Diagnostic meaning of urodynamic studies in pouch incontinence: results of a small series.

INTRODUCTION: To evaluate the meaning of urodynamic parameters in patients with pouch incontinence. MATERIALS AND METHODS: Thirteen urodynamic studies in patients with an ileal nipple as the efferent segment of an ileocecal pouch or ileum/ileocecal-augmented bladder were performed. The recorded parameters included pouch capacity, leak point pressure/volume, maximum pouch pressure, compliance, static and dynamic closure pressure, and functional length. Three patients suffered from urinary incontinence. RESULTS: In all cases of incontinent patients, no functional length or static or dynamic closure pressure could be revealed. In 8 of 10 cases of continent patients, a positive functional length as well as static and/or dynamic closure pressure were measured (mean value in continent patients: 15.9 mm, 14.5 cm H2O and 26.5 cm H2O, respectively). In 2 of 3 cases of incontinent patients, the pouch compliance was restricted (21 and 37 ml/cm H2O). The pouch capacity of continent patients was greater than the capacity of incontinent patients (377.4 vs. 185.7 ml). CONCLUSIONS: Positive functional length, static and dynamic closure pressures, and a high pouch capacity with an unrestricted compliance are predictive for pouch continence. They may individually not determine continence, but combining them can. However, the meaning of urodynamic studies in pouch incontinence is not the same as with the urinary bladder.

Alterations of global histone H3K9 and H3K27 methylation levels in bladder cancer.

BACKGROUND: Epigenetic alterations, including histone modifications, play an important role during carcinogenesis. This study was designed to systematically investigate histone H3K9 and H3K27 methylation levels in bladder cancer (BCa) tissue. METHODS: A tissue microarray with urothelial BCa (150 non-muscle-invasive BCa, NMIBC; 121 muscle-invasive BCa, MIBC; 31 metastatic BCa, MET) and normal urothelium (29, CTRL) specimen was used to determine the global levels of H3K9 and H3K27 mono-, di- and tri-methylation. RESULTS: Global levels of H3K9 and H3K27 methylation were significantly higher in CTRL than in BCa, and levels in NMIBC were higher compared to MIBC. Histone methylation levels of MET resembled MIBC. We observed furthermore a correlation of histone methylation levels with pT stage (H3K9me1, H3K9me2, H3K9me3, H3K27me1, H3K27me3) and grade (H3K9me2, H3K9me3, H3K27me1) in NMIBC. H3K9me1, H3K9me3, H3K27me1 and H3K27me3 levels were also correlated with pT stage in MIBC. Histone modifications were not associated with recurrence-free or cancer-specific survival. CONCLUSIONS: Global histone H3K9 and H3K27 methylation levels are altered in BCa.

Histone methylation defines an epigenetic entity in penile squamous cell carcinoma.

PURPOSE: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue. MATERIALS AND METHODS: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry. RESULTS: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome. CONCLUSIONS: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease.

Urological surgery in patients with hemorrhagic bleeding disorders Hemophilia A, Hemophilia B, von Willebrand disease: a retrospective study with matched pairs analysis.

PURPOSE: To determine retrospectively the perioperative management and outcome of transurethral prostate/bladder surgery (TURP, TURB) and transrectal prostate biopsy in hemophiliacs. METHODS: Thirty-seven hemophilic patients underwent TURP (12 patients), TURB (13 patients), or transrectal prostate biopsy (12 patients) with proactive hemostaseological management (i.e., factor supply, close meshed hemostaseological analysis). Thirty-seven non-hemophiliac patients served as matched pairs who matched for age, gender, accompanying diseases, and the type of surgical procedure. The resulting pairs were analyzed for duration of surgery, hospital stay, and complications. RESULTS: Average TURP length in hemophiliacs was 77.92 min, in the matched pairs group TURP 67.08 min (p = 0.487). Mean TURB length in hemophiliacs was 43.46 min versus 35.38 min in controls (p = 0.678). More important, the length of hospital stay was significant longer in the hemophiliacs undergoing TURP compared to non-hemophiliac control group (12.08 days vs. 5.83 days; p < 0.001). In TURB patients, similar results were found (11.15 days hemophiliacs vs. 6.15 controls; p = 0.018). Regarding complications (bleeding, hemorrhage, readmission), no significant difference between the groups was obtained. CONCLUSION: Urological interventions in hemophiliac patients with factor supply have the same risk for postoperative complications as in non-hemophiliacs. The only significant difference between hemophiliacs and non-hemophiliacs was the length of hospital stay.

Global histone H3K27 methylation levels are different in localized and metastatic prostate cancer.

Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis.

Global histone H3 lysine 27 (H3K27) methylation levels and their prognostic relevance in renal cell carcinoma.

OBJECTIVE: To evaluate if histone H3 lysine 27 (H3K27) methylation plays a role in renal cell carcinoma (RCC) tissue and whether its expression is a predictor of cancer recurrence in RCC. MATERIALS AND METHODS: A tissue microarray (TMA) with 193 RCC specimens (comprising 142 clear-cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC), 10 oncocytoma tissue specimens and a TMA with 30 benign renal tissue samples were stained with antibodies against H3K27-monomethyl (H3K27me1), H3K27-dimethyl (H3K27me2) and H3K27-trimethyl (H3K27me3). Sections were scored according to staining intensity and the proportion of epithelial cells showing nuclear staining. H3K27 methylation levels were correlated with established clinical-pathological variables (tumour-node-metastasis [TNM] stage, Fuhrman grade) and progression-free/cancer-specific survival. RESULTS: H3K27me1/-me2/-me3 staining was significantly more intense in papillary RCC then in clear-cell RCC. H3K27me3 levels were higher in oncocytoma than in RCC. H3K27me1/-me2/-me3 methylation levels were inversely correlated with Fuhrman grading and pT-stage. Global H3K27me1/-me2/-me3 methylation levels were always higher in benign renal tissue than in RCC with tumour relapse (H3K27me1 P < 0.001, H3K27me2 P= 0.032, H3K27me3 P= 0.004). Progression-free survival was shorter in patients with lower levels of H3K27me1 and H3K27me3 in the univariate analysis. The newly created H3K27me score (combining the staining levels of the single modifications) was a significant and independent predictor of RCC progression-free survival. CONCLUSION: The present study on H3K27-methylation supports the hypothesis that global histone modifications are potential markers of cancer prognosis in RCC. One reason could be that decreased H3K27 indicates transcriptional activation and therefore predicts cancer activation.

Clinical studies applying cytokine-induced killer cells for the treatment of renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) seems to be resistant to conventional chemo- and radiotherapy and the general treatment regimen of cytokine therapy produces only modest responses while inducing severe side effects. Nowadays standard of care is the treatment with VEGF-inhibiting agents or mTOR inhibition; nevertheless, immunotherapy can induce complete remissions and long-term survival in selected patients. Among different adoptive lymphocyte therapies, cytokine-induced killer (CIK) cells have a particularly advantageous profile as these cells are easily available, have a high proliferative rate, and exhibit a high antitumor activity. Here, we reviewed clinical studies applying CIK cells, either alone or with standard therapies, for the treatment of RCC. The adverse events in all studies were mild, transient, and easily controllable. In vitro studies revealed an increased antitumor activity of peripheral lymphocytes of participants after CIK cell treatment and CIK cell therapy was able to induce complete clinical responses in RCC patients. The combination of CIK cell therapy and standard therapy was superior to standard therapy alone. These studies suggest that CIK cell immunotherapy is a safe and competent treatment strategy for RCC patients and further studies should investigate different treatment combinations and schedules for optimal application of CIK cells.

Alterations of global histone H4K20 methylation during prostate carcinogenesis.

BACKGROUND: Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. METHODS: Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. RESULTS: Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. CONCLUSIONS: H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

Thulium laser (Revolix) vapoenucleation of the prostate is a safe procedure in patients with an increased risk of hemorrhage.

PURPOSE: To evaluate the feasibility and safety of thulium:yttrium-aluminium-garnet laser vapoenucleation of the prostate (ThuVEP) in patients with chronic anticoagulation and bleeding disorders. METHODS: We retrospectively analyzed the clinical data (transfusion rate, hemoglobin changes, residual urine, bleeding complications, complications and residual urine) of patients with chronic anticoagulation and bleeding disorders treated with ThuVEP. Anticoagulation was not paused for surgery. RESULTS: We identified 39 patients who fulfilled the inclusion criteria (32 with chronic anticoagulation, 3 with bleeding disorder, and 4 with both). Mean preoperative hemoglobin was 12.9 g/l; the postoperative hemoglobin was 11.7 g/l. One patient received a blood transfusion. Mean residual urine was 166 ml preoperatively and 47 ml postoperatively, respectively; spontaneous voiding postoperatively was feasible in 36 patients. During follow-up, 5 patients suffered from gross hematuria, which was treated conservatively. CONCLUSIONS: ThuVEP is a safe procedure in patients with therapeutic anticoagulation, bleeding disorders and platelet aggregation inhibitor medication.

Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe.

OBJECTIVE: To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). STUDY DESIGN: Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were compared with identify factors that contribute to phenotype severity. RESULTS: Males were overrepresented in all subgroups. A relatively high prevalence of cleft lip, with or without cleft palate, was observed. Maternal smoking and medical radiation during the first trimester were associated with the severe cloacal exstrophy phenotype. Compliance with periconceptional folic acid supplementation was associated with the mildest phenotype (epispadias). CONCLUSIONS: Periconceptional folic acid supplementation appears to prevent the development of the severe phenotype of BEEC.

Global histone H4K20 trimethylation predicts cancer-specific survival in patients with muscle-invasive bladder cancer.

OBJECTIVE: •To determine the role of global histone methylation as a prognostic parameter in patients with bladder cancer. PATIENTS AND METHODS: •We used a tissue microarray with samples from patients with non-muscle-invasive bladder cancer (NMIBC; n= 161), muscle-invasive bladder cancer (MIBC, n= 127), normal urothelium (NU; n= 31) and bladder cancer metastases (METS; n= 31) to determine global histone methylation (me) levels at histone H3 lysine 4 (H3K4) and H4K20. RESULTS: •Global histone modification levels (H3K4me1, H3K4me3, H4K20me1, H4K20me2, and H4K20me3) were lower in bladder cancer samples than in NU tissue •Global levels of H3K4me1, H4K20me1, H4K20me2 and H4K20me3 were decreasing from NU over NMIBC and MIBC to METS. •H4K20me1 levels were increased in patients with NMIBC with advanced pTstage and less differentiated bladder cancer. •In patients with MIBC, pTstage was negatively correlated with H3K4me1, H4K20me1 and H4K20me2 levels. •H4K20me3 levels were significantly correlated in a univariate and multivariate model with bladder cancer-specific mortality after radical cystectomy in patients with MIBC. CONCLUSION: •Global histone methylation levels may help to identify patients with bladder cancer with poor prognosis after radical cystectomy.

Evoluting the invaginated--one step closer to the perfect valve? Modified serosal lined tapered ileum (Kälble's procedure) as a continence mechanism for catheterizable pouches.

INTRODUCTION: A sufficient and easily catheterizable continence mechanism is essential in continent cutaneous pouches. Kälble embedded a tapered ileum as efferent segment into a serosal lined tunnel formed by an ileal 'U' according to the principle of Abol-Enein and Ghoneim. We report a modified technique applied in a series of 12 patients who had undergone different urinary diversions. METHODS: All patients received a modified Kälble procedure (first-line urinary diversion, n = 8; revision/undiversion, n = 4) for different forms of continent pouches. To alleviate embedding of the efferent segment, ileal detubularization was performed asymmetrically. Mean follow-up was 9.5 months. RESULTS: All patients were continent and performed self-catheterization easily. Of 12 patients, 2 underwent endoscopic incision for stomal stenosis 8 and 12 months postoperatively. CONCLUSIONS: Subject to our short follow-up, Kälble's technique is a promising alternative in patients undergoing a continent cutaneous urinary diversion but offers an inapplicable or missing appendix.

Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma.

Epigenetic alterations play an important role in carcinogenesis. Recent studies suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone H3 lysine 4 mono-methyl (H3K4me1), -di-methyl (H3K4me2) and -trimethyl (H3K4me3) patterns in renal cell carcinoma (RCC) using a tissue microarray with 193 RCC (including 142 clear cell, 31 papillary, 10 chromophobe and 10 sarcomatoid RCC) and 10 oncocytoma specimens: H3K4me3 staining was more intense in papillary RCC, whereas H3K4me1 and H3K4me2 were similar in the diverse RCC subtypes. H3K4me2 and H3K4me3 levels were increased in oncocytoma. H3K4me1-3 levels were inversely correlated with Fuhrman grading, pT stage, lymph node involvement and distant metastasis. Progression-free survival and cancer-specific survival were shorter in patients with low levels of H3K4me1-3 in the univariate analysis, but we did not observe a significant correlation of a single modification in a multivariate model, which also included the established prognostic parameters TNM-stage and Fuhrman grade. In comparison, the H3K4me score, which combined staining levels of the H3K4 modifications, was an independent predictor of RCC progression-free survival. Our study on H3K4 methylation supports the concept of global histone modifications as potential cancer prognosis markers.

Global histone acetylation levels: prognostic relevance in patients with renal cell carcinoma.

Epigenetic alterations play an important role in carcinogenesis. Recent studies have suggested that global histone modifications are predictors of cancer recurrence in various tumor entities. Global histone acetylation levels (histone H3 lysine 9 acetylation [H3K9Ac], histone H3 lysine 18 acetylation [H3K18Ac], total histone H3 acetylation [H3Ac] and total histone H4 acetylation [H4Ac]) were determined in patients with renal cell carcinoma (RCC) using immunohistochemistry in a tissue micro array with 193 RCC and 10 oncocytoma specimens. The histone acetylation pattern was not different among the diverse histological subtypes of RCC or oncocytoma samples. The H3Ac levels were inversely correlated with pT-stage (P = 0.005), distant metastasis (P = 0.036), Fuhrman grading (P = 0.001) and RCC progression (P = 0.029, hazard ratio 0.87). H4Ac deacetylation was correlated with pT-stage (P = 0.011) and grading (P = 0.029). H3K18Ac levels were an independent predictor of cancer-progression following surgery for localized RCC in the univariate (P = 0.001, hazard ratio 0.78) and multivariate (P = 0.005, hazard ratio 0.82) analysis. In conclusion, our study supports the concept of global histone modification levels as a universal cancer prognosis marker, and provides evidence for the use of histone deacetylases inhibitors as future drugs in the therapy of RCC.

Global levels of histone modifications predict prostate cancer recurrence.

PURPOSE: Epigenetic alterations such as DNA methylation and histone modifications play important roles in carcinogenesis. It was reported that global histone modification patterns are predictors of cancer recurrence in various tumor entities. Our study was performed to evaluate histone lysine (H(x)K(y)) and histone acetyl (H(x)Ac) modifications in prostate tissue. MATERIALS AND METHODS: A tissue microarray with 113 prostate cancer (PCA), 23 non-malignant prostate tissues was stained with antibodies against H3K4 mono-(H3K4me1), di-(H3K4me2), tri-(H3K4me3) methylation, H3K9me1, H3K9me2, H3K9me3, H3 and H4 pan-acetylation (H3Ac, H4Ac). We also analyzed H3K4 methylation in patients with advanced PCA (hormone-refractory PCA-HRPC, n = 34; hormone-dependent PCA, n = 30). Sections were scored according the staining intensity and the proportion of epithelial cells showing nuclear staining. RESULTS: H3K4me1, H3K9me2, H3K9me3, H3Ac, and H4Ac were significantly reduced in PCA compared to non-malignant prostate tissue. H3Ac and H3K9me2 levels allowed discrimination of PCA and non-malignant prostate tissue highly specifically (>91%) and sensitively (>78%) as determined via ROC analyses (AUC >0.91). Histone lysine methylation and histone acetylation marks were correlated with clinical-pathological parameters (i.e., digital rectal examination, preoperative PSA, pT-stage, lymph node metastasis, Gleason score). In addition, H3K4me1 was a significant predictor of PSA recurrence following radical prostatectomy. H3K4me1, H3K4me2, and H3K4me3 levels were significantly increased in HRPC. CONCLUSIONS: Global histone modification levels may help to identify patients with adverse prognosis, and represent a target for the future therapy of PCA.

68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases.

Evaluation of Global Histone Acetylation Levels in Bladder Cancer Patients.

BACKGROUND/AIM: Alterations of global histone modification levels have been identified in various tumor entities, including bladder cancer (BCA). Our study was designed to investigate the value of global histone acetylation levels as diagnostic and prognostic biomarker for BCA patients. MATERIALS AND METHODS: A tissue microarray with formalin-fixed paraffin-embedded tissues (271 BCA and 29 normal urothelial samples) was used to determine global histone acetylation levels (histone H3 acetylation (H3Ac); histone H3 lysine 18 acetylation (H3K18Ac); histone H4 acetylation (H4Ac)). RESULTS: Global H3Ac levels were decreased in BCA patients, whereas H3K18Ac and H4Ac levels were similar in both groups. All studied histone acetylation markers were lower in muscle-invasive BCA compared to non-muscle invasive BCA and normal urothelial tissue, thereby indicating a possible prognostic relevance. CONCLUSION: Global histone acetylation levels undergo quantitative alterations during bladder cancer progression and could be helpful to identify patients at risk for early cancer recurrence.

Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer.

Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64-82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17-2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients.

Matched-pair analysis of dendritic cell versus targeted-therapy in patients with metastatic renal cell carcinoma.

BACKGROUND/AIM: Although targeted-therapy (TT) for patients with metastatic renal cell cancer (mRCC) has shown an improved outcome, their prognosis is still very poor. Immunotherapy with dendritic cells (DC) as one promising new treatment tries to fight cancer by boosting the patient's own immune system. The present analysis matches two different methods of treatment against mRCC, namely sequential TT versus DC vaccine therapy, by comparison of long-term overall survival (OS). PATIENTS AND METHODS: Data of patients treated with DC vaccines (N=30) in three clinical phase I/II trials (1999-2003) and patients treated with clinical standard targeted-therapy (N=30) at the University Hospital of Bonn (2010-2013) were analyzed regarding their OS, as well as specific characteristics such as number and localization of metastatic sites. RESULTS: The mean OS from the first treatment was significantly higher in the TT than in the DC group (48 versus 21 months, range=3-85 months versus 1-57 months, respectively; p=0.0002). Patients with one (p=0.036) or two metastases (p=0.037) and especially patients with bone metastases (52 versus 12 months; p<0.0001) benefited significantly from TT. However, there was no significant difference between therapy types in patients with lung (p=0.147) or liver (p=0.745) metastases, or in patients with more than two metastatic sites (p=0.074). CONCLUSION: Targeted therapy is an effective treatment against mRCC, but is limited due to common adverse events and a higher toxicity when combinations of different-targeted agents are used. Immunotherapy with DC vaccines seems to be a potent and well-tolerated therapy against mRCC, possibly showing higher benefit for patients with specific sites of metastasis, and should be investigated as a co-treatment with TT in further studies.