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Herein we evaluated a series of 21 embryonal rhabdomyosarcomas of the uterine corpus (ucERMS), a rare neoplasm, to characterize their morphology, genomics, and behavior. Patients ranged from 27 to 73 (median 52) years and tumors from 4 to 15 (median 9) cm, with extrauterine disease noted in two. Follow-up (median 16 months) was available for 14/21 patients; nine were alive and well, four died of disease, and one died from other causes. Most tumors (16/21) showed predominantly classic morphology, comprised of alternating hyper- and hypocellular areas of primitive small cells and differentiating rhabdomyoblasts in a loose myxoid/edematous stroma. A cambium layer was noted in all; seven had heterologous elements (six with fetal-type cartilage) and eight displayed focal anaplasia. The remaining five neoplasms showed only a minor component (

Objective: The incidence of non-urothelial bladder cancers is very low, so our knowledge about their treatment protocols and prognosis is limited. We evaluated the clinicopathological characteristics of 26 patients in three different clinics and aimed to determine the prognostic factors affecting oncological outcomes. Materials and Methods: Between January 2012 and October 2019, we retrospectively analyzed the data of twenty-six patients aged between 44-75 years who were diagnosed and treated due to non-urothelial bladder carcinomas in three clinics. Results: Among twenty-six cases, nineteen (73.1%) were male and seven (26.9%) were female. The mean age at diagnosis was 60.77 +/- 8.52. The most common presenting complaint was gross hematuria (84.6%). It was followed by lower urinary tract symptoms (38.4%). Histological types of tumors were squamous cell carcinoma (9 cases, 34.8%), adenocarcinoma (eight cases carrying different histopathologic subtypes: Mucinous, signet ring cell, plasmacytoid/signet ring cell mixed variant and signet ring cell containing osteoclast-like giant cell, 30.8%), small cell carcinoma (3 cases, 11.5%), large cell neuroendocrine carcinoma (2 cases, 7.7%), extra-gastrointestinal stromal tumor (1 case, 3.8%) and malignant undifferentiated mesenchymal tumor (1 case, 3.8%) and leiomyosarcoma (2 cases, 7.6%). At a median follow-up of 13 (2-42) months, the progression-free survival rate was 61.5%, while the overall survival rate was 46.1%. In Kaplan-Meier analysis, the median survival of all cases was found to be 16 (9-33) months. Overall survival times were lower in the presence of advanced (3-4) pathological stages (p=0.006) and higher (>= 2) ECOG scores (p=0.005). Conclusion: In our cases, we observed that overall survival rates increased in patients undergoing multimodal treatments involving radical cystectomy compared to the bladder-sparing approach. The survival rates were higher in squamous cell carcinomas, while the rate of metastasis was higher in adenocarcinoma and neuroendocrine tumors. Up-staging rates after cystectomy were higher in adenocarcinomas, sarcomas and squamous cell carcinomas.

ObjectiveBetween 10 and 20% of bladder cancer patients who are diagnosed with nonmuscle-invasive bladder cancer will progress to muscle-invasive disease. Risk of progression depends on several factors at diagnosis including age, tumour stage, grade, size and number, and the presence or absence of carcinoma in situ. Fluid intake may be related to these factors.MethodsData of 1123 participants from the West Midlands Bladder Cancer Prognosis Programme were used. Data collection was via a semistructured questionnaire, and case report forms were used to collect clinicopathological data. Fluid intake was measured for six main categories: alcoholic fluids, hot fluids, fruit fluids, milk, fizzy drinks, and water, and converted into quintile variables. Multilevel mixed-effects linear regression was performed for every beverage category per clinicopathological variable and corrected for age, gender, and smoking status.ResultsAge at diagnosis was distributed differently amongst those in different total fluid intake quintiles (predicted means 71.5, 70.9, 71.5, 69.9, and 67.4, respectively) and showed a significant inverse linear trend in alcohol (P ConclusionOur results suggest an inverse association for alcohol intake and total fluid intake with age at diagnosis. These results should be confirmed by future studies, alongside a possible (biological) mechanism that could influence tumour growth, and the effect of micturition frequency.

Purpose Enterocystoplasty is adopted for patients requiring bladder augmentation, but significant long-term complications highlight need for alternatives. We established a protocol for creating a natural-derived bladder extracellular matrix (BEM) for developing tissue-engineered bladder, and investigated its structural and functional characteristics. Methods Porcine bladders were de-cellularised with a dynamic detergent–enzymatic treatment using peristaltic infusion. Samples and fresh controls were evaluated using histological staining, ultrastructure (electron microscopy), collagen, glycosaminoglycans and DNA quantification and biomechanical testing. Compliance and angiogenic properties (Chicken chorioallantoic membrane [CAM] assay) were evaluated. T test compared stiffness and glycosaminoglycans, collagen and DNA quantity. p value of Results Histological evaluation demonstrated absence of cells with preservation of tissue matrix architecture (collagen and elastin). DNA was 0.01 μg/mg, significantly reduced compared to fresh tissue 0.13 μg/mg (p p p = 0.011). CAM assay showed significantly increased number of convergent allantoic vessels after 6 days compared to day 1 (p Conclusion Dynamic detergent–enzymatic treatment produces a BEM which retains structural characteristics, increases strength and stiffness and is more compliant than native tissue. Furthermore, BEM shows angiogenic potential. These data suggest the use of BEM for development of tissue-engineered bladder for patients requiring bladder augmentation.

Villous adenomas (VAs) in the female urethra are rare with only seven cases in the English literature to our knowledge. In patients with bladder augmentation cystoplasty, the neoplasia development risk increases and most of these develop in the neobladder or anastomosis line. Only two cases of VA developing from the native bladder mucosa have been reported. Physical examination of a 76-year-old female who had a history of augmentation cystoplasty revealed a caruncula-like structure protruding from the urethral meatus. The urinary USG showed that the lesion had no relation with the bladder. The lesion was excised. Microscopically, it consisted of villous structures covered with pseudostratified intestinal type epithelium. Low-grade dysplasia was present in the epithelium but high-grade dysplasia or in-situ/invasive carcinoma was not observed. Immunohistochemical study showed positivity for CK7, CK20, EMA, CEA and CDX2. The case was reported as VA of the urethra. We presented the first VA case arising in the urethra of a female patient with intestinal bladder augmentation. Excision is curative for pure VAs. Transformation to carcinoma or recurrence has not been reported. However, in one third of the cases, a malignant tumor may accompany the lesion. Therefore, all excision material should be examined carefully. Routine endoscopic follow-up should be performed in cases with bladder augmentation.

AimsThis manuscript aims to address the evidence availale in the literature on the efficacy of Botulinum Toxin A (BoNT-A) and sacral neuromodulation (SNM) in patients suffering from Interstitial Cystitis (IC)/BPS and propose further research to identify mechanisms of action and establish the clinical efficacy of either therapy. MethodsAt the International Consultation on Incontinence-Research Society (ICI-RS) in 2017, a panel of Functional Urologists and Urogynaecologists participated in a Think Tank (TT) discussing the management of IC/BPS by BoNT-A and SNM, using available data from both PubMed and Medicine literature searches. ResultsThe role of BoNT-A and SNM in the treatment of IC/BPS are discussed and mechanisms of actions are proposed. Despite the available randomized trial data on the effect of intravesical BoNT-A treatment on symptoms of IC/BPS, a consistent conclusion of a positive effect cannot be drawn at the moment, as the published studies are small and heterogeneous in design. There is substantive evidence for the positive effects of SNM on symptoms of IC/BPS patients however, during patient selection, it is important to distinguish the degree and the location of pain in order to tailor the best therapy to the right patients. ConclusionsBoth intravesical BoNT-A treatment and SNM have been shown to have positive effects in patients with IC/BPS. However, firm conclusions cannot yet be drawn. Patient-reported outcomes and quality of life should be assessed in addition to urinary and pain symptoms. Since current treatments mainly focus on symptomatic relief, future research should also focus on clarifying the pathogenic mechanisms involved in IC/BPS.

OBJECTIVES: To create an animal model for neurogenic underactive bladder disease (UAB) and identify markers to describe secondary myogenic changes in the bladder wall. MATERIALS AND METHODS: Male rats underwent either bilateral pelvic nerve injury or sham surgery. Four weeks after surgery functional evaluation was performed and tissue was harvested. Functional evaluation consisted of analysis of voiding pattern, 24-h urine collection in a metabolic cage, in vivo cystometry and in-vitro contractile function assessment. PCR and immunohistochemical localization of different smooth muscle cell and extracellular matrix markers was performed on bladder strips. RESULTS: After pelvic nerve injury, dry bladder weight increased and voiding contractions were absent, resulting in overflow incontinence. In-vitro contractile response to carbachol was decreased. This was paired with an upregulation of synthetic smooth muscle cell (SMC) markers mRNA expression such as retinol binding protein 1 (RBP1), myosin 10 (MYH10) and osteopontin (OPN), and a downregulation of contractile SMC marker smoothelin (SMTL). The SMTL/OPN mRNA ratio was 50 times higher in sham bladders compared to PNI bladders. CONCLUSIONS: The loss of in-vivo and in-vitro contractile function following pelvic nerve transection is characterized by a switch from a contractile to synthetic SMC phenotype, which is best characterized by the ratio SMTL/OPN mRNA expression. Modulating this phenotypical switch is a potential target for the development of UAB therapy. We suggest for the first time a set of markers that may be useful to evaluate therapeutic strategies on improvements in bladder wall structure. ispartof: NEUROUROLOGY AND URODYNAMICS vol:37 issue:5 pages:1594-1604 ispartof: location:United States status: published

AIMS This manuscript aims to address the evidence availale in the literature on the efficacy of Botulinum Toxin A (BoNT-A) and sacral neuromodulation (SNM) in patients suffering from Interstitial Cystitis (IC)/BPS and propose further research to identify mechanisms of action and establish the clinical efficacy of either therapy. METHODS At the International Consultation on Incontinence-Research Society (ICI-RS) in 2017, a panel of Functional Urologists and Urogynaecologists participated in a Think Tank (TT) discussing the management of IC/BPS by BoNT-A and SNM, using available data from both PubMed and Medicine literature searches. RESULTS The role of BoNT-A and SNM in the treatment of IC/BPS are discussed and mechanisms of actions are proposed. Despite the available randomized trial data on the effect of intravesical BoNT-A treatment on symptoms of IC/BPS, a consistent conclusion of a positive effect cannot be drawn at the moment, as the published studies are small and heterogeneous in design. There is substantive evidence for the positive effects of SNM on symptoms of IC/BPS patients however, during patient selection, it is important to distinguish the degree and the location of pain in order to tailor the best therapy to the right patients. CONCLUSIONS Both intravesical BoNT-A treatment and SNM have been shown to have positive effects in patients with IC/BPS. However, firm conclusions cannot yet be drawn. Patient-reported outcomes and quality of life should be assessed in addition to urinary and pain symptoms. Since current treatments mainly focus on symptomatic relief, future research should also focus on clarifying the pathogenic mechanisms involved in IC/BPS.

OBJECTIVE. DWI has been increasingly applied in the management of bladder cancer. In this article, we discuss the role of DWI as an imaging biomarker for bladder cancer.CONCLUSION. The DWI signal is derived from the motion of water molecules, which represents the physiologic characteristics of the tissue of interest. The emerging evidence highlights the utility of DWI for bladder cancer detection and characterization. DWI is a potentially useful tool to individualize treatment strategies.

Background We examined the association between kidney stones and renal cell carcinoma (RCC) and upper tract urothelial carcinoma (UTUC) risk in the Netherlands Cohort Study on diet and cancer. Methods In total, 120,852 participants aged 55–69 completed a self-administered questionnaire on diet, medical conditions and other risk factors for cancer at baseline (1986). After 20.3 years of cancer follow-up 4352 subcohort members, 544 RCC cases and 140 UTUC cases were eligible for case-cohort analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated by multivariable-adjusted proportional hazards models. Results Kidney stones were associated with an increased RCC risk (HR: 1.39, 95% CI 1.05–1.84), vs. no kidney stones. Kidney stones were associated with an increased risk of papillary RCC (HR: 3.08, 95% CI 1.55–6.11), but not clear-cell RCC (HR: 1.14, 95% CI 0.79–1.65). UTUC risk was increased for participants with kidney stones (HR: 1.66, 95% CI 1.03–2.68). No heterogeneity of associations was found for UTUC in the ureter and renal pelvis. An early kidney stone diagnosis (≤40 years) was associated with an increased RCC and UTUC risk, compared to later diagnosis. Conclusion Kidney stones were associated with increased papillary RCC risk, but not clear-cell RCC risk. No heterogeneity was found for UTUC subtypes.

We herein reported 2 rare cases of urinary bladder paraganglioma presenting with severe postmicturition syndrome and paroxysmal hypertension, in the absence of hematuria. Biochemical tests of plasma catecholamines after symptoms' onset and determinations of metanephrines in plasma or urine can assist in screening for paragangliomas but can also be falsely negative due to multiple factors such as small tumor size, preanalytical procedures, and concomitant medications. Imaging tests are required to identify the location and size of the tumor, with thorax, abdomen, and pelvis CT scans recommended. Functional imaging examinations including MIBG, octreotide scintigraphy, and positron emission tomography are needed to identify additional lesions and their function via whole-body exploration. Diagnostic accuracy of different functional imaging examinations highly depends on the type and location of tumors and requires further investigation. Genetic tests are valuable for prediction of increased risk of malignancy in affected individuals and their relatives. Surgery after sufficient adrenergic blockage remains the mainstream treatment for localized tumors with generally optimistic outcomes. Longterm follow-up is necessary to monitor tumor recurrence.

Trichodinids are parasites generally found on gills and skin of a broad number of aquatic animals. Only a small number of endozoic species has been reported from the urinary tract, intestine and urogenital system in some fish, amphibians and molluscs. This is the first report on the presence of endozoic trichodinids in the spleen, kidney and liver of shorthorn sculpin (Myoxocephalus scorpius). In the present study, trichodinids displayed some of the typical morphological characteristics of endozoic trichodinids with narrow blades and straight rays of adhesive disc denticles. The parasites were observed at a relatively high prevalence (23.9%). There was a positive correlation between intensity of endozoic trichodinids in the internal organs and ectozoic trichodinids on the gills (R = 0.5, n = 46, P < 0.001) whereas there was no correlation between intensity of endozoic trichodinids and the host's body length, body weight or liver weight. Infection levels of endozoic trichodinids were not dependent upon sculpin sex and there was no effect of sampling locations on prevalence and intensity of endozoic trichodinids.

Objectives To determine the phenotype of the ventrolateral part of the periaqueductal gray matter neurons after bladder stimulation. Methods In the experimental group, electrical stimulation of the bladder was carried out under freely moving condition by a bipolar stimulation electrode implanted in the bladder wall. Thereafter, the brain sections were processed for immunohistochemical analysis using antibodies against c-Fos (neuronal activation marker) together with one of the following: tyrosine hydroxylase (dopaminergic cell marker), vesicular glutamate transporter (glutamatergic cell marker), serotonin, glutamate decarboxylase (glutamate decarboxylase 67, gamma-aminobutyric acid cell marker) and neuronal nitric oxide synthase. We used design-based confocal stereological analysis to quantify the immunohistochemically stained sections. Results A significant increase in the number of c-Fos-positive cells in the ventrolateral part of the periaqueductal gray matter after stimulation was found. Furthermore, the ratio of c-Fos cells double labeled with vesicular glutamate transporter was significantly higher in the ventrolateral part of the periaqueductal gray matter region in the stimulated compared with the sham group. Quantitative analysis of the other four cell types did not show any significant difference. Conclusion These findings suggest that glutamatergic neurotransmission in the ventrolateral part of the periaqueductal gray matter is seemingly the main pathway to be activated after receiving sensory signals from the bladder.

OBJECTIVE. DWI has been increasingly applied in the management of bladder cancer. In this article, we discuss the role of DWI as an imaging biomarker for bladder cancer. CONCLUSION. The DWI signal is derived from the motion of water molecules, which represents the physiologic characteristics of the tissue of interest. The emerging evidence highlights the utility of DWI for bladder cancer detection and characterization. DWI is a potentially useful tool to individualize treatment strategies.

beta(3)-Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the beta(3)-adrenoceptor, was discovered much later than beta(1)- and beta(2)-adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the beta(3)-adrenoceptor a less-understood subtype. This article discusses three aspects of beta(3)-adrenoceptor pharmacology. First, the ligand-recognition profile of beta(3)-adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are beta(3)-sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being beta(3)-selective actually are not, including BRL 37,344 ((+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl] amino] propyl] phenoxy] acetic acid sodium hydrate) or SR 59,230 (3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate). Moreover, the binding pocket apparently differs between the human and rodent beta(3)-adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of beta(3)-adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of beta(3)-adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, beta(3)-adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the beta(3)-adrenoceptor as a novel pharmacological target.

beta(3)-Adrenoceptors play important roles in the regulation of urogenital and probably gastrointestinal function. However, despite recent progress, their detection at the protein level has remained difficult due to a lack of sufficiently validated selective antibodies. Therefore, we have explored the selectivity of two antibodies for the detection of rodent beta(3)-adrenoceptors in immunoblots and immunohistochemistry. Of two reportedly promising candidates, antibody AB15688 did not exhibit subtype selectivity in immunoblots. In contrast, the antibody Sc1473 exhibited at least some selectivity in immunoblots and more promising results in immunocytochemical and immunohistochemical stains in cells transfected with cloned beta-adrenoceptor subtypes and in rat and mouse tissues. In a systematic screening of rat gastrointestinal and urogenital tissues, Sc1473 produced selective staining in the epithelial cell lining of the stomach and the urothelium of ureter and bladder. We conclude that the two tested antibodies are inappropriate or at least insufficient for immunoblotting applications, but Sc1473 appears to be useful for immunohistochemical detection of beta(3)-adrenoceptor protein in rodent tissues. The beta(3)-adrenoceptor protein exhibits a distinct expression pattern in the rat gastrointestinal and urogenital tract, which is at least partly in line with previously reported functional data.

Background: Patients in the ICU are thought to have abnormal circadian rhythms, but quantitative data are lacking.Methods: To investigate circadian rhythms in the ICU, we studied core body temperatures over a 48-h period in 21 patients (59 11 years of age; eight men and 13 women).Results: The circadian phase position for 17 of the 21 patients fell outside the published range associated with morningness/eveningness, which determines the normative range for variability among healthy normal subjects. In 10 patients, the circadian phase position fell earlier than the normative range; in seven patients, the circadian phase position fell later than the normative range. The mean +/- SD of circadian displacement in either direction (advance or delay) was 4.44 +/- 3.54 h. There was no significant day-to-day variation of the 24-h temperature profile within each patient. Stepwise linear regression was performed to determine if age, sex, APACHE (Acute Physiology and Chronic Health Evaluation) III score, or day in the ICU could predict the patient-specific magnitude of circadian displacement. The APACHE III score was found to be significantly predictive of circadian displacement.Conclusions: The findings indicate that circadian rhythms are present but altered in patients in the ICU, with the degree of circadian abnormality correlating with severity of illness.

Current sampling protocols of neoplasms along the digestive tract and in the urinary bladder have to be updated, as they do not respond to the necessities of modern personalized medicine. We show here that an adapted version of multisite tumor sampling (MSTS) is a sustainable model to overcome current deficiencies in digestive and bladder tumors when they are large enough so as to make unaffordable a total sampling. The new method is based on the divide-and-conquer algorithm and includes a slight modification of the MSTS, which proved to be useful very recently in clear cell renal cell carcinoma. This in silico analysis confirms the usefulness of MSTS for detecting intratumor heterogeneity (ITH) in tumors arising in hollow viscera. However, MSTS does not seem to improve routine traditional sampling in detecting tumor budding, extramural venous invasion, and perineural invasion. We conclude that (1) MSTS is the best method for tumor sampling to detect ITH balancing high performance and sustainable cost, (2) MSTS must be adapted to tumor shape and tumor location for an optimal performance. JC acknowledges financial support from Ikerbasque: The Basque Foundation for Science. This work was partially funded by grant SAF2013-48812-R from Ministerio de Economia y Competitividad (Spain) to JL; grant DPI2016-79874-R from Ministerio Economia y Competitividad (Spain) and FEDER to JC.

Bladder carcinoma is the most common malignancy of the urinary tract. The major aim of the present study is to investigate the association between mitochondrial DNA (mtDNA) and p53 gene mutations in bladder carcinoma. A total of 30 patients with transitional cell carcinoma and 27 controls were recruited for the study. Bladder cancer tissues were obtained by radical cystectomy or transurethral resection. Genomic DNA was extracted from peripheral blood. mtDNA and p53 genes were amplified by polymerase chain reaction and sequenced directly. A total of 37 polymorphisms were identified, among which, 2 mutations were significant in the patient group, and 1 mutation was significant in the control group. Additionally, 5 different moderate positive correlations between mtDNA mutations and 3 different positive correlations between p53 gene and mtDNA mutations were detected. The high incidence of mtDNA and p53 gene mutations in bladder cancer suggests that these genes could be important in carcinogenesis.

The disruption of coordinated control between the brain, spinal cord and peripheral nervous system caused by spinal cord injury (SCI) leads to several secondary pathological conditions, including lower urinary tract dysfunction. In fact, urinary tract dysfunction associated with SCI is urinary dysfunction could be a consequence of a lack of neuroregeneration of supraspinal pathways that control bladder function. The object of the current research was to explore the effects of adelmidrol + sodium hyaluronate, on bladder damage generated after SCI in mice. Spinal cord was exposed via laminectomy, and SCI was induced by extradural compression at T6 to T7 level, by an aneurysm clip with a closing force of 24 g. Mice were treated intravesically with adelmidrol + sodium hyaluronate daily for 48 h and 7 days after SCI. Adelmidrol + sodium hyaluronate reduced significantly mast cell degranulation and down-regulated the nuclear factor-κB pathway in the bladder after SCI both at 48 h and 7days. Moreover, adelmidrol + sodium hyaluronate reduced nerve growth factor expression, suggesting an association between neurotrophins and bladder pressure. At 7 days after SCI, the bladder was characterized by a marked bacterial infection and proteinuria; surprisingly, adelmidrol + sodium hyaluronate reduced significantly both parameters. These data show the protective roles of adelmidrol + sodium hyaluronate on bladder following SCI, highlighting a potential therapeutic target for the reduction of bladder changes.

Detailed molecular insights into bladder cancer biology might allow more detailed prognostication and optimization of treatment with the objective of improving patient outcome and quality of life. However, in bladder cancer research the search for biomarkers has been called into question and has even obtained notoriety. It is unlikely that any single marker will be able to improve prognostication for patients with bladder cancer above and beyond grade and stage, but a combination of multiple independent markers might more precisely predict the outcome. From a previous review, we identified seven biomarkers to study within the setting of the Bladder Cancer Prognosis Programme (BCPP), a 5-year multicentre programme of research based at the University of Birmingham and funded by Cancer Research UK, investigating their effectiveness in predicting recurrence and progression. As part of the ongoing quality-assurance process for BCPP we present an updated review of our selected biomarkers, as well as highlighting other recent important developments in bladder cancer research.

Extrapulmonary small cell carcinoma (EPSCC) is usually treated similarly to small cell lung cancer. Differences in aetiology, clinical course, frequency of brain metastases, and survival, however, warrant a differential therapeutic approach. In this review, we focus on the treatment of the most predominant sites of origin of EPSCC; the gastrointestinal tract, the genitourinary tract, the head and neck region, and small cell carcinoma of unknown primary. Furthermore we review the available data concerning the controversial issue of prophylactic cranial irradiation (PCI) after optimal treatment of EPSCC. We found in the literature a significant lower incidence of brain metastases in EPSCC as compared to pulmonary small cell carcinoma when PCI is omitted and therefore we do not recommend PCI. An exception is EPSCC originating from the head and neck region which is associated with a higher incidence of brain metastasis, justifying addition of PCI. (C) 2008 Elsevier Ltd. All rights reserved.

Objective. In a pilot study we evaluated whether implementation of a novel 3D stereologic technique can prove that bladder outlet obstruction (BOO) is associated with morphologic changes in the bladder wall. Material and methods. Ten males (mean age 69.7 years; range 58-84 years) with lower urinary tract symptoms (LUTS) suggestive of BOO and five controls (mean age 48.6 years; range 43-53 years) without LUTS were studied. All participants underwent a full examination, including determination of the International Prostate Symptom Score, laboratory analysis and a urodynamic evaluation. A cold-cup biopsy, taken during cystoscopy, was stereologically evaluated to determine the smooth muscle cell volume and the fractions of collagen and smooth muscle using light and electron microscopy. Results. The collagen fraction was higher in patients than in controls (probably because the patients were older). There was no relation between the Abrams-Griffiths number and either the interstitial fraction or the collagen fraction. Furthermore, the results suggest an age-associated effect of morphological changes in the bladder wall. The smooth muscle volume also showed no relationship with the severity of obstruction. Conclusions. This pilot study shows that, even with the implementation of subtle morphometric techniques, there seems to be no relationship between the severity of BOO and bladder wall morphology. It is possible that interstitial collagen in the bladder wall increases with age. It seems that bladder wall morphology is heterogeneous within small areas.

Introduction: The study aimed to investigate oncological outcomes of patients with concomitant bladder cancer (BC) and urethral carcinoma. Methods: This is a multicenter series of 110 patients (74 men, 36 women) diagnosed with urethral carcinoma at 10 referral centers between 1993 and 2012. Kaplan-Meier analysis was used to investigate the impact of BC on survival, and Cox regression multivariable analysis was performed to identify predictors of recurrence. Results: Synchronous BC was diagnosed in 13 (12%) patients, and the median follow-up was 21 months (interquartile range 4-48). Urethral cancers were of higher grade in patients with synchronous BC compared to patients with non-synchronous BC (p = 0.020). Patients with synchronous BC exhibited significantly inferior 3-year recurrence-free survival (RFS) compared to patients with non-synchronous BC (63.2 vs. 34.4%; p = 0.026). In multivariable analysis, inferior RFS was associated with clinically advanced nodal stage (p < 0.001), proximal tumor location (p < 0.001) and synchronous BC (p = 0.020). Conclusion: The synchronous presence of BC in patients diagnosed with urethral carcinoma has a significant adverse impact on RFS and should be an impetus for a multimodal approach.

Niet-steroïdale, anti-inflammatoire geneesmiddelen (NSAID’s) verhinderen de omzetting van arachidonzuur naar prostanoïden door inhibitie van cyclo-oxygenase iso-enzymen. Bij mens en dier worden NSAID’s voornamelijk gebruikt als pijnstillend en ontstekingsremmend geneesmiddel bij aandoeningen van de gewrichten, het skelet en de spieren, bij abdominale pijn en in mindere mate bij postoperatieve pijn. De farmacokinetiek, farmacodynamiek en toxiciteit van NSAID’s zijn sterk verschillend per geneesmiddel, per diersoort en per vogelsoort, bijvoorbeeld zangvogels, papegaaien, roofvogels, watervogels, hoendervogels en duiven. Speciesspecifieke verschillen in de farmacokinetische processen (absorptie, distributie, biotransformatie en excretie) bemoeilijken de extrapolatie van gegevens tussen de verschillende vogelsoorten. Uit farmacodynamische studies blijken effectieve doseringen bij de behandeling van onder meer artritis eveneens speciesafhankelijk te zijn, wat opnieuw het belang weergeeft van farmacodynamische studies van de doeldiersoort. De meeste neveneffecten van NSAID’s bij vogels zijn geassocieerd met nefrotoxiciteit, spiernecrose en gastro-intestinale toxiciteit. Het is dan ook belangrijk om met deze farmacologische en toxicologische eigenschappen rekening te houden bij het gebruik van NSAID’s bij vogels.

Conditions associated with hypertrophy of the urinary bladder have repeatedly been associated with an increased urinary excretion of transforming growth factor ( TGF)beta in both rats and patients. Because TGF beta can have both growth- promoting and - inhibiting effects, we have studied its effects on cell growth and death in primary cultures of rat bladder smooth muscle cells. TGF beta 1, TGF beta 2, or TGF beta 3 did not cause apoptosis, but all three isoforms inhibited DNA synthesis with similar potency (EC50 of approximately 0.1 ng/ ml) and efficacy. Such inhibition was antagonized by a specific TGF beta receptor antagonist and independent of the presence of serum. Mitogen- activated protein kinases ( MAPKs) are involved in the control of cell growth, and all three TGF beta isoforms inhibited activation of the extracellular signal- regulated kinase, c- Jun NH 2- terminal kinase, and p38 MAPK subfamilies. Nevertheless, the inhibitory effects of the TGF beta isoforms on DNA synthesis were not affected by presence of inhibitors of the three MAPK pathways. TGF beta did not alter cell size as measured by flow cytometry or mitochondrial activity, an integrated measure of cell size and number. We conclude that our data do not support the hypothesis that TGF beta is a mediator of rat bladder hypertrophy.

Previous work of our laboratory has shown that neurons in the lateral sacral cord in cat project heavily to the periaqueductal grey (PAG), in all likelihood conveying information from bladder and genital organs. In humans this information usually does not reach consciousness, which raises the question of whether the lateral sacral cell group projects to the thalamus. After wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) injections into the sacral cord, anterogradely labelled fibers were found in the thalamus, specifically in the ventral anterior and ventral lateral nuclei, the medial and intralaminar nuclei, the lateral ventrobasal complex/ventroposterior lateral nucleus, and the nucleus centre median, lateral to the fasciculus retroflexus. Much denser projections were found to the central parts of the PAG, mainly to its dorsolateral and ventrolateral parts at caudal levels and lateral parts at intermediate levels. In a subsequent retrograde tracing study, injections were made in those parts of the thalamus that received sacral fibers, as found in the anterograde study. Labelled neurons were observed in the sacral cord, but not in the lateral sacral cell group. In contrast, a small control injection in the caudal PAG resulted in many labelled neurons in the lateral sacral cord. These results suggest that afferent information regarding micturition and sexual behaviour is relayed to the PAG, rather than to the thalamus.

Background and hypothesis - Detrusor smooth muscle cells (DSMCs) of the urinary bladder are electrically connected to one another via gap junctions and form a three dimensional syncytium. DSMCs exhibit spontaneous electrical activity, including passive depolarizations and action potentials. The shapes of spontaneous action potentials (sAPs) observed from a single DSM cell can vary widely. The biophysical origins of this variability, and the precise components which contribute to the complex shapes observed are not known. To address these questions, the basic components which constitute the sAPs were investigated. We hypothesized that linear combinations of scaled versions of these basic components can produce sAP shapes observed in the syncytium.Methods and results - The basic components were identified as spontaneous evoked junction potentials (sEJP), native AP (nAP), slow after hyperpolarization (sAHP) and very slow after hyperpolarization (vsAHP). The experimental recordings were grouped into two sets: a training data set and a testing data set. A training set was used to estimate the components, and a test set to evaluate the efficiency of the estimated components. We found that a linear combination of the identified components when appropriately amplified and time shifted replicated various AP shapes to a high degree of similarity, as quantified by the root mean square error (RMSE) measure.Conclusions - We conclude that the four basic components—sEJP, nAP, sAHP, and vsAHP—identified and isolated in this work are necessary and sufficient to replicate all varieties of the sAPs recorded experimentally in DSMCs. This model has the potential to generate testable hypotheses that can help identify the physiological processes underlying various features of the sAPs. Further, this model also provides a means to classify the sAPs into various shape classes.

Micropapillary carcinoma (MPC) is a rare aggressive tumor, which generally accompanies the primary carcinoma of the organ of its origin, while the pure form is extremely uncommon. Angiolymphatic involvement is widespread and a considerable proportion of the cases present with metastases. The current study presents eight pure MPC cases arising from the breast (n=3), urinary bladder (n=3), parotid gland (n=1) and lung (n=1, presenting with pericardial effusion), with the cytological findings. The eight patients included three female and five male cases aged between 48 and 74 years. The most common cytological findings were three-dimensional aggregates, cell clusters with angulated or scalloped borders, single cells with a columnar configuration and eccentric nuclei, and high-grade nuclear features. Histopathological sections showed accompanying in situ ductal carcinoma in the cases of MPC arising in the parotid gland and breast (n=3), and one case in the bladder exhibited only in situ MPC. The average follow-up period was 20 months (range, 6-54 months) and, during this period, three patients succumbed to the disease. At present, four patients are alive with disease and one patient is alive and disease-free. In conclusion, cytology is an important tool for the diagnosis and management of MPC.

Hemorrhagic cystitis is a well-defined clinical emergency, usually occurring in the course of treatment with toxic agents such as cyclophosphamide. We present a case of hemorrhagic cystitis in an otherwise completely healthy female. The three documented attacks it-ere severe and started during intercontinental flights. This type of hemorrhagic cystitis as a disease proved to be a boon, treatable by drinking large amounts of water, and was diagnosed by and in Dr. Boon; thus was the appellation Boon's disease coined. Cellular changes in the urine specimen taken after onset of the disease indicated massive exfoliation of degenerated urothelial cells with morphological features suggestive of apoptosis. It seems likely that this process can be initiated by any event which is associated with compromise of vitality of the urinary bladder lining, such as may occur in hypovolemia. This type of hemorrhagic cystitis is most probably not uncommon in susceptible individuals during intercontinental flights. (C) 2001 Wiley-Liss, Inc.

To evaluate the concordance and prognostic role of histologic variants of bladder urothelial carcinoma in transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) specimens. METHODS Clinicopathologic information available at the time of RC and follow-up data from 4110 RC specimens, collected between January 2000 and December 2009 at 17 tertiary referral centers were retrospectively analyzed and evaluated for the presence or absence of uncommon variants of bladder urothelial carcinoma. The presence or absence of uncommon variants of bladder urothelial carcinoma was evaluated on previous TURBT specimens of patients undergoing RC. Cox regression was used to assess the impact of these parameters on cancer-specific survival, and the Kaplan-Meier test for disease-free survival was plotted for survival estimate. RESULTS Of 4110 patients, 579 were found to have uncommon variants of bladder urothelial carcinoma at RC (14.1%), whereas 266 (6.4%) at TURBT. A lack of agreement about uncommon variants was observed between TURBT and RC specimens in the entire population (P

Background and Purpose: The aim of the study was to determine whether KCNQ channels are functionally expressed in bladder smooth muscle cells (SMC) and to investigate their physiological significance in bladder contractility. Experimental Approach: KCNQ channels were examined at the genetic, protein, cellular and tissue level in guinea pig bladder smooth muscle using RT-PCR, immunofluorescence, patch-clamp electrophysiology, calcium imaging, detrusor strip myography, and a panel of KCNQ activators and inhibitors. Key Results: KCNQ subtypes 1-5 are expressed in bladder detrusor smooth muscle. Detrusor strips typically displayed TTX-insensitive myogenic spontaneous contractions that were increased in amplitude by the KCNQ channel inhibitors XE991, linopirdine or chromanol 293B. Contractility was inhibited by the KCNQ channel activators flupirtine or meclofenamic acid (MFA). The frequency of Ca2+-oscillations in SMC contained within bladder tissue sheets was increased by XE991. Outward currents in dispersed bladder SMC, recorded under conditions where BK and KATP currents were minimal, were significantly reduced by XE991, linopirdine, or chromanol, and enhanced by flupirtine or MFA. XE991 depolarized the cell membrane and could evoke transient depolarizations in quiescent cells. Flupirtine (20M) hyperpolarized the cell membrane with a simultaneous cessation of any spontaneous electrical activity. Conclusions and Implications: These novel findings reveal the role of KCNQ currents in the regulation of the resting membrane potential of detrusor SMC and their important physiological function in the control of spontaneous contractility in the guinea pig bladder.

In this study the modulation of the pharmacological profile from agonist to antagonist was successfully obtained by replacing the methyl group in position 6 of the 1,4-dioxane scaffold of the potent M(2)/M(3) muscarinic agonist 1 with bulkier groups. In particular, the 6,6-diphenyl substitution provided the potent M(3) preferring antagonist (±)-17, which in in vivo study proved to be effective in reducing the volume-induced contractions of rat urinary bladder and was devoid of cardiovascular effects.

Racemic N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM-5), a putative postsynaptic agonist and presynaptic antagonist at muscarinic receptors, was resolved into the enantiomers by a new method suitable for large scale preparation. The method involves a chemoselective N-debenzylation as the key step. The enantiomers of BM-5 were obtained after six separate steps in 25% overall yield. The ability of the enantiomers to release acetylcholine was evaluated in vivo by use of brain dialysis. (R)-BM-5 was the more potent enantiomer in this assay.

Detailed molecular insights into bladder cancer biology might allow more detailed prognostication and optimization of treatment with the objective of improving patient outcome and quality of life. However, in bladder cancer research the search for biomarkers has been called into question and has even obtained notoriety. It is unlikely that any single marker will be able to improve prognostication for patients with bladder cancer above and beyond grade and stage, but a combination of multiple independent markers might more precisely predict the outcome. From a previous review, we identified seven biomarkers to study within the setting of the Bladder Cancer Prognosis Programme (BCPP), a 5-year multicentre programme of research based at the University of Birmingham and funded by Cancer Research UK, investigating their effectiveness in predicting recurrence and progression. As part of the ongoing quality-assurance process for BCPP we present an updated review of our selected biomarkers, as well as highlighting other recent important developments in bladder cancer research.

Background Autonomous contractile activity (ACA) is a well-known phenomenon in isolated bladders from different species and seems to be important in the physiology of both normal and dysfunctional voiding. Objective To determine whether ACA is changed in bladders from paraplegic rats at different periods post–spinal cord injury (post-SCI). Design, setting, and participants ACA was studied in bladders (at least six per group) from normal and paraplegic female Wister rats at different times post-SCI (2h, 24h, 1 wk, and 3 wk). A group of normal rats was used as a control group. For measurements bladders were incubated in organ baths under standardised conditions. Measurements ACA was measured as pressure change, which was defined as either a transient change or a spiked change according to its characteristics. The effects of intravesical volume load and muscarinic agonists were studied. Results and limitations Following spinal cord injury (SCI) a clear evolution in ACA was observed. In bladders from SCI rats in the acute areflexive voiding phase (1 wk post-SCI), we observed decreased ACA associated with a highly increased compliance and a changed response to muscarinic agonists. ACA in bladders from SCI rats with renewed voiding reflexes (3 wk post-SCI) was increased, together with a moderately increased compliance and a (moderately) changed response to muscarinic agonists. Conclusions From these observations it is apparent that SCI leads to alterations in the behaviour and muscarinic response of ACA in the isolated bladder. These changes in ACA may play an important role in the pathophysiology of overactive bladder disease (OAB), and interacting with changed ACA might be promising in the search for newer treatments for OAB.

Here we provide evidence for a critical role of the transient receptor potential cation channel, subfamily V, member 4 (TRPV4) in normal bladder function. Immunofluorescence demonstrated TRPV4 expression in mouse and rat urothelium and vascular endothelium, but not in other cell types of the bladder. Intracellular Ca2+ measurements on urothelial cells isolated from mice revealed a TRPV4-dependent response to the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate and to hypotonic cell swelling. Behavioral studies demonstrated that TRPV4-/- mice manifest an incontinent phenotype but show normal exploratory activity and anxiety-related behavior. Cystometric experiments revealed that TRPV4-/- mice exhibit a lower frequency of voiding contractions as well as a higher frequency of nonvoiding contractions. Additionally, the amplitude of the spontaneous contractions in explanted bladder strips from TRPV4-/- mice was significantly reduced. Finally, a decreased intravesical stretch-evoked ATP release was found in isolated whole bladders from TRPV4-/- mice. These data demonstrate a previously unrecognized role for TRPV4 in voiding behavior, raising the possibility that TRPV4 plays a critical role in urothelium-mediated transduction of intravesical mechanical pressure. ispartof: Journal of Clinical Investigation vol:117 issue:11 pages:3453-3462 ispartof: location:United States status: published

Despite the ongoing search for "replacement" alternatives, animal models continue to play a crucial role in bio-medical research. However, both in vivo and in vitro models usually employed, such as rodents and/or cell lines, display intrinsic limits related to the specific characteristics of the biological systems used, whose management is very complex, and whose pathology, usually induced under artificial laboratory conditions, is frequently dissimilar to the studied human spontaneous disease. It has been suggested that carrying out clinical trials based on pre-clinical data obtained after a screening on animal models developing the neoplastic disease in a more similar way to human beings, as represented by spontaneous canine tumours, could accelerate the entry of new effective drugs into the clinical practice. In this paper the authors discuss the scientific foundation as well as the ethic and legal concerns related to the use of this "pet model" in comparative oncology, suggesting some "key words" as the necessary starting point for a correct approach to the matter.

We present a case of a solitary fibrous tumour, located at the epididymis, in a 65-year-old man, presented with a scrotal mass. Ultrasound and MRI of the scrotum revealed a paratesticular mass, with rich vascularity, arising in the left epididymis. Radiological findings were non-specific and the patient underwent surgery. British Journal of Radiology

Fluorine-18 fluorodeoxyglucose (FDG), the most widely used radiopharmaceutical in positron emission tomography (PET) for oncological purposes, is unsuitable for imaging of bladder cancer owing to high excretion into the urine. More specific PET radiopharmaceuticals which are not excreted into urine would be welcome. Carbon-11 labelled choline (CHOL) is a new radiopharmaceutical potentially useful for tumour imaging and is not excreted into the urine. We prospectively studied the visualisation of bladder cancer using CHOL PET. Eighteen patients with bladder cancer and five healthy volunteers were included. Bladder cancer was first diagnosed by transurethral resection or by biopsy of the tumour. Next, PET images were performed before surgical treatment by cystectomy. The histopathological findings after cystectomy were used as the gold standard. PET images were performed on either an ECAT 951/31 or an ECAT Exact HR+ system. Attenuation-corrected PET images were obtained after injection of 400 MBq CHOL. PET images were analysed by two independent physicians using visual analysis and calculation of the standardised uptake value (SUV). In the normal bladder wall, the uptake of CHOL was low, and the bladder margin was only outlined by minimal urinary radioactivity, if present. In ten patients the tumour was detected correctly by CHOL PET, with an SUV of 4.7+/-3.6 (mean+/-SD). One false positive CHOL PET scan was seen in a patient with an indwelling catheter for 2 weeks prior to the PET scan. In two patients, lymph node metastases were detected by CHOL PET. A micrometastasis5 mm was not visualised with CHOL PET. In seven patients, no residual tumour was found after surgery. In six of seven patients CHOL PET imaging was negative. In situ carcinoma, dysplasia and a non-invasive urothelial tumour (pTa) remained undetected in three of these six patients. Minimal to no urinary tract radioactivity was seen in 22/23 subjects. Non-specific uptake of CHOL was observed in the small bowel, rectum and prostate gland. CHOL uptake in bladder cancer was avid, visualising the tumour in the virtual absence of urinary radioactivity. No uptake of CHOL was seen in pre-malignant lesions or in small non-invasive tumours. Our results warrant further research into the value of CHOL PET in the clinical management of patients with bladder cancer.

Hemorrhagic cystitis is a well-defined clinical emergency, usually occurring in the course of treatment with toxic agents such as cyclophosphamide. We present a case of hemorrhagic cystitis in an otherwise completely healthy female. The three documented attacks it-ere severe and started during intercontinental flights. This type of hemorrhagic cystitis as a disease proved to be a boon, treatable by drinking large amounts of water, and was diagnosed by and in Dr. Boon; thus was the appellation Boon's disease coined. Cellular changes in the urine specimen taken after onset of the disease indicated massive exfoliation of degenerated urothelial cells with morphological features suggestive of apoptosis. It seems likely that this process can be initiated by any event which is associated with compromise of vitality of the urinary bladder lining, such as may occur in hypovolemia. This type of hemorrhagic cystitis is most probably not uncommon in susceptible individuals during intercontinental flights. (C) 2001 Wiley-Liss, Inc.

Information concerning the rate of bladder filling is determined by receptors in the bladder wall and conveyed via afferent fibers in the pelvic nerve to sensory neurons in the lumbosacral cord. It was assumed that this information is relayed from the lumbosacral cord to a medial cell group in the dorsolateral pontine tegmentum, called the M-region, the pontine micturition center, or Barrington's nucleus. The M-region, in turn, projects via long descending pathways to the sacral parasympathetic motoneurons. In the present electron microscopic study, it was investigated in cats whether monosynaptic projections from lumbosacral neurons to the M-region indeed exist. Wheat-germ agglutinin-horseradish peroxidase injections were made into the lumbosacral, cord. Many retrogradely labeled dendrites and somata were found in the M-region, but no labeled terminals were found on retrogradely labeled dendrites or somata. Only a small number of anterogradely labeled terminals, which were filled with mainly round vesicles, contacted unlabeled dendrites in the M-region. In contrast, many more anterogradely labeled terminals, which were filled with mainly round and, to a limited extent, dense core vesicles and with asymmetrical synapses, were found on dendrites in the lateral part of the periaqueductal gray (PAG). Previously (Blok and Holstege [1994] Neurosci. Lett. 166:93-96), it was demonstrated that the lateral part of the FAG contains neurons projecting to the M-region. A concept for the central organization of the micturition reflex is presented in which ascending projections from the lumbosacral cord convey information on bladder filling to the FAG. When the bladder contains so much urine that voiding is necessary, the FAG, in turn, triggers the M-region. The M-region, however, also receives afferents from the preoptic area, which might be involved in the final decision to start micturition. (C) 1995 Wiley-Liss, Inc.