Increased HRD score in cisplatin resistant penile cancer cells.

BACKGROUND/INTRODUCTION: Penile cancer is a rare disease in demand for new therapeutic options. Frequently used combination chemotherapy with 5 fluorouracil (5-FU) and cisplatin (CDDP) in patients with metastatic penile cancer mostly results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance against standard therapy could help to understand molecular mechanisms underlying chemotherapy resistance and to identify candidate treatments for an efficient second line therapy. METHODS: We generated a cell line from a humanpapilloma virus (HPV) negative penile squamous cell carcinoma (UKF-PEC-1). This cell line was subject to chronic exposure to chemotherapy with CDDP and / or 5-FU to induce acquired resistance in the newly established chemo-resistant sublines (PEC-1rCDDP2500, adapted to 2500 ng/ml CDDP; UKF-PEC-1r5-FU500, adapted to 500 ng/ml 5- FU; UKF-PEC1rCDDP2500/r5-FU500, adapted to 2500 ng/ml CDDP and 500 ng/ml 5 -FU). Afterwards cell line pellets were formalin-fixed, paraffin embedded and subject to sequencing as well as testing for homologous recombination deficiency (HRD). Additionally, exemplary immunohistochemical stainings for p53 and gammaH2AX were applied for verification purposes. Finally, UKF-PEC-1rCDDP2500, UKF-PEC-1r5-FU500, UKF-PEC1rCDDP2500/r5-FU500, and UKF-PEC-3 (an alternative penis cancer cell line) were tested for sensitivity to paclitaxel, docetaxel, olaparib, and rucaparib. RESULTS AND CONCLUSIONS: The chemo-resistant sublines differed in their mutational landscapes. UKF-PEC-1rCDDP2500 was characterized by an increased HRD score, which is supposed to be associated with increased PARP inhibitor and immune checkpoint inhibitor sensitivity in cancer. However, UKF-PEC-1rCDDP2500 did not display sensitivity to PARP inhibitors.

The routine use of LCD-Array hybridisation technique for HPV subtyping in the diagnosis of penile carcinoma compared to other methods.

BACKGROUND: Routine human papillomavirus (HPV) testing is performed in cervival cancer and is required for classification of some head and neck cancers. In penile cancer a statement on HPV association of the carcinoma is required. In most cases p16 immunohistochemistry as a surrogate marker is applied in this setting. Since differing clinical outcomes for HPV positive and HPV negative tumors are described we await HPV testing to be requested more frequently by clinicians, also in the context of HPV vaccination, where other HPV subtypes are expected to emerge. METHOD: Therefore, a cohort of archived, formalin-fixed paraffin embedded (FFPE) penile neoplasias was stained for p16 and thereafter tested for HPV infection status via PCR based methods. Additionally to Sanger sequencing, we chose LCD-Array technique (HPV 3.5 LCD-Array Kit, Chipron; LCD-Array) for the detection of HPV in our probes expecting a less time consuming and sensitive HPV test for our probes. RESULTS: We found that LCD-Array is a sensitive and feasible method for HPV testing in routine diagnostics applicable to FFPE material in our cohort. Our cohort of penile carcinomas and carcinomas in situ was associated with HPV infection in 61% of cases. We detected no significant association between HPV infection status and histomorphological tumor characteristics as well as overall survival. CONCLUSIONS: We showed usability of molecular HPV testing on a cohort of archived penile carcinomas. To the best of our knowledge, this is the first study investigating LCD-Array technique on a cohort of penile neoplasias.

Influence of Body Mass Index on Clinical Outcome Parameters, Complication Rate and Survival after Radical Cystectomy: Evidence from a Prospective European Multicentre Study.

Background/Aims/Objectives: To evaluate the influence of body mass index (BMI) on complications and oncological outcomes in patients undergoing radical cystectomy (RC). METHODS: Clinical and histopathological parameters of patients have been prospectively collected within the "PROspective MulticEnTer RadIcal Cystectomy Series 2011". BMI was categorized as normal weight (<25 kg/m2), overweight (≥25-29.9 kg/m2) and obesity (≥30 kg/m2). The association between BMI and clinical and histopathological endpoints was examined. Ordinal logistic regression models were applied to assess the influence of BMI on complication rate and survival. RESULTS: Data of 671 patients were eligible for final analysis. Of these patients, 26% (n = 175) showed obesity. No significant association of obesity on tumour stage, grade, lymph node metastasis, blood loss, type of urinary diversion and 90-day mortality rate was found. According to the -American Society of Anesthesiologists score, local lymph node (NT) stage and operative case load patients with higher BMI had significantly higher probabilities of severe complications 30 days after RC (p = 0.037). The overall survival rate of obese patients was superior to normal weight patients (p = 0.019). CONCLUSIONS: There is no evidence of correlation between obesity and worse oncological outcomes after RC. While obesity should not be a parameter to exclude patients from cystectomy, surgical settings need to be aware of higher short-term complication risks and obese patients should be counselled -accordingly.

Prostate Cancer on the Web-Expedient Tool for Patients' Decision-Making?

Many patients diagnosed with cancer search for health information on the Web. We aimed to assess the quality and reliability of online health information on prostate cancer. Google, Yahoo, and Bing were searched for the term "prostate cancer." After selecting the most frequented websites, quality was measured by DISCERN score, JAMA benchmark criteria, and presence of HONcode certification. Popularity was assessed by Alexa tool, while accessibility, usability, and reliability were investigated by LIDA tool. Readability was analyzed by Flesch-Kincaid Reading Grade Level and Automated Readability Index. All 13 selected websites were rated as being of high quality according to the DISCERN instrument (76.5 ± 2.6 out of 80 points). JAMA benchmark criteria were fulfilled by 87 % of websites, whereas only 37 % were certified by the HONcode. Median Alexa Traffic Rank was 2718 ranging from 7 to 679,038. Websites received 2.3 ± 0.5 daily pageviews per visitor and users spent an average of 2 min 58 s ± 39 sec on the website. Accessibility (92 ± 5 %) and usability (92 ± 3 %) scores were high and reliability (88 ± 8 %) moderate according to the LIDA tool. Flesch-Kincaid Grade Level was 7.9 ± 2.2, and Automated Readability Index was 7.5 ± 2.4, rating the websites as fairly difficult to read. In conclusion, quality, accessibility, and usability of websites on prostate cancer provided a high rating in the current analysis. These findings are encouraging in view of the growing frequency of patients' access of health information online.

Prediction of cancer-specific survival after radical cystectomy in pT4a urothelial carcinoma of the bladder: development of a tool for clinical decision-making.

OBJECTIVE: To externally validate the pT4a-specific risk model for cancer-specific survival (CSS) proposed by May et al. (Urol Oncol 2013; 31: 1141-1147) and to develop a new pT4a-specific nomogram predicting CSS in an international multicentre cohort of patients undergoing radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB) PATIENTS AND METHODS: Data from 856 patients with pT4a UCB treated with RC at 21 centres in Europe and North-America were assessed. The risk model proposed by May et al., which includes female gender, presence of positive lymphovascular invasion (LVI) and lack of adjuvant chemotherapy administration as adverse predictors for CSS, was applied to our cohort. For the purpose of external validation, model discrimination was measured using the receiver-operating characteristic-derived area under the curve. A nomogram for predicting CSS in pT4a UCB after RC was developed after internal validation based on multivariable Cox proportional hazards regression analysis evaluating the impact of clinicopathological variables on CSS. Decision-curve analyses were applied to determine the net benefit derived from the two models. RESULTS: The estimated 5-year-CSS after RC was 34% in our cohort. The risk model devised by May et al. predicted individual 5-year-CSS with an accuracy of 60.1%. In multivariable Cox proportional hazards regression analysis, female gender (hazard ratio [HR] 1.45), LVI (HR 1.37), lymph node metastases (HR 2.54), positive soft tissue surgical margins (HR 1.39), neoadjuvant (HR 2.24) and lack of adjuvant chemotherapy (HR 1.67, all P < 0.05) were independent predictors of an adverse CSS rate and formed the features of our nomogram with a predictive accuracy of 67.1%. Decision-curve analyses showed higher net benefits for the use of the newly developed nomogram in our cohort over all thresholds. CONCLUSIONS: The risk model devised by May et al. was validated with moderate discrimination and was outperformed by our newly developed pT4a-specific nomogram in the present study population. Our nomogram might be particularly suitable for postoperative patient counselling in the heterogeneous cohort of patients with pT4a UCB.

Chemoresistance is associated with increased cytoprotective autophagy and diminished apoptosis in bladder cancer cells treated with the BH3 mimetic (-)-Gossypol (AT-101).

BACKGROUND: Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (-)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (-)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown. METHODS: Cisplatin (5637(r)CDDP(1000), RT4(r)CDDP(1000)) and gemcitabine (5637(r)GEMCI(20), RT4(r)GEMCI(20)) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation. RESULTS: Here we demonstrate that (-)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (-)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (-)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637(r)GEMCI(20) and 5637(r)CDDP(1000) cells. CONCLUSIONS: Our findings show for the first time that (-)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their "autophagy addiction" and acquired resistance to current therapy.

Risk stratification for locoregional recurrence after radical cystectomy for urothelial carcinoma of the bladder.

PURPOSE: To externally validate the Christodouleas risk model incorporating pathological tumor stage, lymph node (LN) count and soft tissue surgical margin (STSM) and stratifying patients who develop locoregional recurrence (LR) after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). In addition, we aimed to generate a new model including established clinicopathological features that were absent in the Christodouleas risk model. METHODS: Prospectively assessed multicenter data from 565 patients undergoing RC for UCB in 2011 qualified for final analysis. For the purpose of external validation, risk group stratification according to Christodouleas was performed. Competing-risk models were calculated to compare the cumulative incidences of LR after RC. RESULTS: After a median follow-up of 25 months (interquartile range 19-29), the LR-rate was 11.5 %. The Christodouleas model showed a predictive accuracy of 83.2 % in our cohort. In multivariable competing-risk analysis, tumor stage ≥pT3 (HR 4.32, p < 0.001), positive STSM (HR 2.93, p = 0.005), lymphovascular invasion (HR 3.41, p < 0.001), the number of removed LNs <10 (HR 2.62, p < 0.001) and the administration of adjuvant chemotherapy (HR 0.40, p = 0.008) independently predicted the LR-rate. The resulting risk groups revealed significant differences in LR-rates after 24 months with 4.8 % for low-risk patients, 14.7 % for intermediate-risk patients and 38.9 % for high-risk patients (p < 0.001 for all), with a predictive accuracy of 85.6 %, respectively. CONCLUSIONS: The Christodouleas risk model has been successfully externally validated in the present prospective series. However, this analysis finds that overall model performance may be improved by incorporating lymphovascular invasion. After external validation of the newly proposed risk model, it may be used to identify patients who benefit from an adjuvant therapy and suit for inclusion in clinical trials.

Prognostic impact of infiltration of the vagina and/or uterus in women undergoing anterior pelvic exenteration for urothelial carcinoma of the bladder: results of a contemporary multicentre series.

PURPOSE: To evaluate for the first time the prognostic significance of female invasive patterns in stage pT4a urothelial carcinoma of the bladder in a large series of women undergoing anterior pelvic exenteration. PATIENTS AND METHODS: Our series comprised of 92 female patients in total of whom 87 with known invasion patterns were eligible for final analysis. Median follow-up for evaluation of cancer-specific mortality (CSM) was 38 months (interquartile ranges, 21-82 months). The impact on CSM was evaluated using multivariable Cox proportional-hazards regression analysis; predictive accuracy (PA) was assessed by receiver operating characteristic analysis. RESULTS: Vaginal invasion was noted in 33 patients (37.9 %; group VAG), uterine invasion in 20 patients (23 %; group UT), and infiltration of both vagina and uterus in 34 patients (39.1 %; group VAG + UT). Groups VAG and UT significantly differed from group VAG + UT with regard to the presence of positive soft tissue margins (STM) only. Five-year-cancer-specific survival probabilities in the groups VAG, UT, and VAG + UT were 21, 20, and 21 %, respectively (p = 0.955). On multivariable analysis, only STM status (HR = 2.02, p = 0.023) independently influenced CSM. C-indices of multivariable models for CSM with and without integration of invasive patterns were 0.570 and 0.567, respectively (PA gain 0.3 %, p = 0.526). CONCLUSIONS: Infiltration of the vagina, the uterus or both is associated with poor 5-year survival rates. With regard to CSM, no difference was detectable between patients with different invasion patterns, thus justifying further collectively including these invasive patterns as stage pT4a.

Concomitant seminal vesicle invasion in pT4a urothelial carcinoma of the bladder with contiguous prostatic infiltration is an adverse prognosticator for cancer-specific survival after radical cystectomy.

PURPOSE: To evaluate the prognostic value of concomitant seminal vesicle invasion (cSVI) in patients with urothelial carcinoma of the bladder (UCB) and contiguous prostatic stromal infiltration in a large cystectomy series. METHODS: A total of 385 patients with UCB and contiguous prostatic infiltration comprised our study. Patients were divided in two groups according to cSVI. Median follow-up was 36 months (interquartile range 11-74); the primary end point was cancer-specific mortality. The prognostic impact of cSVI was evaluated using multivariable Cox regression analysis. The predictive accuracy was assessed by a receiver operating characteristic analysis. RESULTS: A total of 229 patients (59.5 %) without cSVI comprised group A, and 156 patients (40.5 %) with cSVI comprised group B. Positive lymph nodes (63 vs. 44 %, p < 0.001) and positive surgical margins (34 % vs. 14 %, p < 0.001) were more common in patients with cSVI. The 5- and 10-year cancer-specific survival rates were 41 % and 32 % (group A) and 21 and 17 % (group B) (p < 0.001). In multivariable analysis, pathological nodal stage (hazard ratio [HR] 2.19, p < 0.001), soft tissue surgical margin (HR 1.57, p = 0.010), clinical tumor stage (HR 1.46, p = 0.010), adjuvant chemotherapy (HR 0.40, p < 0.001), and cSVI (HR 1.69, p < 0.001) independently impacted cancer-specific mortality. The c-indices of the multivariable models with and without inclusion of cSVI were 0.658 (95 % confidence interval 0.60-0.71) and 0.635 (95 % confidence interval 0.58-0.69), respectively, resulting in a predictive accuracy gain of 2.3 % (p = 0.002). CONCLUSIONS: In patients with UCB and prostatic stromal invasion, cSVI adversely affected cancer-specific survival compared to patients without cSVI. The inclusion of cSVI significantly improved the predictive accuracy of our multivariable model regarding survival.

MR-guided laser-induced thermotherapy in ex vivo porcine kidney: comparison of four different imaging sequences.

PURPOSE: To evaluate the clinical value of different magnetic resonance imaging (MRI) sequences for a real-time thermo-monitoring during laser-induced thermotherapy (LITT) in kidneys. METHODS: Twenty-eight ex vivo pig kidneys were treated with laser ablation under MR guidance in a high-field MR scanner (Magnetom Espree or Avanto Fit, Siemens, Germany). For the thermal ablation of the kidney, a neodymium yttrium-aluminum-garnet (Nd:YAG) laser was used in combination with a special protective catheter (length 43 cm, 4 French) which is sealed at the distal end. First, ablation was performed for 7, 10, and 13 minutes using FLASH sequences for investigation of time-dependent growth of lesion size. In the second step, we evaluated the optimal imaging sequence during a 7 minutes ablation of the kidney and after cooling using four different MR sequences (Haste, FLASH, radial VIBE, and Caipirinha DIXON). RESULTS: Macroscopic lesion volume increased from 3,784 ± 1,525 mm(3) to 7,683 ± 5,756 mm(3) after the ablation from 7 to 13 minutes and MR volume ranged from 2,107 ± 1,674 mm(3) to 2,934 ± 1,549 mm(3) after the ablation from 7 to 13 minutes. During ablation, FLASH (132 ± 34%) and radial VIBE (120 ± 43%) sequences displayed lesion volumes most efficiently with a trend to overestimation. The Caipirinha DIXON (323 ± 24%) sequence overestimated the volumes significantly during real-time monitoring. The volumes measured by MRI with FLASH (61 ± 30%), Haste (67 ± 28%), or radial VIBE (48 ± 14%) sequences after cooling of the kidney after ablation were always underestimated. The Caipirinha DIXON (142 ± 2%) sequence still overestimated the lesion volume after cooling of the kidney. CONCLUSION: LITT is a feasible ablation modality in kidney tissue. Moreover, macroscopic and MR lesion volume increases time-dependently. For online monitoring, radial VIBE and FLASH sequences seem to be most efficient.

The prostate cancer blocking potential of the histone deacetylase inhibitor LBH589 is not enhanced by the multi receptor tyrosine kinase inhibitor TKI258.

Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.

Decreasing susceptibility of bacteria to ampicillin/ sulbactam and third generation cephalosporins in urinary tract infections.

Background: Urinary tract infections (UTIs) are among the most common bacterial infections worldwide and have become more difficult to treat over the years. Inappropriate antibiotic use has led to increased antibiotic resistance. Materials and methods: We examined 1921 urine culture samples from a single hospital and analyzed them for bacterial spectrum and antibiotic susceptibility. We further analyzed changes in the rates of detected bacteria and of the sensitivity of these uropathogens to antibiotics over the years. Results: In our hospital-based analysis, cystitis was the most frequently diagnosed UTI in women (76%) and men (79%). Escherichia coli (48%) was the most commonly identified uropathogen. Samples demonstrated an increase in the proportion of E. coli (p < 0.001) and a decrease in Enterococcus faecalis (p < 0.001) over the study time period. Antimicrobial susceptibility analysis showed an increase over time in the number of isolates with resistance to ampicillin/sulbactam (p < 0.001) and to third-generation cephalosporins cefotaxime (p = 0.043) and ceftazidime (p < 0.001). Conclusions: Ampicillin/sulbactam and third-generation cephalosporins are antibiotics frequently used in the treatment of UTIs. When selecting an optimal antimicrobial treatment regimen for patients with UTIs, it is imperative to understand regional and timedependent differences in the prevalence of various uropathogens and antimicrobial resistance patterns. Therefore, continuous surveillance of local pathogen and antimicrobial susceptibility patterns for frequently used antibiotics should be prioritized.

Tumor-associated immune cell infiltrate density in penile squamous cell carcinomas.

Penile squamous cell carcinomas are rare tumor entities throughout Europe. Early lymphonodal spread urges for aggressive therapeutic approaches in advanced tumor stages. Therefore, understanding tumor biology and its microenvironment and correlation with known survival data is of substantial interest in order to establish treatment strategies adapted to the individual patient. Fifty-five therapy naïve squamous cell carcinomas, age range between 41 and 85 years with known clinicopathological data, were investigated with the use of tissue microarrays (TMA) regarding the tumor-associated immune cell infiltrate density (ICID). Slides were stained with antibodies against CD3, CD8 and CD20. An image analysis software was applied for evaluation. Data were correlated with clinicopathological characteristics and overall survival. There was a significant increase of ICID in squamous cell carcinomas of the penis in relation to tumor adjacent physiological tissue. Higher CD3-positive ICID was significantly associated with lower tumor stage in our cohort. The ICID was not associated with overall survival. Our data sharpens the view on tumor-associated immune cell infiltrate in penile squamous cell carcinomas with an unbiased digital and automated cell count. Further investigations on the immune cell infiltrate and its prognostic and possible therapeutic impact are needed.

HDAC inhibition delays cell cycle progression of human bladder cancer cells in vitro.

Our aim was to analyze the impact of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on bladder cancer cell growth in vitro. RT-4, TCCSUP, UMUC-3, and RT-112 bladder cancer cells were treated with VPA (0.125-1 mmol/l) without and with preincubation periods of 3 and 5 days. Controls remained untreated. Tumor cell growth, cell cycle progression, and cell cycle-regulating proteins were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and western blotting, respectively. Effects of VPA on histone H3 and H4 acetylation and HDAC3 and HDAC4 were also determined. Without preincubation, no tumor cell growth reduction was observed with 0.125 and 0.25 mmol/l VPA in TCCSUP, UMUC-3, and RT-112 cells, whereas 0.5 and 1 mmol/l VPA diminished the cell number significantly. VPA (0.25 mmol/l) did exert tumor growth-blocking effects after a 3-day preincubation. To achieve antitumor effects with VPA (0.125 mmol/l), a 5-day preincubation was necessary. A 3-day or 5-day preincubation was also necessary to distinctly delay cell cycle progression, with maximum effects at VPA (1 mmol/l). After the 5-day preincubation, the cell cycle-regulating proteins cdk1, cdk2, cdk4, and cyclins B, D1, and E were reduced, whereas p27 was enhanced. Diminished HDAC3 and 4 expression induced by VPA was accompanied by elevated acetylation of H3 and H4. VPA exerted growth-blocking properties on a panel of bladder cancer cell lines, commensurate with dose and exposure time. Long-term application induced much stronger effects than did shorter application and should be considered when designing therapeutic strategies for treating bladder carcinoma.

A 27-Year-Old Primigravida with a Right Renal Cell Carcinoma Removed at 30 Weeks of Gestation by Robot-Assisted Retroperitoneoscopic Partial Nephrectomy.

BACKGROUND Large renal tumors during pregnancy are rare findings (0.07-0.1%). Current guidelines recommend surgical removal. This surgery should be carefully planned in an interdisciplinary team and involves special risks for mother and fetus. This report describes a case of a 27-year-old primigravida woman with a right renal cell carcinoma involving the lower pole of the kidney, which was removed at 30 weeks of gestation by robot-assisted retroperitoneoscopic partial nephrectomy (RARPN). CASE REPORT The patient was referred by the treating obstetrician with a newly diagnosed right lower pole renal mass of 6×4 cm in greatest diameter extending deeply into the parenchyma. No metastasis or enlarged lymph nodes were described in subsequent magnetic resonance tomography. Clinical and laboratory examinations documented a healthy mother and fetus. A right-sided RARPN was advised and planned by an interdisciplinary team of treating physicians (gynecologists, oncologists, and urologists). The surgery was conducted under general anesthesia with an obstetrician on stand-by. Surgery was performed without any complications (operation time 95 min, renal-ischemia time 15 min, and negligible blood loss) and histopathology confirmed the diagnosis of a chromophobe renal cell carcinoma. Further follow-up consultations showed regular wound healing and normal progression of pregnancy, and the patient gave birth to a healthy child at term. Follow-up examinations of the patient were uneventful. CONCLUSIONS This case shows that RARPN can be a safe and effective surgical procedure for partial nephrectomy during pregnancy, where surgery is performed in a specialist center and by an interdisciplinary experienced surgical team. It seems to offer advantages and better risk profile over the laparoscopic approach.

Retrospective Evaluation of the Clinical Values of Minimally Invasive Marsupialization of Symptomatic Giant Renal Cysts.

Background: To evaluate the indication and benefit of minimally invasive laparoscopic marsupialization (MIS) of symptomatic giant renal cysts. Materials and Methods: Sixty-four consecutive patients who underwent MIS for large renal cysts (Bosniak I; 4 × 5-16 × 12 cm) by one surgeon were included in the study. Presenting symptoms were renal pain (100%), associated with hypertension (28%), renal dysfunction (4.7%), hematuria (4.7%), ureteropelvic junction obstruction (UPJO) (7.8%), ipsilateral urolithiasis (4.7%), polycystic kidney (6.3%), adrenal cyst (1.6%), and retroperitoneal cysts (1.6%). Seven patients with peripelvic cysts and previous retroperitoneal operations were treated by a laparoscopic approach; all other patients underwent retroperitoneoscopic marsupialization. Single-port retroperitoneoscopy was performed in 4 patients. Follow-up included clinical examination, abdominal ultrasound, and computed tomography scan. Postoperative radiologic success was defined as a minimum of 50% in size reduction and no recurrence. Results: Mean patients' age was 46 (21-65) years. All procedures were successfully completed without conversion or revision. Mean operative time was 55 (40-85) minutes with a mean hospital stay of 3 days. All patients underwent uneventful postoperative recovery. Observed minor complications (transitory fever/pain) were found in 4 patients during the first postoperative month. Median follow-up was 12 months (10 months-2 years). About 98.5% of patients reported of no relevant postoperative pain. A relief from UPJO and hematuria was achieved in 100% of patients. Ten patients with known hypertensive disease (55.6%) had a significant reduction of mean blood pressure resulting in a reduction of antihypertensive medication. Ureterorenoscopic stone extractions were performed successfully afterward. No cyst recurrences were detected during the follow-up period. Conclusion: Treatment indications for symptomatic renal cysts could include not only symptoms but also associated diseases like UPJO and hypertension. Retroperitoneoscopic MIS may be curative for these cyst-associated pathologies. The feasibility, safety and efficacy of these techniques could be demonstrated.

Evaluation of Testicular Self Examination and Testicular Partner Examination in Medical versus Non-Medical Students.

OBJECTIVES: Although testicular cancer (TC) is the most common tumor in young men in Western countries, there is no official cancer detection/screening program for young men in Germany. The most important TC detection tool is self-examination of the testis. Hypothetically medical students may have a diagnosis lead time and detection superiority. This study was designed to analyze whether medical students have a possible knowledge advantage over students of other faculties concerning TC and to compare male and female cancer screening demeanor and mentality. METHODS: Male and female students of various faculties at the Goethe University Frankfurt/Main, Germany were invited to participate in this internet-based anonymous questionnaire with questions about TC awareness/knowledge, testicular (self) examination, and cancer screening behavior. RESULTS: In total 1,049 students (329 medical and 716 non-medical students) completed the questionnaire. In general, medical students had a significantly higher TC knowledge, especially in the more advanced stages of their medical studies (year 3-6). About 50% of medical students had knowledge of TC whereas only 21.3% of non-medical students knew about the disease (p < 0.01). In addition, medical students conducted scrotal examinations more frequently (34.7%) than non-medical students (18.8%). CONCLUSION: The knowledge about TC is low among students. In general, medical students are more aware of TC and perform more frequent testicular examinations compared to non-medical students. Female TC knowledge rises in the clinical part of studies to the same level as their male counterparts, with the result of more testicular partner examinations.

Quality of Patient Information by Urologists Is Associated with Mental Distress in Bladder Cancer Patients.

AIMS: The study aimed to evaluate the prevalence of mental distress in patients with newly diagnosed bladder cancer, the cancer-information search behavior, and the influence of information seeking on distress. METHODS: One hundred and one bladder cancer patients answered 2 established questionnaires ("Hospital Anxiety and Depression Scale" [HADS] and the "Fragebogen zur Belastung von Krebskranken" [FBK-R23]) for evaluation of mental distress and a self-developed questionnaire with questions concerning information seeking and socioeconomic facts. RESULTS: Regarding risk group stratification, 57.4% were classified as high-risk and 42.6% as low-risk tumor-bearing patients. Analysis of mental distress showed that 23.2% had a score above the HADS-A cutoff, 25.3% above the HADS-D cutoff, and 21.4% showed a pathologic FBK-R23 score. Overall, 75% felt well informed about their illness. Risk group stratification did not correlate with HADS-A, HADS-D, or FBK-R23 score. Furthermore, active search for information or the use of the Internet did not correlate with the HADS-A, HADS-D, or FBK-R23 score. However, the quality of the urologist's information and the feeling of being informed correlated with the grade of mental distress. CONCLUSION: Besides the treatment of bladder cancer, informing the patient about the disease in a psychologically wholesome manner and working together with psycho-oncologically trained psychologists are essential tasks for the treating urologist.

Tumor necrosis factor­related apoptosis­inducing ligand as a therapeutic option in urothelial cancer cells with acquired resistance against first­line chemotherapy.

Patients with urothelial carcinoma frequently fail to respond to first­line chemotherapy using cisplatin and gemcitabine due to development of resistant tumor cells. The aim of the present study was to investigate whether an alternative treatment with tumor necrosis factor­related apoptosis­inducing ligand (TRAIL) that induces tumor cell death via the extrinsic apoptotic pathway may be effective against chemotherapy­resistant urothelial cancer cell lines. The viability of the urothelial cancer cell line RT112 and its chemotherapy­adapted sublines was investigated by MTT assay. The expression of anti­apoptotic proteins was determined by western blotting and the individual roles of cellular inhibitor of apoptosis protein (cIAP)1, cIAP2, x­linked inhibitor of apoptosis protein (XIAP) and induced myeloid leukemia cell differentiation protein (Mcl­1) were investigated by siRNA­mediated depletion. In particular, the bladder cancer sublines that were resistant to gemcitabine and cisplatin were cross­resistant to TRAIL. Resistant cells displayed upregulation of anti­apoptotic molecules compared with the parental cell line. Treatment with the second mitochondrial activator of caspases (SMAC) mimetic LCL­161 that antagonizes cIAP1, cIAP2 and XIAP resensitized chemoresistant cells to TRAIL. The resensitization of tumor cells to TRAIL was confirmed by depletion of antiapoptotic proteins with siRNA. Collectively, the findings of the present study demonstrated that SMAC mimetic LCL­161 increased the sensitivity of the parental cell line RT112 and chemotherapy­resistant sublines to TRAIL, suggesting that inhibiting anti­apoptotic molecules renders TRAIL therapy highly effective for chemotherapy­sensitive and ­resistant urothelial cancer cells.

HDAC Inhibition Counteracts Metastatic Re-Activation of Prostate Cancer Cells Induced by Chronic mTOR Suppression.

This study was designed to investigate whether epigenetic modulation by histone deacetylase (HDAC) inhibition might circumvent resistance towards the mechanistic target of rapamycin (mTOR) inhibitor temsirolimus in a prostate cancer cell model. Parental (par) and temsirolimus-resistant (res) PC3 prostate cancer cells were exposed to the HDAC inhibitor valproic acid (VPA), and tumor cell adhesion, chemotaxis, migration, and invasion were evaluated. Temsirolimus resistance was characterized by reduced binding of PC3res cells to endothelium, immobilized collagen, and fibronectin, but increased adhesion to laminin, as compared to the parental cells. Chemotaxis, migration, and invasion of PC3res cells were enhanced following temsirolimus re-treatment. Integrin α and ß receptors were significantly altered in PC3res compared to PC3par cells. VPA significantly counteracted temsirolimus resistance by down-regulating tumor cell⁻matrix interaction, chemotaxis, and migration. Evaluation of integrin expression in the presence of VPA revealed a significant down-regulation of integrin α5 in PC3res cells. Blocking studies demonstrated a close association between α5 expression on PC3res and chemotaxis. In this in vitro model, temsirolimus resistance drove prostate cancer cells to become highly motile, while HDAC inhibition reversed the metastatic activity. The VPA-induced inhibition of metastatic activity was accompanied by a lowered integrin α5 surface level on the tumor cells.