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Objectives: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC., Methods: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD)., Results: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions., Conclusions: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial., (© 2023 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

We report the case of a 48-year-old man who presented with fatigue and weight loss. A local physician observed elevated alkaline phosphatase levels, anemia, thrombocytopenia, and renal dysfunction. Fever also appeared, and the patient was admitted to our hospital. Computed tomography revealed hepatosplenomegaly, pleural and ascitic fluid, and left axillary lymphadenopathy. Bone marrow biopsy indicated hyperplasia with increased megakaryocytes and reticulin fibrosis. Axillary lymph node biopsy showed Castleman's disease-like features. Liver biopsy revealed proliferation of reticulin fibrosis. Therefore, TAFRO syndrome was diagnosed and treatment with 1 mg/kg prednisolone was started. Anemia and thrombocytopenia improved, and after 24 weeks of treatment, serum hyaluronic acid and type IV collagen decreased to the normal range. Bone marrow biopsy after 18 weeks of treatment showed decreased reticular fibers. In TAFRO syndrome, improvement of liver and bone marrow fibrosis can be expected with adequate intervention, and serum hyaluronic acid and type IV collagen are useful for evaluating fibrosis.

Purpose: To evaluate 10-year outcome of infliximab (IFX) treatment for uveitis in Behçet disease (BD) patients using a standardized follow-up protocol., Design: Retrospective longitudinal cohort study., Participants: 140 BD uveitis patients treated with IFX enrolled in our previous study., Methods: Medical records were reviewed for demographic information, duration of IFX treatment, number of ocular attacks before IFX initiation, best corrected visual acuity (VA) at baseline and 1, 2, 3, 4, 5, and 10 years after IFX initiation, uveitis recurrence after IFX initiation and main anatomical site, concomitant therapies, and adverse events (AEs)., Main Outcome Measures: 10-year IFX continuation rate and change in LogMAR VA., Results: Of 140 BD patients, 106 (75.7%) continued IFX treatment for 10 years. LogMAR VA improved gradually after initiation of IFX, and the improvement reached statistical significance from 2 years of treatment. Thereafter, significant improvement compared with baseline was maintained until 10 years, despite a slight deterioration of logMAR VA from 5 years. However, eyes with worse baseline decimal VA < 0.1 showed no significant improvement from baseline to 10 years. Uveitis recurred after IFX initiation in 50 patients (recurrence group) and did not recur in 56 (non-recurrence group). Ocular attacks/year before IFX initiation was significantly higher in the recurrence group (2.82 ± 3.81) than in the non-recurrence group (1.84 ± 1.78). In the recurrence group, uveitis recurred within 1 year in 58% and within 2 years in 74%. Seventeen patients (34%) had recurrent anterior uveitis, 17 (34%) had posterior uveitis, and 16 (32%) had panuveitis, with no significant difference in VA outcome. In addition, logMAR VA at 10 years did not differ between the recurrence and non-recurrence groups. AEs occurred among 43 patients (30.7%), and 24 (17.1%) resulted in IFX discontinuation before 10 years., Conclusions: Among BD patients with uveitis who initiated IFX, approximately 75% continued treatment for 10 years, and their VA improved significantly and was maintained for 10 years. Uveitis recurred in one-half of the patients, but visual acuity did not differ significantly from the patients without recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takeuchi, Usui, Namba, Keino, Takeuchi, Takase, Kamoi, Hase, Ito, Nakai, Maruyama, Kobayashi, Mashimo, Sato, Ohguro, Hori, Okada, Sonoda, Mizuki and Goto.)

Robot-assisted laparoscopic partial nephrectomy (RAPN) is being used in Japan as a less invasive procedure. RENAL nephrometry (RN) score, Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) Classification and Simplified PADUA Renal (SPARE) nephrometry system are tumor-specific morphometry scoring systems used for predicting the difficulty of partial nephrectomy. Adherent perinephric fat (APF) is one of the patient-specific factors related to the difficulty of partial nephrectomy. Mayo Adhesive Probability (MAP) score measures the difficulty of partial nephrectomy due to APF. Whether these scoring systems were associated with perioperative outcome of RAPN was retrospectively analyzed in 57 patients who underwent RAPN by two experienced surgeons at our hospital from December 2016 to March 2020. Forty-five patients were male and 12 were female. The right side was resected in 25 and the left side in 32 patients. The approach was transperitoneal in 42 and retroperitoneal in 15 patients. There were significant correlations among RN, PADUA and SPARE scores, while MAP score was independent from the other scores. Warm ischemic time was significantly correlated with RN (r＝0.46, p＜0.001), PADUA (r＝0.45, p＜0.001) and SPARE scores (r＝0.44, p＜0.001). Time for console was significantly correlated with MAP score (r＝0.28, p＝0.035). In conclusion, RN and MAP scores might be useful parameters to predict warm ischemic time and time for console during RAPN, respectively.

Like many other countries, the economy and society of Japan have been deeply affected by the Covid-19 outbreak, and the fishery sector is no exception. This study takes an interdisciplinary approach to analyze the economic and social impacts of the pandemic on Japanese fisheries, gauging the extent and nature of the damages incurred from Covid-19 while helping to provide tailored post-recovery recommendations for the industry. Using results from an online survey questionnaire (N = 429) and compiling additional economic information from public sources, this study revealed the overwhelmingly negative changes in sales figures and overall financial security that survey participants experienced when compared to a year earlier. High-value and fresh fish species were also significantly affected in 2020 across Japan, in line with similar trends across the developed world. Aquaculture businesses were shown to be more vulnerable to the spread of Covid-19 than small-scale fishing operations, which tend to be more diverse and flexible. Bonding social capital was also shown to be important for mutual help and human well-being, especially among small-scale fishers. This "customary nature" of Japanese fisheries, at the same time, can be seen as a barrier to the transformation of the industry. Given these results, several policy implications are discussed to help fisheries stakeholders and their communities build back better from the Covid-19 pandemic., (© 2022 The Authors.)

Purpose: To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt-Koyanagi-Harada (VKH) disease., Study Design: A prospective, multicenter, randomized, non-inferiority trial., Methods: Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year., Results: Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03-0.27) in the combination group and 0.25 (95% CI 0.11-0.39) in the corticosteroid group, with a risk difference of - 0.10 (90% CI - 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42-71) and 4.3% in the combination group and 0.91 (95% CI 0.78-1.04) and 34.0% in the corticosteroid group, respectively., Conclusions: Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group., (© 2021. Japanese Ophthalmological Society.)

Scleritis involves inflammation of the sclera, which constitutes 75% of the wall of the eye. This pathology is often seen as an ocular lesion associated with systemic inflammatory diseases. Severe types of scleritis such as posterior scleritis require urgent immunosuppressive treatments, including molecularly targeted therapies to avoid permanent visual impairment. Which molecules should be selected as targets has remained unclear. To clarify the pathogenesis of scleritis and propose appropriate target molecules for therapy, we have established novel animal model of scleritis by modifying the Collagen-II Induced Arthritis (CIA) model. Immunization twice with collagen II emulsified with complete Freund's adjuvant (CFA) caused arthritis and scleritis. The clinical appearance resembled human diffuse scleritis. Histopathological analysis suggested that macrophages, plasma cells, deposition of immune complexes, and growth of blood and lymphatic vessels are involved in the pathogenesis of CIA-associated scleritis. In addition, we analysed the background diseases of posterior scleritis and responses to molecularly targeted therapies as a case series study. We inferred from both the animal model and case series study that targets should not be T cells, but factors inhibiting macrophage activity such as tumor necrosis factor (TNF) and interleukin (IL)-6, and molecules suppressing antibody-producing cells such as CD20 on B cells should be targeted by molecularly targeted therapies.

The patient was a 69-year-old man diagnosed with stage ⅣB lung adenocarcinoma with 95% programmed death- ligand 1 expression, and pembrolizumab monotherapy was initiated. The patient exhibited fatigue from the 12th course(36 weeks after treatment initiation) of treatment. Chest computed tomography revealed scattered ground-glass opacities in the upper lobes of both lungs, and he was subsequently diagnosed with interstitial pneumonia. Fatigue persisted even after a drug holiday from pembrolizumab, and the patient was diagnosed with hypopituitarism based on the results of endocrinological examinations. Rashes appeared on both legs 40 weeks after treatment initiation, which led to the patient being diagnosed with a drug-induced skin disorder. All the adverse events resolved upon treatment with hydrocortisone. Immune- related adverse events due to pembrolizumab may occur in multiple organs simultaneously.

Purpose: The posterior approach is widely used in femoral hemiarthroplasty. The major problem with this approach is the high risk of postoperative dislocation. A modified posterior approach, the conjoined tendon preserving posterior approach (CPP), was developed to reduce postoperative dislocations. The objective of this multicenter study was to evaluate the efficacy and safety of hemiarthroplasty performed using the CPP approach for femoral neck fractures., Methods: A total of 322 patients with femoral neck fracture, from 10 facilities, were prospectively studied. Bipolar hemiarthroplasty using the CPP approach was performed, using the same type of implants. Hip joint movement was not restricted following surgery, regardless of a patient's cognitive status. Final follow-up was performed 9.1 ± 1.5 months after surgery., Results: Hemiarthroplasty was undertaken in 320 patients using the CPP approach. The mean age, operative time, and intraoperative blood loss were 83.3 ± 7.4 years, 70.0 ± 22.7 min, and 134.8 ± 107.9 mL, respectively. No postoperative dislocations were observed during the study period. Intraoperative adverse events related to the hip joint included femoral fractures in five patients (1.6%) and trochanteric fractures in four patients (1.3%). Postoperative hip joint adverse events included a periprosthetic fracture in one patient (0.3%), deep infection in two patients (0.6%), and stem subsidence in one patient (0.3%). Postoperative deaths occurred in 23 patients (7.2%). One patient (0.3%) had a severe non-hip adverse event unrelated to surgery that prevented independent living, while five patients (1.6%) had a moderate non-hip adverse event that required treatment., Conclusion: The CPP approach prevented postoperative dislocation following femoral hemiarthroplasty in elderly patients, with no CPP-associated specific adverse events.

We retrospectively investigated the clinical course of α1 blocker discontinuation in patients who had lower urinary tract symptoms with benign prostate hypertrophy (LUTS/BPH) and received combination therapy ofdutasteride and α1 blocker. Among the patients with LUTS/BPH who had been receiving combination therapy, those who wished to reduce the number ofprescribed drugs and discontinue the use of α1 blocker because ofsymptom improvement were recruited in this study. Symptom scores including International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS), parameters ofuroflowmetry and prostate volume (PV) were evaluated at the time of α 1 blocker discontinuation. Twenty-two patients discontinued the use of α 1 blocker. The mean PV at the time of α 1 blocker discontinuation was 43.2 ml, and the mean duration ofcombination therapy was 39.4 months. In 11 (50%) patients, dutasteride monotherapy without α1 blocker was maintained for a mean follow-up of 10.5 months (9-12 months) after α1 blocker discontinuation (Non-resumption group). In the other 11 patients (50%), α1 blocker was resumed because ofthe patient's request to resume the use of α1 blocker (Resumption group). The mean length ofdutasteride monotherapy was 4. 5 months (1-8 months) in the resumption group. Compared with the non-resumption group, IPSS total score and storage sub-score ofIPSS at the time of α1 blocker discontinuation were significantly higher in the resumption group. Based on the ROC curve, IPSS total score <16, IPSS voiding/storage symptom score <7, OABSS <7 and PV 54 ml or more at the time of α1 blocker discontinuation were predictors ofnon-resumption of α1 blocker. These results suggest that if LUTS is controlled by a long-term combination therapy ofdutasteride and α1 blocker and still PV is large enough, α1 blocker can be discontinued.

Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10 -8 ) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

The eye is provided with immune protection against pathogens in a manner that greatly reduces the threat of inflammation-induced vision loss. Immune-mediated inflammation and allograft rejection are greatly reduced in the eye, a phenomenon called 'immune privilege'. Corneal tissue has inherent immune privilege properties with underlying three mechanisms: (1) anatomical, cellular, and molecular barriers in the cornea; (2) an immunosuppressive microenvironment; and (3) tolerance related to regulatory T cells and anterior chamber-associated immune deviation. This review describes the molecular mechanisms of the immunosuppressive microenvironment and regulatory T cells in the cornea that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, it also provides an update on immune checkpoint molecules in corneal and systemic immune regulation, and its relevance for dry eye associated with checkpoint inhibitor therapy.

Psoas muscle mass index (PMI) is related to sarcopenia. We examined whether PMI is associated with early complications after radical cystectomy. Seventy one male and 29 female patients who were 65 years old or older and who had undergone radical cystectomy at our hospital from April 2005 to March 2018 were retrospectively analyzed. Psoas muscle section area was measured manually on preoperative computed tomography (CT) scan and normalized by patient's height. Early postoperative complications of grade 3 or more occurred in 12 male (16.9%) and 5 female (17.2%) patients. PMI was lower in male patients who had early postoperative complications of grade 3 or more than in those without complications (5.61 vs 6.54 cm2 /m2, p=0. 08), although the difference was not statistically significant. There was suggested to be a relationship between early postoperative complications after radical cystectomy and preoperative PMI in elderly male patients.

Purpose: V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel immune checkpoint receptor and ligand for regulating T cell proliferation and cytokine production. The purpose of the present study was to determine the role of VISTA in the immune privilege of corneal allografts., Methods: Expression of VISTA mRNA in mouse eyes was assessed with reverse-transcription PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of BALB/c wild-type recipients treated with anti-VISTA mAb, and graft survival was assessed. A separate set of BALB/c mice treated with anti-VISTA mAb or rat IgG received injection of C57BL/6 splenocytes into the anterior chamber, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. CD4+ and CD8+ T cells in the spleen were assessed with flow cytometry., Results: VISTA mRNA was constitutively expressed in the cornea, and the expression of VISTA was localized to CD11b+ cells on the corneal stroma. Survival of allografts treated with anti-VISTA mAb was less than that of the control. ACAID was induced less efficiently in BALB/c mice treated with VISTA mAb. The proportions of CD8+ T cells and CD8+ CD103+ T cells (CD8+ T regulatory cells) in the spleen of BALB/c mice treated with anti-VISTA mAb were significantly lower than those of the control., Conclusions: VISTA may play an essential role in the acceptance of corneal allografts via involvement with allospecific ACAID, which suppresses T cell infiltration into the cornea.

Objectives: To examine the long-term outcomes of transurethral resection of the prostate., Methods: We retrospectively collected the data of patients who had undergone transurethral resection of the prostate before December 2010. Patients had been evaluated by urodynamics and the International Prostate Symptom Score preoperatively, and they were re-evaluated by using the International Prostate Symptom Score at the minimum 7 years after transurethral resection of the prostate. Patients who received any treatments to improve voiding symptoms were defined as having a relapse of voiding dysfunction. The Schäfer nomogram was used to assess the degree of obstruction and detrusor contractility. We assessed the change in International Prostate Symptom Score over time depending on obstruction (Schäfer grade 3-6) versus no obstruction (Schäfer grade 0-2), and normal detrusor contractility (strong and normal) versus detrusor underactivity (weak and very weak). Relapse rates of voiding dysfunction were determined using the Kaplan-Meier method., Results: A total of 39 patients were included. The mean age at transurethral resection of the prostate was 69.8 years, and the mean observation period after transurethral resection of the prostate was 114 months. During the observation period, eight patients (21%) were categorized as relapse of voiding dysfunction and the mean time to relapse was 4.2 years. Patients categorized as no obstruction or detrusor underactivity had a higher recurrence rate of voiding dysfunction with a statistical significance between those with versus without obstruction. Except for patients with relapse of voiding dysfunction, improvement of the International Prostate Symptom Score was maintained over a period of 10 years after transurethral resection of the prostate., Conclusions: Favorable long-term symptomatic outcome after transurethral resection of the prostate is likely in patients with urodynamic obstruction. Patients without urodynamic obstruction are likely to have a relapse of voiding symptoms and require additional treatments in the long term., (© 2019 The Japanese Urological Association.)

Corneal transplantation is the most successful solid organ transplantation performed in humans. The extraordinary success of orthotopic corneal allografts, in both humans and experimental animals, is related to the phenomenon of "immune privilege". Inflammation is self-regulated to preserve ocular functions because the eye has immune privilege. At present, three major mechanisms are considered to provide immune privilege in corneal transplantation: 1) anatomical, cellular, and molecular barriers in the cornea; 2) tolerance related to anterior chamber-associated immune deviation and regulatory T cells; and 3) an immunosuppressive intraocular microenvironment. This review describes the mechanisms of immune privilege that have been elucidated from animal models of ocular inflammation, especially those involving corneal transplantation, and its relevance for the clinic. An update on molecular, cellular, and neural interactions in local and systemic immune regulation is provided. Therapeutic strategies for restoring immune privilege are also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The patient was a 66-year-old man who had undergone ileocystoplasty and right nephrectomy at the age of 21 for the treatment of urinarytract tuberculosis. He had been receiving hemodialysis from the age of 58. Regular computed tomography (CT) examination at the age of 63 revealed a bladder mass, but the transurethral biopsyof the bladder mass did not reveal malignant findings. At the age of 66, his urine cytology indicated a suspicion of malignancy, and bladder tumor was detected by cystoscopy. The patient was referred to our hospital and we performed transurethral resection of the bladder tumor. Pathological diagnosis was papillaryadenocarcinoma. Because left lower ureteral cancer was also suspected byCT scan, we performed left nephroureterectomy and radical cystectomy. Pathological examination revealed adenocarcinoma of the reconstructed bladder. The patient remains free of disease for 1 year and 11 months after the operation. Forty-five cases of bladder cancer after enterocystoplasty have been reported in Japan. There are no guidelines for follow-up protocols after enterocystoplasty. A long-term follow-up is mandatory because of the possibilityof development of bladder malignancylong after the enterocystoplasty.

The classification accuracy of an event-related potential (ERP) induced by a tactile stimulus is investigated to create a brain-computer interface (BCI). Mechanical tactile stimuli were applied to the left and right index fingers using two piezo actuator probes that were used as a Braille display for the visually impaired. In an experiment, two-class classification was investigated using three kinds of tactile stimulus pattern. The subjects were instructed to pay attention to unusual target stimuli while avoiding other frequent nontarget stimuli. The extracted features were classified using stepwise linear discriminant analysis. As a result, high accuracy was obtained by the task of random intervals compared with the task of constant intervals. It was suggested that the accuracy of the BCI using tactile stimuli is influenced by the concentration on the task.

Objectives: To examine the long-term persistence rate with mirabegron in a real-world clinical setting., Methods: We retrospectively collected the data of patients who were prescribed mirabegron. We investigated the persistence rate and the reason for the discontinuation. The analysis included patient's age, diagnosis, Overactive Bladder Symptom Score, prostatic volume, the prescription by specialists for lower urinary tract dysfunction, drug-naïve patients, replacement of antimuscarinics or add-on therapy to antimuscarinics., Results: A total of 556 patients were included. Among them, 401 patients (72%) had overactive bladder and the other 155 (28%) were categorized as having other storage symptoms. During the observation period, 170 patients (42%) with overactive bladder discontinued mirabegron. The reasons for discontinuation in patients with overactive bladder included unmet expectation of treatment (45 patients, 26%), any adverse events (38 patients, 22%) or symptom improvement (37 patients, 22%). The persistence or discontinuation was not related with age, Overactive Bladder Symptom Score, prostatic volume or the prescription by specialists, while older male patients tended to continue mirabegron. The 3-year persistence rates in female and male overactive bladder patients were 46% and 51%, respectively, and these were better than those in patients with storage symptoms without urgency. In female overactive bladder patients, the persistence rate with mirabegron used as add-on therapy to antimuscarinics was higher than that in the drug-naïve patients on the Kaplan-Meier curve., Conclusions: The present study shows a relatively good long-term persistence rate with mirabegron in overactive bladder patients, notwithstanding the retrospective study in an academic hospital. The combined treatment with antimuscarinics could result in a good persistence rate with mirabegron., (© 2018 The Japanese Urological Association.)

Objectives: To evaluate the diagnostic efficacy of percutaneous renal tumor biopsy., Methods: We retrospectively investigated 23 patients who underwent percutaneous renal tumor biopsy since 2008 at Department of Renal and Urologic Surgery, Asahikawa Medical University Hospital. We examined indications of biopsy, diagnostic concordance rate between urologists, radiologists and biopsy findings, pathological findings and biopsy-related complications., Results: Renal tumor biopsy was performed under ultrasonography guidance in 21 patients and computed tomography guidance in 2. The most frequent indication to perform biopsy was to determine histological subtype of renal cell carcinoma(RCC)before treatment. The second indication was to clarify the nature of renal tumor. Biopsy findings revealed RCC in 17 patients and urothelial carcino- ma(UC)in 6. Diagnostic concordance rate between urologist's diagnosis and biopsy findings was 91%(21/23), which showed the same result between radiologists and biopsy findings. Biopsy-related adverse event included needle tract implantation in 1 patient with UC. Another patient who had central necrosis in the tumor showed insufficient material causing repeat biopsy with frozen section. Except this patient, initial renal tumor biopsy was successful in all patients by concomitant use of frozen section for tumor with central necrosis. The overall diagnostic rate of initial biopsy was 95.7%(22/23)., Conclusions: Despite a small number of patients and a retrospective nature, the present study shows that renal tumor biopsy plays an important role in diagnosis of renal tumor. Concomitant use of frozen section might be considered at the time of renal tumor biopsy in patients with necrotic renal tumor to avoid repeat biopsy. However, we should take into consideration that there are some possible risks of needle tract implantation in cases with UC when we perform percutaneous renal tumor biopsy.

Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca ++ -activated K + conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K + efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K + efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca ++ -activated K + channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca ++ -activated K + channels.

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Purpose: Corneal endothelial cell density undergoes a progressive decrease for many years after transplantation, eventually threatening patients with late endothelial failure. The purpose of this study was to investigate the possibility of an immunologic response in successfully grafted corneal endothelium., Methods: The corneal endothelium of patients who had undergone corneal transplantation was evaluated by specular microscopy. Rabbit models were subjected to penetrating keratoplasty (PK) with either syngeneic or allogeneic corneal transplants and Descemet's stripping endothelial keratoplasty (DSEK) with allogeneic corneal transplants. The presence of immune cells and expression of proinflammatory cytokines were determined by immunostaining. The corneal endothelium and immune cells were also evaluated by scanning electron microscopy., Results: Scanning slit contact specular microscopy of patients with no features of graft rejection revealed cell-like white dots on the grafted corneal endothelium. The corneal endothelium of the allogeneic PK and DSEK rabbit models displayed the presence of immune cells, including CD4+ T-helper cells, CD8+ cytotoxic T cells, CD20+ B lymphocytes, CD68+ macrophages, and neutrophils, but these immune cells were rarely observed in the syngeneic PK model. These immune cells also produced proinflammatory cytokines. Notably, some of the corneal endothelial cells situated near these immune cells exhibited features of apoptosis., Conclusions: T lymphocytes, B lymphocytes, macrophages, and neutrophils are present on the grafted corneal endothelium in both PK and DSEK allogeneic rabbit models. The potential involvement of immune cells as an underlying pathophysiology for late endothelial failure deserves further examination.

Purpose: The interaction between the inducible costimulatory molecule (ICOS) and ICOS ligand (ICOSL) has been implicated in the differentiation and functions of T cells. The purpose of the present study was to determine the role of ICOS-ICOSL in the immune privilege of corneal allografts., Methods: Expression of ICOS and ICOSL mRNA from mouse eyes was assessed by RT-PCR. Corneas of C57BL/6 mice were orthotopically transplanted into the eyes of ICOS-/- BALB/c recipients and BALB/c wild-type (WT) recipients treated with anti-ICOSL mAb, and graft survival was assessed. A separate set of WT and ICOS-/- BALB/c mice received an anterior chamber injection of C57BL/6 splenocytes, and induction of allospecific anterior chamber-associated immune deviation (ACAID) was assessed. In vitro, cornea was incubated with T cells from WT and ICOS-/- BALB/c mice, and destruction of corneal endothelial cells (CECs) and the population of Foxp3+ CD25+ CD4+ T cells was assessed., Results: Inducible costimulatory molecule ligand mRNA was constitutively expressed in the cornea, iris-ciliary body, and retina. Allograft survival in ICOS-/- recipients and WT recipients treated with anti-ICOSL mAb was significantly shorter than in control recipients. Anterior chamber-associated immune deviation was induced less efficiently in ICOS-/- mice. Destruction of CECs by alloreactive ICOS-/- T cells was enhanced compared with WT T cells. After coincubation with allogeneic corneal tissue, the proportion of regulatory T cells was significantly greater among WT T cells than in ICOS-/- T cells., Conclusions: The expression of ICOSL in the cornea and the ICOS-mediated induction of Foxp3+ CD4+ regulatory T cells may contribute to successful corneal allograft survival.

Objectives: Behçet's disease (BD) is a systemic inflammatory disorder polarised to the Th1 and Th17 immune systems. Allergic diseases are polarised to the Th2 immune system. The aim of the present study is to investigate the prevalence of allergic diseases in patients who have BD., Methods: The study involved a large-scale interview survey of Japanese patients with BD at 21 institutes of ophthalmology; 353 patients (255 males and 98 females) were recruited for this study. We analysed the history of allergic diseases such as atopic dermatitis (AD), allergic rhinitis (AR), bronchial asthma (BA) and drug/food allergies (FA)., Results: Oral aphthous ulcers, ocular lesions, skin lesions, genital ulcers, arthritis, neurological lesions, intestinal lesions, deep vein thrombosis and epididymitis were reported in 95.8%, 98.6%, 72.5%, 44.8%, 13.9%, 6.8%, 6.2%, 3.7% and 1.4% of the patients, respectively. It was also reported that 73 patients (20.7%) had histories of allergic diseases: AD (5 cases, 1.4%), AR (36 cases, 10.2%), BA (19 cases, 5.4%) and FA (30 cases, 8.5%). This percentage was significantly lower than in a survey that Japan's Ministry of Health, Labour and Welfare conducted for healthy population (47.6%) (odds ratio = 0.29, 95% confidence interval = 0.22-0.38, p=4.9×10-22). Frequencies of posterior/pan-uveitis, relatively severe ocular findings, and visual prognosis were not affected by a history of allergic diseases in BD., Conclusions: Patients with BD had fewer complications from allergic diseases than did the entire population of Japan.

Objectives: To investigate the efficacy of combination treatment of degarelix and antiandrogen in patients with prostate cancer., Methods: We prospectively investigated the efficacy of combination treatment of degarelix and antiandrogen in 12 patients with treatment-naive prostate cancer. We surveyed PSA, LH, FSH and testosterone at day 3, 7, 14 and 28 during the initial month and thereafter once a month for 1 year. In cases with bone metastasis, we analyzed serum bone markers such as alkaline phosphatase(ALP), bone-type ALP and carboxyterminal telopeptide of type- I collagen once a month. Skeletal related events (SREs) were also monitored., Results: PSA progression free survival was 65%. PSA was reduced from baseline by 80% at day 14 and by 93% at day 28. In all patients serum testosterone immediately reached castrate level at day 3 and was maintained for 1 year without breakthrough escape. Both LH and FSH were reduced to within normal range at day 3. In contrast, all bone markers temporarily increased at day 28, and thereafter decreased. Although 2 patients had suffered from SREs before treatment, there were no SREs after combination treatment., Conclusions: The present study showed that combination of degarelix and antiandrogen could lead to favorable PSA reduction and immediate castrate level at an earlier phase. However, further study is needed to compare the difference between degarelix monotherapy and these combinations.

An 81-year-old man was referred to our hospital because of a right renal tumor with vena cava thrombus and multiple lung metastases that were detected by computed tomography (CT) scan during evaluation of respiratory discomfort. We started medical treatment with sunitinib at a dose of 50 mg daily in a 2-week-on, 1-week-off schedule after confirming clear cell renal cell carcinoma by tumor biopsy. After 2-week sunitinib treatment, thrombocytopenia continued and platelet count decreased to 1.8×10(9)/l at day 11 after stopping sunitinib. We needed to administer a total of 60 units platelet transfusion because of persistent thrombocytopenia. Bone marrow aspiration did not reveal myelosuppression or carcinoma invasion to bone marrow. Under the clinical diagnosis of drug-induced thrombocytopenia secondary to sunitinib, we started immunoglobulin therapy at day 23 after stopping sunitinib. Platelet count returned to normal 10 days after starting immunoglobulin. The patient developed exacerbating lung metastasis and carcinomatous lymphangiosis during subsequent course and died of renal cell carcinoma 79 days after starting sunitinib. Thrombocytopenia after sunitinib therapy is often encountered but prolonged thrombocytopenia is rare after stopping sunitinib. This case suggests that immunoglobulin therapy is effective for drug-induced prolonged thrombocytopenia through immunological mechanism.

A 66-year-old male patient was referred to our hospital for bilateral renal pelvic tumors. Ureteroscopic biopsy revealed urothelial carcinoma (UC) of low grade (G1) of the renal pelvis. Renal sparing treatment with systemic chemotherapy and percutaneous tumor resection was performed. However, during subsequent follow up, a recurrent tumor was found on the left ureter. After ureteroscopic laser ablation of the tumor, Bacillus Calmette-Guerin (BCG) perfusion therapy (once a week, total 6 weeks) was performed via a single J ureteral catheter with no adverse events. Later, another recurrent recurrence was found on the right ureter, and was managed by ureteroscopic laser ablation followed by BCG perfusion therapy via a single J ureteral catheter. However, the patient developed high fever with chill from the day after initial BCG perfusion therapy on the right side. Although we started antibiotics, high fever continued. Then antituberculous drugs were administered and his condition was improved. Computed tomographic scan revealed a right renal mass 57 mm in diameter, which was consistent with tuberculous granuloma. The tuberculous granuloma persisted despite the continuation of anti-tuberculous drugs. In exceptional cases of upper tract UC such as single kidney and bilateral tumor, BCG perfusion therapy has been used as adjunctive treatment to cure or prevent UC. However, dosages and administration methods of BCG perfusion therapy for upper tract UC still remain to be standardized. Serious adverse events after BCG perfusion therapy require prompt and proper management including the use of anti-tuberculous drugs.

Cortical dipole imaging has been developed to visualize brain electrical activity in high spatial resolution. It is necessary to solve an inverse problem to estimate the cortical dipole distribution from the scalp potentials. In the present study, the accuracy of cortical dipole imaging was improved by focusing on filtering property of the spatial inverse filter. We proposed an inverse filter that optimizes filtering property using a sigmoid function. The ability of the proposed method was compared with the traditional inverse techniques, such as Tikhonov regularization, truncated singular value decomposition (TSVD), and truncated total least squares (TTLS), in a computer simulation. The proposed method was applied to human experimental data of visual evoked potentials. As a result, the estimation accuracy was improved and the localized dipole distribution was obtained with less noise.

We retrospectively reviewed 67 patients who presented with metastatic urothelial carcinoma to the Department of Urology, Asahikawa Medical University Hospital between 2000 and 2013. Furthermore, 13 patients with comparatively longer survival (2 years or longer after diagnosis) were analyzed to find any clinical characteristics among these patients. The primary site was the upper tract in 41 patients and bladder in 26. The most frequent metastatic site was regional lymph nodes (49 patients), followed by viscera (36 patients) and distant lymph nodes (17 patients). Primary tumor resections were performed on 83% of the patients with only regional lymph node metastasis, but on only 35% of the patients with distant metastasis. Median overall survival (OS) of patients was 8.5 months in this series. Median OS of patients with only regional lymph node metastasis was 15 months, which was significantly longer than that (8 months) of patients with distant metastasis. Multivariate analysis revealed only regional lymph node metastasis and the number of metastatic sites were significant prognostic factors for OS. We further investigated the clinical characteristics of 13 patients with comparatively longer survival. Other than a small number of metastatic sites (1 or 2) and no distant lymph node metastasis, we could not find any significant characteristics to predict longer prognosis. The present study showed that primary tumor resection did not have a significant benefit on survival in patients with metastatic urothelial carcinoma at initial presentation. However, primary tumor resection should be considered when there is only regional lymph node metastasis and few metastatic sites.

Purpose: To report the clinical statistical analysis of patients with endogenous intraocular inflammation who visited Nippon Medical School Hospital during the 8 years from 2004 to 2012., Subjects and Methods: This retrospective study involved 759 new patients with endogenous intraocular inflammation who visited Nippon Medical School Hospital during the 8 years from April 2004 to April 2012., Results: The subjects comprised 357 men and 402 women. The ratio of men to women was 1 : 1.1. The age averaged 50.8 ± 16.6 years. Definitive diagnosis was made in 464 cases (61.1%). The most frequent clinical entity was sarcoidosis, followed by scleritis, Vogt-Koyanagi-Harada disease, herpetic iridocyclitis without acute retinal necrosis, acute anterior uveitis associated with human leukocyte antigen (HLA) -B27 and Behçet's disease. Anterior uveitis was the most frequent compared with intermediate, posterior, and pan-uveitis. The incidence of secondary glaucoma was 28.6%, and steroid responder was 28.6%., Conclusion: Sarcoidosis, scleritis and Vogt-Koyanagi-Harada disease were frequent intraocular inflammations in ophthalmologic patients at Nippon Medical School Hospital.

Objective: To investigate the relationship between chronic periodontal disease (CPD) and lower urinary tract symptoms (LUTS) in both sexes., Methods: The interview sheet of the CPD self-checklist and LUTS was distributed to 600 adult men and women (300 each) who visited the first dental examination at dental clinics. The International Prostate Symptom Score (IPSS) questionnaire/Quality Of Life (IPSS/QOL) and Overactive Bladder Symptom Score (OABSS) were used to assess LUTS. The relationship between the CPD score and LUTS or OAB was examined., Results: The interview sheet was collected from 88 men (50.9 ± 16.6 years old) and 97 women (51.1 ± 15.5 years old). There was no statistically significant correlation between the CPD score and age, or between the CPD score and the presence of LUTS in either men or women. However, urgency and weak stream score of IPSS were significantly correlated with the severity of CPD in both sexes. Significant correlation between the severity of CPD and the presence of OAB was only noted in men but not in women., Conclusions: The present study demonstrated for the first time that some storage and voiding symptoms were significantly associated with CPD in both sexes. Thus, although CPD and LUTS seem to have common pathophysiological factors, the interrelationship between CPD and LUTS is slightly different between men and women., (© 2013 Wiley Publishing Asia Pty Ltd.)

In the existing walking support system, the range of detection is limited, and it is very difficult to detect obstacles such as a step or a hollow. Therefore, we aim at the development of a new walking support system for a visually-impaired person detecting neighboring obstacles by making use of a smartphone which is a high-performance portable information terminal. In this study, we have developed a walking support system combining the orientation sensor of the smartphone and a small distance sensor at the first stage. When we investigated its precision in detecting an obstacle, it was found that the system could detect obstacles which disturbed the walking of a visually-impaired person such as a step and a wall. We will find an appropriate key to detection to improve the detection precision of the system and make further improvements in the system by trial experiments in the future.

A 60-year-old woman was referred to our hospital because of gross hematuria, right lumbar pain and lower abdominal pain. Computed tomography (CT) scan revealed hydronephrosis of the right kidney, irregular bladder wall thickening at the right lateral and posterior portion and external iliac lymph node swelling of the right side. Laboratory data revealed disseminated intravascular coagulation syndrome (DIC) and eosinophilia. Because she developed a high fever that was caused by acute obstructive pyelonephritis of the right kidney, percutaneous nephrostomy was placed and the therapy for DIC was initiated. Pathological examination of transurethral resection of bladder tumor performed twice showed no malignancy but inflammatory infiltration of many eosinocytes, leading to the diagnosis of eosinophilic cystitis (EC). We considered the possibility of allergic reaction to the drugs she was taking as the etiology of EC and discontinued all drugs. Although eosinophilia was resolved afterward, she then developed brain infarction, followed by cerebral hemorrhage. She was transferred to a rehabilitation hospital for long-term care. CT scan that was performed 4 months after the initial presentation showed the resolution of hydronephrosis of the right kidney and external iliac lymph node swelling and the improvement of bladder wall thickness. Hydronephrosis of the right kidney has not recurred after removing the nephrostomy catheter. EC is a rare condition that could mimic an invasive bladder cancer. EC should be considered if bladder tumor is associated with eosinophilia. Therapeutic consideration for thromboembolic events should be made in patients with EC.

We examined perioperative complications of transurethral resection of bladder tumor (TURBT) in patients receiving antithrombotic therapy. We retrospectively studied 276 patients who underwent TURBT in our institute from January 2007 to March 2013. The study group consisted of 105 patients (38%) who were receiving antithrombotic agents, and the other 171 patients (62%) without antithrombotic agents were assigned to the control group. The period of discontinuation of antithrombotic agents complied with our institutional rule. The most frequently used agent was aspirin (69 patients : 66%), followed by warfarin (25 patients : 24%). Fourteen patients receiving warfarin (56%) needed heparin bridging therapy. There was no significant difference in average operative time (51 minutes versus 54 minutes), or average days to removal of urethral catheter (3.7 days versus 3.3 days) between the study and control groups. Hemorrhagic and ischemic complications were noted in 11 (10.5%) and 2 (1.9%) patients in the study group and 11 (6.4%) and none (0%) of the patients in the control group, respectively, with no significant difference between the 2 groups. However, prevalence of hemorrhagic complications in patients receiving heparin bridging therapy (21.4%) was significantly higher than that in the control group. Ischemic complications in the study group included chest pain suggestive of angina in one patient and acute myocardial infarction leading to death in another patient. We should pay attention to hemorrhagic complications in patients receiving heparin bridging therapy and keep in mind the possibility of lethal ischemic complications after discontinuation of antithrombotic agents.