Efficacy and safety of intravesical dimethyl sulfoxide treatment for patients with refractory Hunner-type interstitial cystitis: Real-world data postofficial approval in Japan.

OBJECTIVES: To examine real-world data regarding intravesical dimethyl sulfoxide (DMSO) therapy after official approval as a treatment for Hunner-type interstitial cystitis (HIC) in Japan. METHODS: This single institution, retrospective observational study was conducted between 2021 and 2022 to evaluate the outcomes of 30 patients with refractory HIC who received intravesical DMSO therapy according to the approved standardized regimen: administration of DMSO every 2 weeks for a total of 12 weeks. Treatment outcomes were evaluated using a 7-graded global response assessment scale, O'Leary and Sant's symptom and problem indices (OSSI/OSPI), the overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, quality of life (QOL) score, and frequency volume chart variables. Related complications were also documented. RESULTS: The response rates at 2, 4, 6, 8, 10, and 12 weeks were 36.7%, 43.3%, 53.3%, 60.0%, 70.0%, and 70.0%, respectively. Compared with baseline, OSSI/OSPI, pain intensity, urinary frequency, and the QOL score improved significantly from 4 weeks of treatment. The OABSS score and functional bladder capacity also showed a tendency toward moderate improvement, but the difference was not significant. The mean duration of symptom relapse after termination of treatment was 6.4 ± 3.9 months. No patients discontinued treatment due to adverse events, although acute bladder irritation during infusion was noted in 21 patients (70%), which disappeared within 3 days. CONCLUSIONS: This study verifies the safety, moderately durable efficacy, and tolerability of the standard intravesical treatment with DMSO for HIC in Japan.

Subclassification of pT3 upper tract urothelial carcinoma: a multicenter retrospective study.

PURPOSE: The prognosis of patients with pT3 upper tract urothelial carcinoma (UTUC) varies. The current study aimed to further classify patients with pT3 UTUC into different survival outcome groups based on tumor location and site of invasion. METHODS: This retrospective study included 323 patients with pT3 UTUC who underwent nephroureterectomy at 11 hospitals in Japan. Histological and clinical data were obtained via a chart review. Univariate and multivariate Cox proportional hazards analyses showed the effect of different variables on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median age of the patients was 72 years. Patients with pT3 UTUCs were divided into two groups: those with renal parenchymal invasion only (pT3a, n = 95) and those with peripelvic or periureteral fat invasion (pT3b, n = 228). pT3b UTUC was significantly associated with hydronephrosis, low preoperative estimated glomerular filtration rate (eGFR), histological nodal metastasis, nuclear grade 3, lymphovascular invasion (LVI), carcinoma in situ, and positive surgical margin. Based on the univariate analyses, patients with pT3b UTUC had a significantly lower 5-year RFS (42.4% vs. 70.1%, p < 0.0001), 5-year CSS (54.3% vs. 80.0%, p = 0.0002), and 5-year OS (47.8% vs. 76.8%, p < 0.0001) than those with pT3a UTUC. According to the multivariate analyses, nodal metastasis, LVI, adjuvant chemotherapy, preoperative eGFR, nuclear grade (RFS only), surgical margin (RFS only), and Charlson comorbidity index (OS only), but not pT3b stage, were associated with survival. CONCLUSION: Compared with pT3a UTUC, pT3b UTUC was significantly associated with worse histological features, consequently resulting in unsatisfactory survival outcomes.

Molecular Taxonomy of Interstitial Cystitis/Bladder Pain Syndrome Based on Whole Transcriptome Profiling by Next-Generation RNA Sequencing of Bladder Mucosal Biopsies.

PURPOSE: We systematically characterized gene expression, inflammation and neovascularization in patients with interstitial cystitis/bladder pain syndrome to obtain biological evidence supporting diagnosis and classification. MATERIALS AND METHODS: We sequenced RNA obtained from bladder mucosal biopsies of 33 patients with 3 subtypes of interstitial cystitis/bladder pain syndrome, including Hunner lesions in 12, no Hunner lesions in 11 but with glomerulations and neither Hunner lesions nor glomerulations in 10, and 9 controls. Differentially expressed genes of each subtype were searched to identify subtype specific biological pathways and candidate genes important for pathogenesis. Candidate genes were validated by quantitative polymerase chain reaction and immunohistochemistry. Digital immunohistochemical quantification was performed to assess subepithelial lymphoplasmacytic cell and microvessel density. Relationships between candidate gene over expression and symptom severity were explored. RESULTS: Patients with Hunner lesions showed a distinct gene expression profile associated with significant up-regulation of biological processes involving immune responses and infection, and an increase in subepithelial lymphoplasmacytic cell and microvessel density. Over expression of 2 candidate genes, VEGF and BAFF, correlated with symptom severity. Meanwhile, the gene expression profiles of patients with the 2 subtypes without Hunner lesions were similar to those of controls. No difference in biological pathways or subepithelial lymphoplasmacytic cell and microvessel density were detected between these 2 subtypes and controls. CONCLUSIONS: Interstitial cystitis/bladder pain syndrome with Hunner lesions shows distinct genomic and histological features associated with immune responses and infection. In addition, VEGF and BAFF are potential disease biomarkers and therapeutic targets. This subtype should be considered separate from the syndrome.

Extent of Hunner lesions: The relationships with symptom severity and clinical parameters in Hunner type interstitial cystitis patients.

AIMS: To assess the clinical impact of Hunner lesions in patients with Hunner type interstitial cystitis (HIC). METHODS: The clinical records of 94 HIC patients who underwent their first hydrodistension (with lesion fulguration) were retrospectively reviewed. At surgery, the extent of each lesion was classified in terms of the relative involvement for the whole-bladder luminal surface; we defined four grades of involvement: <10%, 10-24%, 25-49%, and ≥50%; and two grades of severity: <25% (focal) and ≥25% (extensive). We examined the relationships between the extent of the lesions and all demographic characteristics, symptom scores, voiding symptoms, and bladder capacity. Factors predictive of the need for repeat hydrodistension were also explored. RESULTS: Symptom severity worsened as the lesional extent rose. Those with extensive lesions scored higher on the O'Leary and Sant Symptom (P = 0.004) and Problem Index scales (P < 0.001), the pain visual analog scale (P = 0.011), the International Prostate Symptom Score scale (P = 0.012), and a quality-of-life index (P = 0.020); and exhibited greater daytime urinary frequency (P = 0.040), more nocturia (P = 0.041), and a smaller bladder capacity (P = 0.007) than the focal group. No symptomatic or clinical parameters predicted the need for repeat hydrodistension. CONCLUSIONS: The extent of Hunner lesions was associated with both symptom severity and bladder capacity but not with other clinical parameters, including the need for repeat hydrodistension, in patients with HIC.

Digital quantitative analysis of mast cell infiltration in interstitial cystitis.

AIMS: To evaluate the significance of mast cell infiltration in interstitial cystitis (IC) by comparison with equally inflamed controls using a digital quantification technique. METHODS: Bladder biopsy specimens from 31 patients with Hunner type IC and 38 patients with non-Hunner type IC were analyzed. Bladder biopsy specimens from 37 patients without IC, including 19 non-specific chronic cystitis ("non-IC cystitis") specimens and 18 non-inflamed bladder ("normal bladder") specimens, were used as controls. Mast cell tryptase-, CD3-, CD20-, and CD138-immunoreactive cells were quantified using digital image analysis software to evaluate both mast cell and lymphoplasmacytic cell densities. Mast cell and lymphoplasmacytic cell densities were counted independently in the entire lamina propria and detrusor areas and compared among the four groups. RESULTS: In the lamina propria, there were no significant differences in mast cell and lymphoplasmacytic cell densities between Hunner type IC and non-IC cystitis or between non-Hunner type IC and normal bladder specimens. In the detrusor, the mast cell densities were not significantly different among the four groups. Mast cell density was correlated with lymphoplasmacytic cell density, but not with clinical parameters. CONCLUSIONS: Mast cell density is not significantly different between IC specimens and non-IC control specimens with a similar degree of background inflammation. The intensity of mast cell infiltration generally correlated with that of lymphoplasmacytic cells. We conclude that mast cell count is of no value in the differential diagnosis between IC and other etiologies.

Diagnostic value of urinary CXCL10 as a biomarker for predicting Hunner type interstitial cystitis.

AIM: To investigate the feasibility of chemokines and cytokines potentially elevated in the bladder tissue of Hunner type interstitial cystitis (HIC) as urinary markers for distinguishing HIC from non-Hunner type interstitial cystitis (NHIC) METHODS: Urine specimens were collected from 41 HIC patients, 25 NHIC patients, and 31 healthy volunteers (control). The supernatants of urine specimens were subjected to ELISA kits for measurements of 10 cytokines and chemokines, whose gene expression was known to be elevated in HIC bladder tissue. Urinary levels normalized by urinary creatinine (Cr) concentration were compared among three groups. Efficiency in differentiating IC and IC subtypes was explored by ROC analysis. The correlation of marker levels with symptom severity, assessed by O'Leary-Sant's symptom index (OSSI) and problem index (OSPI), was examined. RESULTS: The urinary levels of CXCL10 and NGF were significantly higher in HIC than NHIC. CXCL10 and NGF differentiated HIC against NHIC with AUC of 0.78 and 0.68, respectively. Combination of CXCL10 and NGF levels yielded an AUS of 0.81. The CXCL10 cut-off of 53.2 pg/mg Cr had sensitivity of 46.1%, specificity of 93.7%, positive predictive value of 97.7%, and negative predictive value of 60.0%. The urinary level of other cytokines showed no significant difference between HIC and NHIC. Significant correlation with symptoms was detected for CXCL10 alone. CONCLUSION: The results suggested that increased urinary level of CXCL10 combined with or without high NGF level could be a promising supplementary biomarker for differentiating HIC from NHIC with modest sensitivity and high specificity.

Hydrodistension with or without fulguration of hunner lesions for interstitial cystitis: Long-term outcomes and prognostic predictors.

AIMS: Hydrodistension of the bladder, with optional fulguration of Hunner lesions, is one of the recommended therapies for interstitial cystitis (IC). The aims of this study are to evaluate long-term outcomes of hydrodistension and identify outcome predictors. METHODS: The study cohort was 191 newly diagnosed IC patients (155 women and 36 men) who underwent hydrodistension with fulguration of Hunner lesions if detected between 2007 and 2013 at our institution. The primary outcome was therapeutic failure, which was defined as repeat hydrodistension, bladder instillation therapy, or narcotic use for pain control. Clinical features, including comorbidities and endoscopic findings, were analyzed along with the outcome. RESULTS: The cohort comprised 126 patients of Hunner type IC and 65 patients of non-Hunner type IC. The mean time to therapeutic failure was 28.5 months in Hunner type IC and 25.2 months in non-Hunner type IC. The therapeutic failure rate was higher in non-Hunner type IC at 17.3 months; however, the long-term outcomes reversed thereafter. The mean time to therapeutic failure was shorter in patients with lumbar spinal stenosis (LSS) or irritable bowel syndrome (IBS). Multivariate analysis identified LSS as a predictor for failure in Hunner type IC and non-Hunner type IC (HR = 18.8, P = 0.001; HR = 3.8, P = 0.028, respectively) and IBS in non-Hunner type IC (HR = 18.0, P = 0.008). CONCLUSIONS: Bladder hydrodistension, with fulguration of the Hunner lesions, improved IC symptoms. The outcome was worse in non-Hunner type IC shortly after hydrodistension but eventually comparable across the two types. Concomitant LSS and IBS were predictors for poor outcome. Neurourol. Urodynam. 35:965-969, 2016. © 2015 Wiley Periodicals, Inc.

Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response.

OBJECTIVES: To determine whether botulinum toxin type A can represent an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies. METHODS: This is a single-center, prospective, open labeled, randomized comparative study. Patients with refractory interstitial cystitis were randomly divided into two groups: immediate injection (group A) or 1-month delayed injection (group B) of botulinum toxin type A after allocation. The rate of treatment response (global response assessment ≥+1: slightly improved), and changes in symptom scores and frequency volume chart variables were compared between groups 1 month after allocation. Using subjects of both groups as a single cohort, predictive factors for treatment response at 1 month post-injection and the duration of response were explored. RESULTS: A total of 34 patients (group A n = 18, group B n = 16) were allocated. The response rate was significantly higher in group A than group B (72.2% vs 25.0%, P = 0.01). All symptom measures showed significant improvement in group A than group B. When both groups were combined as a single cohort, the response rate was 73.5% at 1 month, 58.8% at 3 months, 38.2% at 6 months and 20.6% at 12 months. The mean duration of response was 5.4 months. Multivariate analysis showed that past exposure to hydrodistension more than three times correlated with better outcomes. CONCLUSIONS: Botulinum toxin type A injection could be an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies, especially for those who have received repeated hydrodistensions and transurethral fulguration.

Improvement of symptoms of aging in males by a preparation LEOPIN ROYAL containing aged garlic extract and other five of natural medicines - comparison with traditional herbal medicines (Kampo).

"LEOPIN ROYAL®" (LER), a non-prescription health-promoting medication in Japan, is a preparation containing six natural medicines, namely, aged garlic extract, ginseng, oriental bezoar, velvet antler, cuscuta seed and epimedium herb. To determine the effect of LER on symptoms of aging in males, we conducted an open-labeled, randomized clinical trial using Kampo (mainly kamishoyosan) as a control. Forty-nine male patients (age, 62.7 (SD 11.8) years) with mild or more pronounced symptoms of aging were enrolled and randomly assigned to the LER (n = 24) or Kampo group (n = 25) for 6 months. The Aging Males' Symptoms (AMS) scale and the International Index of Erectile Function with 5 questions (IIEF-5) were tested at baseline, and after 3 and 6 months of administration of the medications. In the AMS scale, the somatic and psychological sub-scores and total score decreased depending on the time course in both groups. However, the decrease in the slope of the LER group was greater than that of the Kampo group. There was a significant difference between the groups and the group and month interaction (G × M), as revealed by a linear mixed model analysis (p < 0.05). The IIEF-5 score increased in the LER group (p = 0.02 with regard to G × M). In conclusion, the present results indicate that LER is possibly superior to mainly kamishoyosan on the rate of improvement of symptoms of aging, including erectile dysfunction, in males.

Urethral metastasis from a sigmoid colon carcinoma: a quite rare case report and review of the literature.

BACKGROUND: Urethral metastatic adenocarcinoma is extremely rare. Moreover, only 9 previous cases with metastases from colorectal cancer have been reported to date, and not much information on urethral metastases from colorectum is available so far. CASE PRESENTATION: We report our experience in the diagnosis and the management of the case with urethral metastasis from a sigmoid colon cancer. A 68-year-old man, who underwent laparoscopic sigmoidectomy for sigmoid colon carcinoma four years ago, presented gross hematuria with pain. Urethroscopy identified a papillo-nodular tumor 7 mm in diameter in the bulbar urethra. CT-scan imaging revealed the small mass of bulbous portion of urethra and solitary lung metastasis. Histological examination of the tumor obtained by transurethral resection showed moderately differentiated adenocarcinoma, which was diagnosed as a metastasis of a sigmoid colon carcinoma pathologically by morphological examination. Immunohistochemical analysis of the urethral tumor revealed the positive for cytokertin 20 and CDX2, whereas negative for cytokertin 7. These features were consistent with metastatic adenocarcinoma of the sigmoid colon cancer. As the management of this case with urethral and lung metastasis, 6-cycle of chemotherapy with fluorouracil with leucovorin plus oxaliplatin was administered to the patient, and these metastases were disappeared with no recurrence of disease for 34 months. CONCLUSION: Urethral metastasis from colorectal cancer is a very rare occurrence. However, in the presence of urinary symptoms, the possibility of the urethral metastasis should be considered.

A Genome-Wide Association Study of Prostate Cancer Susceptibility Using Occupational and Environmental Factors as Confounding Factors.

Background In addition to genetic predisposition, occupational and environmental factors are important for the risk of prostate cancer. We investigated the effect of single nucleotide polymorphisms (SNPs) on the development of prostate cancer in Japan, including occupational and industrial history as confounding factors in addition to age, smoking, and alcohol drinking. Methods We enrolled 210 prostate cancer patients and 504 male control patients. We conducted four genome-wide association study (GWAS) patterns for prostate cancer development. In the association test, logistic regression models incorporated age, smoking history, alcohol consumption history, and each pattern of industrial/occupational classification. Results No SNPs satisfying the genome-wide significance level of 5×10-8 were detected in GWAS. SNPs with a suggestive association level of 1×10-6 were found near the long intergenic non-protein coding RNA 1824 (LINC01824) and tripartite motif family like 2 (TRIML2) genes in the GWAS using occupational history as a confounder and near the ribosomal protein S2 pseudogene 25 (RPS2P25) gene in the GWAS using industrial history as a confounder. No SNPs that met the suggestive association level were observed in the GWAS that did not include occupational and industrial history. Conclusion By adding occupational and industrial history to the confounding factors, there were SNPs detected in the GWAS for prostate cancer development. The consideration of occupational and industrial history may increase the usefulness of GWAS.

Increased mRNA expression of genes involved in pronociceptive inflammatory reactions in bladder tissue of interstitial cystitis.

PURPOSE: We assayed mRNA expression of the TRP family of channels and ASIC1 in bladder tissue from patients with interstitial cystitis. MATERIALS AND METHODS: Bladder biopsies of 1) nonclassic interstitial cystitis, 2) nonulcerative portions of classic interstitial cystitis, 3) ulcerative portions of classic interstitial cystitis and 4) noncancerous portions of bladder cancer as the control were placed immediately in ice-cold RNAlater® and subjected to real-time reverse transcriptase-polymerase chain reaction. We compared the mRNA expression of TRP channels, ASIC1, NGF, CXCL9 and UPK3A with that of controls, and correlated expression with symptom severity. RESULTS: We analyzed specimens from 17 patients with nonclassic interstitial cystitis, 22 with classic interstitial cystitis and 11 controls. In nonclassic interstitial cystitis samples TRPV2 and NGF showed significantly increased expression. In classic interstitial cystitis samples nonulcerative portions demonstrated a significant increase in the expression of TRPA1, TRPM2 and 8, TRPV1 and 2, ASIC1, NGF and CXCL9, and a significant decrease in UPK3A and TRPV4. Ulcerative portions showed similar changes for TRPM2, TRPV1, 2 and 4, CXCL9 and UPK3A. Increased expression of TRPM2, first noted in interstitial cystitis tissue, was the most pronounced one of the TRP family. All symptom measures correlated with TRPM2 and TRPV2 expression, and partially with that of the other genes. CONCLUSIONS: This study showed increased expression of the genes involved in pronociceptive inflammatory reactions in interstitial cystitis, including TRPV1, 2 and 4, ASIC1, NGF and CXCL9, and to our knowledge TRPM2 for the first time. The different expression patterns suggest distinct pathophysiologies for classic and nonclassic interstitial cystitis. The genes and their products are potential candidates for use as biomarkers or novel therapy targets.

Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1.

INTRODUCTION: Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats. AIM: The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone. We also compared the effect of the combination therapy with that of treatment with vascular endothelial growth factor-A (VEGF-A). METHODS: Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Adenoviruses expressing AM (AdAM), Ang-1 (AdAng-1), and VEGF-A (AdVEGF-A) were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology, and protein expression were analyzed 4 weeks after the injection of the adenoviruses. MAIN OUTCOME MEASURES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of α-smooth muscle actin (SMA), VE-cadherin and type I collagen was assessed by Western blot analysis. RESULTS: Infection with AdAM plus AdAng-1 more effectively restored erectile function than infection with AdAM alone or AdAng-1 alone. This combination therapy restored erectile function to a level similar to that observed in the age-matched Wistar rats. Expression of SMA and VE-cadherin increased more significantly in the AdAM plus AdAng-1-treated group than in the AdAM- or AdAng-1-treated group. Although AdVEGF-A infection restored erectile function significantly, it also caused enlargement of the trabeculae of the cavernous body, aberrant angiogenesis, and overproduction of type I collagen. CONCLUSIONS: These results suggested that combination therapy with AM and Ang-1 potently restored erectile function and normal morphology of the cavernous body compared with VEGF-A administration. This combination therapy will be useful to treat ED patients with a severely damaged cavernous body.

Usefulness of perflubutane microbubble-enhanced ultrasound in imaging and detection of prostate cancer: phase II multicenter clinical trial.

PURPOSE: To explore the possibility of targeted biopsy (TBx) using transrectal ultrasound (US) with perflubutane microbubbles, we studied the findings of different cancerous tissue imaging modalities and evaluated needle biopsy in prostate cancer (PCa) using contrast-enhanced US (CEUS) in a multicenter clinical trial. METHODS: Seventy-one patients undergoing prostate biopsy received intravenous injection of perflubutane microbubbles (Sonazoid(®)). We evaluated and compared images obtained by CEUS. The safety observation period was 2 days after contrast administration. RESULTS: Among the 30 patients with cancer, one or more sites with findings suggestive of cancer in CEUS were detected in 23 patients (32.4%) by TBx. Although 22 patients had positive cores of cancer by systematic biopsy (SBx), 8 patients had positive cores of cancer in TBx alone (11.3%). There was a significant difference in cancer detection rate by TBx between two cohorts with PSA < 10 ng/mL (22.9%) and PSA ≥ 10 ng/mL (52.2%) (P < 0.02). Close observation of various CEUS findings with Sonazoid(®) enabled targeting of cancerous areas, and consequently, a significant difference (P < 0.05) in the detection rate of cancer was recognized in the transition zone (TZ): SBx; 21/120 (17.5%) and TBx; 17/55 (30.9%). The incidence of adverse events was 6.7% and that of adverse reactions was 4%. CONCLUSIONS: CEUS with Sonazoid(®) improved the detection rate of PCa by visualizing cancerous lesions. More detailed examination of CEUS images provided efficient characterization especially in the TZ area. TBx according to this procedure is expected to enable a lower number of biopsies and more accurate diagnosis of PCa.

On- and post-treatment symptom relief by repeated instillations of heparin and alkalized lidocaine in interstitial cystitis.

OBJECTIVES: To examine outcomes of intravesical instillations of heparin and alkalized lidocaine in patients with interstitial cystitis. METHODS: Patients with interstitial cystitis refractory to conventional therapies were given a solution of 20 000 U heparin, 5 mL 4% lidocaine and 25 mL 7% sodium bicarbonate, intravesically, weekly for 12 weeks consecutively. The treatment was regarded as "effective", when patients rated "slightly improved" or "better" on a seven-graded scale of global response assessment. Other assessment measures included O'Leary and Sant's symptom index and problem index, visual analog scale for pain, and frequency volume chart variables. RESULTS: A total of 32 patients were enrolled in the study. The average age was 63.3 years. All participants had received hydrodistension 2.2 times on average, and fulfilled National Institute of Diabetes and Digestive and Kidney Diseases criteria. The therapy was effective in 60.0% of the patients at the fourth instillation, in 76.7% at the last instillation, and 90.0%, 46.7% and 16.7% at 1, 2 and 6 months after the last instillation, respectively. Most of other assessment measures improved significantly at the fourth instillation and further beyond until the end of therapy. On termination of therapy, the efficacy gradually diminished, yet mostly maintained statistical significance by 2 months post-instillation. No severe adverse events occurred. CONCLUSIONS: A 12-week course of weekly intravesical instillations of heparin combined with alkalized lidocaine is safe and effective in relieving symptoms in interstitial cystitis patients. The effect of the treatment is maintained for 6 months. Further studies are required to optimize the number of instillations and maintenance intervals in order to maximize the therapeutic potential of simple or combined instillations in the management of interstitial cystitis.

Hypomethylation of a CpG Site in the CpG Island of the Aquaporin 1 Gene May Be Involved in the Formation of Adult-Onset Non-communicating Hydrocele Testis.

Background Water channel aquaporin 1 (AQP1) protein expression is enhanced in the tunica vaginalis of patients with adult-onset non-communicating hydrocele testis and may contribute to the development of non-communicating hydrocele testis. We performed genetic and epigenetic analyses of the AQP1 gene in the tunica vaginalis of patients with adult-onset non-communicating hydrocele testis to elucidate the cause of enhanced AQP1 protein expression. Methodology The genotype was determined for Tag single-nucleotide polymorphisms (SNPs) representing the AQP1 gene and SNPs in the 5'-upstream region of the AQP1 gene. Then, by performing association analysis, the applicability of various genetic models was investigated for each SNP. Moreover, the methylation rate of CpG sites was examined for the CpG island related to the AQP1 gene. Results There was no significant association between each SNP and hydrocele testis for any of the genetic models. The average methylation rate of the 17 CpG sites evaluated was not significantly different between controls and hydrocele testis, but the methylation rate was lower in hydrocele testis than in controls at one CpG site. Conclusions There was a significant decrease in the methylation rate at one of the CpG sites in the CpG island associated with the AQP1 gene in the tunica vaginalis of patients with non-communicating hydrocele testis. This may increase AQP1 protein expression and contribute to the formation of hydrocele testis. SNPs related to the AQP1 gene were not associated with hydrocele testis.

Structural Analysis of the Colony-Stimulating Factor 3 Gene of Granulocyte Colony-Stimulating Factor-Producing Urothelial Cancer.

Background Granulocyte colony-stimulating factor (G-CSF) is a member of the CSF family of glycoproteins that regulate the proliferation, differentiation, and mobilization of neutrophils. G-CSF-producing malignant cancers have been reported to occur in various organs and are mostly associated with poor clinical prognosis. Here, we analyzed the structure of the CSF3 gene encoding the G-CSF protein to delineate the mechanism of G-CSF production by the cancer cells. Methodology Two cases of G-CSF-producing urothelial cancers and three cases of G-CSF-nonproducing bladder cancers were enrolled for genetic analysis. Results In one case of G-CSF-producing bladder cancer, six somatic mutations were detected in the 5'- upstream region of the CSF3 gene. No somatic mutations in the CSF3 gene were detected in another case of G-CSF-producing renal pelvic cancer and G-CSF-nonproducing bladder cancers. Copy numbers of the CSF3 gene were not increased in G-CSF-producing urothelial cancers. Conclusions Somatic mutations in the 5'- upstream region of the CSF3 gene may cause G-CSF protein overproduction.

Efficacy and Safety of Low-dose Oral Prednisolone for Patients with Refractory Hunner-type Interstitial Cystitis.

Background: Hunner-type interstitial cystitis (HIC) is an immunological, chronic inflammatory disease. The efficacy of corticosteroid as a treatment for HIC is unclear. Objective: To assess the efficacy and safety of low-dose oral prednisolone (PSL) treatment for patients with refractory HIC. Design setting and participants: This retrospective observational study reviewed the clinical outcomes of 31 patients with refractory HIC who received oral PSL daily (initial dose, 5.0 or 7.5 mg) for at least 12 mo between 2016 and 2023. The dose was tapered to the minimum that maintained symptom relief during follow-up. Outcome measurements and statistical analysis: Treatment outcomes were evaluated using a seven-graded global response assessment (scores ≥+2, moderately or markedly improved, were defined as treatment response), O'Leary and Sant symptom and problem indices (OSSI/OSPI), overactive bladder symptom score (OABSS), an 11-point pain intensity numerical rating scale, a quality of life (QOL) score, and frequency-volume chart variables. Related complications were also documented. Results and limitations: The mean follow-up period was 20.1 ± 14.6 mo. The overall response rates at 1, 3, 6, 9, and 12 mo at doses of 6.7, 6.7, 5.2, 4.0, and 3.0 mg were 38.7%, 48.4%, 54.8%, 61.3%, and 64.5%, respectively. Compared with baseline, OSSI/OSPI and pain intensity improved significantly from 1 mo after PSL induction. The OABSS, QOL score, urinary frequency, and voided volume improved significantly from 9 mo after PSL induction. No patients discontinued treatment due to adverse events, although hypertension and glucose intolerance occurred in two patients, but these were resolved by temporal medications. Conclusions: This study showed that low-dose oral PSL significantly improves bladder pain, urinary symptoms, and QOL in patients with HIC, without serious adverse events. Further prospective evaluation is warranted to verify the potential efficacy and safety of low-dose PSL for HIC. Patient summary: This retrospective observational study reviewed the clinical outcomes of 31 patients suffering from refractory Hunner-type interstitial cystitis treated with low-dose oral prednisolone. Low-dose prednisolone improved bladder pain, urinary symptoms, and quality of life significantly, without serious adverse events. The response rate of 64.5% at 12 mo was comparable with the rates reported in previous studies that used higher doses of prednisolone. This study provides a rationale for further prospective evaluation of low-dose prednisolone for this intractable disease.

Assessment of lower urinary tract symptoms in men by international prostate symptom score and core lower urinary tract symptom score.

UNLABELLED: Study Type - Therapy (symptom prevalence). Level of Evidence 2a. What's known on the subject? and What does the study add? The International Prostate Symptom Score (IPSS) has been most commonly used for the symptom assessment of men with lower urinary tract symptoms (LUTS). However, LUTS in men are so variable that they may not be fully captured by the IPSS questionnaire alone. This study has demonstrated that the Core Lower Urinary Tract Symptom Score (CLSS) questionnaire, which addresses 10 important symptoms, is an appropriate initial assessment tool for LUTS in men with various diseases/conditions. OBJECTIVE: International Prostate Symptom Score (IPSS) has been commonly used to assess lower urinary tract symptoms (LUTS). We have recently developed Core Lower Urinary Tract Symptom Score (CLSS). The aim of this study is to compare IPSS and CLSS for assessing LUTS in men. PATIENTS AND METHODS: Consecutive 515 men fulfilled IPSS and CLSS questionnaires. IPSS QOL Index was used as the QOL surrogate. The clinical diagnoses were BPH (n = 116), BPH with OAB wet (n =80), prostate cancer (n = 128), prostatitis (n = 68), underactive bladder (n = 8), others (n = 72), and controls (e.g., occult blood) (n = 42). Simple statistics and predictability of poor QOL (QOL Index 4 or greater) were examined. RESULTS: All symptom scores were significantly increased in symptomatic men compared with controls. Scores of corresponding symptoms of two questionnaires were significantly correlated (r = 0.58-0.85, all P < 0.0001). A multivariate regression model to predict poor QOL indicated nine symptoms (daytime frequency, nocturia, urgency, urgency incontinence, slow stream, straining, incomplete emptying, bladder pain and urethral pain) as independent factors. The hazard ratios for bladder pain (2.2) and urgency incontinence (2.0) were among the highest. All the nine symptoms are addressed in CLSS, while three symptoms (urgency incontinence, bladder, and urethral pain) are dismissed in IPSS. CONCLUSION: CLSS questionnaire is more comprehensive than IPSS questionnaire for symptom assessment of men with various diseases/conditions, although both questionnaires can capture LUTS with possible negative impact on QOL.

Adrenomedullin mediates adipose tissue-derived stem cell-induced restoration of erectile function in diabetic rats.

INTRODUCTION: Erectile dysfunction (ED) is a major health problem. It is known that diabetic patients are more refractory to common treatments for ED. AIM: To explore the better treatment for ED, we examined the effects of adipose-derived stem cells (ASC) on ED using a diabetic rat model. We also analyzed the cytokines produced by ASC and implicated in ASC-induced restoration of erectile function. METHODS: Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. ASC or adenoviruses were injected into the penis 6 weeks after STZ administration. Erectile function, penile histology and protein expression were analyzed 4 weeks after the injection of ASC or adenoviruses. MAIN OUTCOME MEASURES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. The morphology of the penis was analyzed by Elastica van Gieson stain and immunohistochemistry. The expression of proteins specific for vascular endothelial cells (VEC) was assessed by Western blot analysis. RESULTS: ASC restored erectile function especially when they were cultured in medium containing growth factors for VEC. This restoration was associated with improvement in the histology of the cavernous body, and increased expression of VEC markers such as VE-cadherin and endothelial nitric oxide synthase (eNOS). When the expression of adrenomedullin (AM), a vasoactive peptide originally isolated from human pheochromocytoma tissue, was knocked down, the effect of ASC on ED was significantly diminished. Knockdown of AM was associated with decreased expressions of VE-cadherin and eNOS. Furthermore, overexpression of AM induced by adenovirus infection significantly improved erectile function in these diabetic rats. Overexpression of AM was associated with increased expressions of VE-cadherin and eNOS. CONCLUSIONS: These results suggested that ASC have the potentials to restore erectile function and that AM produced by ASC plays a major role in the restoration of erectile function.