system (UCS) invasion by renal cell carcinoma (RCC) are highly conflicting. The aim of the present study was to assess incidence and long-term prognosis of RCC patients with and without UCS involvement. Methods: We evaluated 780 patients who had undergone renal surgery between 1990 and 2005. The mean follow-up was 5.44 years. Results: Sixty-seven patients (8.6%) demonstrated UCS invasion. These patients had a significant increase in the likelihood of cancer-related death (hazard ratio [HR] 1.9, 95% confidence interval: 1.4–2.7; P = 0.001). Their median 5-year tumor-specific survival rate was 61%, as opposed to 79% for patients without UCS invasion ( P = 0.001). UCS invasion was significantly associated with tumor stage, grade, clinical symptoms, lymph node and visceral metastasis at diagnosis, but not with age, gender, histologic subtype or body mass index. However, by means of multivariate analysis, UCS invasion was disqualified as an individual prognostic marker for RCC. Conclusion: We do not advocate the inclusion of UCS invasion into upcoming Tumor-Nodes-Metastasis staging systems. In contrast, future research should focus on the prognostic role of novel molecular tumor markers and/or specific immunological characteristics of RCC patients. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine interobserver variations in assessing grade and stage of penile squamous cell carcinoma (SCC). PATIENTS AND METHODS We retrospectively reviewed the pathological features and clinical outcome in 75 patients with SCC of the penis, who were treated in participating urological centres between 1996 and 2005; the assessments of the local pathologists and the review pathologists were compared. RESULTS There was conformity in tumour grade in 67% and the assessment of tumour stage conformed in 84%; the combination assessment of both grade and stage conformed in 56%. CONCLUSION Accurate histological subtyping by the surgical pathologist demands standardized guidelines, in particular for histological grading, which is crucial for clinical treatment, but shows significant interobserver variation. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine the potential effect of tumour-induced lymphangiogenesis in squamous cell carcinoma of the penis as a possible mechanism responsible for lymphatic spread. PATIENTS AND METHODS Specimens from 65 patients with invasive tumours (31 with and 34 without metastases) were evaluated for lymphatic vessel density (LVD) by the ‘hot-spot’ method as the density of lymphatic endothelium hyaluronan receptor (LYVE-1)-positive lymphatic vessels per unit area of tissue. LVD was examined in peritumoral, intratumoral and normal tissue areas. The LVD of each tumour in these locations was calculated as the mean of the three highest lymph vessel counts in three to five hot-spots. The nodal status was based on histopathological examination or an uneventful follow-up of ≥2 years. RESULTS In all patients the mean (sd) peritumoral LVD of 8.05 (3.14)/0.75 mm2 was significantly higher than for intratumoral and normal tissue, of 4.67 (2.58) and 5.20 (1.87), respectively ( P < 0.001). The slightly lower intratumoral LVD than in normal tissue was not significant. The peritumoral LVD was 8.07 (3.29) in metastatic and 8.03 (3.03) in non-metastatic carcinomas. The intratumoral LVD was 5.13 (3.01) in node-positive carcinomas and 4.28 (2.15) in tumours with no lymphatic node metastasis (LNM). Comparing tumours with and without LNM, there was no statistically significant difference between intra- and peritumoral LVD. CONCLUSION Increased LVD does not significantly affect the lymphatic spread in penile carcinomas, indicating that there must be alternative mechanisms that selectively enable tumour cells to invade lymph vessels and to metastasize into the lymph nodes. [ABSTRACT FROM AUTHOR]

Innervation of prostate cancer (CaP) tissue favors tumor progression and metastasis but the regulation of innervation in CaP is unclear. The oncogenic transcription factor ERG is commonly induced by a typical TMPRSS2-ERG (TE) gene fusion in CaP and may affect innervation. Here, we analyzed whether nerve density of CaP tissue is related to TE status or perineural infiltration status of CaP tissue. In parallel, we measured several members of the neuropilin/plexin/semaphorin family (NRP, PLXN, and SEMA) as possible targets mediating innervation. The TE-gene-fusion status was determined at the mRNA level in CaP tissues by nested RT-PCR. Transcript levels were analyzed by quantitative RT-PCR in CaP tissue or cell line homogenate. ERG was analyzed by immunostaining, and the nerve density was evaluated by immunostaining for PGP9.5 and axonal neurofilament. Data were analyzed by correlation (Spearman), linear regression, Mann-Whitney U test, and contingency table analyses. TE-positive (TE-1) vs. TE-negative (TE-0) CaP tissues displayed significantly enhanced ERG-mRNA levels (TE-0: -4.183; TE-1: -2.994, P < 0.001) and ERG immunostaining (Erg-IH score; TE-0: 0.4211; TE-1: 1.391; P < 0.0001). Notably, the nerve density was significantly increased in CaP tissue samples with positive TE status compared to negative TE status (TE-0, ND score = 1.5; TE-1, ND score = 2.0; P <0.01). NRP1, NRP2, PLXNA2, PLXNB1, SEMA3A, and SEMA4B mRNAs were detectable in CaP tissues and CaP cell lines at quite heterogeneous levels. In CaP tissues, we observed significant positive correlations of ERG with NRP2, PLXNA2, PLXNB1, and SEMA4B. TE-positive CaP tissues displayed enhanced nerve density. ERG correlated with some NRP/PLXN/SEMA components suggesting possible regulatory relevance of ERG for CaP innervation. [ABSTRACT FROM AUTHOR]

Objectives Adjuvant immunotherapy of bladder cancer by instillation of bacillus Calmette-Guérin (BCG) is highly recommended within certain groups of non–muscle-invasive stages but only partially effective. Toll-like receptors (TLRs) TLR4 and TLR9 likely mediate BCG effects by triggering innate systemic immune cell responses. In addition, TLR4 and TLR9 expressed in bladder cancer cells may contribute to the outcome of BCG treatment. Here, we studied the expression and function of TLR4 and TLR9 in human bladder cancer cell lines. Methods TLR4 and TLR9 messenger RNA and protein levels were determined by real-time reverse transcription polymerase chain reaction and Western blot. Selected cell lines were analyzed with respect to cytokine induction, proliferation, and cell invasion after addition of BCG, TLR4-specific agonist lipopolysaccharide (LPS), or TLR9 agonist (CpG-oligodeoxynucleotide [ODN]). Results TLR4 and TLR9 were expressed quite heterogeneously in human bladder cancer cells. BCG caused induction of interleukin (IL)-6 or IL-8 in BFTC905 and T24 cells as representatives for TLR4-/TLR9-expressing cells. The study aimed to dissect TLR4- and TLR9-mediated effects. For functional analysis of TLR4 with LPS, we selected T24 and BFTC905 cells with high and undetectable TLR4 levels, respectively. For TLR9 analysis with CpG-ODN, we selected UMUC3 and RT112 cells with high and low TLR9 levels, respectively. Addition of LPS caused significant induction of TNFα and IL-6 messenger RNA in T24 cells but not in BFTC905 cells. Addition of CpG-ODN induced interferon ß (INFß), IL-8, tumor necrosis factor α (TNFα) and the angiogenic factors vascular endothelial growth factor-A and placental growth factor in UMUC3 cells; whereas in RT112 cells, induction of IL-8 and TNFα was noticed. Interestingly, addition of CpG-ODN significantly reduced cell viability and increased cell invasion in UMUC3 and RT112 cells. Conclusions Our findings demonstrate that bladder cancer cell lines express functional TLR4 and TLR9 with possible effects on cancer progression and outcome of BCG-based immunotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Apalutamide plus androgen-deprivation therapy (ADT) improved outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nevertheless real-world data are limited. The aim of this multicenter study was to generate real-world data from nmCRPC patients treated with ADT plus apalutamide., Methods: In this observational cohort based investigator initiated trial data of nmCRPC patients receiving apalutamide plus ADT were collected focusing on patient demographic data, prostate-specific antigen (PSA) declines, safety profile including dose modification/discontinuation as well as subsequent therapy and metastasis-free survival (MFS)., Results: Data from a total of 31 nmCRPC patients were documented. Compared to the Phase III study Spartan real-world patients are older, showed a higher ECOG-PS and more aggressive tumors. In the cohort PSA decreased about 98.1%, 74% of patients showed a PSA decrease over 90% and 54.8% reached a PSA-level < 0.2ng/ml. Apalutamide was well tolerated in real world patients: adverse events occurred in 67.7% but were in the majority mild (≥ grade 3: 6.5%). Dose reduction was necessary in 38.7% and 32.2% discontinued apalutamide treatment. MFS was 43 months and majority of patients were subsequently treated with abiraterone., Conclusion: In real world more comorbid nmCRPC patients with a higher ECOG-PS and more aggressive tumors are treated with apalutamide plus ADT. Nevertheless efficacy results as well as side effects are similar in real-world compared to Spartan trial showing also a rapid, durable and deep PSA response with a median MFS of 43 months., (© 2024. The Author(s).)

Background: Radiotherapy is essential in the treatment of prostate cancer. An alternative to conventional photon radiotherapy is the application of carbon ions, which provide a superior intratumoral dose distribution and less induced damage to adjacent healthy tissue. A common characteristic of prostate cancer cells is their dependence on androgens which is exploited therapeutically by androgen deprivation therapy in the advanced prostate cancer stage. Here, we aimed to analyze the transcriptomic response of prostate cancer cells to irradiation by photons in comparison to carbon ions, focusing on DNA damage, DNA repair and androgen receptor signaling., Methods: Prostate cancer cell lines LNCaP (functional TP53 and androgen receptor signaling) and DU145 (dysfunctional TP53 and androgen receptor signaling) were irradiated by photons or carbon ions and the subsequent DNA damage was assessed by immuno-cytofluorescence. Furthermore, the cells were treated with an androgen-receptor agonist. The effects of irradiation and androgen treatment on the gene regulation and the transcriptome were investigated by RT-qPCR and RNA sequencing, followed by bioinformatic analysis., Results: Following photon or carbon ion irradiation, both LNCaP and DU145 cells showed a dose-dependent amount of visible DNA damage that decreased over time, indicating occurring DNA repair. In terms of gene regulation, mRNAs involved in the TP53-dependent DNA damage response were significantly upregulated by photons and carbon ions in LNCaP but not in DU145 cells, which generally showed low levels of gene regulation after irradiation. Both LNCaP and DU145 cells responded to photons and carbon ions by downregulation of genes involved in DNA repair and cell cycle, partially resembling the transcriptome response to the applied androgen receptor agonist. Neither photons nor carbon ions significantly affected canonical androgen receptor-dependent gene regulation. Furthermore, certain genes that were specifically regulated by either photon or carbon ion irradiation were identified., Conclusion: Photon and carbon ion irradiation showed a significant congruence in terms of induced signaling pathways and transcriptomic responses. These responses were strongly impacted by the TP53 status. Nevertheless, irradiation mode-dependent distinct gene regulations with undefined implication for radiotherapy outcome were revealed. Androgen receptor signaling and irradiations shared regulation of certain genes with respect to DNA-repair and cell-cycle., (© 2024. The Author(s).)

Background: Immunostimulatory CpG oligodeoxynucleotides (CpG-ODN) have been verified as an effective antineoplastic agent for intravesical application in a murine orthotopic C57-BL6 /MB-49 urothelial cell carcinoma (UCC). To date, many details in the mode of action have remained unclear. Preceding studies pointed towards a Th1-weighted response. The aim of this work was to identify the local lymphocyte subsets in murine tumour-bearing bladders and to examine effects on the expression of Intercellular Adhesion Molecule 1 (ICAM-1) after treatment with CpG-ODN., Material and Methods: Different instillation schedules were applied in an established orthotopic C57-BL6 /MB49 UCC model. After 13 days, fresh frozen sections of the harvested bladders were immunohistochemically examined for the infiltration density of lymphocytes expressing CD 3, CD4, CD8 and CD19. In a second series of the same animal model, healthy and tumour-bearing bladders were exposed to CpG-ODN or PBS and later stained for the expression of ICAM-1., Results: CpG-ODN instillation led to augmented T-cell infiltration (represented by CD3). Further T-cell subdifferentiation between T-helper cells (CD4) and cytotoxic T cells (CD 8a) did not show a perceptible variety between groups. The B-cell population (CD19) was found to decrease over the course of treatment. In the second series, treatment provoked a strong expression of ICAM-1 by infiltrating leukocytes, endothelial cells and particularly by the cancer cells themselves., Discussion: The previously observed augmented lymphocyte density was classified as T-cell infiltration. The decline of the B-cell concentration over the course of treatment suggests a Th2 suppression in favour of a Th-1 polarisation. These findings support the assumption that a cell-mediated immune response is the mode of action underlying the antineoplastic CpG-ODN capacities. The marked upregulation of ICAM-1 expression, especially on tumour cells, suggests a crucial role of this membrane protein for the initiation and maintenance of anticancer immune response., Conclusion: CpG-ODN might be a prospective alternative to established instillation therapies. With a view to the current BCG shortage and the well-known toxicities, an amplification of the topic therapy armamentarium could be achievable. The now described capability of ICAM-1 induction on carcinoma cells and, by association, the reversal of escape strategies to cancer immunity may also make the agent interesting as an adjuvant for modern checkpoint inhibition., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Exploring the regulation of co-inhibitory (PD-1, PD-L1, CTLA-4) and co-stimulatory (CD28) genes by chemotherapeutic drugs is important for combined immune checkpoint blockade (ICB) therapy. ICB interferes with T-cell receptor and major histocompatibility complex (MHC) signaling by antibody drugs directed against the co-inhibitors. Here, we analyzed urothelial (T24) cell line with respect to cytokine signaling by interferon γ (IFNG) and the leukemia lymphocyte (Jurkat) cell line with respect to T-cell activation as mimicked by phorbolester and calcium ionophore (pma/iono). Alongside, we considered possible intervention with the chemotherapeutics gemcitabine, cisplatin and vinflunine. Noteworthy, cisplatin significantly induced PD-L1-mRNA in naïve and IFNG treated cells whereas gemcitabine and vinflunine had no effect on PD-L1-mRNA. At the protein level, PD-L1 showed typical induction in IFNG treated cells. In Jurkat cells, cisplatin significantly induced PD-1-mRNA and PD-L1-mRNA. Pma/iono administration did not alter PD-1-mRNA and PD-L1-mRNA but significantly increased CTLA-4-mRNA and CD28-mRNA levels where vinflunine suppressed the CD28-mRNA induction. In sum, we demonstrated that certain cytostatic drugs being relevant for the therapy of urothelial cancer, affect co-inhibitory and co-stimulatory modulators of immune signaling with potential impact for perspective combined ICB therapy of patients. MHC-TCR signaling between antigen presenting cells and T-lymphocytes with co-stimulator (blue) and co-inhibitors (red) and interacting proteins (blank). Co-inhibitory connections are shown by lines and co-stimulatory connections by dotted lines. The inducible or suppressive actions of the drugs (underlined) on the respective targets are indicated., (© 2023. The Author(s).)

Immune checkpoint blockade therapy is a treatment option of various metastatic cancer diseases including renal cell carcinoma (RCC). Approved antibody drugs target the co-inhibitory signaling of Programmed Cell Death Ligand-1 (PD-L1) and its receptor Programmed Cell Death-1 (PD-1). The combined evaluation of PD-L1 and PD-1 at the mRNA and protein levels in tumor tissue with differentiation of tumor and immune cells as well as of soluble forms (sPD-L1) and (sPD-1) in blood is of basic interest in assessing biomarker surrogates. Here, we demonstrate that PD-L1 determined as fraction of stained tumor cells (TPS-score) correlates with PD-L1-mRNA in tumor tissue, reflecting the predominant expression of PD-L1 in tumor cells. Conversely, PD-1 in immune cells of tumor tissue (IC-score) correlated with PD-1-mRNA tissue levels reflecting the typical PD-1 expression in immune cells. Of note, sPD-L1 in blood did not correlate with either the TPS-score of PD-L1 or with PD-L1-mRNA in tumor tissue. sPD-L1 released into the supernatant of cultured RCC cells closely followed the cellular PD-L1 expression as tested by interferon γ (IFNG) induction and siRNA knockdown of PD-L1. Further analysis in patients revealed that sPD-L1 significantly increased in blood following renal tumor resection. In addition, sPD-L1 correlated significantly with inflammation marker C-reactive protein (CRP) and with PD-L1 mRNA level in whole blood. These results indicate that the major source of sPD-L1 in blood may be peripheral blood cells and not primarily tumor tissue PD-L1., (© 2022. The Author(s).)

Although growth differentiation factor-15 (GDF-15) is highly expressed in PCa, its role in the development and progression of PCa is unclear. The present study aims to determine the density of GDF-15+ cells and immune cells (M1-/M2 macrophages [MΦ], lymphocytes) in PCa of different Gleason scores (GS) compared to BPH. Immunohistochemistry and double immunofluorescence were performed on paraffin-embedded human PCa and BPH biopsies with antibodies directed against GDF-15, CD68 (M1 MΦ), CD163 (M2 MΦ), CD4, CD8, CD19 (T /B lymphocytes), or PD-L1. PGP9.5 served as a marker for innervation and neuroendocrine cells. GDF-15+ cell density was higher in all GS than in BPH. CD68+ MΦ density in GS9 and CD163+ MΦ exceeded that in BPH. GDF-15+ cell density correlated significantly positively with CD68+ or CD163+ MΦ density in extratumoral areas. Double immunoreactive GDF-15+/CD68+ cells were found as transepithelial migrating MΦ. Stromal CD68+ MΦ lacked GDF-15+. The area of PGP9.5+ innervation was higher in GS9 than in BPH. PGP9.5+ cells, occasionally copositive for GDF-15+, also occurred in the glandular epithelium. In GS6, but not in BPH, GDF-15+, PD-L1+, and CD68+ cells were found in epithelium within luminal excrescences. The degree of extra-/intra-tumoral GDF-15 increases in M1/M2Φ is proposed to be useful to stratify progredient malignancy of PCa. GDF-15 is a potential target for anti-tumor therapy.

Background/aim: Cervical cancer is the most common gynecological indication for pelvic exenteration (PE). It is an ultima ratio approach to cure advanced or recurring tumors. This study aimed to evaluate data from a Single Center Institution in order to assess morbidity, mortality and survival data., Patients and Methods: Data of 24 patients, who underwent anterior (APE) or total PE (TPE) for cervical cancer at the University Hospital Marburg between 2011 and 2016, were extracted and retrospectively evaluated. Survival analysis was conducted using the Kaplan-Meyer method., Results: Lymph node status was pN0, pN1 and pNX in 33.3%, 20.8% and 45.8% respectively. Negative margins could be achieved in 70.8%. A total of 16.7% of patients presented with metastatic disease, while 20.8%, 37.5% and 20.8% received 1, 2 or 3 modalities of treatment respectively; 20.8% underwent up-front PE. Predominant urinary diversion was an ileum conduit (66.7%). No complications were noted for 16.7%, major complications (≥Clavien Dindo 3) in 41.7%. Overall survival was 29.2% with a median overall survival (mOS) of 19.1 months. Curative PE was undertaken in 20 cases, with 2- and 3-year survival rates of 52.6% and 29.4% respectively. and a mOS of 24 months. Positive margins, metastatic disease, positive lymph nodes, TPE and a surgical time >6 h had a significant impact on OS., Conclusion: PE for cervical cancer remains a feasible option in cases of advanced or recurring tumors when alternative treatment options would fail. For selected patients it may represent a chance of cure with acceptable complication and satisfactory survival rates., Competing Interests: The Authors declare no conflicts of interest in relation to this study., (Copyright 2022, International Institute of Anticancer Research.)

Background/aim: Up to 30% of all patients will present with an advanced or a metastatic stage (mUCC) at the moment of the initial diagnosis of urothelial cell carcinoma of the bladder (UCC). We investigated the numbers, the efficacy and toxicity of different chemotherapies for mUCC in daily practice and "real-life" conditions and evaluated them substance-specifically., Patients and Methods: All patients with a mUCC, who were treated between January 1, 2006 and October 31, 2016 at the Department of Urology and Pediatric Urology at University Hospital Marburg (Germany), were retrospectively analyzed. We set the focus on demographic and tumor-specific data as well as on effectiveness, therapy sequences, and drug tolerance., Results: Forty-one patients were identified. Of the 41 patients, 85.4% of the patients in first-line therapy received gemcitabine/cisplatin. A large proportion of 85.4% received a second-line therapy and 40% a third-line therapy due to progress or relapse. Median overall survival (mOS) was 18 months including all patients and increased up to 29.5 months in the cases of three therapy lines., Conclusion: Our data reveal that chemotherapy of mUCC is effective and side effects are manageable in daily clinical practice., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Fischer et al.)

Background: Programmed death ligand (PD-L1)-based immune checkpoint blockade therapy for metastatic renal cell carcinoma (RCC) achieves significant response rates in a subgroup of patients. The relevance of PD-L1 gene regulation for disease outcome is not clear., Objective: To evaluate PD-L1 expression and its dependence on interferon-γ (IFN-γ) in RCC cell lines and tissues in relation to disease outcome., Methods and Patients: Regulation of PD-L1-mRNA and PD-L1 protein was studied in cell lines from clear cell RCC (ccRCC) and papillary RCC (pRCC) by quantitative RT-PCR and Western-blot analysis. PD-L1-mRNA correlation and gene-set enrichment analysis (GSEA) of the IFN-γ pathway were conducted with RNA-Seq from ccRCC, pRCC, and skin cutaneous melanoma (SKCM) tissue. In addition, patient overall survival (OS) and disease-free survival (DFS) (cBioPortal for Cancer Genomics) were considered., Results: In ccRCC-like cell lines, PD-L1 was induced by canonical IFN-γ signaling, whereas in a pRCC-like cell line, PD-L1 was refractory towards IFN-γ signaling. In ccRCC and SKCM tissues, GSEA revealed significant IFN-γ pathway activation in tissue samples with high PD-L1-mRNA levels. This was not observed in pRCC tissue. ccRCC and SKMC patients with low PD-L1-mRNA levels had significantly shorter OS and DFS than those with high PD-L1-mRNA levels. In pRCC patients, no significant difference in OS and DFS with regard to PD-L1-mRNA tissue levels was obvious., Conclusions: The findings suggest that ccRCC and pRCC differ with respect to PD-L1 regulation by IFN-γ-signaling. High PD-L1-mRNA levels in tumor tissues with a positive IFN-γ signature favorably affect OS and DFS.

Background: Non-Hodgkin lymphomas, which include Burkitt's lymphoma, affect the prostate in only 0.1% of cases. They most commonly present as painless lymphadenopathy elsewhere in the body and can cause abdominal or thoracic pain and systemic symptoms such as fever, weight loss and night sweats. Here we report a rare case of sporadic Burkitt's lymphoma of the prostate whose initial clinical presentation was acute urinary retention., Case Presentation: A 28-year-old Caucasian male presented repeatedly with urinary retention. First, he was misdiagnosed with alcohol-induced urinary retention and later with benign prostatic hyperplasia. After the appearance of new symptoms, including hematuria and hydronephrosis, endoscopic and radiographic evaluation was performed. Transurethral biopsy of the prostate secured the diagnosis of Burkitt's lymphoma. The symptoms receded under chemotherapy and complete remission of the disease was established., Conclusion: This case report brings lymphomas into focus as a differential diagnosis for urinary retention in young males. Early use of extensive diagnostic measures is advised in patients with urinary retention for uncertain reasons to make prompt diagnosis and start appropriate treatment early.

Introduction: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC)., Methods: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC., Results: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036)., Conclusions: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC.

We report an extremely low birth weight infant with anuria caused by bilateral Candida albicans fungus balls it was treated with a combination of antifungal therapy, irrigation and pyelotomy. This lead to a recovery of renal function, after a follow-up of 77 month no more Candida was cultured from urine., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Fabian Brüning et al.)

Background: Vinflunine (VFL) is approved in Europe as second-line treatment of metastatic urothelial cancer after failure of platinum-containing therapy. We performed a systematic review and meta-analysis of real-world data (RWD) to assess utilization, efficacy and safety of VFL., Methods: We performed a MEDLINE search for the period of 1/1/2000-31/8/2017. Full-length articles providing post-marketing RWD on VFL in patients failing previous chemotherapy were eligible. Interventional clinical trials were excluded., Results: Ten studies with 797 patients were identified. According to pooled REs analysis, overall response rate was 19%, most frequent, all-grade toxicities were fatigue (41%), constipation (39%), nausea/vomiting (25%), and most prevalent Grade 3-4 toxicities were neutropenia (13%), anaemia (9%), fatigue (8%). Median OS was comparable to results reported in recent randomized studies., Conclusion: Our findings confirm the efficacy and safety of VFL in an unselected population and support the use of VFL in the changing treatment paradigm of relapsed mUC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: NOD1 and NOD2 (nucleotide-binding oligomerization domain)-receptors are intracellular receptors and belong to the family of pattern recognition receptors being present in both human and murine renal tubular cells. Besides, NOD1 has been proved to promote apoptosis, upon its overexpression. Hence, we aimed to investigate NOD1 and NOD2 expression in human clear cell renal cell carcinoma (ccRCC)., Methods: Tumor and corresponding adjacent healthy tissues from 41 patients with histopathological diagnosis of ccRCC as well as primary isolated renal tubular epithelial cells (TECs) and tumor tissue from a murine xenograft model using CAKI-1 ccRCC cells were analyzed., Results: NOD1 and NOD2 mRNA was constitutively expressed in both tumor and adjacent healthy renal tissue, with NOD1 being significantly lower and in contrast NOD2 significantly higher expressed in tumor tissue compared to healthy tissues. Immunohistochemically, NOD1 was located not only in the cytoplasm, but also in the nucleus in ccRCC tissue whereas NOD2 was solely localized in the cytoplasm in both human ccRCC as well as in the healthy tubular system. Focusing on the vasculature, NOD2 displayed broader expression than NOD1. In primary TECs as well as CAKI-1 cells NOD1 and NOD2 was constitutively expressed and increasable upon LPS stimulation. In the mouse xenograft model, human NOD1 mRNA was significantly higher expressed compared to NOD2. In contrast hereto, we observed a shift towards lower mouse NOD1 compared to NOD2 mRNA expression., Conclusion: In view of reduced apoptosis-associated NOD1 expression in ccRCC tissue opposed to higher expression of NOD2 in tumor vasculature, inducibility of NOD expression in TECs as well as the detected shift of NOD1 and NOD2 expression in the mouse xenograft model, modulation of NOD receptors might, therefore, provide a molecular therapeutic approach in ccRCC.

A 41-year-old man without previous illness presented at our clinic with progressive pain in the lower abdomen and intermittent pain in the left flank. We found a lesion of unknown dignity which had anatomical contact to the bladder and rectum. Histological examination confirmed the diagnosis of hemangiopericytoma. It is grouped under the general term solitary fibrous tumor (SFT). The potential for malignancy varies. To calculate the tendency of metastases or recurrence and overall survival, it is necessary to use a risk stratification model to individualize treatment. Our rare case with an appearance of a relapse 14 and 20 years after the primary resection and progressive proliferation rate underlines the importance of individualized management and long-term and close follow-up of this tumor entity.

We are living in exciting times for urological oncology. The numbers of clinical trials are ever rising, a stream of new substances for tumour therapy is introduced. As it is more challenging than ever to obtain an overview as a clinician, this article aims to summarise the most important news with regard to the 3 most eminent urological tumour entities. Recent data from the most relevant urological and oncological conferences in 2018 on prostate cancer, renal cell carcinoma, and urothelial cancer are reported and their relevance for clinical practice is discussed., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Urothelial cell carcinoma (UCC), also called transitional cell cancer, occurs significantly more often in males than in females. Essential for the prognosis of recovery is depth of infiltration (muscle-invasive or non-muscle invasive) and tumor-differentiation at initial diagnosis. The current study aimed to explore sex-related differences after initial diagnosis of UCC in Germany., Methods: We identified patients who underwent transurethral resection of the bladder tumor (TUR-BT). Data were retrospectively analyzed, including TNM classification, histopathological grading, risk group according to the European Association of Urology (EAU), use of photody-namic diagnosis (PDD), and early intravesical chemotherapy (IVC)., Results: A total of 539 male and 190 female patients with UCC underwent TUR-BT. Approximately 75% were non-muscle invasive bladder cancer (NMIBC). Females evidenced significantly higher rates of muscle-invasive bladder cancer (MIBC; P =0.04). Carcinoma in situ (CIS) was significantly more common among males ( P =0.01). Recurrence and progression rates showed no significant sex differences - only in the small subgroup of EAU low-risk NMIBC females, we found a significantly higher progression rate ( P =0.03). In a Cox proportional hazards model, we found for MIBC, an HR for progression of 6.5 (95% CI, 1.29-33.2; P =0.02) after a median follow-up of 56 months. Use of PDD or IVC showed no significant differences in recurrence and progression between females and males., Conclusion: Females were significantly more likely to suffer from MIBC at the time of first diagnosis. In NMIBC, males showed a significantly higher prevalence of CIS and EAU low-risk NMIBC females showed significantly higher rates of progression. Sex was not associated with recurrence rates in NMIBC. PDD and IVC were equally effective in both sexes. Based on the collected data we suggest to further investigate possible sex differences in UCC with therapeutical impact. Additional prospective multicenter studies are needed to evaluate both sex-related long-term disease courses and effectiveness of therapies., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC)., Materials and Methods: CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis., Results: CD200 was detectable at mRNA and protein levels in TCC homogenate and TCC cell lines (T24, UMUC3). TCC tissues showed significantly higher CD200 expression (p<0.005) than normal bladder tissues. CD200 signals were also higher in metastasized compared to localized TCC (p<0.05). CD200 was significantly correlated to tumor grading (p<0.001) and was strongest in the subgroup with high-grade G2 TCC (vs. low-grade G2 p<0.05)., Conclusion: This is the first report of CD200 expression in patients with TCC. The significant correlation between CD200 expression and tumor grading may suggest CD200 as a potential target and marker for immunotherapeutic approaches., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Cystoscopy, the standard diagnostic for bladder tumors, is uncomfortable, invasive, and expensive. The available urine-based marker systems all lack accuracy. Measuring volatile organic compounds (VOCs) from urine is a promising alternative. This pilot study evaluates the feasibility of discriminating bladder cancer patients' urine from healthy controls with an electronic nose., Materials and Methods: Headspace measurements of urine samples of 30 patients with confirmed transitional cell carcinoma (TCC) and 30 healthy controls were performed with Cyranose 320 calculating Mahalanobis distance and linear discriminant analysis. Histology reports following TUR-BT were correlated with urine findings., Results: After storage at -20°C, Cyranose correctly detected 28/30 already confirmed TCC samples and 26/30 healthy controls (p<0.01), sensitivity 93.3%, specificity 86.7%. Storage at -80°C led to similar results: 28/30 tumor samples and 28/30 control samples were correctly allocated; sensitivity and specificity both 93.3%., Conclusion: VOC detection is a promising tool to detect bladder tumors. Further research will test against possible confounders like bacteriuria., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Despite an expected prognostic disadvantage for upper tract versus lower tract metastatic urothelial carcinomas (UTUC/LTUC), only few studies have been conducted to elucidate potential differences in chemotherapy treatment., Patients and Methods: A post-hoc subgroup analysis of a non-interventional study investigating vinflunine after failure of a platinum-based chemotherapy in metastatic/locally advanced UC patients was performed., Results: A total of 18 and 59 out of 77 patients had UTUC and LTUC, respectively. The effectiveness of vinflunine treatment was comparable with an overall response rate of 22.2% and 23.7% respectively and a median progression-free survival of 2.76 months in both groups. Median overall survival was 5.0 months in UTUC compared to 8.2 months in the LTUC group (p=0.478). The safety profile was in accordance with previous vinflunine experiences, with a comparable frequency of adverse events in both groups., Conclusion: Vinflunine can be applied in the 2nd line for UC regardless of the primary tumor localization., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To evaluate the safety, efficacy and outcome of percutaneous balloon-expandable covered stent graft placement for uretero-iliac artery fistula (UAF) treatment., Methods: This retrospective study evaluated the single-center experience of percutaneous balloon-expandable covered stent graft placement (ADVANTA™, Atrium Hudson, NH, USA) in UAF. Data were obtained from a prospective institutional database. Patient follow-up included complications, symptoms recurrence and mortality rate., Results: Ten UAFs in eight patients (3 males; 5 females) with a mean age of 64.5 (35-77) years were identified. All patients had a history pelvic malignancy, extirpative surgery (n = 6), long-term ureteral stenting (n = 7) and pelvic radiation (n = 5). All procedures were completed successfully without complications. Thirty-day mortality rate was zero. At a median follow-up of 6 (1-60) months, one patient suffered recurrent hematuria requiring a secondary stent graft placement 26 months after the initial treatment. During follow-up, five patients died of the underlying disease (43, 66, 105, and 183 and 274 days after the last procedure)., Conclusion: Percutaneous balloon-expandable stent graft placement in UAF is a safe and effective treatment option. Implantation of stent grafts should be considered as treatment of choice in UAF.

Background: Increasing numbers of tyrosine kinase inhibitors (TKIs) were studied and approved for therapy of malignancies and other diseases. The aim of this study was to develop and validate a specific, simple and rapid quantification method for various TKIs in human plasma., Methods: A simultaneous test for six TKIs (erlotinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib) was developed using liquid chromatography tandem mass spectrometry in a multiple reaction monitoring mode. After protein precipitation the specimens were applied to the HPLC system and separated using a gradient of acetonitrile containing 1% formic acid with 10 mM ammoniumformiate on an analytic RP-C18 column., Results: The calibration range was 10-1000 ng/mL for sunitinib and 50-5000 ng/mL for the other TKIs with coefficients of determination ≥0.99 for all analytes. The intra- and inter day coefficients of variation were ≤15% and the chromatographic run time was 12 min. Plasma specimens were stable for measurement for at least 1 week at 4°C. Clinical applications of the assay are exemplarily discussed., Conclusions: This novel high-throughput method is suitable for specific simultaneous determination of different TKIs in routine clinical practice., (Copyright © 2011. Published by Elsevier B.V.)

Background: Clear cell renal cell carcinoma, a solid growing tumor, is the most common tumor in human kidney. Evaluating the usefulness of β-galactoside binding galectin-3 as a diagnostic marker for this type of cancer could open avenues for preventive and therapeutic strategies by employing specific inhibitors of the lectin. To study a putative correlation between the extent of galectin-3 and the development of clear cell renal cell carcinoma, we monitored the quantity and distribution of this lectin in tissue samples from 39 patients., Methods: Galectin-3 concentrations in normal, intermediate and tumor tissues were examined by immunofluorescence microscopy and on immunoblots with antibodies directed against galectin-3 and renal control proteins. The cell nuclei were isolated to determine quantities of galectin-3 that were transferred into this compartment in normal or tumor samples., Results: Immunofluorescence data revealed a mosaic pattern of galectin-3 expression in collecting ducts and distal tubules of normal kidney. Galectin-3 expression was significantly increased in 79% of tumor samples as compared to normal tissues. Furthermore, we observed an increase in nuclear translocation of the lectin in tumor tissues., Conclusions: Our data indicate that changes in the cellular level of galectin-3 correlate with the development of clear cell renal cell carcinoma, which is in line with previously published data on this specific type of tumor. In most of these studies the lectin tends to be highly expressed in tumor tissues. Furthermore, this study suggests that the increase in the proportion of galectin-3 affects the balance from a cytosolic distribution towards translocation into the nucleus.

Purpose: To compare the accuracy of the robot-assisted needle positioning with that of the conventional template-guided method with the help of a prostate model in high dose rate (HDR) brachytherapy., Materials and Methods: A prostate model of fresh porcine abdomen and special polyvinylchloride (PVC) sheets was developed. To verify the model, deviations from 311 needle placements of real prostate implants were analyzed. Second, the accuracy of the template-guided positioning versus robot-assisted positioning was measured with 20 needle insertions in the model. For robot-assisted positioning, different velocities (2.7, 5.4, 9.8 mm/s) of needle insertion were investigated., Results: The average needle positioning accuracies of manual template guidance on the model closely resembled those of real patients (approximately 3 mm). The average needle positioning accuracy for the robot-assisted method on the prostate model was 1.8 ± 0.6 mm, at a velocity of 2.7 mm/s and, in comparison to the template-guided method (2.7 ± 0.7 mm), was statistically more precise (p < 0.001). At higher robotic velocities, the measured needle positioning accuracy showed no significant difference from that of the manual insertion procedure., Conclusion: By employing a prostate model, we showed for the first time that robot-assisted needle placement for HDR brachy-therapy is significantly more precise than the conventional method at a velocity of 2.7 mm/s. The robot-assisted needle positioning technique improves the degree of freedom by providing additional oblique insertion channels and could be potentially exploited not only for LDR but also for HDR brachytherapy.

Background: Reliable blood and urine markers for transitional cell carcinoma of the bladder (TCC) do not currently exist. The aim of this prospective study was the serological and immunohistochemical evaluation of CA19.9 and CEA in TCC and to assess the correlation with different TCC stages., Patients and Methods: CA19.9 and CEA levels were prospectively determined in samples from 231 patients with TCC suspected bladder lesions, before transurethral tumor resection. Additionally, these serum parameters were determined in 11 patients with initial metastatic TCC. Immunohistochemical analysis on CA19.9 and CEA was performed in 83 patients., Results: Neither CA19.9 nor CEA levels were significantly elevated in TCC patients. Patients with muscle-invasive TCC showed significantly higher levels of CEA (p = 0.008) and CA19.9 (p<0.001) compared to those with superficial TCC. Significantly higher levels were also evident with increasing grade of malignancy. Metastatic TCC showed significantly elevated CA19.9 levels compared to muscle invasive TCC as well as locally advanced (pT3/pT4/pN+) compared to localized TCC (pT2/pN0). Immunohistochemical staining revealed a strong correlation between CA19.9 serum levels and staining intensity., Conclusion: CEA and CA19.9 are not useful markers in primary diagnosis of TCC. However, in instances of elevated CEA and CA19.9 levels where gastrointestinal malignancy has been excluded, evidence of TCC should be sought. If elevated CEA and CA19.9 are present in TCC, serum levels correlate with tumor invasion and grade of malignancy.

Unlabelled: The aim of this study was to detect lymphatic spread by serial step-section technique in non-sentinel lymph nodes (NSLNs), which were earlier assessed as negative by histological examination., Patients and Methods: Inguinal dissection specimens of 13 men with penile cancer were investigated. The LNs were sectioned at multiple levels (150 mum-intervals) and then H&E- and immuno-stained for cytokeratin (Lu-5)., Results: 196 LNs of 13 men were examined. In 2 out of 13 patients (15%) previously ranked as pN0, minimal lymph node involvement was detected by serial step sections and both immunohistochemistry and H&E staining. Both patients have had an uneventful follow-up of currently 62 and 16 months., Conclusion: Conventional histological examination of NSLNs fails to detect lymphatic spread in penile cancer. Step-section technique at 3 section levels, rather than immunohistochemistry, helps to safely detect minimal metastatic disease. The prognostic relevance is still unclear and has to be investigated in larger cohort studies.

Background: Intravesical BCG instillation is established and efficient in the prophylaxis of recurrent transitional cell carcinoma. A Th-1 biased immune response is postulated. Recent work has proven the efficacy of synthetic CpG-Oligodeoxynucleotides (ODN) as inducers and adjuvants for a strong Th1-response and there is evidence for a direct and/or adjuvant anti-neoplastic effect. The purpose of this study was to examine the local effects of CpG-ODN on the murine bladder wall after intravesical instillation and the effects on cytokine expression in an orthotopic murine bladder cancer model., Materials and Methods: Histopathology, immunohistochemistry and fluorescence microscopy were performed after different instillation schedules of stimulatory, non-stimulatory biotinylized and FITC-labelled CpG-ODN into the murine bladder. MB-49 murine bladder cancer cells were tested for TLR-9 expression to exclude a potential direct responsiveness to CpG-ODN. Furthermore induction of apoptosis was tested by annexin V staining and FACS analysis of CpG-ODN stimulated tumor cells. In an orthotopic C57/Bl6 murine bladder cancer model, the expressions of IL-12, IFNgamma, IL-10 and TGF-beta were evaluated after repeated CpG-ODN treatment., Results: Single and repeated instillation of CpG-ODN induced subepithelial and urothelial lymphocytic infiltrations with consecutive apoptoses. PBS and non-stimulative ODN induced no visible reaction. Bladder submucosa stained positive for biotin. Controls showed no endogenic biotin staining. FITC-labelled ODN adhered to the bladder mucosa and penetration of the mucosal barrier was not detected. MB-49 TCC cells did not express TLR-9 and CpG-ODN did not induce apoptosis in these cells. Repeated intravesical instillations of CpG-ODN in orthotopic murine tumor bearing urinary bladders resulted in significant up-regulation of both Th-1 and Th-2 cytokines., Conclusion: CpG-ODNs have promising anti-neoplastic potential. They exert a pronounced immunological response both in the native murine urinary bladder and in murine TCC. The mechanisms of action appear to be mediated immunologically, There was no direct effect of CpG-ODN on the tumor cells in this model.

Non-clear cell (ncc) renal cell carcinoma (RCC) accounts for approximately 25% of all patients with metastatic RCC. It is refractory to standard immuno(chemo)therapy and, to date, no specific trials have been reported to evaluate the efficacy of novel targeted drugs in the different subtypes of metastatic nccRCC. We review all available data from subgroup analyses of the global sorafenib and sunitinib expanded access programmes, current phase-III trials, and smaller multi- and single-centre studies focusing on the activity of targeted agents in these specific and rare RCC subtypes. Both sorafenib and sunitinib have significant activity in metastatic nccRCC, but the efficacy of each agent seems to vary between different nccRCC forms. Preliminary clinical data for temsirolimus appear to be promising but more extensive and long-term data are awaited. With the advent of novel therapeutic options, specific controlled multicentre trials are urgently needed to define their exact value and efficacy for treating the historically resistant nccRCC forms. The medium-term aim should be to tailor the most advantageous therapy for each patient with respect to his/her individual RCC subtype and physical condition.

Percutaneous nephrolitholapaxy (PCNL) with modern stone disintegration technologies is the treatment of choice for patients with extensive stone burden or stones refractory to extracorporeal shock wave lithotripsy. However, little is known about factors predicting unfavourable outcome in terms of perioperative complications, residual stone burden or prolonged hospitalization. The aim of this study was to evaluate preoperative, patient- and stone-related parameters that might influence the perioperative course and short-term clinical outcomes. In a prospective study, age, sex, body mass index (BMI), bidimensional size, side, pre-existent urinary tract infection, pre-existent hydronephrosis and previous kidney surgery were used as independent variables in both univariate and multiple regression models in 109 PCNL patients in order to predict the partition of patients rendered stone free at hospital discharge, duration of surgery, length of inpatient hospital stay and the occurrence of major complications. Univariate and multiple regression analysis revealed that stone size was the only factor influencing duration of surgery (P < 0.001) and hospitalization (P = 0.02), but had no predictive potential for major complications. Univariate analysis showed a trend towards longer inpatient hospital stay and clinically relevant residuals in patients with lower BMI (P = 0.05 and 0.06); however, after controlling for the other confounding variables, this was only reproducible for residual stone burden. The other patient- and stone-related factors did not adversely affect the outcome measures. In our patient sample treated with PCNL by LithoClast Master/Ultra we found evidence that large stone burden is a prognostic factor predicting longer surgery and prolonged hospitalization. In addition, patients with lower BMIs might be at higher risk of not being stone free at hospital discharge accompanied by prolonged inpatient treatment.

Objective: To evaluate and compare the value of several markers of bone turnover in different stages of prostate cancer, as bone metastases are a common feature in this disease, and for assessing bone metastases both bone formation and bone resorption markers are diagnostic., Patients and Methods: The prospective study included 219 men, i.e. 129 undergoing radical retropubic prostatectomy (RRP) and 25 with bone metastases due to prostate cancer, and 65 with benign urological disorders who served as controls. Before any treatment the concentrations of alkaline phosphatase (ALP), osteocalcin, serum C-terminal telopeptide of type I collagen (S-CTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were determined., Results: Men undergoing RRP were divided into those with lymph node-negative, localized (pT3, 101) and lymph node-positive (28) disease, after histological examination. The controls had the lowest marker levels while patients with bone metastases due to prostate cancer had the highest levels, with significance for ALP, osteocalcin and TRACP5b. Patients with lymph node-positive cancer had significantly high serum levels of TRACP5b and ALP but not for osteocalcin and S-CTX., Conclusions: Bone turnover markers represent a new diagnostic tool in prostate cancer; the present data show that both bone resorption and bone formation are crucial for detecting bone metastases in prostate cancer. The value of bone turnover markers in high-risk patients should be evaluated in a longitudinal study.

Objectives: Repeat retroperitoneal lymph node dissection (RPLND) for the treatment of metastatic testicular cancer is an uncommonly performed procedure. We evaluated the location, pathohistological results, postoperative complications and therapeutic outcome in 17 patients being referred for repeat RPLND after failure of the primary retroperitoneal approach., Patients and Methods: 18 patients underwent repeat RPLND after failed primary RPLND or residual tumour resection. We retrospectively analyzed preoperative patient characteristics, operative and pathohistological data from primary and repeat RPLND, morbidity and oncological outcome after surgery., Results: All patients had nonseminomatous primaries with metastatic retroperitoneal lymph nodes; 4 and 14 patients had undergone primary RPLND and residual tumor resection (RTR), respectively, for metastatic testicular cancer. Prior to repeat RPLND all patients had undergone 4 cycles of salvage chemotherapy for locoregional recurrences only with negative tumour markers at time of surgery. All patients demonstrated residual masses requiring repeat RPLND. Retroperitoneal recurrences were located at multiple sites: retrocaval area with infiltration of the vena cava, interaortocaval and paraaortic region, retrocrural space, suprahilar region, outfield metastases in the iliac region. Two cases required resection of the vena cava due to infiltration, in one case an aortic graft and an iliac graft was necessary due to tumour infiltration of the adventitial layer of the vessels; nephrectomy and resection of the sigmoid was required in another 2 patients. The most significant complication was chylous ascites 1 and prolonged paralytic ileus in 1 patient. Pathohistological examination of the resected specimen revealed viable germ cell tumour elements in 4 patients (22.2%), necrosis/fibrosis in 8 patients (44.4%) and mature teratoma in 6 patients (33.3%). At a mean follow-up of 22 (1-45) months, the disease specific survival rate was 89% with significant differences between patients with necrosis (100%), mature teratoma (85%) and viable cancer (50%)., Conclusion: Recurrences after RPLND usually reflect inadequate primary surgery especially in the retrocaval and suprahilar region. Repeat RPLND is safe and effective in the majority of patients; however, it requires careful preoperative planning with regard to potential involvement of adjacent vascular and visceral structures making close interdisciplinary collaboration necessary in many cases. Repeat RPLND is a mandatory surgery to be performed at centres of expertise.

Background: Intravesical BCG installation is the standard of care in the prophylaxis of recurrent intermediate and high-risk transitional cell carcinoma (TCC), but its mode of action has not yet been elucidated. However, a Th-1 biased immune response is postulated Cell culture and animal models demonstrated the efficacy of synthetic CpG-oligodeoxynucleotides (ODN) as inducer and adjuvant for a strong Th1-response. The purpose of our study was to evaluate the antineoplastic effect of locally administered CpG ODN in a subcutaneous murine bladder cancer model., Materials and Methods: A subcutaneous murine TCC model was established in female C57/BL6 mice using the corresponding syngeneic MB49 TCC cell line. Three groups of 5 animals received a cell suspension, standardized for 1x10(6) cells/50 microl, injected s.c. into the right and left flank. Group I received 10 nmol of CpG-ODN only into the right cell depot. Group II received 10 nmol of GpC ODN. Group III served as untreated control and received only PBS. The animals were examined at various time points after injection until sacrifice on day 14. Tumor or scar tissue were excised, weighed and examined histopathologically (HE-stain)., Results: Tumor sizes and weights showed no side differences. The average tumor weight on day 14 was 171 mg (SD +/- 8.9), 110 mg (SD +/- 19.2) and 18 mg (SD +/- 6.1), respectively, in groups III, II and I (p<0.05). Histopathology revealed solid vital epithelial tumors in group III and reduced vital tumor mass with central necrosis and moderate mononuclear infiltration in group II. Group I showed almost complete tumor necrosis and a considerable mononuclear inflammatory response., Conclusion: Immunostimulatory DNA has promising antineoplastic activity in a murine subcutaneous TCC-model. The histological findings suggest an immunologically-mediated mode of action. Further investigations are necessary to elucidate the immunological response.

Various tumor markers for transitional cell carcinoma (TCC) of the bladder have been described, but none of them are used in clinical routine. Fibronectin, a glycoprotein, seems to play a very important role in both the progression and invasion of cancer. The aim of this study was to evaluate cellular fibronectin (cFN) in the urine and blood of patients with TCC of the bladder and to determine its possible role as a tumor marker and prognostic factor. Morning urine samples and blood were collected from 20 patients (8 women, 12 men, mean age 69.9 years) before they underwent transurethral resection of bladder tumors (TURB). Twenty patients (10 women, 10 men, mean age 63.4 years) with nonmalignant urological disorders were recruited as the control group. Determination of cFN in plasma and urine was performed by using a newly developed time-resolved fluorescence immunoassay (TRFIA). Patients with nonmalignant diseases had mean cFN plasma levels of 404 ng/ml (range 181-746 ng/ml). Patients with TCC of the bladder showed significantly higher cFN plasma levels of 686 ng/ml (range 274-1999 ng/ml, p<0.05). Subdivided according to the TNM system, muscle-invasive bladder tumors (n=5) demonstrated higher cFN plasma levels (mean 944 ng/ml) than superficial bladder tumors (n=15, mean 463 ng/ml). There were no differences of plasma cFN concentrations concerning tumor grade and also no differences in urine levels between the different groups. We found a significant difference (p<0.04) of cFN plasma levels between patients with TCC of the bladder and the control group. The difference in cFN plasma levels between pTa/pT1 and >or=pT2 tumors indicates a clinically useful potential of this tumor marker for preoperative staging and postoperative follow-up. Our data underline the important but still unclear role of cFN as a tumor marker in TCC, and this will be the focus of future studies.

Objectives: A new device for percutaneous nephrolithotomy, combining Lithoclast (LC) and ultrasound (US) lithotripsy, was developed. Under standardized in vitro conditions, we evaluated the efficacy of the new technique using artificial stones. Combined application of pneumatic and US lithotripsy was compared with each of the two components alone., Methods: Five different artificial stones of defined hardness were used. Disintegration was performed under defined pressure in a water bath. The time until the first fragmentation and until complete disintegration to fragments of 2 mm or smaller was measured for LC and US alone and for combined lithotripsy. Furthermore, the disintegrated partition after 1 minute and time until 50% disintegration of each stone was determined., Results: With regard to first fragmentation and complete disintegration, LC and US combination showed superior efficacy. First fragmentation was achieved 25 to 200 times faster and complete disintegration in a range of 11 to 15 minutes. No complete disintegration was possible by LC and US alone within a time limit of 20 minutes. The disintegrated stone mass after 1 minute was 1.5 to 4 times larger in combined lithotripsy and the 50% disintegration time was 30% to 50% compared with LC or US alone. No technical defects occurred., Conclusions: Combining LC and US in one device for percutaneous nephrolithotomy shows promising in vitro results in an artificial stone model. It seems to provide superior efficacy in the disintegration parameters important for clinical practice.

Up to now, clinical tumor-markers for renal cell carcinoma (RCC) have been lacking. Increased plasma levels of transforming growth factor-beta1 (TGF-beta1) were described as a tumor-marker and prognostic factor in RCC. The aim of this study was to test the clinical suitability of plasma TGF-beta1 as a tumor-marker for RCC. The concentrations of active and latent TGF-beta1 were determined in plasma of patients with localized (n = 39) and metastasised (n = 17) RCC. A newly developed, highly sensitive ELISA, which is specific for the isoform beta1, was used. Active TGF was directly measured in the EDTA plasma. To determine the amount of latent TGF-beta1, which is bound predominantly at beta2-macroglobulin, an optimized activation procedure was applied. Patients with localized RCC showed median concentrations of 16,700 ng/l (6,200-54,800 ng/l) for latent TGF-beta1. A total of 94 patients with various nonmalignant urological diseases were recruited as a control group. In comparison, this group had median concentrations of 19,900 ng/l (2,640-52,300 ng/l) for latent TGF-beta1. There was no significant difference (nonparametric Kruskal-Wallis ANOVA) between these groups. Patients with metastatic RCC showed median concentrations of 34,500 ng/l (6,800-48,960 ng/l) for latent TGF-beta1. In comparison to the localized RCC group, a statistically significant difference was found. Plasma levels after operative therapy (days 1, 5 and 10) and during follow-up without evidence of disease (2-6 months) showed no significant differences. Contrary to other study groups, our results suggest that TGF-beta1 is not a suitable tumor-marker for the diagnosis of localized RCC. In the face of higher TGF-beta1 plasma levels in metastatic disease, TGF-beta1 may be useful in the early detection of RCC recurrence or to control the success of immunochemotherapy.

Introduction: A total of 80-90% of all testicular masses are malignant germ cell tumors. Benign testicular lesions are recognized in approximately 10-20% enabling a testis-preserving surgery on the findings of frozen section examination (FSE). However, there are only sparse information with regard to the reliability of FSE in testicular tumors of uncertain dignity. Therefore, we retrospectively reviewed our experience concerning the reliability of FSE in primary testicular tumors by comparing each FSE result to the final diagnosis., Patients and Methods: From 1974 to 2000, 354 patients were operated on a testicular tumor. During inguinal exploration and after clamping of the spermatic cord and appropriate dressing, a representative biopsy of the tumor was taken and sent for FSE. In case of malignancy radical orchiectomy was performed, in case of benign findings or in case of a germ cell tumor in a solitary testicle, the tumor was enucleated. Slides of FSE and the permanent sections were reviewed and compared with regard to the histological diagnosis and presence/absence of malignancy., Results: Based on FSE, 317 tumors (89.5%) were found to be malignant ((100 seminomas (38.5%), 217 nonseminomas (61.5%)) and 37 tumors (10.5%) were benign (17 epidermoid cysts, 14 Leydig cell tumors, two cystadenomas, two simple cysts, two hemangiomas). Comparing FSE and definitive diagnosis, FSE correctly identified all malignant and benign lesions. There was a failure rate of 10 and 8% to differentiate seminomatous from nonseminomatous tumors and vice versa based on FSE, which, however, was irrelevant for the surgical management. Complications of the enucleations (n = 37) were: testicular atrophy in three cases, testicular hematoma in three cases, orchitis/epididymitis in one case. Not a single case disclosed a local relapse after a mean follow-up of 105 (12-240) months., Conclusions: Intraoperative FSE correctly identified all malignant and benign testicular masses including radical orchiectomy or organ-preserving surgery. Surgical management of testicular tumors based on FSE results is clinically practicable.

Introduction: Renal angiomyolipoma (RAML) is a benign tumor composed of varying amounts of mature adipose tissue, smooth muscle and thick-walled blood vessels. RAML tend to grow over time requiring active intervention due to serious associated complications, such as hemorrhage and pain. Although RAML is an ideal tumor for organ preservation, data concerning efficacy of nephron-sparing surgery (NSS) are sparse. The aim of the study was to evaluate the efficacy of NSS in RAML with regard to renal function, tumor recurrence and surgical feasibility., Patients and Methods: Charts of patients with pathologically confirmed RAML were reviewed and data recorded: tumor size, associated symptoms, intraoperative blood loss, serum creatinine, follow-up data with regard to tumor recurrence and long-term renal function. A total of 28 patients were identified with RAML who underwent NSS because of tumor size > 4 cm, pain and/or to rule out malignancy due to radiographic features of uncertain interpretation., Results: The median follow-up of all patients is 58 (3-114) months; median age was 55.6 (34-78) years, 24 patients were women, 4 patients were men. None of the patients developed a local recurrence. Median size of enucleated tumors was 5.5 (2.5-15) cm; indication for NSS was symptomatic tumor with hemorrhage in 4 patients (16%), prophylaxis of hemorrhage in 5 patients (20%) and radiographic features suspicious for malignancy in 16 patients (64%). In those cases, unenhanced and enhanced CT scans exhibit a hyperdense and a hypodense lesion as compared to the adjacent normal renal cortex, respectively. There were no intraoperative complications, median blood loss was 320 (50-1200) ml, none of the patients required blood transfusions. Post-operative course was uneventful in 26 patients (96%), 2 patients (7.1%) developed a urinary fistula managed by an endoluminal stent. Pre-operative serum creatinine was 0.9 (0.7-1.3) mg/dl, post-operative creatinine was 1.23 (0.7-1.5) mg/dl and serum creatinine at last follow-up was 0.95 (0.7-1.2) mg/dl., Conclusions: NSS can be performed with a high success rate in RAML when surgical management is indicated. Long-term follow-up reveals no local tumor recurrences and stable renal function even in patients with a solitary kidney.