The prominent role of the S100A8/S100A9-CD147 axis in the progression of penile cancer.

Currently, no established biomarkers are recommended for the routine diagnosis of penile carcinoma (PeCa). The rising incidence of this human papillomavirus (HPV)-related cancer entity highlights the need for promising candidates. The Calprotectin subunits S100A8 and S100A9 mark myeloid-derived suppressor cells in other HPV-related entities while their receptor CD147 was discussed to identify patients with PeCa at a higher risk for poor prognoses and treatment failure. We thus examined their expression using immunohistochemistry staining of PeCa specimens from 74 patients on tissue microarrays of the tumor center, the invasion front, and lymph node metastases. Notably, whereas the tumor center was significantly more intensively stained than the invasion front, lymph node metastases were thoroughly positive for both S100 subunits. An HPV-positive status combined with an S100A8+S100A9+ profile was related with an elevated risk for metastases. We observed several PeCa specimens with S100A8+S100A9+-infiltrating immune cells overlapping with CD15 marking neutrophils. The S100A8+S100A9+CD15+ profile was associated with dedifferentiated and metastasizing PeCa, predominantly of HPV-associated subtype. These data suggest a contribution of neutrophil-derived suppressor cells to the progression of HPV-driven penile carcinogenesis. CD147 was elevated, expressed in PeCa specimens, prominently at the tumor center and in HPV-positive PeCa cell lines. CD147+HPV+ PeCa specimens were with the higher-frequency metastasizing cancers. Moreover, an elevated expression of CD147 of HPV-positive PeCa cell lines correlated negatively with the susceptibility to IgA-based neutrophil-mediated tumor cell killing. Finally, stratifying patients regarding their HPV/S100A8/S100A9/CD15/CD147 profile may help identify patients with progressing cancer and tailor immunotherapeutic treatment strategies.

DKK1 inhibits canonical Wnt signaling in human papillomavirus-positive penile cancer cells.

Penile squamous cell cancer (PSCC) is the most frequent penile malignant disease. Infections with human papillomaviruses (HPV) are a major etiologic driver of PSCC. However, the molecular details of the underlying carcinogenesis are understudied because of rare clinical specimens and missing cell lines. Here, we investigated if the expression of high-risk HPV16 oncogenes causes an augmentation of the Wnt pathway using unique HPV-positive penile cancer (PeCa) cell lines in monolayer and organotypic 3D raft cultures as well as tissue micro arrays containing clinical tissue specimens. The HPV oncoproteins enhanced the expression of Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and the HPV-positive PeCa cells expressed a signature of Wnt target and stemness-associated genes. However, the notable lack of nuclear ß-catenin in vitro and in situ raised the question if the enhanced expression of Wnt pathway factors is tantamount to an active Wnt signaling. Subsequent TOP-flash reporter assays revealed Wnt signaling as absent and not inducible by respective Wnt ligands in PeCa cell lines. The HPV-positive PeCa cells and especially HPV-positive PeCa specimens of the tumor core expressed the Wnt antagonist and negative feedback-regulator Dickkopf1 (DKK1). Subsequent neutralization experiments using PeCa cell line-conditioned media demonstrated that DKK1 is capable to impair ligand-induced Wnt signaling. While gene expression analyses suggested an augmented and active canonical Wnt pathway, the respective signaling was inhibited due to the endogenous expression of the antagonist DKK1. Subsequent TMA stainings indicated Dkk1 as linked with HPV-positivity and metastatic disease progression in PeCa suggesting potential as a prognostic marker.

The HPV and p63 Status in Penile Cancer Are Linked with the Infiltration and Therapeutic Availability of Neutrophils.

Squamous penile cancer displays a rare human papillomavirus (HPV)-associated tumor entity. Investigations on the molecular pathogenesis of HPV-driven penile cancer are impaired by the rareness of clinical specimens and, in particular, are missing relevant cell culture models. Here, we identified in HPV-positive penile cancer cell lines that HPV16 oncoproteins control TP63 expression by modulating critical regulators, while integration into the TP63 open reading frame facilitates oncogene expression. The resulting feed-forward loop leads to elevated p63 levels that in turn enhance the release of the neutrophil-recruiting chemokine CXCL8. Remarkably, elevated CXCL8 amounts lead to the increased surface exposition of the Fc receptor of human IgA antibodies, FcαRI, on neutrophils and correlated with a higher susceptibility to antibody-dependent neutrophil-mediated cytotoxicity (ADCC) using an EGFR-specific IgA2 antibody. IHC staining of tissue microarrays proved that elevated expression of p63 together with neutrophil infiltration were significantly more frequent in HPV-positive penile cancer displaying a higher tumor grade. In summary, we identified a promising marker profile of patients with penile cancer at higher risk for worse prognosis. However, these patients may benefit from immunotherapeutic approaches efficiently engaging neutrophils for tumor cell killing.

Patient Selection in Surgical Centers of Expertise in the Treatment of Patients with Moderate to Severe Male Urinary Stress Incontinence.

OBJECTIVE: To analyze decision-making in patients with male urinary incontinence (SUI) in centers of expertise. The artificial urinary sphincter (AUS) remains the gold standard for male patients with moderate to severe SUI but adjustable male slings are a minimally invasive treatment option with good results, hence without a high level of evidence regarding the optimal patient selection. MATERIALS AND METHODS: In total, 220 patients (88 AUS; 132 adjustable slings) were investigated from the DOMINO database that underwent surgery between 2010 and 2012 in 5 urological departments that offer adjustable sling systems as well as AUS systems for patients with moderate to severe urinary incontinence. For statistical analysis, the Mann-Whitney U test was used to identify differences between both groups. RESULTS: Patients selected for an adjustable male sling were less likely to have a neurological disease (5.3 vs. 9.1%; p = 0.030), a prior urethral stricture (22.7 vs. 50.0%; p = 0.001), a prior incontinence surgery (24.4 vs. 45.5%; p = 0.01), or a prior radiation therapy (26.5 vs. 40.1%; p = 0.001). The severity of preoperative incontinence was higher in patients selected for an AUS with a mean pad usage per day of 7.60 versus 5.80 (p < 0.001). Mean postoperative pad usage and patients' subjective perception were comparable in both groups. CONCLUSION: In centers offering both options, the decision-making is mainly based upon presence of radiation therapy and previous failed incontinence surgery. Despite the more complex patient cohort selected for an AUS implantation with a possible impact on the postoperative outcome, the functional results seem to be comparable indicating a proper preoperative patient assessment and selection in this cohort.

Secondary Sling Implantation after Failure of Primary Surgical Treatment for Male Stress Urinary Incontinence: A Retrospective Study.

OBJECTIVE: The artificial urinary sphincter (AUS) is the surgical gold standard after previously failed surgical treatment for male urinary stress incontinence. The evidence for a male sling as salvage treatment is poor, but there is a proportion of patients that refuse implantation of an AUS or have a relative contraindication. The goal of our retrospective study was an analysis of outcome and complications of patients with a secondary sling after previously failed surgery for stress urinary incontinence (SUI). MATERIALS AND METHODS: Data on 186 patients who had a prior incontinence surgery were extracted from the DOMINO database. 139 patients (74.7%) received an AUS and 41 patients (22.0%) who had received a secondary sling system between 2010 and 2012 after previously failed surgery for male urinary incontinence could be identified and were further analyzed. RESULTS: Eight patients (19.5%) received a secondary repositioning sling and 33 patients (80.5%) received a secondary adjustable sling system. A prior surgery for urethral stricture was performed in 4 patients (9.8%). No major intraoperative complications were reported. A simultaneous explantation was performed in 12 patients (29.3%). The mean number of pad reductions was 4.93 (p = 0.026). No intraoperative complications and no postoperative surgical revisions were reported. The mean follow-up of the patient cohort with a secondary sling was 16 months. CONCLUSION: We provide the largest cohort of male patients up to date with a secondary sling after primary failure of surgery for male SUI. Although the procedure is a rarely performed surgery and without a high level of evidence, a secondary adjustable male sling system might be a feasible option in selected patients with acceptable complication rates, whereas a valuable outcome regarding continence rates cannot be sufficiently supplied by our data.

Retropubic vs transobturator Argus adjustable male sling: Results from a multicenter study.

AIMS: To comparatively analyse outcomes after ARGUS classic and ArgusT adjustable male sling implantation in a real-world setting. METHODS: Inclusion criteria encompassed: non-neurogenic, moderate-to-severe stress urinary incontinence (≥2 pads), implantation of an ARGUS classic or ArgusT male sling between 2010 and 2012 in a high-volume center (>150 previous implantations). Functional outcomes were assessed using daily pad usage, 24-hour pad testing, and International Consultation on Incontinence (ICIQ-SF) questionnaires. Continence was defined as zero pads per 24 hours. Complications were graded using Clavien-Dindo scale. For multivariate analysis, binary logistic regression models were used (P < .05). RESULTS: A total of 106 patients (n = 74 [ARGUS classic], n = 32 [ArgusT]) from four centers were eligible. Median follow-up was 44.0 months (24-64). Patient cohorts were well-balanced. We observed a statistical trend in favor of ARGUS classic regarding postoperative urine loss based on standardized 24-hour pad test (71 ± 162 g [ARGUS classic] vs 160 ± 180 g [ArgusT]); P = .066]. Dry rates were 33.3% (ARGUS classic) and 11.8% (ArgusT, P = .114). In multivariable analysis, ArgusT male sling could not be confirmed as an independent predictor of decreased success (OR, 0.587; 95% CI; 0.166-2.076, P = .408). There were no Clavien IV and V complications. Inguinal pain was significantly higher after ArgusT implantation (P = .033). Explantation rates were higher for ArgusT compared to ARGUS classic (14.0 vs 23.3%; P = .371). Longer device survival for the ARGUS classic male sling was observed in Kaplan-Meier analysis (P = .198). CONCLUSIONS: In the largest comparative analysis of ARGUS classic and ArgusT male sling with the longest follow-up to date, we observed low continence rates with superior functional outcomes and decreased explantation rates after ARGUS classic implantation.

The Diagnosis and Treatment of Penile Cancer.

BACKGROUND: The incidence of penile cancer in Europe lies in the range of 0.9 to 2.1 cases per 100 000 persons per year. Carcinogenesis is associated with human papilloma virus (HPV) infection and with chronic inflammation. METHODS: This review is based on publications (2010-2017) retrieved by a selective search in PubMed and EMBASE and on the guidelines of the European Association of Urology, the European Society of Medical Oncology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence (NICE). RESULTS: 95% of cases of penile cancer are accounted for by squamous cell carcinoma, whose numerous subtypes have different clinical courses. Chronic preputial inflammation due to phimosis or lichen sclerosus is often associated with penile cancer. Circumcision lowers the risk of penile cancer (hazard ratio: 0.33). Maximally organ-preserving surgery with safety margins of no more than a few millimeters is the current therapeutic standard, because a local recurrence, if it arises, can still be treated locally with curative intent. Local radiotherapy can be performed in early stages. Lymphogenic metastasis must be treated with radical lymphadenectomy and adjuvant chemotherapy. Patients with clinically unremarkable inguinal lymph nodes nonetheless need invasive lymph node staging because of the high rate of lymphogenic micrometastasis. CONCLUSION: Penile cancer is curable in all early stages with the appropriate treatment, but its prognosis depends crucially on the proper management of the regional (i.e., inguinal) lymph nodes. In many countries, the treatment of this rare disease entity has been centralized.

The TiLOOP® Male Sling: Did We Forejudge.

INTRODUCTION: To evaluate the safety and efficacy of the TiLOOP® male sling (pfm medical, Cologne, Germany) used in the treatment for male stress urinary incontinence (SUI). MATERIAL AND METHODS: We retrospectively evaluated a total of 34 patients with a TiLOOP® male sling. Perioperative complication rates were assessed and validated questionnaires were prospectively evaluated to assess quality of life and satisfaction rate. Outcome and complication rates were analysed by using descriptive statistics. Correlation of continence outcome and risk factors was performed with the chi-square test. A p value below 0.05 was considered statistically significant. RESULTS: The majority of patients (70.6%) were diagnosed with mild or moderate male SUI. During surgery, one instance (2.9%) of intraoperative urethral injury was observed. There were no immediate postoperative complications. The mean follow-up time was 44.6 months. An improvement of male SUI was reported by 61.9% of the patients and 38.1% reported no change according the Patient Global Impression of Improvement. The mean perineal pain score was 0.5 according to the international index of pain. CONCLUSIONS: The TiLOOP® is a safe treatment option for male SUI in our cohort with a low complication rate. However, the functional outcome of the TiLOOP® was inferior when compared to the outcome of the AdVance® male sling.

Evaluation of the diagnostic value of preoperative sentinel lymph node (SLN) imaging in penile carcinoma patients without palpable inguinal lymph nodes via single photon emission computed tomography/computed tomography (SPECT/CT) as compared to planar scintigraphy.

BACKGROUND: Sentinel lymph node (SLN) biopsy represents a well-established diagnostic tool for the assessment of lymphatic metastasis. Correct pre- and intraoperative visualization of SLN is of the utmost importance to ensure the safety and feasibility of the procedure. Aim of this study was to evaluate the diagnostic value of preoperative SLN imaging via single photon emission computed tomography/computed tomography (SPECT/CT) and planar scintigraphy in patients with penile carcinoma with nonpalpable inguinal lymph nodes. MATERIALS AND METHODS: After peritumoral intradermal tracer injection (150MBq/4.05mCi Tc-99m nanocolloid), we acquired planar scintigraphies including indirect body contouring using a twin head gamma camera. Subsequently we acquired SPECT/CT images of the abdomen via a hybrid system. Prospective evaluation of 52 groins in 26 examined patients was done for all image files obtained with both techniques by 2 trained experts in consensual assessment. RESULTS: A total of 71 SLNs in 37 groins were identified by means of planar scintigraphy. In these images, no radiolabeled lymph nodes were visualized in 15 out of 52 groins (28.8%). The SPECT/CT images showed a total of 82 SLNs in 42 groins. In 19.2% (10 of the 52 groins), there was no visualization of lymph nodes in SPECT/CT. 8 SLNs in 7 groins that were visualized in the planar technique were found to be false positive by SPECT/CT. In total, 19 SLNs in 16 groins that were overlooked by planar imaging could only be detected by SPECT/CT. In contrast to planar scintigraphy, SPECT/CT imaging enabled clear and precise anatomical localization of SLNs in all 42 groins where radiolabeled SLNs were visible. Even under consideration of all lymphatic drainage regions, statistical evaluation showed a significantly higher number of detected SLNs with SPECT/CT in comparison to the planar technique (P = 0.0022). CONCLUSION: In these patients SPECT/CT is capable of visualizing SLNs that cannot be detected with planar imaging. The SPECT/CT technique reduces the number of false positive findings from planar SLN imaging and is able to show anatomic SLN localization more precisely. If possible, preoperative SLN imaging should be performed by means of the SPECT/CT technique in patients with this tumor entity.

Risk Factors for Failure of Male Slings and Artificial Urinary Sphincters: Results from a Large Middle European Cohort Study.

INTRODUCTION: We analysed the impact of predefined risk factors: age, diabetes, history of pelvic irradiation, prior surgery for stress urinary incontinence (SUI), prior urethral stricture, additional procedure during SUI surgery, duration of incontinence, ASA-classification and cause for incontinence on failure and complications in male SUI surgery. MATERIALS AND METHODS: We retrospectively identified 506 patients with an artificial urinary sphincter (AUS) and 513 patients with a male sling (MS) in a multicenter cohort study. Complication rates were correlated to the risk factors in univariate analysis. Subsequently, a multivariate logistic regression adjusted to the risk factors was performed. A p value <0.05 was considered statistically significant. RESULTS: A history of pelvic irradiation was an independent risk factor for explantation in AUS (p < 0.001) and MS (p = 0.018). Moreover, prior urethral stricture (p = 0.036) and higher ASA-classification (p = 0.039) were positively correlated with explantation in univariate analysis for AUS. Urethral erosion was correlated with prior urethral stricture (p < 0.001) and a history of pelvic irradiation (p < 0.001) in AUS. Furthermore, infection was correlated with additional procedures during SUI surgery in univariate analysis (p = 0.037) in MS. CONCLUSIONS: We first identified the correlation of higher ASA-classification and explantation in AUS. Nevertheless, only a few novel risk factors had a significant influence on the failure of MS or AUS.

A study on the value of computer-assisted assessment for SPECT/CT-scans in sentinel lymph node diagnostics of penile cancer as well as clinical reliability and morbidity of this procedure.

BACKGROUND: Because of the increasing importance of computer-assisted post processing of image data in modern medical diagnostic we studied the value of an algorithm for assessment of single photon emission computed tomography/computed tomography (SPECT/CT)-data, which has been used for the first time for lymph node staging in penile cancer with non-palpable inguinal lymph nodes. In the guidelines of the relevant international expert societies, sentinel lymph node-biopsy (SLNB) is recommended as a diagnostic method of choice. The aim of this study is to evaluate the value of the afore-mentioned algorithm and in the clinical context the reliability and the associated morbidity of this procedure. METHODS: Between 2008 and 2015, 25 patients with invasive penile cancer and inconspicuous inguinal lymph node status underwent SLNB after application of the radiotracer Tc-99m labelled nanocolloid. We recorded in a prospective approach the reliability and the complication rate of the procedure. In addition, we evaluated the results of an algorithm for SPECT/CT-data assessment of these patients. RESULTS: SLNB was carried out in 44 groins of 25 patients. In three patients, inguinal lymph node metastases were detected via SLNB. In one patient, bilateral lymph node recurrence of the groins occurred after negative SLNB. There was a false-negative rate of 4 % in relation to the number of patients (1/25), resp. 4.5 % in relation to the number of groins (2/44). Morbidity was 4 % in relation to the number of patients (1/25), resp. 2.3 % in relation to the number of groins (1/44). The results of computer-assisted assessment of SPECT/CT data for sentinel lymph node (SLN)-diagnostics demonstrated high sensitivity of 88.8 % and specificity of 86.7 %. CONCLUSIONS: SLNB is a very reliable method, associated with low morbidity. Computer-assisted assessment of SPECT/CT data of the SLN-diagnostics shows high sensitivity and specificity. While it cannot replace the assessment by medical experts, it can still provide substantial supplement and assistance.

10-Year experience regarding the reliability and morbidity of radio guided lymph node biopsy in penile cancer patients and the associated radiation exposure of medical staff in this procedure.

BACKGROUND: The guidelines of the European Association of Urologists (EAU), of the German Society of Nuclear Medicine (DGN), and the European Society for Medical Oncology (ESMO) recommend sentinel lymph node biopsy (SLNB) for lymph node staging in penile cancer with non-palpable inguinal lymph nodes as one diagnostic method. Despite this, the method is neither widely nor regularly applied in Germany - the same applies to many other countries, which may be due to insecurity in dealing with open radioactive tracers. This study aims to assess the reliability and morbidity of this method, as well as the associated radioactive burden for clinical staff. METHODS: Between 2006 and 2016, 34 patients with an invasive penile carcinoma and inconspicuous inguinal lymph node status underwent SLNB in 57 groins after application of a radiotracer (Tc-99 m nanocolloid). We collected the results prospectively. The reliability of the method was assessed by determining the false-negative rate. In addition, we evaluated complication rates and determined the radioactive burden for the clinical staff both pre- and intraoperatively. RESULTS: SLNB was performed in 34 patients with penile cancer with non-palpable inguinal lymph nodes in 57 groins. In two patients inguinal lymph node metastases were detected by means of SLNB. In one patient recurrent inguinal lymph node disease was found after negative SLNB in both groins. Thus, the false negative rate was 3.13 % per patient (1/32 patients) and 3.51 % per groin (2/57 groins). The morbidity rate was 2.94 % per patient (1/34 patients) and 1.75 % per groin (1/57 groins). Radiation exposure for the clinical staff during this procedure was low at a maximum of ca. four µSV per intervention. CONCLUSIONS: SLNB is a reliable method with low morbidity that is associated with a low radiation burden for clinical staff. Due to the enhanced methodological and logistic demands, this intervention should be performed in specialized centres and in an interdisciplinary approach.

Value and efficiency of sentinel lymph node diagnostics in patients with penile carcinoma with palpable inguinal lymph nodes as a new multimodal, minimally invasive approach.

PURPOSE: The international guidelines recommend sentinel lymph node biopsy (SLNB) for lymph node staging in penile cancer with non-palpable inguinal lymph nodes (LN) but it is not recommended with palpable inguinal LN. The aim of this study was to evaluate the reliability and morbidity of SLNB in combination with an ultrasound-guided resection of suspect inguinal LNs as a new multimodal, minimally invasive staging approach in these patients. METHODS: We performed SLNB in 26 penile cancer patients with 42 palpable inguinal LNs. Prior to the combined staging procedures the patients underwent an ultrasound examination of the groins as well as planar lymphatic drainage scintigraphy and SPECT/CT scans. During the surgical procedure, the radioactive-labelled sentinel lymph nodes and, in addition, sonographically suspect LNs, were resected under ultrasound guidance. Follow-up screening was done by ultrasound examination of the groins according to the guidelines of the European Association of Urology. RESULTS: Nineteen groins of 42 preoperatively palpable inguinal findings were histologically tumor-positive. SLNB alone showed lymphogenic metastases in 14 groins. Sonography revealed five further metastatic groins, which would not have been detected during SLNB due to a tumor-related blockage of lymphatic drainage or a so-called re-routing of the tracer. During follow-up, none of the 28 groins with tumor-negative LN status showed any LN recurrence in this combined investigation technique. The median follow-up period was 46 (24 to 92) months. Morbidity of this procedure was low at 4.76 % in relation to the number of groins resp. 7.69 % in relation to the number of patients. CONCLUSIONS: The results show that this combined procedure is a reliable multimodal diagnostic approach for treatment of penile cancer patients with palpable inguinal LNs. It is associated with low morbidity rates. SLNB alone would lead to a significantly higher false-negative rate in these patients. The encouraging results of this work can extend the range of indications for nuclear medicine in the form of SLNB using radioactive tracers in this patient group.

Complications and Short-Term Explantation Rate Following Artificial Urinary Sphincter Implantation: Results from a Large Middle European Multi-Institutional Case Series.

UNLABELLED: Background/Aims/Objectives: To analyze perioperative complication and short-term explantation rates after perineal or penoscrotal single-cuff and double-cuff artificial urinary sphincter (AUS) implantation in a large middle European multi-institutional patient cohort. METHODS: 467 male patients with stress urinary incontinence underwent implantation of a perineal single-cuff (n = 152), penoscrotal single-cuff (n = 99), or perineal double-cuff (n = 216) AUS between 2010 and 2012. Postoperative complications and 6-month explantation rates were assessed. For statistical analysis, Fisher's exact test and Kruskal-Wallis rank sum test, and a multiple logistic regression model were used (p < 0.05). RESULTS: Compared to perineal single-cuff AUS, penoscrotal single-cuff implantation led to significantly increased short-term explantation rates (8.6% (perineal) vs. 19.2% (penoscrotal), p = 0.019). The postoperative infection rate was significantly higher after double-cuff compared to single-cuff implantation (6.0% (single-cuff) vs. 13.9% (double-cuff), p = 0.019). The short-term explantation rate after primary double-cuff placement was 6.5% (p = 0.543 vs. perineal single-cuff). In multivariate analysis, the penoscrotal approach (p = 0.004), intraoperative complications (p = 0.005), postoperative bleeding (p = 0.011), and perioperative infection (p < 0.001) were independent risk factors for short-term explantation. CONCLUSIONS: Providing data from a large contemporary multi-institutional patient cohort from high-volume and low-volume institutions, our results reflect the current standard of care in middle Europe. We indicate that the penoscrotal approach is an independent risk factor for increased short-term explantation rates.

Value and Efficacy of Sentinel Lymph Node Diagnostics in Patients With Penile Carcinoma With Nonpalpable Inguinal Lymph Nodes: Five-Year Follow-up.

PURPOSE: Sentinel lymph node biopsy (SLNB) has been described as a minimally invasive method for lymph node staging in patients with a penile carcinoma and nonpalpable inguinal nodes in national and international guidelines of involved professional societies. However, this method is rarely used. The aim of this study was to validate reliability and morbidity of this method and to discuss radiation exposure of persons involved. METHODS: Twenty-eight patients with histologically negative sentinel lymph nodes in 47 groins with nonpalpable inguinal lymph nodes were included in this study (17 T1(a/b)-, 8 T2- and 3 T3-stages). We recorded prospectively all cases of lymph node recurrence and complications in patients with initially nonpalpable inguinal lymph nodes and histologically negative sentinel lymph nodes. False-negative findings and morbidity were calculated as qualitative criteria. Inguinal regions with palpable lymph nodes and/or evidence of metastases were not considered in accordance with the guidelines. RESULTS: During a median follow-up of 68 (4-131) months, we observed one case of bilateral lymph node recurrence and one case of prolonged inguinal lymphorrhea, which could be managed conservatively. Per inguinal region, false-negative rate was 4.25%, and morbidity rate was 2.12%; seen per patient, the rates were both 3.57%. CONCLUSIONS: Sentinel lymph node biopsy under use of radioactive tracers is a reliable method of lymph node staging in patients with penile carcinoma and nonpalpable inguinal lymph nodes. The methodical complexity is justified by high reliability and low radiation exposure for both patient and medical staff and low morbidity rates.

Reliability of dynamic sentinel node biopsy combined with ultrasound-guided removal of sonographically suspicious lymph nodes as a diagnostic approach in patients with penile cancer with palpable inguinal lymph nodes.

INTRODUCTION AND OBJECTIVES: Dynamic sentinel node biopsy (DSNB) is considered "unsuitable" in patients with penile cancer and palpable inguinal lymph nodes. The aim of this study was to determine the diagnostic reliability of DSNB combined with ultrasound (US)-guided removal of additional suspicious lymph nodes as a minimally invasive diagnostic approach in these patients. MATERIAL AND METHODS: A total of 23 consecutive patients with penile cancer and unilaterally or bilaterally palpable inguinal lymph nodes underwent DSNB according to the 2-day protocol. Before the combined staging procedure, the patients underwent preoperative US of both groins. During surgery, sentinel nodes and additional suspicious lymph nodes as determined by the US examination were removed under US guidance. A complete inguinal lymph node dissection was only performed in patients who had tumor-positive nodes. Follow-up consisted of control visits according to the European Association of Urology guidelines, including US investigation of the groins. RESULTS: The primary tumors were staged as T1, T2, and T3 carcinomas in 12, 8, and 3 patients, respectively. Grading was good, moderate, and poor in 2, 16, and 4 cases, respectively. Tumor grading could not be determined in 1 patient who underwent surgery of the invasive part of the primary tumor elsewhere. Sentinel nodes or nonsentinel nodes or both were positive in 15 of 36 palpatory-positive groins. DSNB alone showed lymphatic spread in 10 inguinal regions. US-guided removal of suspicious nonsentinel nodes revealed 5 further inguinal basins with metastases, which would have been missed by DSNB owing to rerouting or complete blockage of the lymphotropic tracer. So far, no lymph node relapse has been observed in the 12 patients with node-negative disease by this combined diagnostic approach with a median follow-up of 42 (16-84) months. The morbidity (postoperative bleeding and prolonged lymphorrhea) associated with this procedure was minor (6%). CONCLUSIONS: The results of this study imply that DSNB combined with US-guided removal of suspicious lymph nodes is a reliable diagnostic approach in patients with penile cancer with palpable inguinal lymph nodes. DSNB alone in these patients leads to a significant false-negative rate. These early and promising results have to be confirmed in larger cohort studies.

[Robot-assisted surgery in visceral and thoracic surgery gynaecology, urology--importantanaesthetic considerations]. / Roboterassistierte Operationen in Viszeral- und Thoraxchirurgie, Gynäkologie und Urologie - Was ist relevant für die Anästhesieführung?

Robot-assisted surgery, as a development of laparoscopic surgery, has an increasing field of application. Beside urology, this technique has also been implemented in visceral and thoracic surgery and gynaecology. For the surgeon an enhanced view of the surgical field and a better mobility of the instruments are the most important advantages. Thus, it is possible to work more accurate and prevent inadvertent tissue damage. For the anaesthesiologist several characteristics are of importance. Limited access to the patient as a result of a special positioning requires adequate anaesthetic preparation. For many visceral and thoracic surgical interventions the head and airway of the patient is bedded remote from the anaesthesiologist. Therefore, a standardised order and protection of all i. v.-lines, cables and the ventilation-hose of the (double-lumen) tube is essential. After the roboter is connected to the patient, it is nearly impossible to change or extend patient monitoring. Especially in case of emergency, e. g. respiratory complications or heart failure, a close communication with the surgeon and a team approach are indispensable.

Establishment and characterization of primary cell lines of squamous cell carcinoma of the penis and its metastasis.

PURPOSE: We established cell lines from penile squamous cell carcinoma and its lymph node metastasis, and investigated the role of chemokines, chemokine receptors and podoplanin in cancer progression. MATERIALS AND METHODS: Tumor specimen of primary tumors, and lymph node and distant metastases were cultured in vitro and xenotransplanted in SCID beige mice. Specimens were analyzed by hematoxylin and eosin staining, and immunohistochemistry. Comparative screening for chemokines, chemokine receptors and podoplanin was done by polymerase chain reaction, fluorescence activated cell sorting and enzyme-linked immunosorbent assay. RESULTS: We established 2 cell lines from a primary tumor and its corresponding lymph node metastasis, respectively. Heterotopic xenotransplantation revealed reliable tumor growth in vivo. Morphological and immunohistological analysis showed comparable features for human tumors, cell lines in vitro and xenotransplanted tumors in mice regarding the primary tumor and metastasis. Comprehensive analysis of chemokines and chemokine receptors in the metastasis derived cell line and in the cell line originating from the primary tumor revealed the most pronounced changes for CXCL14. This pattern was confirmed on the protein level. Comparative analysis of podoplanin showed marked down-regulation in the metastatic variant on the mRNA and protein levels. CONCLUSIONS: To our knowledge we established the first pair of cell lines of a human primary penile tumor and the corresponding lymph node metastasis. These cell lines offer unique possibilities for further comparative functional investigations in in vitro and in vivo settings. They enable studies of new potential therapeutic agents and other assays to better understand the molecular mechanisms of penile cancer progression.

Microvessel density as a prognostic factor in penile squamous cell carcinoma.

OBJECTIVE: To examine the potential effect of tumor-induced angiogenesis in squamous cell carcinoma of the penis as a possible prognostic factor. PATIENTS AND METHODS: Immunohistochemistry was preformed to detect microvessels in tumor samples of 64 patients with squamous cell carcinoma of the penis. We used a monoclonal mouse antibody directed against CD34 antigen. Only 61 (30 with and 31 without metastasis) patients had good staining properties and were included. After immunostaining, the entire tumor section was scanned microscopically at low power (× 40) to identify hot spots within the tumor and at its periphery. Individual tumor microvessels were then counted under high power (× 200) to obtain a vessel count in a defined area, and the mean of the 3 highest microvessel counts was taken as the microvessel density (MVD). Microvessel counting was performed using a computer-aided image analysis system. The nodal status was based on histopathologic examination or an uneventful follow-up ≥ 2 years. RESULTS: The 5-year overall survival (OAS) was 75% and 30 % for those with high and low peritumoral MVD, respectively (log rank P = 0.01). No difference was noticed within the tumor with regard to high (5-year OAS of 65.03%) and low (5-year OAS of 60.56%) intratumoral MVD (log rank P = 0.99). The mean intratumoral MVD was 32.35 (3.16), 37.94 (3.35), and 62.66 (5.47) in T1, T2, and T3 respectively (ANOVA P = 0.0006), with increasing tendency. The mean peritumoral MVD was 55.91 (5.60), 56.8 (4.00), and 78.86 (8.71), respectively (P = 0.06). No correlation between MVD lymph node status and tumor grade was seen (P > 0.05). CONCLUSION: In our group of patients, a high peritumoral MVD was associated with a better 5-year OAS. However, for a reliable and reproducible assessment of tumor angiogenesis in penile squamous cell carcinoma, validation procedures and quality control protocols are mandatory.

Management of recurrent post-prostatectomy incontinence after previous failed retrourethral male slings.

OBJECTIVE: Our objective was to establish the feasibility of combining 2 minimally invasive procedures in patients with failed primary treatment (male sling) in post-prostatectomy incontinence (PPI) patients. METHODS: From January 2007 to July 2008, 40 men with PPI were implanted with a suburethral tape (2 patients with Seratim, 3 with I-Stop and 35 with Advance). The median preoperative pad count was 4 (range 2-10). Prior to sling placement, 6 patients had undergone ProACT implantation. Of these, 4 patients required explantation due to balloon migration and 2 patients had their balloons kept in situ, with the balloons deflated. RESULTS: Twenty-five patients were socially continent at this time. Fifteen patients (37.5%) did not improve or their improvement was not significant. These patients had a preoperative pad count between 7 and 10. Two of these patients had prostate adjustable continence therapy (ProACT) systems still in place. By gradually filling the balloons to 3 mL, both of these patients achieved complete continence, which was maintained at a mean follow-up of 8.5 months. Three patients with prior pelvic irradiation received an artificial urinary sphincter and achieved continence at mean follow-up of 8.3 months. The remaining 10 patients received a ProACT system in addition to the already implanted sling. After appropriate healing and filling of the balloons (average balloon volume 5 mL), all 10 patients reached complete continence; they were pad-free at a mean follow-up of 6 months (range 3-9). CONCLUSIONS: The combination of ProACT and a suburethral tape was demonstrated to be a possible treatment option in recurrent or persistent PPI.