Contemporary role of palliative cystoprostatectomy or pelvic exenteration in advanced symptomatic prostate cancer.

OBJECTIVE: To access the feasibility of palliative cystoprostatectomy/pelvic exenteration in patients with bladder/rectal invasion due to prostate cancer (PC). PATIENTS AND METHODS: Twenty-five men with cT4 PC were retrospectively identified in the institutional databases of six tertiary referral centers in the last decade. Local invasion was documented by CT or MRI scans and was confirmed by urethrocystoscopy. Oncological therapies, local symptoms, previous local treatments, time from diagnosis to intervention and type of surgical procedure were recorded. Patients were divided into groups: ADT group (12 pts) and 13 pts without any history of previous local/systemic treatments for PCa (nonADT groups). Perioperative complications were classified using the Clavien-Dindo system. Overall survival (OS) was defined as the time from surgery to death from any cause. A Cox regression analysis, stratified for ISUP score and previous hormonal treatment (ADT) was also performed for survival analysis. RESULTS: Ileal conduit was the main urinary diversion in both cohorts. For the entire cohort, complication rate was 44%. No significant differences regarding perioperative complications and complication severity between both subgroups were observed (p = 0.2). Median follow-up was 15 months (range 3-41) for the entire cohort with a median survival of 15 months (95% CI 10.1-19.9). In Cox regression analysis stratified for ISUP score, no statistically significant differences in OS in patients with and without previous ADT before cystectomy or exenteration were observed (HR 3.26, 95% CI 0.62-17.23, p = 0.164). CONCLUSION: Palliative cystoprostatectomy and pelvic exenteration represent viable treatment options associated with acceptable morbidity and good short-term survival outcome.

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Comparison of adjustable male slings and artificial urinary sphincter in the treatment of male urinary incontinence: a retrospective analysis of patient selection and postoperative continence status.

PURPOSE: To analyze and compare preoperative patient characteristics and postoperative results in men with stress urinary incontinence (SUI) selected for an adjustable male sling system or an artificial urinary sphincter (AUS) in a large, contemporary, multi-institutional patient cohort. METHODS: 658 male patients who underwent implantation between 2010 and 2012 in 13 participating institutions were included in this study (n = 176 adjustable male sling; n = 482 AUS). Preoperative patient characteristics and postoperative outcomes were analyzed. For statistical analysis, the independent T test and Mann-Whitney U test were used. RESULTS: Patients undergoing adjustable male sling implantation were less likely to have a neurological disease (4.5% vs. 8.9%, p = 0.021), a history of urethral stricture (21.6% vs. 33.8%, p = 0.024) or a radiation therapy (22.7% vs. 29.9%, p = 0.020) compared to patients that underwent AUS implantation. Mean pad usage per day (6.87 vs. 5.82; p < 0.00) and the ratio of patients with a prior incontinence surgery were higher in patients selected for an AUS implantation (36.7% vs. 22.7%; p < 0.001). At maximum follow-up, patients that underwent an AUS implantation had a significantly lower mean pad usage during daytime (p < 0.001) and nighttime (p = 0.018). Furthermore, the patients' perception of their continence status was better with a subjective complete dry rate of 57.3% vs. 22.0% (p < 0.001). CONCLUSIONS: Patients selected for an AUS implantation showed a more complex prior history and pathogenesis of urinary incontinence as well as a more severe grade of SUI. Postoperative results reflect a better continence status after AUS implantation, favoring the AUS despite the more complicated patient cohort.

Impact of preoperative hemoglobin and CRP levels on cancer-specific survival in patients undergoing radical cystectomy for transitional cell carcinoma of the bladder: results of a single-center study.

PURPOSE: Different blood parameters have shown to be associated with patient's oncological outcome. There is only limited knowledge about the prognostic relevance of routine blood parameters in patients undergoing radical cystectomy for transitional cell carcinoma (TCC). Therefore, we retrospectively analyzed the influence of preoperative C-reactive protein (CRP) and hemoglobin (Hb) levels on overall survival (OS) and cancer-specific survival (CSS). MATERIALS AND METHODS: Preoperative CRP and Hb levels were available in 664 patients who underwent RC due to TCC from 2004 to 2013 at our institution. More men than women (77 vs. 23 %) underwent surgery with a median age of 70 years (35-97). Median follow-up time was 24 months (max. 108). Outcome was analyzed using Kaplan-Meier method, log-rank test, and Cox regression models. RESULTS: Median CRP level was 0.5 mg/dl (0.1-28.3), and median Hb level was 13.4 g/dl (6.7-17.9). Patients with CRP value above the median died significantly earlier due to their disease than those with CRP below the median (median CSS 19 vs. 70 months; p < 0.001). Patients with preoperative Hb level below the median had significantly worse outcome than those with Hb level above the median (median CSS 25 vs. 78 months; p < 0.001). In multivariate analysis, CRP and Hb levels were independent prognostic parameters regarding CSS/OS (CRP p = 0.016/p = 0.004; Hb p = 0.006/p = 0.004, respectively). CONCLUSIONS: In our single-center study, preoperative CRP and Hb levels were found to be independent prognostic factors, indicating impaired outcome in patients undergoing RC for TCC. These findings could be used for individual risk stratification and optimization of therapeutic strategies.

A polymorphism in the TH 2 locus control region is associated with changes in DNA methylation and gene expression.

BACKGROUND: Genomewide association and epigenetic studies found a region within the RAD50 gene on chromosome 5q31 to be associated with total serum IgE levels and asthma. In mice, this region harbors a locus control region for nearby TH 2 cytokines, which is characterized by four Rad50 DNase I hypersensitive sites (RHS4-7). Among these, RHS7 seems to have the strongest impact on TH 2 differentiation. We investigated whether within the human homolog of RHS7, functional polymorphisms exist, which could affect DNA methylation or gene expression in the 5q31 locus and might have an influence on asthma status or IgE regulation. METHODS: The human RHS7 region was fine mapped using 1000 genomes database information. In silico analysis and electrophoretic mobility shift assays were used to assess SNP function. Allele-specific effects on DNA methylation were evaluated in cord blood (n = 73) and at age of 4.5 years (n = 61) by pyrosequencing. Allele-specific effects on RAD50, IL4, and IL13 expression were analyzed in 100 subjects. Associations with asthma and IgE levels were investigated in the MAGICS/ISAAC II population (n = 1145). RESULTS: Polymorphism rs2240032 in the RHS7 region is suggestive of allele-specific transcription factor binding, affects methylation of the IL13 promoter region and influences RAD50 and IL4 expression (lowest P = 0.0027). It is also associated with total serum IgE levels (P = 0.0227). CONCLUSION: A functional relevant polymorphism in the TH 2 locus control region, equivalent to RHS7 in mice, affects DNA methylation and gene expression within 5q31 and influences total serum IgE on the population level.

A common atopy-associated variant in the Th2 cytokine locus control region impacts transcriptional regulation and alters SMAD3 and SP1 binding.

BACKGROUND: Type 2 immune responses directed by Th2 cells and characterized by the signature cytokines IL4, IL5, and IL13 play major pathogenic roles in atopic diseases. Single nucleotide polymorphisms in the human Th2 cytokine locus in particular in a locus control region within the DNA repair gene RAD50, containing several RAD50 DNase1-hypersensitive sites (RHS), have been robustly associated with atopic traits in genome-wide association studies (GWAS). Functional variants in IL13 have been intensely studied, whereas no causative variants for the IL13-independent RAD50 signal have been identified yet. This study aimed to characterize the functional impact of the atopy-associated polymorphism rs2240032 located in the human RHS7 on cis-regulatory activity and differential binding of transcription factors. METHODS: Differential transcription factor binding was analyzed by electrophoretic mobility shift assays (EMSAs) with Jurkat T-cell nuclear extracts. Identification of differentially binding factors was performed using mass spectrometry (LC-MS/MS). Reporter vector constructs carrying either the major or minor allele of rs2240032 were tested for regulating transcriptional activity in Jurkat and HeLa cells. RESULTS: The variant rs2240032 impacts transcriptional activity and allele-specific binding of SMAD3, SP1, and additional putative protein complex partners. We further demonstrate that rs2240032 is located in an RHS7 subunit which itself encompasses repressor activity and might be important for the fine-tuning of transcription regulation within this region. CONCLUSION: The human RHS7 critically contributes to the regulation of gene transcription, and the common atopy-associated polymorphism rs2240032 impacts transcriptional activity and transcription factor binding.

Postoperative change in Gleason score of prostate cancer in fusion targeted biopsy: a matched pair analysis.

OBJECTIVE: To evaluate if MRI/ultrasound fusion based targeted biopsy (FBx) leads to a reduced rate of change in Gleason score (GS) compared to prostatectomy specimen. METHODS: The histopathological findings of the biopsy of the prostate and the radical prostatectomy (RP) specimen of 210 patients who were referred to our hospital between 2012 and 2017 were compared retrospectively in this study. One hundred and five patients who underwent FBx combined with ultrasound-guided 12-core biopsy of the prostate (SBx) were matched with 105 patients who underwent SBx only. This study evaluated the rate of up- or downgrading in the RP specimen in both groups and compared the results via matched pair analysis. RESULTS: Concordance in Gleason grade group (GGG) was found in 52/105 patients (49.5%) in SBx and in 49/105 patients (46.7%) with FBx (p = 0.679). The rate of downgrading was statistically significant (p = 0.014) and was higher in the FBx group (14/105 patients, 13.3%) than in the SBx group (4/105 patients, 3.8%). A higher rate of upgrading was seen in SBx (49/105 patients; 46.7%) compared to FBx (42/105 patients; 40%), with no statistical significance (p = 0.331). The change in GGG from biopsy to final pathology in patients with GGG 1 and 2 at biopsy level was not statistically significant (p = 0.168). CONCLUSION: FBx does not decrease the rate of upgrading between biopsy and final pathology in RP specimens. Our results indicate that FBx tends to overestimate the final GGG compared to SBx.

Online magnetic bead dynamic protein-affinity selection coupled to LC-MS for the screening of pharmacologically active compounds.

The online, selective isolation of protein-ligand complexes using cobalt(II)-coated paramagnetic affinity beads (PABs) and subsequent liquid chromatography-mass spectrometry (LC-MS) determination of specifically bound ligands is described. After in-solution incubation of an analyte mixture with His-tagged target proteins, protein-analyte complexes are mixed with the Co(II)-PABs and subsequently injected into an in-house built magnetic trapping device. Bioactive ligands bound to the protein-Co(II)-PABs are retained in the magnetic field of the trapping device while inactive compounds are removed by washing with a pH 7.4 buffer. Active ligands are online eluted toward the LC-MS system using a pH shift. In the final step of the procedure, the protein-Co(II)-PABs are flushed to waste by temporarily lowering the magnetic field. The proof-of-principle is demonstrated by using commercially available Co(II)-PABs in combination with the His-tagged human estrogen-receptor ligand-binding domain. The system is characterized with a number of estrogenic ligands and nonbinding pharmaceutical compounds. The affinities of the test compounds varied from the high micromolar to the subnanomolar range. Typical detection limits are in the range from 20 to 80 nmol/L. The system is able to identify binders in mixtures of compounds, with an analysis time of 9.5 min per mixture. The standard deviation over 24 h is 9%.

Carcinoembryonic antigens: alternative splicing accounts for the multiple mRNAs that code for novel members of the carcinoembryonic antigen family.

The recent cloning of complete cDNAs encoding carcinoembryonic antigen (CEA) and non-specific cross-reacting antigen has revealed the existence of a new gene family belonging to the immunoglobulin gene superfamily. We have reported the isolation of a partial CEA cDNA and of L-cell transfectant cell lines that express human antigens cross-reactive with commercial antibodies directed to native CEA (Kamarck, M., J. Elting, J. Hart, S. Goebel, P. M. M. Rae, J. Nedwin, and T. Barnett. 1987. Proc. Natl. Acad. Sci. USA. 84:5350-5354). In this study, we describe the identification and cloning of 3.9-, 3.7-, 2.2-, and 1.8-kb cDNAs and a 23-kb genomic transcription unit, which code for new members of the CEA gene family. DNA sequence analysis of these cloned DNAs establishes the existence of a set of four alternatively spliced mRNAs which are expressed in several tumor cell lines, in human fetal liver, and in L-cell transfectants. Deduced amino acid sequences of the encoded isoantigens show extensive similarity to CEA and nonspecific cross-reacting antigens, but in addition demonstrate transmembrane and cytoplasmic domains. We designate members of this antigen family transmembrane CEAs. The transmembrane CEA isoantigens share general structural characteristics with members of the immunoglobulin gene superfamily and can be specifically compared to the cell adhesion molecules, N-CAM (neural cell adhesion molecule) and MAG (myelin-associated glycoprotein).

[Influence of modern diagnostic methods on the treatment of nonmetastatic castration-resistant prostate cancer]. / Einfluss moderner Diagnostikverfahren auf die Therapie des nichtmetastasierten kastrationsresistenten Prostatakarzinoms.

Until 2018, patients with nonmetastatic castration-resistant prostate cancer (nmCRPC/M0CRPC) did not have a generally acknowledged standard of care therapy. As a result, these patients were often managed in a nonstandardized individual fashion and comparative analyses were lacking. In the current narrative review, we give an overview on the respective entities of nmCRPC and summarize novel treatment options that arose from the publication of the results of the SPARTAN and PROSPER trials and their subanalyses. We critically address the role that novel imaging modalities, namely 68Ga-PSMA-PET/CT (68Ga prostate-specific membrane antigen positron emission tomography/computed tomography) will play in the diagnosis of nmCRPC and raise the question whether incidence rates of true nmCRPC will significantly decline in the nearer future.

[Management of ureteral injuries]. / Management von Harnleiterverletzungen.

Ureteral injuries account for less than 3% of genitourinary injuries. Most of them are caused iatrogenically during abdominal surgery. The symptoms are often non-specific and do not aid in diagnosis. The later the injury is detected, the more often complications occur. Therefore, in such situations it is important to consider the possibility of ureteral injury and initiate further diagnostic steps as soon as possible. A variety of diagnostic tests are available. In addition to the direct inspection of the ureters and retrograde ureteropyelography, computed tomography (CT) urography is routinely used. Based on the time of diagnosis as well as the extent and the localization of the injury, the further procedure can be determined. For minor injuries, the insertion of a ureteral splint is usually the treatment of choice. In the case of higher grade damage, operative reconstruction by one of several possible surgical procedures is indicated.

[Active surveillance of prostate cancer : An update]. / Active Surveillance beim Prostatakarzinom : Ein Update.

Prostate cancer is a heterogeneous disease. In cases of low-risk prostate cancer, active surveillance represents an attractive alternative treatment. Significant complications of a definitive treatment can therefore be delayed or completely avoided. Despite strict inclusion criteria for active surveillance, the diagnosis of low-risk prostate cancer can be inaccurate and there is therefore a risk of missing the optimal point in time for definitive treatment. Multimodal diagnostics and continuous aftercare are therefore crucial.

[Current controversies in the treatment of localized prostate cancer]. / Aktuelle Kontroversen in der Therapie des lokal begrenzten Prostatakarzinoms.

In the prostate-specific antigen (PSA) era, most prostate cancers (PCa) are diagnosed in a localized stage and a plethora of therapeutic options are warranted in different clinical settings and disease stages of localized PCa. In the current narrative review, we give an overview of the current controversies in the therapeutic landscape of localized PCa and focus on organ-sparing approaches, percutaneous radiotherapy, brachytherapy as well as retropubic and robot-assisted prostatectomy by summarizing studies that have been published within the last two years.

Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosis.

BACKGROUND: Systemic mastocytosis (SM) is a mast cell neoplasm in which neoplastic cells usually display the D816V-mutated variant of KIT. Cladribine (2CdA) and dasatinib are two drugs that counteract the in vitro growth of neoplastic mast cells in SM. However, only little is known about the in vivo effects of these drugs in SM. PATIENT AND METHODS: We report on a patient with highly aggressive interferon-alpha-resistant SM who was treated with 2CdA and dasatinib. In vitro pretesting revealed a response of neoplastic mast cells to both compounds with reasonable IC(50) values. RESULTS: The patient was treated with six cycles of 2CdA (0.13 mg kg(-1) intravenously daily on 5 consecutive days). Despite a short-lived major clinical response and a decrease in serum tryptase, the patient progressed to mast cell leukaemia after the sixth cycle of 2CdA. The patient then received two further courses of 2CdA followed by treatment with dasatinib (100 mg per os daily). However, no major response was obtained and the patient died from disease progression after 2 months. CONCLUSIONS: In a patient with rapidly progressing aggressive SM, neither 2CdA nor dasatinib produced a long-lasting response in vivo, despite encouraging in vitro results. For such patients, alternative treatment strategies have to be developed.

[Stricture of the vesicourethral anastomosis after radical prostatectomy]. / Die Striktur der vesikourethralen Anastomose nach radikaler Prostatektomie.

BACKGROUND: The development of a stricture of the vesicourethral anastomosis is a serious complication after radical prostatectomy. Strictures occur in 5-8% of patients after radical prostatectomy. SYMPTOMS: Usually the clinical symptoms include an irritative and obstructive component similar to benign prostatic hyperplasia. In rare cases, patients suffer from partial or complete stress incontinence as a result of the anastomotic stricture. DIAGNOSTICS: The diagnostic workup is similar to the procedure for urethral strictures. In addition to uroflowmetry, a cystourethrogram (CUG) or, if necessary, a micturating cystourethrogram (MCU) can be performed. A urethrocystoscopy can be performed to ensure the diagnosis. THERAPY: In most cases, endoscopic procedures were performed for treatment. Beside a transurethral dilation of the stricture or the Sachse urethrotomy, the most common procedure is transurethral resection to treat the stricture. However, all procedures are associated with a high recurrence rate. In recurrent strictures, open surgical procedures, usually a perineal reanastomosis, should performed early. CONCLUSION: Endourological procedures like transurethral resection are a good treatment option, but due to the high recurrence rates, open surgical procedures should be discussed and if necessary should be performed early.

[Diagnostic workup of urethral strictures]. / Diagnostischer Workup bei der Harnröhrenstriktur.

Urethral stricture is a narrowing of the urethra due to scar tissue. It causes obstructive voiding dysfunction and can lead to long-term damage of the entire urinary tract. The probability of therapeutic success is dampened by a high rate of recurrence. Therefore, a careful taking of the patient's history and further diagnostics are crucial for finding the appropriate form of therapy. This review highlights the clinical presentation and diagnostic workup of urethral strictures.

[Molecular biomarkers and prognostic factors for prostate cancer]. / Genetische Marker und Prognosefaktoren beim Prostatakarzinom.

In the era of personalized medicine and precision oncology, innovative genetic biomarkers are of emerging interest to close the diagnostic and prognostic gap that is left by current clinicopathologic risk classifiers. The current review article summarizes evidence regarding prognostic and predictive genetic biomarkers that are currently in widespread clinical use at initial diagnosis as well as following definitive treatment of prostate cancer. We give a brief summary about basic principles of biomarker research studies and present current data for the Progensa PC3 test, TMPRSS2:ERG gene fusion, ConfirmMDx, Prolaris gene panel, OncotypeDX Genomic Prostate score, and Decipher classifier. Evidence regarding those genetic biomarkers has heavily increased recently. However, there is still a lack of large, multicentric and prospective clinical validation studies. Furthermore, comparative studies that investigate the prognostic value of various genetic biomarkers are needed.

[When is surgical treatment indicated in metastatic prostate cancer and what is the scientific rationale?] / Wann ist die operative Versorgung von Metastasen beim Prostatakarzinom angezeigt und gibt es eine wissenschaftliche Grundlage hierfür?

BACKGROUND: Recent improvements in imaging diagnostics has led to a rising incidence of oligometastatic prostate cancer and, most notably, an increasing incidence of nodal-only biochemical recurrences. In this clinical setting, systemic therapy is still the treatment of choice. However, there is increasing evidence for surgical approaches in this challenging clinical setting. AIM OF THE STUDY: In this comprehensive review article, current evidence regarding surgical approaches of primary nodal metastases, nodal-only biochemical recurrence following radical prostatectomy, and osseous metastatic prostate cancer will be discussed. RESULTS: If nodal metastasis is clinically suspected, a significant survival benefit was observed in retrospective studies if radical prostatectomy and extended pelvic lymphadenectomy was performed within a multimodal therapeutic setting. Salvage lymphadenectomy as a therapeutic option for nodal-only biochemical recurrence is clinically feasible and can postpone systemic therapy significantly. However, since most patients do not have a lasting PSA response, a survival benefit of this therapeutic approach is questionable based on current evidence. Regarding osseous metastatic prostate cancer, the surgical approach has an inferior position compared to conservative management and radiotherapy. CONCLUSION: Evidence regarding a surgical approach towards oligometastatic prostate cancer is increasing. However, current evidence is mainly based on retrospective studies that were conducted in the pre-PSMA-PET/CT era.

[Primary prostatic sarcoma - a rare malignancy]. / Das primäre Prostatasarkom ­ ein seltenes Malignom.

Primary prostatic sarcomas are rare, reportedly comprising less than 1% of all prostate malignancies. Most patients present with lower urinary tract symptoms due to bladder outlet obstruction. Prostate-specific antigen (PSA) is typically normal. Histological confirmation and staging by a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the pelvis and abdomen are essential for diagnosis and treatment planning. The differential diagnosis includes sarcomatoid prostate cancer or benign spindle cell tumors. Primary prostatic sarcomas are often aggressive and require multimodal treatment with surgery and (neo)adjuvant radiation and/or chemotherapy. The risk of local recurrence is high and the long-term prognosis is poor.

Risks and benefits of pelvic lymphadenectomy in octogenarians undergoing radical cystectomy due to urothelial carcinoma of the bladder.

OBJECTIVES: According to current guidelines, radical cystectomy (RC) should be combined with an extended pelvic lymphadenectomy (PLND) as therapeutic and staging instrument. Objective of this study was to analyze the influence of PLND on survival rates and complication rates in a selected group of elderly patients with a minimum age of 80 years. MATERIALS AND METHODS: In this single-center retrospective analysis, we evaluated 102 patients who underwent RC due to UCB from 2004 to 2015 at our institution. In 74 patients (73%), RC was combined with PLND; in 28 cases (27%), RC was performed without PLND. Impact of PLND on cancer specific survival (CSS), overall survival (OS) and progression-free survival (PFS) was analyzed using log-rank test and COX regression model. RESULTS: In univariate analysis of the data, we were not able to show a significant impact of PLND on CSS (p = 0.606), OS (p = 0.979) or PFS (p = 0.883). Also in multivariate analysis of the data, we were not able to identify PLND as an independent prognostic parameter on survival rates of patients undergoing RC, neither for CSS (p = 0.912) nor OS (p = 0.618) or PFS (p = 0.900). CONCLUSIONS: Our small and single-center study was not able to demonstrate a significant independent influence of PLND on CSS, OS and PFS in octogenarians undergoing RC due to UCB. There is no doubt that RC should usually be combined with PLND, but the results of this small data set with a selected patient cohort indicate that RC without PLND might be an option in selected cases of elderly patients.