Search

Objective: To investigate the efficacy of fesoterodine vs placebo on nocturia, sleep disturbance, and sleep-related quality of life (QoL) in patients with overactive bladder and nocturia. Methods: This posthoc analysis used data from a 12-week, randomized, placebo-controlled trial of fesoterodine 4 and 8 mg per day in Asian adults reporting ≥8 micturitions and ≥1 urgency urinary incontinence episodes per 24 hours at baseline. Patients who reported ≥1 nocturnal micturition/24 h were included in this analysis. Efficacy variables included change from baseline to week 12/end of treatment in nocturnal micturitions/24 h, nocturnal voided volume/micturition, and hours of undisturbed sleep. Sleep-related QoL was assessed using King's Health Questionnaire Sleep/Energy domain. Treatment comparisons were made using analysis of covariance. Results: Among 555 patients, reductions in nocturnal micturitions with fesoterodine 4 mg (−0.63) and 8 mg (−0.77) were numerically greater vs placebo (−0.56), but differences were not significant (P >.05). When patients with a nocturnal polyuria index >33% were excluded, the decrease in nocturnal micturitions was significantly greater with fesoterodine 8 mg vs placebo (−0.24; P = .031). Increases in nocturnal voided volume/micturition were significantly greater with fesoterodine 4 (38.07 mL; P = .013) and 8 mg (42.05 mL; P <.001) vs placebo (14.89 mL). Hours of undisturbed sleep was significantly longer with fesoterodine 4 mg vs placebo (80 vs 54 minutes; P = .032); improvement in King's Health Questionnaire Sleep/Energy scores was significantly greater with fesoterodine 4 (P = .034) and 8 mg (P = .019) vs placebo. Conclusion: These results suggest that fesoterodine may reduce nocturnal micturitions and improve sleep quality and QoL in overactive bladder patients with nocturia. [Copyright &y& Elsevier]

Objective: To evaluate the efficacy of imidafenacin for nocturia and nocturnal polyuria in patients with overactive bladder. Materials and Methods: A stratified analysis was conducted on data from a phase III randomized, double-blind, controlled trial of imidafenacin performed at 158 centers in Japan. The subjects received imidafenacin (0.1 mg) twice daily (group I) or placebo twice daily (group P). The 24-hour urine volume, daytime and nighttime voiding frequency, and volume voided/micturition were evaluated from 3-day voiding diaries recorded every 4 weeks during the 12-week study period. Longitudinal data analysis was performed, with all values expressed as the least squares mean ± standard error. Results: A total of 46 patients (mean age 66.54 ± 9.38 years, 9 men and 37 women) with nocturia and nocturnal polyuria (>33% of urine production at night) were enrolled. Group I (n = 35) and group P (n = 11) showed no baseline differences in the daily voided volume, concomitant diseases, age, or body weight. However, the average daily number of micturitions differed (11.22 ± 2.17 vs 14.45 ± 2.85). Therefore, longitudinal data analysis was performed for each micturition pattern. After 12 weeks of treatment, nighttime micturition was significantly less frequent in group I than in group P (P = .0292), and the nocturnal percentage of 24-hour production was significantly smaller (P = .0053). The interval to the first nighttime void was significantly longer in group I than in group P, but no difference was found in the first nighttime voided volume. Conclusion: The novel antimuscarinic agent, imidafenacin, decreases the number of urinations and reduces nocturnal urine production, thereby improving both nocturia and nocturnal polyuria. [ABSTRACT FROM AUTHOR]

Abstract: Human memory systems contain self-monitoring mechanisms for evaluating their progress. People can change their learning strategy on the basis of confidence in their performance at that time. However, it has not been fully understood how the brain is engaged in reliable rating of confidence in past recognition memory performance. We measured the brain activity by fMRI while healthy subjects performed a visual short-term recognition memory test and then rated their confidence in their answers as high, middle, or low. As shown previously, their behavioral performance in the confidence rating widely varied; some showed a positive confidence–recognition correlation (i.e., “rate reliably”) while others did not. Among brain regions showing greater activity during rating their confidence relative to during a control, non-metamemory task (discriminating brightness of words), only a posterior-dorsal part of the right frontopolar cortex exhibited higher activity as the confidence level better correlated with actual recognition memory performance. These results suggest that activation in the right frontopolar cortex is key to a reliable, retrospective rating of confidence in short-term recognition memory performance. [ABSTRACT FROM AUTHOR]

Iliac artery–ureteral fistula (IAUF) is a rare entity that has a potential risk of life-threatening hemorrhage. It is difficult to diagnose and treat appropriately. Conventional treatment for the disease consists of surgical ligation and vascular reconstruction or coil embolization. Surgical treatment is usually difficult for patients with several risk factors. In recent years, endovascular stent-graft treatment for iliac artery pseudoaneurysm has been reported. The present report describes two cases in which endovascular covered stent-graft treatment was successfully applied to treat IAUF, with good clinical outcomes. [Copyright &y& Elsevier]

Abstract: Yokoyama O, Sakuma F, Itoh R, Sashika H. Paraplegia after aortic aneurysm repair versus traumatic spinal cord injury: functional outcome, complications, and therapy intensity of inpatient rehabilitation. Objective: To compare outcomes, complications, and therapy intensity of inpatient rehabilitation in patients with paraplegia caused by spinal cord injury associated with aortic aneurysm repair (SCI-AA) versus patients with traumatic spinal cord injury (SCI). Design: Case-controlled study. Setting: SCI unit in a rehabilitation center. Participants: Seventeen patients with SCI-AA and 17 patients with traumatic SCI. Intervention: Standard rehabilitation therapy for SCI. Main Outcome Measures: Length of stay (LOS) in acute and rehabilitation hospitals; FIM instrument scores; FIM change; FIM efficiency; complications; therapy intensity; and ambulatory state and return to community at discharge. Results: No significant differences were noted in acute and rehabilitation LOS and admission FIM scores. Discharge FIM scores, FIM change, and FIM efficiencies were significantly lower in the SCI-AA group, which had many complications related to AA and SCI. Intensity of rehabilitation sports therapy in the SCI-AA group was significantly lower than that of the traumatic SCI group, but total therapy intensity did not differ significantly. Both had similar rates of return to ambulatory state and discharge to the community. Conclusions: SCI-AA patients had many complications that interfered with rehabilitation therapy, and could not achieve functional gains comparable to those with traumatic SCI. However, both groups achieved comparable success with return to ambulatory state and discharge to the community. [Copyright &y& Elsevier]

Telomere maintenance is essential for continued cell proliferation. Although most cells accomplish this by activating telomerase, a subset of immortalized tumors and cell lines do so in a telomerase-independent mannet, a process called alternative lengthening of telomeres (ALT). DNA recombination has been shown to be involved in ALT, but the precise mechanisms remain unknown. A fraction of cells in a given ALT population contain a unique nuclear structure called APB (ALTassociated promyelocytic leukemia (PML) body), which is characterized by the presence of telomeric DNA in the PML body. Here we describe that hRad9, hHusl, and hRadl, which form a DNA clamp complex that is associated with DNA damage, as well as its clamp loader, hRadl7, are constitutive components of APB. Phosphorylated histone H2AX (γ-H2AX), a molecular marker of double-strand breaks (DSBs), also colocalizes with some APBs. The results suggest that telomeric DNAs at APBs are recognized as DSBs. PML staining and fluorescence in situ hybridization analyses of mitotic ALT cells revealed that telomeric DNAs present at APBs are of both extrachromosomal and native telomere origins. Furthermore, we demonstrated that DNA synthesis occurs at APBs and is significantly inhibited by caffeine, an inhibitor of phosphatidylinositol 3-kinase-related kinases. Taken together, we suggest that telomeric DNAs at APBs are recognized and processed as DSBs, leading to telomeric DNA synthesis and thereby contributing to telomere maintenance in ALT cells. [ABSTRACT FROM AUTHOR]

Objective: To assess the responsiveness and minimal clinically important change (MCIC) in the Overactive Bladder Symptom Score (OABSS), a single score used to quantify overactive bladder symptoms. Methods: The data were derived from a clinical trial of propiverine in patients with overactive bladder. The analysis included participants who completed the OABSS, a bladder diary, and patient-reported outcome measures (urgency and incontinence impact) at baseline and 12 weeks. Responsiveness was assessed with effect sizes, correlations between the OABSS items and bladder diary variables, and comparisons between the score changes and symptom improvement. The MCIC was comprehensively estimated from the discriminating thresholds for minimal symptom improvement, and the receiver operating characteristics curve analyses were used to derive cutoff scores for symptom improvement. Results: A total of 282 participants were included in the present analysis. The effect sizes for the OABSS ranged from −0.369 to −1.485, and correlations between the changes in the OABSS items and the corresponding bladder diary variables were moderate to large. A linear tendency was found between the changes in the OABSS and symptom improvement. The mean change for urgency and incontinence impact was −2.59 and −2.49 for “no change” and −3.67 and −3.78 for “minor improvement,” respectively. The optimal cutoff score ranged from −4 to −3. Integrating the MCIC analyses, −3 was estimated as the minimal threshold for a meaningful change. Conclusion: With good responsiveness, the OABSS is a useful tool for assessing the treatment of OAB symptoms. Furthermore, the results of our study suggest that the MCIC of the OABSS is −3. [ABSTRACT FROM AUTHOR]

Objectives: Despite the well-known association between lower urinary tract symptoms (LUTS) and male sexual dysfunction, few data are available that describe the relationship between LUTS and sex hormones. The aim of this study was to investigate a possible association between the severity of LUTS and the serum levels of sex hormones in men. Methods: A total of 182 randomly selected men attending our general urology clinic were recruited. All participants completed the International Prostate Symptom Score (IPSS), and their sera were evaluated for serum levels of prostate-specific antigen, total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol. Storage symptoms were evaluated by the sum of IPSS questions 2, 4, and 7. Voiding symptoms were evaluated by the sum of IPSS questions 3, 5, and 6. The relationship between the IPSSs and serum hormone levels was determined. Results: On univariate analysis, the total IPSS was significantly associated with age, DHEA-S, and free testosterone. Storage symptoms were significantly associated with age, DHEA-S, free testosterone, and prostate-specific antigen. Voiding symptoms were significantly associated with age and DHEA-S. On multivariate linear regression analysis, only age was significantly associated with LUTS. However, within the subgroup of men 65-82 years old, DHEA-S was significantly associated with the total IPSS and storage symptoms. Conclusions: In our study, the severity of LUTS was not associated with serum levels of sex hormones in men. However, in older men, storage symptoms could be affected by the serum DHEA-S level. [Copyright &y& Elsevier]

Aims Androgen deprivation therapy has been widely used for the treatment of prostate cancer. While sexual side effects including decreased sexual desire and function are well studied, there are only limited reports about its influences on lower urinary tract symptoms. The aim of this study is to clarify the influences of castration in male rats. Methods Ten-week-old male rats were divided into treatment group (bilateral orchiectomy) and control group (sham surgery). Two-months after the surgery, adenosine triphosphate (ATP), prostaglandin E2 (PGE2), and nerve growth factor (NGF) released from stretched bladder epithelium were measured by luciferin-luciferase assay or ELISA. The mRNA levels of bladder cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were determined by real-time PCR. The protein level of bladder COX-2 was analyzed by western blot analysis. Bio-Plex Pro cytokine assay was performed to quantify the level of proinflammatory cytokine interleukin (IL)-1β in the bladder. Results The PGE 2 release from stretched bladder epithelium was significantly increased after castration, which increased more than 50% compared with control. On the other hand, those of ATP and NGF were not different from those of the controls. Testosterone replacement restored the PGE 2 increase. Castration significantly increased bladder IL-1β protein level and COX-2 at both mRNA and protein levels, whereas caused no marked changes in the COX-1 mRNA level. Conclusions These findings suggest that castration induces inflammation in the rat bladder, which causes elevated PGE 2 release from bladder epithelium and may finally contribute to the disruption of bladder storage function. [ABSTRACT FROM AUTHOR]

Aims Spontaneous hypertensive rats provide a genetic model for exploring the pathogenesis of urine storage dysfunction related to hypertension (HT). In humans, however, HT develops by both genetic and environmental factors including lifestyle factors such as a high-calorie diet, excessive salt intake and stress. We investigated the influence of salt-loading on bladder function and the underlying mechanisms of storage dysfunction related to HT. Main methods Six-week-old male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats were fed with a normal or high-salt diet for 12 weeks. Micturition parameters were obtained from a metabolic cage. Whole bladders were excised from 18-week-old rats and distended in an organ bath. The releases of adenosine triphosphoric acid (ATP) and prostaglandin E 2 (PGE 2 ) from the distended bladder epithelia were measured. Changes in bladder blood flow (BBF) were determined with a laser-speckle-blood-flow imaging system. Key findings An increase in mean blood pressure (BP) was noted only in DS rats after salt-loading. During the inactive (sleeping) period, voided volume per micturition gradually increased in DR rats fed a normal or high-salt diet and normal-diet DS rats, while it did not change in the DS rats fed a high-salt diet. Bladder distension significantly increased ATP and PGE 2 release from the urothelium in DS rats fed a high-salt diet. BBF was significantly decreased in high-salt-diet DS rats. Significance One mechanism behind the relationship between salt-sensitive HT and urine storage dysfunction may be an increase in ATP and PGE 2 release from the urothelium via suppression of BBF. [ABSTRACT FROM AUTHOR]

Aims: Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively. Materials and Methods: OLETF and LETO rats were treated with oral tadalafil (100 μg/kg/day) or vehicle for 12 wks from at the age of 36 wks. Key findings: Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-β); especially IL-6, TNF-α, IGF-1, bFGF and TGF-β increased with T2D. Tadalafil suppressed these cytokines and growth factors. Significance: These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Renal uptake of Tc-99m-MG3 involves organic anion transporter (OAT). Treatment with drugs showing OAT affinity might interfere with renal uptake of Tc-99m-MAG3, leading to misinterpretation in Tc-99m-MAG3. This study was conducted to discuss a possible drug interference with Tc-99m-MAG3 diagnosis on OAT sites. Methods: Renal uptake and plasma clearance of Tc-99m-MAG3 were analyzed in healthy volunteers under control and OAT1 and OAT3 related drug treatment conditions. An in vitro uptake study using OAT1 or OAT3 expressing cells was also conducted. Results: Both PAH and probenecid treatment induced delays in Tc-99m-MAG3 clearance from blood, and reductions in the renal uptake clearance. As a result, the normalized effective renal plasma flow estimated from Tc-99m-MAG3 clearance was significantly underestimated, whereas the glomerular filtration rate estimated from plasma creatinine levels was unchanged. The transport activity of Tc-99m-MAG3 was higher in OAT1-expressing cells than in OAT3-expressing cells. Conclusion: Drugs with OAT1 affinity affect the renal uptake of Tc-99m-MAG3 and blood clearance. This might cause misinterpretation of functional diagnosis of the kidney using Tc-99m-MAG3. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate the potential of monoclonal antibody (mAb) RM2 as a ligand for a radioimmunotracer for prostate cancer imaging. Methods: Labeling was conducted with mAb RM2 and 125I using the chloramine-T method. The cell study was conducted with PC-3 and LNCaP, which are prostate cancer cell lines, and MCF-7, which is a breast cancer cell line. The cells were treated or untreated with unlabeled mAb RM2 to block the haptoglobin-β chains expressed on the surface of the prostate cancer cells. 125I-mAb RM2 was added into the cell culture media and cellular uptake of 125I-mAb RM2 was evaluated at 1, 3 and 6 hours of incubation. For the in vivo biodistribution study, PC-3 cells were implanted in athymic male mice. The animals were injected intravenously with 125I-mAb RM2. At 24, 48 and 72 hours after tracer injection, the animals were sacrificed and the activity levels of blood and tissue samples were determined. Results: The uptake of 125I-mAb RM2 in the PC-3 and LNCaP cells increased according to the incubation time, while the uptake of 125I-mAb RM2 in MCF-7 cells did not show any increase up to 6 hours. The increase of 125I-RM2 uptake was not observed when the PC-3 and LNCaP cells were pre-treated with unlabeled RM2. In the biodistribution studies, 125I-mAb RM2 showed marked uptake into the implanted PC-3 cells. In PC-3 tumor-bearing mice, the tumor muscle ratio of 125I-RM2 was increased for up to 72 hours in a time-dependent manner. Conclusions: 125I-mAb RM2 showed excellent prostate cancer cell targeting in vitro and in vivo. Therefore, mAb RM2 seems to be a potential candidate for an immunoligand for prostate cancer imaging. [Copyright &y& Elsevier]

Objectives: To assess the efficacy and safety of solifenacin add-on therapy to tamsulosin in lower urinary tract symptoms (LUTS) men with residual overactive bladder (OAB) symptoms despite tamsulosin monotherapy. Methods: In this randomized, multicenter, double-blind study, male LUTS patients aged ≥50 years with urgency episodes/24 hours ≥2 and micturitions/24 hours ≥8 were randomized to 3 groups: 12-weeks tamsulosin plus placebo (TAM + PBO), tamsulosin plus solifenacin 2.5 mg (TAM + SOL), and tamsulosin plus solifenacin 5 mg (TAM + SOL). Changes from baseline to end of treatment in the number of urgency episodes/24 hours (primary endpoint), micturitions, nocturia, urgency incontinence episodes, International Prostate Symptom Scores (IPSS), and Overactive Bladder Symptom Score (OABSS) were compared between the TAM + SOL groups and TAM + PBO. Safety was assessed on adverse events, postvoid residual volume, and maximal urinary flow rate (Qmax.). Results: Six-hundred thirty-eight men were randomized. Urgency was reduced by 2.2 and 2.4 episodes in the TAM + SOL 2.5 and 5 mg groups, respectively. The TAM + SOL 5 mg group showed significant improvement compared with TAM + PBO (−2.4 vs −1.9, P = .049). The number of micturitions in both TAM + SOL groups were significantly reduced compared with TAM + PBO (both P <.001). IPSS storage symptom score and OABSS significantly improved in both TAM + SOL groups compared with TAM + PBO. Changes in IPSS voiding symptom score and Qmax. were similar in all groups. Four patients (1.9%) in the TAM + SOL 5 mg group had urinary retention, but all recovered after catheterization. Conclusions: In male LUTS patients with residual OAB symptoms despite tamsulosin monotherapy, TAM + SOL showed efficacy on urgency, which represents OAB symptoms and was well tolerated. [ABSTRACT FROM AUTHOR]

Objectives: To compare the Overactive Bladder Symptom Score (OABSS) and a bladder diary as a tool for assessing symptoms of overactive bladder (OAB). Methods: Treatment-naive OAB patients received an antimuscarinic agent, solifenacin. At baseline and 12 weeks after treatment, patients completed a 3-day bladder diary and the OABSS. Relationships between the 2 methods were evaluated by comparison of changes after treatment, agreement between variables and correlation between changes. Results: In total, 79 patients (42 male and 37 female, mean age 71.1 years) were included in the analysis. Statistically significant improvements were noted for all the OABSS and the corresponding diary variables. The effect size (ES) was largest for the OABSS urgency score (2.00), followed by the OABSS total score (1.54), and then by the diary urgency score (0.92). All of the ESs for the OABSS, except daytime frequency, were larger than those of the corresponding diary variables. The standard response means followed a similar pattern to the ESs. A fairly good agreement between OABSS items and the corresponding diary variables was found at baseline and 12 weeks (kappa coefficient, 0.33-0.80). High correlations (Spearman''s rho, ≥ 0.5) between changes in OABSS items and the corresponding diary variables were found for urgency incontinence and night-time frequency. Conclusions: The OABSS is highly sensitive to treatment-related changes of OAB symptoms. Because of its simplicity and dependability, the OABSS can be an alternative to a bladder diary for symptom and efficacy assessment in daily clinical practice. [Copyright &y& Elsevier]

Objectives: Although invasive and expensive, the pressure-flow study is known as the reference standard for the diagnosis of bladder outlet obstruction. We investigated the usefulness of ultrasound-estimated bladder weight (UEBW) as a predictor of the need for surgery for benign prostatic hyperplasia (BPH). Methods: A total of 97 consecutive male patients >50 years old with lower urinary tract symptoms (LUTS) were prospectively enrolled in this study. The surgery rate was correlated with the UEBW, the results of uroflowmetry, the postvoid residual urine volume, prostate volume, and International Prostate Symptom Score. Results: Surgery for BPH was performed in 37 of the 97 patients studied. The surgery rate was associated with a high UEBW (>or=35 g), severe LUTS (International Prostate Symptom Score of >or=20), a voided volume of <100 mL at free uroflowmetry, and poor uroflow (maximal flow rate of <10 mL/s). Multivariate analysis revealed that severe LUTS and a high UEBW were the risk factors for surgery for BPH. Conclusions: The results of our study have shown that the UEBW can be regarded as a useful parameter to identify patients with LUTS who are at risk of needing surgery for BPH. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Overactive bladder (OAB) is a common symptom syndrome with urgency, urinary frequency, and urgency incontinence. To collectively express OAB symptoms, we developed the overactive bladder symptom score (OABSS). Methods: Four symptoms—daytime frequency, nighttime frequency, urgency, and urgency incontinence—were scored. The weighing score was based on a secondary analysis of an epidemiologic database. Psychometric properties were examined in five patient groups: OAB (n = 83), asymptomatic controls (n = 34), stress incontinence (n = 29), benign prostatic hyperplasia (n = 28), and other diseases with urinary symptoms (n = 26). Results: The maximal score was defined as 2, 3, 5, and 5 for daytime frequency, nighttime frequency, urgency, and urgency incontinence, respectively. The sum score (OABSS 0 to 15) was significantly greater in the patients with OAB (8.36) than in the other patient groups (1.82 to 5.14). The distribution of the OABSS showed a clear separation between those with OAB and asymptomatic controls. The OABSS correlated positively with the individual scores (Spearman’s r = 0.10 to 0.78) and quality-of-life scores assessed by the King’s Health Questionnaire (Spearman’s r = 0.20 to 0.49). The weighted kappa coefficients were 0.804 to 1.0 for each symptom score and 0.861 for OABSS. The posttreatment reduction in the OABSS was consistent with the global impression of patients of the therapeutic efficacy. Conclusions: The OABSS, the sum score of four symptoms (daytime frequency, nighttime frequency, urgency, and urgency incontinence), has been developed and validated. OABSS may be a useful tool for research and clinical practice. [Copyright &y& Elsevier]

Objectives: Given the relatively high frequency of metastatic recurrence of clear cell renal cell carcinoma (ccRCC), reliable prognostic markers of ccRCC, particularly those associated with metastasis, are needed. Here, in search of those factors, we assessed the contribution of sialyl Lewis x (sLex) and sialyl Lewis a (sLea), as well as functional E-selectin ligand carbohydrates expressed on carcinoma cells, to metastasis and consequent poor prognosis in ccRCC.Materials and Methods: Patients who underwent surgical resection (curative nephrectomy) for RCC, and whose post-operative pathological diagnosis was ccRCC (n = 117) were enrolled in this study. Expression of sLex/sLea carbohydrate antigens in ccRCC was evaluated by immunohistochemistry with an anti-sLex/sLea monoclonal antibody HECA-452. To evaluate membrane expression of sLex/sLea carbohydrate antigens quantitatively, we employed a histological scoring system used to evaluate membrane expression of human epidermal growth factor receptor 2 (HER2) in breast cancer. We also conducted an E-selectin•IgM chimera in situ binding assay to assess expression of functional E-selectin ligand carbohydrates in ccRCC. We then carried out statistical analysis to determine whether membrane expression of HECA-452-reactive sLex/sLea glycans as well as of E-selectin•IgM-binding functional E-selectin ligand carbohydrates correlates with progression-free, overall, or cancer-specific survival.Results: Based on HECA-452 immunochemistry, 106 of 117 ccRCC specimens expressed detectable levels of sLex/sLea glycans, primarily on the plasma membrane, and of those, 31 that showed robust membrane expression were judged as HECA-452-positive. Membrane expression of HECA-452-positive sLex/sLea glycans correlated with shortened progression-free and overall survival. Moreover, in in situ analysis, these HECA-452-positive ccRCC tissues were decorated with E-selectin•IgM chimeric proteins, calcium-dependently. Comparable analysis in normal kidney showed both HECA-452 positivity and chimera binding almost exclusively in epithelial cells that constitute proximal tubules. Membrane expression of functional E-selectin ligand carbohydrates, as detected by the E-selectin•IgM chimera, correlated more significantly with poor prognosis of patients, namely, shortened progression-free, overall and cancer-specific survival, than did HECA-452 positivity.Conclusions: Expression of E-selectin•IgM-binding functional E-selectin ligand carbohydrates can serve as a reliable and potentially superior prognostic biomarker of patients with ccRCC. [ABSTRACT FROM AUTHOR]

Objectives: Bladder urothelial carcinoma (UC) comprises more than 90% of all bladder cancers. Among several UC variants, micropapillary UC (MPUC) is a rare one with high potential for lymphovascular invasion and subsequent lymph node metastasis. Histologically, MPUC is characterized by the presence of small papillary carcinoma cell clusters surrounded by lacunar spaces. Immunohistochemically, the outer circumference of these clusters, that is, the stroma-facing membrane of carcinoma cells, is reportedly almost invariably positive for mucin 1 (MUC1) protein and to a lesser extent for sialyl Lewis X (sLeX) carbohydrates; however, the clinicopathological implications of these expression patterns have not been fully investigated.Materials and Methods: We performed immunohistochemical analysis of MPUC (n = 11) and conventional UC (n = 57) for MUC1 and sLeX to determine whether these factors immunolocalized. Dual immunofluorescence staining was also carried out to assess MUC1 and sLeX colocalization. We also performed Western blot analysis of Chinese hamster ovary cells misexpressing both recombinant epitope-tagged MUC1 and glycosyltransferases enabling sLeX biosynthesis.Results: MPUC samples preferentially exhibited both MUC1 protein and sLeX carbohydrate expression on the stroma-facing membrane of carcinoma cells. Based on univariate analysis, MUC1 expression in that pattern was positively correlated with tumor extension, lymphovascular invasion, lymph node metastasis, disease stage, and relatively poor patient prognosis. A comparable sLeX expression pattern also correlated positively with tumor extension and nodal metastasis. Based on multivariate analysis, localization of MUC1 and sLeX on the stroma-facing side of the membrane was positively correlated with lymph node metastasis.Conclusions: Overall, our immunofluorescence findings as well as immunoprecipitation analyses of Chinese hamster ovary cell transfectants strongly suggest that MUC1 is a potential scaffold protein for sLeX carbohydrates in MPUC. Both MUC1 and sLeX may cooperatively contribute to MPUC histogenesis and clinicopathological characteristics. [ABSTRACT FROM AUTHOR]

Objectives: It is widely accepted that sialyl Lewis X (sLeX) and sialyl Lewis A (sLeA, also known as CA 19-9) glycans expressed on cancer cells function in E-selectin-mediated metastasis. Recently, it was reported that 6-sulfo sLeX glycans detected by the MECA-79 monoclonal antibody are expressed in roughly a quarter of gastric adenocarcinoma cases, and that these cases show a poorer prognosis than MECA-79-negative cases do. The present study was undertaken to assess expression of 6-sulfo sLeX glycans in bladder urothelial carcinoma and evaluate potential clinical implications.Materials and Methods: We analyzed 78 specimens representing bladder urothelial carcinoma, as well as 4 bladder urothelial carcinoma cell lines, by immunostaining with a battery of anticarbohydrate antibodies. We also undertook an E-selectin·IgM chimera binding assay to assess E-selectin binding to 6-sulfo sLeX expressed on bladder urothelial carcinoma cells and performed reverse transcription polymerase chain reaction and complementary DNA transfection to determine which N-acetylglucosamine-6-O-sulfotransferases function in 6-sulfo sLeX biosynthesis in those cells. Finally, we performed double-immunofluorescence staining for MECA-79 and either CD3 or CD8 to evaluate potential association between high endothelial venule (HEV)-like vessels and tumor-infiltrating T lymphocytes.Results: 6-Sulfo sLeX glycans were expressed in ~20% of bladder urothelial carcinoma cases, particularly in plasmacytoid and micropapillary variants. Positive cells were also bound by E-selectin·IgM chimeras in a calcium-dependent manner. Transcripts encoding N-acetylglucosamine-6-O-sulfotransferase-2 were detected preferentially in HT-1197 bladder urothelial carcinoma cells expressing 6-sulfo sLeX, and transfection of the enzyme complementary DNA into HT-1376 cells, which do not express 6-sulfo sLeX glycans, resulted in cell surface expression of 6-sulfo sLeX. Furthermore, 6-sulfo sLeX glycans were expressed in HEV-like vessels induced in and around lymphocyte aggregates formed near carcinoma cell nests. These HEV-like vessel-associated tumor-infiltrating lymphocytes were composed primarily of CD3(+) T cells, with a fraction of CD8(+) cytotoxic T cells.Conclusions: Our findings indicate that 6-sulfo sLeX glycans likely play 2 roles in bladder urothelial carcinoma progression: one in lymphocyte recruitment to enhance antitumor immune responses, and the other in E-selectin-mediated tumor cell adhesion to vascular endothelial cells, which is potentially associated with metastasis. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between the urinary levels of prostaglandins (PGE2 and PGF2α), nerve growth factor (NGF) and substance P, and overactive bladder (OAB) symptoms in patients with suprapontine brain diseases. Materials and Methods: The subjects were 114 patients in the chronic phase of a brain disease and 27 healthy controls with no brain disease or lower urinary tract symptoms (LUTS). The OAB symptoms were assessed with the OAB symptom score and the subjects were then classified into 5 groups: healthy control, patients without LUTS, increased bladder sensation (IBS), OAB dry, and OAB wet. Urinary mediator concentrations were measured using enzyme-linked immunosorbent assay and normalized to the urinary creatinine concentration, and then compared among the 5 groups. Results: The urinary PGE2 level was significantly higher in patients with brain diseases than in healthy controls, even in the patients without any OAB symptoms, and compared with patients without LUTS, a significant increase in the urinary PGE2 was observed in patients with OAB dry or wet (P = .004 or .015, respectively). The PGF2α level showed a significant increase in OAB wet compared with patients without LUTS (P = .001). The urinary levels of NGF and substance P were not significantly associated with OAB as a result of this type of brain disease. Conclusion: The urinary PGE2 level was putatively elevated in patients with suprapontine brain diseases and associated with the presence of OAB. The PGF2α level may also be associated with OAB. [Copyright &y& Elsevier]