Overactive bladder syndrome: an underestimated long-term problem after treatment of patients with localized prostate cancer?

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? In this study we observed courses of micturition symptoms and differentiated degrees of symptoms for each point in time while also considering the impact of bothersomeness. Our data show that not only significantly more patients who have undergone BT suffer from OAB than those who have undergone RP, but also that those affected show significantly higher values for severity of OAB symptoms throughout the whole observation period of 36 months. Our data analysis further shows that variability of OAB symptoms as well as fluctuation of severity of OAB symptoms vary to a significantly higher degree after BT than after RP. Looking only at mean figures at a given point in time clearly underestimates the underlying problem. This fact is not reflected in the literature. OBJECTIVE: • To look at individual courses of postoperative micturition symptoms, especially urgency, in patients treated either with radical prostatectomy (RP) or with brachytherapy (BT). PATIENTS AND METHODS: • In a prospective longitudinal study we investigated individual changes in micturition symptoms before treatment, and 6, 12, 24 and 36 months after treatment. • All patients received the European Organization for the Research and Treatment of Cancer quality-of-life questionnaire, QLQ-C30, and the International Continence Society male questionnaire at each assessment. • We looked at long-term results as well as changes in time using repeated measures analysis of variance. We further analysed fluctuation of symptoms using sum of changes. RESULTS: • Of the 389 patients treated consecutively in our clinic over the last few years, 99 patients with a mean (sd) age of 65 (6.3) years had completed all five questionnaires and thus were further analysed. Of these, 66 (66.7%) were treated with RP and 33 (33.3%) with BT. • With the exception of age, no significant difference was found between the treatment groups either in physical functioning or in prevalence and severity of overactive bladder (OAB) symptoms. • Adjusted for age and pretreatment symptoms in analysis of covariance, we found that there were statistically more symptoms of OAB 36 months after BT compared with those patients treated with RP (P < 0.025). Whereas 30% of patients complained about severe symptoms of urgency after BT, only 11% did so after RP. • Changes of severity of OAB symptoms over the course of time (P < 0.007) using analysis of repeated measures as well as variability of OAB symptoms (P < 0.033) using the two-sided Wilcoxon t-test were significantly higher in patients treated with BT than in patients treated with RP. CONCLUSIONS: • Independently of age and physical functioning, BT is significantly associated with higher rates of long-term urgency symptoms, even after 3 years. • Repeated measurements show that OAB symptoms are highly fluctuating and that in patients treated with BT, severity of symptoms as well as variability of symptoms was significantly higher than in those patients treated with RP. • Persistent OAB seems to be an underestimated problem after treatment for localized prostate cancer, especially in patients treated with BT.

Clonal architecture of human prostatic epithelium in benign and malignant conditions.

The location of stem cells in the epithelium of the prostatic acinus remains uncertain, as does the cellular origin of prostatic neoplasia. Here, we apply lineage tracing to visualize the clonal progeny of stem cells in benign and malignant human prostates and understand the clonal architecture of this epithelium. Cells deficient for the mitochondrially-encoded enzyme cytochrome c oxidase (CCO) were identified in 27 frozen prostatectomy specimens using dual colour enzyme histochemistry and individual CCO-normal and -deficient cell areas were laser-capture microdissected. PCR-sequencing of the entire mitochondrial genome (mtDNA) of cells from CCO-deficient areas found to share mtDNA mutations not present in adjacent CCO-normal cells, thus proving a clonal origin. Immunohistochemistry was performed to visualize the three cell lineages normally present in the prostatic epithelium. Entire CCO-deficient acini, and part-deficient acini were found. Deficient patches spanned either basal or luminal cells, but sometimes also both epithelial cell types in normal, hyperplastic or atrophic epithelium, and prostatic intraepithelial neoplasia (PIN). Patches comprising both PIN and invasive cancer were observed. Each cell area within a CCO-deficient patch contained an identical mtDNA mutation, defining the patch as a clonal unit. CCO-deficient patches in benign epithelium contained basal, luminal and endocrine cells, demonstrating multilineage differentiation and therefore the presence of a stem cell. Our results demonstrate that the normal, atrophic, hypertrophic and atypical (PIN) epithelium of human prostate contains stem cell-derived clonal units that actively replenish the epithelium during ageing. These deficient areas usually included the basal compartment indicating the basal layer as the location of the stem cell. Importantly, single clonal units comprised both PIN and invasive cancer, supporting PIN as the pre-invasive lesion for prostate cancer.

The human urothelium consists of multiple clonal units, each maintained by a stem cell.

Little is known about the clonal architecture of human urothelium. It is likely that urothelial stem cells reside within the basal epithelial layer, yet lineage tracing from a single stem cell as a means to show the presence of a urothelial stem cell has never been performed. Here, we identify clonally related cell areas within human bladder mucosa in order to visualize epithelial fields maintained by a single founder/stem cell. Sixteen frozen cystectomy specimens were serially sectioned. Patches of cells deficient for the mitochondrially encoded enzyme cytochrome c oxidase (CCO) were identified using dual-colour enzyme histochemistry. To show that these patches represent clonal proliferations, small CCO-proficient and -deficient areas were individually laser-capture microdissected and the entire mitochondrial genome (mtDNA) in each area was PCR amplified and sequenced to identify mtDNA mutations. Immunohistochemistry was performed for the different cell layers of the urothelium and adjacent mesenchyme. CCO-deficient patches could be observed in normal urothelium of all cystectomy specimens. The two-dimensional length of these negative patches varied from 2-3 cells (about 30 µm) to 4.7 mm. Each cell area within a CCO-deficient patch contained an identical somatic mtDNA mutation, indicating that the patch was a clonal unit. Patches contained all the mature cell differentiation stages present in the urothelium, suggesting the presence of a stem cell. Our results demonstrate that the normal mucosa of human bladder contains stem cell-derived clonal units that actively replenish the urothelium during ageing. The size of the clonal unit attributable to each stem cell was broadly distributed, suggesting replacement of one stem cell clone by another.

Impact of age and comorbidities on health-related quality of life for patients with prostate cancer: evaluation before a curative treatment.

BACKGROUND: Interpretation of comparative health-related quality of life (HRQOL) studies following different prostate cancer treatments is often difficult due to differing patient ages. Furthermore, age-related changes can hardly be discriminated from therapy-related changes. The evaluation of age-and comorbidity-related changes was in focus of this study. METHODS: HRQOL of 528 prostate cancer patients was analysed using a validated questionnaire (Expanded Prostate Cancer Index Composite) before a curative treatment. Patients were divided into age groups 75 years. The impact of specific comorbidities and the Charlson Comorbidity Index (CCI) were evaluated. The questionnaire comprises 50 items concerning the urinary, bowel, sexual and hormonal domains for function and bother. For assessment of sexual and hormonal domains, only patients without prior hormonal treatment were included (n = 336). RESULTS: Urinary incontinence was observed increasingly with higher age (mean function scores of 92/88/85/87 for patients 75 years) complete urinary control in 78%/72%/64%/58% (p < 0.01). Sexual function scores decreased particularly (48/43/35/30), with erections sufficient for intercourse in 68%/50%/36%/32% (p < 0.01) a decrease of more than a third comparing patients 75 years; p < 0.05). A multivariate analysis revealed an independent influence of both age and comorbidities on urinary incontinence, specifically diabetes on urinary bother, and both age and diabetes on sexual function/bother. Rectal domain scores were not significantly influenced by age or comorbidities. A CCI>5 particularly predisposed for lower urinary and sexual HRQOL scores. CONCLUSION: Urinary continence and sexual function are the crucial HRQOL domains with age-related and independently comorbidity-related decreasing scores. The results need to be considered for the interpretation of comparative studies or longitudinal changes after a curative treatment.

Comparing two types of botulinum-A toxin detrusor injections in patients with severe neurogenic detrusor overactivity: a case-control study.

OBJECTIVE: To compare the efficacy of two types of botulinum toxin type A (BTX-A; Dysport, Ipsen Ltd, Slough, UK) or Botox (Allergan Inc., Irvine, CA, USA) and examine the possible dose-effect relation for Dysport in those patients, as multifocal detrusor injections with BTX-A are effective for severe neurogenic detrusor overactivity in adults. PATIENTS AND METHODS: This was an open-label, observational case-control study comparing Dysport and Botox, and the dose-effect relation for Dysport. The patients included were treated with either Dysport (cases; 500, 750, or 1000 IU), or with Botox (controls: 300 IU, and exceptionally 200 or 400 IU). The continence volume (primary), mean and maximum catheterized volume, and antimuscarinic use were assessed, and cystometric variables measured were overactivity volume (primary), detrusor compliance, and cystometric capacity. All variables were assessed at baseline, 3 and 9 months after treatment, and results analysed using analysis of variance (paired) t-tests, chi-square tests and regression analysis. RESULTS: There were 28 cases and 28 matched controls; their demographic characteristics, bladder management, and baseline values were comparable between the groups. At 3 months there was a significant improvement in cystometric variables and continence volume in both groups, but in mean catheterized volume and reduced use of antimuscarinics in cases only. At 9 months there was no significant improvement over baseline except for the continence volume in the cases. There were no significant differences in results between the groups except for the continence volume at 3 months (459 mL after Dysport and 396 mL after Botox; P=0.015). There was no dose-related response for Dysport at 3.8 months of follow-up. The interval between injections (9.5, 14.5 and 16.1 months for Dysport 500, 750, and 1000 IU; 10.1 months for Botox) was not significant. There were nine non-responders in the Dysport group and seven in the Botox group; the patient characteristics and baseline data were comparable to those of the responders. There was transient hypoasthenia in one of the responders (750 IU Dysport). CONCLUSIONS: A single treatment session with either Dysport or Botox in a setting combined with antimuscarinics might improve the patient's condition for up to a year. There was no clear dose-related effect for Dysport in adults.

Solitary fibrous tumor of the kidney: a case report.

A solitary fibrous tumor of the kidney is a rare neoplasm that was often misdiagnosed as hemangiopericytoma, until recently. We report a case of a 35-year-old male patient with a solid, 7 cm tumor located centrally in a solitary right kidney. The patient underwent successful bench surgery and autotransplantation.

Rectourethral fistula following LDR brachytherapy.

Modern LDR brachytherapy has drastically reduced rectal toxicity and decreased the occurrence of rectourethral fistulas to <0.5% of patients. Therefore, symptoms of late-onset sequelae are often ignored initially. These fistulas cause severe patient morbidity and require interdisciplinary treatment. We report on the occurrence and management of a rectourethral fistula which occurred 4 years after (125)I seed implantation.

Endosew: new device for laparoscopic running sutures.

PURPOSE: In 2002, the first completely laparoscopic cystectomy and orthotopic ileal neobladder procedure was reported to take more than 10 hours, with the most time-consuming portion being suturing. Therefore, to improve the quality and reduce the time to place running sutures, we developed a new sewing device for laparoscopic use. MATERIALS AND METHODS: We compared running sutures made by hand with those made by machine in the ilea of six pigs. The tightness of the closures was examined and the suturing time recorded. Two animals each were sacrificed after 3, 6, and 9 days, and then the explanted ilea were examined at both the macroscopic and microscopic levels. RESULTS: No animal died during the course of the experiment and no leaks were found postoperatively. Moreover, no significant differences were seen on macroscopic or microscopic examination in the quality of the two sets of sutures. The time taken to place 1 cm of running suture, including initial preparation, was 7.2 and 3 minutes for hand and machine suturing, respectively. The hand sutures were always initially tight, whereas those placed by machine required adjustment to stop leaks on four occasions. CONCLUSION: Using the Endosew device reduces the time needed to place running sutures by 2.4-fold. The quality of the hand- and machine-made sutures was nearly identical at both the macroscopic and microscopic level. Thus, the functionality of this new sewing device is more than satisfactory, and the amount of time saved by using it far outweighs the need for occasional adjustments to stop suture leakage.

Evaluation of source displacement and dose--volume changes after permanent prostate brachytherapy with stranded seeds.

BACKGROUND AND PURPOSE: The aim of the study was to analyze source displacements and dose-volume changes in the first month after a permanent implant. MATERIALS AND METHODS: In 51 consecutive patients, CT scans were performed at the postoperative day (day 1) and one month (day 30) after an (125)I implant with stranded seeds. Seed positions were determined relative to pelvic bones for five seeds at the base and five seeds at the apex for each patient (n=510) and compared. To verify these results, treatment margins (TM=distance of prescription isodose to prostate) and displacements of the prostate surface (anterior/posterior/right/left/superior/inferior) relative to pelvic bones were measured. RESULTS: Seed positions have moved significantly between day 1 and 30 in the posterior (mean 1.0mm; p<0.001) and inferior (mean 3.8mm; p<0.001) directions. TM increased particularly at the posterior (mean 2.2mm; p<0.001) and apical (median 3.0mm; p<0.001) prostate contour with decreasing oedema. With a stable apex position and a mean inward posterior surface displacement of 1.1mm (p<0.001) relative to pelvic bones, seed displacements could be well correlated with prescription isodose displacements (Pearson correlation coefficients >or=0.81; p<0.001). CONCLUSIONS: Both changes of prostate volume and seed displacements need to be considered to explain dosimetric changes after permanent prostate brachytherapy.

Identifying prostate carcinoma by MALDI-Imaging.

Prostate cancer has become one of the most common malignancies worldwide. Although lacking in specificity its diagnosis is still based partially on the serum-based test for prostate-specific antigen. As its pathogenesis has not yet been deciphered, the ongoing search for new and more reliable biomarkers remains a challenge to stratify disease onset and progression. Matrix-assisted laser desorption/ionization (MALDI)-Imaging is a promising technique to assist in this endeavor. It delivers accurate mass spectrometric information of the sample's proteins and enables the visualization of the spatial distribution of protein expression profiles and correlation of the information with the histomorphological features of the same tissue section. This study describes the analysis of 22 prostate sections (11 with and 11 without prostate cancer) by MALDI-Imaging. Specific protein expression patterns were obtained for normal and cancerous regions within the tissue sections. Applying a 'support vector machine' algorithm to classify the cancerous from the non-cancerous regions, an overall cross-validation, a sensitivity and specificity of 88, 85.21 and 90.74%, respectively, was achieved. Additionally four distinctively overexpressed peaks were identified: 2,753 and 6,704 Da for non-cancerous glands, and 4,964 and 5,002 Da for cancerous glands. The results of this first clinical study utilizing the new technique of MALDI-Imaging underline its vast potential to identify candidates for more reliable prostate cancer tumor markers and to enlighten the pathogenesis of prostate cancer.

Laparoscopic heminephrectomy and resection of ectopic ureter in an adult.

We report a unique case of a duplex kidney and ectopic ureter presenting as a cystic tumor of the seminal vesicle with consecutive dysuria in an adult. The medical history of the patient, the diagnostic pathway and the laparoscopic treatment as well as the key points in laparoscopic surgery are described.

Dose-volume impact in high-dose-rate Iridium-192 brachytherapy as a boost to external beam radiotherapy for localized prostate cancer--a phase II study.

BACKGROUND AND PURPOSE: Evaluation of dose-volume-time-related factors in 64 patients treated with high-dose-rate brachytherapy (HDR-BT) as a boost to external beam radiotherapy (EBRT) for localized prostate cancer. PATIENTS AND METHODS: Clinical parameters were correlated with morbidity scores of the EPIC (Expanded Prostate Cancer Index) questionnaire. Median time after radiotherapy (HDR-BT up to 18 Gy in two fractions and EBRT up to a median dose of 50.4 Gy) was 1.5 and 3 years (first and second questionnaire). RESULTS: A significant impact of a urethra D1 exceeding 15 Gy in at least one HDR fraction concerning urinary morbidity and a rectum D1 exceeding 6 Gy to the rectal mucosa in the first and second HDR fraction concerning the rectal bleeding rate was found. A higher number of needles was associated with lower urinary and bowel scores after 1.5 years. A prostate length >4.8 cm and a longer duration of EBRT (independently of the dose) predisposed for lower urinary and bowel scores. In contrast to a urethra D1 > 15 Gy as an independent factor, a rectum D1 > 6 Gy per HDR fraction correlated with a higher number of needles and an increased prostate length. CONCLUSIONS: To minimize morbidity in HDR-BT for prostate cancer, a maximum dose to the urethra of 15 Gy and a maximum dose to the rectal mucosa of 6 Gy is advisable. Treatment- and patient-related factors have a major impact on toxicity.

Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors.

We evaluated clinical characteristics, patient outcome (mean follow-up, 47 months), and cytogenetic abnormalities in the largest as yet reported cytogenetic series of 47 primary and 11 secondary papillary renal cell carcinomas for differences between the recently proposed type 1 and type 2 subtypes. Secondary tumors were more often of type 2 morphology (P = 0.02), whereas primary type 2 tumors were associated with higher clinical stage (P = 0.001) and worse patient outcome (P = 0.02). Although both subtypes had at least one of the primary chromosomal gains at 17q, 7, and 16q, type 2 tumors had moderately lower frequencies of primary gains at 17p (61 versus 94%; P = 0.007) and 17q (72 versus 97%; P = 0.02). On the other hand, type 2 tumors overall had more chromosomal alterations than type 1 tumors (P = 0.01), particularly gains of 1q (28 versus 3%; P = 0.02) and losses of 8p (33 versus 0%; P = 0.001), 11 (28 versus 3%; P = 0.02), and 18 (44 versus 9%; P = 0.01). Hierarchical clustering suggested cytogenetic patterns common but not restricted to type 2 morphology, one characterized by multiple additional gains, and another predominantly showing additional losses. These findings provide genetic evidence that type 1 and type 2 tumors arise from common cytogenetic pathways and that type 2 tumors evolve from type 1 tumors. Independently of type, losses of 9p were statistically correlated with advanced disease (P = 0.0008) and may serve as a potential adverse prognostic marker in papillary renal cell carcinomas.

In cystectomy specimens with bladder cancer whole organ embedding increases the detection rate of histopathological parameters, but not of those with prognostic significance.

Histological tumor subtyping, staging, and grading are of utmost importance to stratify patients with bladder cancer for treatment and should be as precise as possible. In the presented study, we investigated the prognostic impact of standard clinicopathological parameters in cystectomy patients and compared embedding of the entire bladder with standard partial embedding via a virtual superimposed approach. The study included 121 cystectomy specimens, which were completely embedded. Clinical and histopathological data of patients were obtained (median follow-up 21.5 months; range 1-67 months). For 88 patients two-dimensional tumor maps (macrophotographs and histology-based maps) were prepared, and embedding of the entire bladder was compared with a virtual standard partial embedding, created by a virtual overlay and data extraction of the tumor maps. Kaplan-Meier plots, Cox regression estimators, Chi-square, and McNemar tests were used. In a multivariate Cox regression model for overall survival, only venous invasion (p = 0.008, HR = 3.35, 95 % CI 1.375-8.161) and organ-confined (pTis-pT2) versus non-organ-confined diseases (pT3-pT4; p = 0.021, HR 2.669, 95 % CI 1.157-6.159) were found significant. Advanced versus standard embedding revealed significant improvement in the detection of carcinoma in situ (50 versus 61, p = 0.003) and lymphatic invasion (18 versus 24, p = 0.041), but no significant advantage in the detection of tumor stage, tumor multifocality, or venous invasion (all p > 0.05). TNM classification, including lymphatic and venous invasion, is of utmost importance to stratify patients with advanced invasive bladder cancer. Histopathological details are detected more reliably by whole organ embedding, but this approach showed no significant benefit in terms of outcome-related parameters (max. tumor stage, venous invasion) in our cohort.

Quality of life following radical prostatectomy.

Radical prostatectomy is a procedure performed with increasing frequency in patients with localized prostate cancer. Although, the operative morbidity is considerably low, urinary incontinence and erectile dysfunction remain an important and persistent problem. Since several years the impact of radical prostatectomy on the quality of life (HRQOL) is investigated. However, there are only few prospective studies dealing with rather small groups of patients. These studies indicate that urinary and sexual function have major impact on HRQOL. Although, there is a steady improvement in urinary function and decrease in urinary bother only about 65% of the patients reach the baseline at the end of the first year. In spite of this almost 90% of patients reach baseline in all other HRQOL domains such as general health perception, physical and social function after a mean period of 5 months. The importance of sexual desire and erectile capacity decreases with age; being important in 75 and 84% of men at the 5th decenium and 48 and 59% at the 6th decenium. After standard radical prostatectomy almost all of the patients are impotent. Applying so-called nerve sparing techniques erectile function may be preserved in careful selected patients. It is the common theme that preservation of the 'neurovascular bundles' equals a high rate, but still age depended postoperative potency; however difficulties in regaining urinary control may embarrass the patient to such an extent to withdraw from sexual activity. Furthermore, the change of sexual ability and quality may have impact on the partner who do not want to initiate sexual activity because of the possible failure. This may cause an increased level of emotional distance, which again is deleterious for sexual activities. Patients who are sexually active prior to surgery report major distress in case of postoperative erectile impotence, but even in case of maintained erectile capacity some patients are bothered by the sexual dysfunction. Sexual counselling and providing the optimal erectile aid is therefore very important. Psychological distress of spouses may be significantly greater than that of the patients; general cancer distress, treatment related worries, concerns on physical limitations and pain are the main reasons. However, it may well be that women are willing to report their problems more often than their partners who may have a grin-and-bear-it attitude. In spite of this caveate, it is important to include the patient's spouse into the discussions on therapy and associated morbidity early on. Since radical prostatectomy for localized prostate cancer is only one of the possible treatment options, the patient has to be informed about the incidence and various types of morbidity which is associated with treatment and their possible impact on HRQOL. Appropriate and honest counselling will have significant influence on the well being of the patient after completing therapy.

Therapy of local recurrence of renal cell carcinoma.

Local recurrence (LR) of renal cell carcinoma (RCC) after nephrectomy is a rare event with a poor prognosis. The clinical outcome of 15 patients with LR after tumor nephrectomy was analyzed retrospectively. Within a mean follow-up of 28 months (1-110 months) the mean time to recurrence (TTLR) was 23 months. Mean time to further tumor progression (TTP) after surgery was 22.2 months (11-32 months), after surgery and adjunctive therapy 6.8 months (3-15 months+) and after chemoimmunotherapy alone 3.6 months (3-6 months). Tumor specific survival (TSS) rate was 47% at 1 year and 33% at 3 years. Mean TSS after surgery was 62.2 months (38-110 months), after resection and adjunctive treatment 26 months (8-74 months) and after chemoimmunotherapy 9.2 months (7-15 months). In conclusion, surgery is recommended for treatment of LR. Additional benefit is not confirmed for any adjuctive therapy.

Levels of acyl-coenzyme A synthetase 5 in urothelial cells and corresponding neoplasias reflect cellular differentiation.

Metabolic components like fatty acids and acyl-Coenzyme A (acyl-CoA) thioesters have been implicated in the pathogenesis of various tumours. The activation of fatty acids to acyl-CoAs is catalysed by long chain acyl-CoA synthetases (ACSLs), and impairment of ACSL expression levels has been associated with tumourigenesis and progression. Since ACSLs have never been investigated in bladder tissues, the study aims to characterize ACSL expression and acyl-CoA synthesis in normal and neoplastic bladder tissues, as well as cell lines. ACSL isoforms 1, 3, 4 and 5 and synthesis of acyl-CoAs were analysed using qRT-PCR, western blot analysis, immunohistochemistry and lipid mass spectrometry. In normal urothelium, expression of ACSL1, 3, 4 and 5, with highest levels of ACSL isoform 5 was found. However, ACSL5 expression was reduced in corresponding neoplastic tissues and urothelial cell lines depending on the grade of cellular differentiation. Anti-ACSL5 immunostainings showed expression in normal urothelium and a gradual loss of ACSL5 protein via pre-invasive lesions to invasive carcinomas. High expression of ACSL5 correlated with increased α-galactosidase activity and positive Uroplakin III staining in tumours. In contrast, synthesis of acyl-CoAs was enhanced in neoplastic bladder tissues compared to normal urothelium, and reflected an increase with respect to cellular differentiation. These results confirm an expression of ACSLs, especially isoform 5, in human urothelium, prove enzymatic/lipidomic changes in bladder cancer tissues, and suggest an involvement of ACSL5 in cellular maturation and/or senescence with possible effects onto induction of tumour formation or progression. Further work may identify responsible pathway alterations, and attempting to re-balance the metabolic equilibrium of the urothelium may offer a further opportunity for tumour treatment and prevention.