Aya Niimi

Hunner-Type (Classic) Interstitial Cystitis: A Distinct Inflammatory Disorder Characterized by Pancystitis, with Frequent Expansion of Clonal B-Cells and Epithelial Denudation

Interstitial cystitis (IC) is a chronic bladder disease with urinary frequency, bladder discomfort or bladder pain of unknown etiology. Based on cystoscopic findings, patients with IC are classified as either Hunner-type/classic IC (HIC), presenting with a specific Hunner lesion, or non-Hunner-type IC (NHIC), presenting with no Hunner lesion, but post-hydrodistension mucosal bleeding. Inflammatory cell infiltration, composed predominantly of lymphocytes, plasma cells and epithelial denudation, has in the past been documented as a major pathological IC finding. However, the significance of the pathological evaluation of IC, especially with regard to the difference between HIC and NHIC, has been downplayed in recent years. In this study, we performed immunohistochemical quantification of infiltrating T-lymphocytes, B-lymphocytes and plasma cells, and measured the amount of residual epithelium in urinary bladder biopsy specimens taken from patients with HIC and NHIC, and those with no IC, using image analysis software. In addition, in situ hybridization of the light chains was performed to examine clonal B-cell expansion. Lymphoplasmacytic infiltration was significantly more severe in HIC specimens than in NHIC specimens (P <0.0001). Substantial lymphoplasmacytic inflammation (≥200 cells/mm2) was observed in 93% of HIC specimens, whereas only 8% of NHIC specimens were inflamed. Plasmacytic infiltration was more prominent in HIC specimens compared with NHIC and non-IC cystitis specimens (P <0.005). Furthermore, expansion of light-chain-restricted B-cells was observed in 31% of cases of HIC. The amount of residual epithelium was decreased in HIC specimens compared with NHIC specimens and non-IC cystitis specimens (P <0.0001). These results suggest that NHIC and HIC are distinct pathological entities, with the latter characterized by pancystitis, frequent clonal B-cell expansion and epithelial denudation. An abnormality in the B-cell population may be involved in the pathogenesis of HIC.

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

To examine outcomes of intravesical instillations of heparin and alkalized lidocaine in patients with interstitial cystitis.

Prognostic Factors for Metastatic Urothelial Carcinoma Undergoing Cisplatin-based Salvage Chemotherapy

OBJECTIVE To assess the clinicopathologic factors influencing survival in patients with metastatic urothelial carcinoma undergoing salvage chemotherapy. METHODS A retrospective review was conducted on cases of metastatic urothelial carcinoma who underwent cisplatin-based salvage chemotherapy at our institution between April 2003 and July 2011. The association of various clinicopathologic factors with survival was assessed. Survival curves were constructed by the Kaplan-Meier method. A log-rank test for univariate analysis and a Cox proportional hazards model for multivariate analysis were used. RESULTS Eighty-three cases were identified in the study. Among them, 64 patients were dead during the follow-up. The median survival was 14.6 months. Multivariate analysis evaluating variables at the start of chemotherapy demonstrated that liver metastasis, performance status score ≥ 2 and leukocyte counts ≥ 8000/µl were significant predictive factors for poor outcome. Based on these three pre-induction variables, a risk model predicting the overall survival from the initiation of chemotherapy was constructed, which classified patients into three groups with significantly different overall survival (P < 0.0001). Additionally, factors after induction of chemotherapy were studied, and poor response for chemotherapy and absence of focal treatment for metastatic lesions were also significantly associated with poorer survival. CONCLUSIONS Liver metastasis, poor performance status and higher leukocyte counts were independent poor prognostic indicators for metastatic urothelial carcinoma. Our risk classification enables an accurate prediction of survival that can be useful in deciding which patients are likely to benefit from salvage chemotherapy.

Increased CXCR3 Expression of Infiltrating Plasma Cells in Hunner Type Interstitial Cystitis

An up-regulated CXCR3 pathway and affluent plasma cell infiltration are characteristic features of Hunner type interstitial cystitis (HIC). We further examined these two features using bladder biopsy samples taken from 27 patients with HIC and 15 patients with non-IC cystitis as a control. The number of CD3-positive T lymphocytes, CD20-positive B lymphocytes, CD138-positive plasma cells, and CXCR3-positive cells was quantified by digital image analysis. Double-immunofluorescence for CXCR3 and CD138 was used to detect CXCR3 expression in plasma cells. Correlations between CXCR3 positivity and lymphocytic and plasma cell numbers and clinical parameters were explored. The density of CXCR3-positive cells showed no significant differences between HIC and non-IC cystitis specimens. However, distribution of CXCR3-positivity in plasma cells indicated co-localization of CXCR3 with CD138 in HIC specimens, but not in non-IC cystitis specimens. The number of CXCR3-positive cells correlated with plasma cells in HIC specimens alone. Infiltration of CXCR3-positive cells was unrelated to clinical parameters of patients with HIC. These results suggest that infiltration of CXCR3-positive plasma cells is a characteristic feature of HIC. The CXCR3 pathway and specific immune responses may be involved in accumulation/retention of plasma cells and pathophysiology of the HIC bladder.

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

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.

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

To determine whether botulinum toxin type A can represent an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies.

Validation of an educational program balancing surgeon training and surgical quality control during robot-assisted radical prostatectomy

To establish a mentoring program that allows novice surgeons to use robotics while maintaining surgical quality during robot‐assisted radical prostatectomy.

Combination of docetaxel, ifosfamide and cisplatin (DIP) as a potential salvage chemotherapy for metastatic urothelial carcinoma

OBJECTIVE The aim of this study was to evaluate the efficacy and toxicity of the combination of docetaxel, ifosfamide and cisplatin as salvage chemotherapy after failure of standard cisplatin-based regimens for metastatic urothelial carcinoma. METHODS We prospectively administered docetaxel, ifosfamide and cisplatin chemotherapy to patients with metastatic urothelial carcinoma refractory to standard cisplatin-based regimens from 2003 to 2013. Patients who had received only adjuvant and/or neoadjuvant chemotherapy were excluded. Eligible patients received every 28 days docetaxel 60 mg/m(2) on Day 1, ifosfamide 1.0 g/m(2) on Days 2-6 and cisplatin 20 mg/m(2) on Days 2-6. The primary endpoints were progression-free survival and overall survival, calculated from the start of docetaxel, ifosfamide and cisplatin chemotherapy. Secondary endpoints included objective response and related toxicity. RESULTS Twenty-six cases received a median of 3.0 cycles of docetaxel, ifosfamide and cisplatin chemotherapy (interquartile range: 2-5), resulting in a median progression-free survival of 3 months (interquartile range: 2-9.5 months) and median overall survival of 8.5 months (interquartile range: 6.5-18.75 months), respectively. Of 26 patients, seven (27%) achieved major treatment responses, with one complete response (4%) and six partial responses (23%). Most of Grade 3/4 toxicities were hematologic events, including leukopenia (77%), anemia (54%) and thrombocytopenia (46%). No death from toxicity was observed. CONCLUSIONS Our results indicate that docetaxel, ifosfamide and cisplatin chemotherapy is a tolerable and moderately active regimen for metastatic urothelial carcinoma after failure of standard cisplatin-based regimens.

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)

Abstract “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.

Neuromedin B Restores Erectile Function by Protecting the Cavernous Body and the Nitrergic Nerves from Injury in a Diabetic Rat Model.

Erectile dysfunction (ED) is a major health problem worldwide and affects approximately 75% of diabetic patients, likely due to severely damaged cavernous body. While screening for cytokines produced by adipose tissue-derived stem cells, we detected neuromedin B (NMB). To explore a potential treatment option for ED, we examined whether NMB was capable of restoring erectile function. We also examined the potential mechanism by which NMB could restore erectile function. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. An adenovirus expressing NMB (AdNMB) was injected into the penis 6 weeks after STZ administration. Four weeks after the injection of AdNMB, erectile function, penile histology, and protein expression were analyzed. As assessed by the measurement of intracavernous pressure, AdNMB injection significantly restored erectile function compared with the injection of an adenovirus expressing green fluorescent protein. This restoration was associated with conservation of the cavernous body structure and neural nitric oxide synthase (nNOS)-expressing nerves, together with recovery of α-smooth muscle actin, vascular endothelial-cadherin, and nNOS expression. Furthermore, NMB significantly stimulated the survival of SH-SY5Y cells derived from human neuroblastoma tissue with characteristics similar to neurons. Collectively, these results suggested that NMB restored erectile function via protection of the cavernous body from injury and stimulation of the survival of the associated nerves. NMB may be useful to treat ED patients with a severely damaged cavernous body.