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Cell surface hyaluronidase transmembrane protein 2 (TMEM2), which also serves as a reportedly functions in malignancy of several solid tumors. However, TMEM2 involvement in bladder cancer (BCa) is unknown. Therefore, we investigate potential changes in expression of TMEM2 during BCa invasion and over the course of the epithelial mesenchymal transition (EMT). Immunohistochemical analysis of 127 clinical specimens revealed that TMEM2 expression changed with pathological stage (pT) and infiltration pattern (INF) and was highest in pTa-pT1 of INFa tumors and significantly lower at stages from pTa-pT1 to pT2 or 3 in INFb or INFc. E-cadherin expression was highest in INFa and lowest in INFc, a pattern comparable to TMEM2 expression. TMEM2 protein expression analysis of BCa cell lines showed that muscle-invasive T24 and YTS-1 cells with low TMEM2 expression exhibited EMT phenotypes in vitro, in contrast to high TMEM2-expressing non-muscle invasive RT4 cells. EMT-induced non-muscle invasive RT4 cells also showed significantly decreased plasma membrane expression of TMEM2. Our data suggested TMEM2 expression is higher in non-invasive cancers, whereas invasive cancer cells are less likely to express TMEM2 during muscle-invasion and "partial EMT".

Noonan syndrome (NS) is a congenital genetic abnormality characterized by short stature, delayed onset of puberty, cardiac malformations, and characteristic external malformations. Congenital chromosomal or genetic abnormalities are sometimes associated with carcinomas. Furthermore, they are difficult to manage perioperatively because of multiple complications and mental retardation. The safety of kidney transplantation for patients with NS has not been established. We are reporting the case of a 31-year-old man with NS who received a kidney transplantation after a donor's brain death. He received kidney transplantation safely and was discharged without issues. Kidney transplantation for patients with congenital chromosomal or genetic abnormalities is feasible without serious complications, with a regular follow-up, and psychological support from patients and families.

To examine the oncological and urinary functional outcomes of reproductive organ-sparing radical cystectomy (ROS-RC) and U-shaped ileal neobladder construction in females compared with male patients.We retrospectively examined 357 patients (281 male and 76 female) with muscle-invasive bladder cancer who were treated with RC plus U-shaped ileal neobladder construction between May 1996 and July 2021. All female patients were treated with ROS-RC. We compared disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and urinary functional outcomes between male and female patients. We evaluated the effect of gender on DFS, CSS, and OS. Furthermore, urinary functional outcomes were evaluated in 140 males and 48 females using a pressure-flow study at 3, 6, 9, and 12 months postoperatively.Female patients were considerably older than male patients at the time of radical cystectomy. No significant difference was noted in the tumor stage preoperatively. The multivariable Cox regression analysis with an inverse probability treatment weighted model revealed that the female gender was not significantly related to DFS, CSS, and OS. Moreover, urinary functions at 12 months were not markedly different between males and females, except for the capacity of the neobladder, detrusor pressure, and maximum urethral closure pressure.This study demonstrates that female patients with ROS-RC and U-shaped ileal neobladder construction did not significantly correlate with worse oncological outcomes. The combination of ROS-RC and U-shaped ileal neobladder construction might attain adequate urinary function without sacrificing oncologic outcomes.

Kidney transplantation from marginal donors is an important solution for organ shortage problems. In this study, we evaluated the safety and effectiveness of living kidney transplantation from marginal donors at our hospitals.Between June 2006 and April 2019, 107 patients underwent living kidney transplantation at our hospitals. Marginal donors were defined as those with 1. age70 years, 2. hypertension, 3. creatinine clearance 80 mL/min, 4. body mass index30 kg/mThirty-one (29%) donors were defined as marginal. The primary reason for being defined as marginal was hypertension (74%). The mean age of the marginal donors (62 ± 10 years) was higher than that of standard donors (52 ± 12 years, P .001). The estimated glomerular filtration rate (eGFR) before and after transplantation was lower in the marginal group, whereas the decline ratio of eGFR was not different between the marginal and standard donors. Five-year graft survival of transplantations from marginal donors (89%) was not significantly inferior to that from standard donors (95%). Meanwhile, recipient eGFR was lower in transplantation from marginal donors than standard donors from 1 month through 5 years after transplantation.No significant differences were observed between the groups regarding the decline ratios of donor eGFR and graft survival. Thus, transplantation from marginal donors may be a feasible solution for donor shortage problems.

Introduction We aimed to evaluate the treatment sequence for patients with metastatic castration-resistant prostate cancer (mCRPC) in real-world practice and compare overall survival in each sequential therapy. Patients and Methods We retrospectively evaluated 146 patients with mCRPC who were initially treated with androgen deprivation therapy as metastatic hormone-naive prostate cancer in 14 hospitals between January 2010 and March 2019. The agents for the sequential therapy included new androgen receptor-targeted agents (ART: abiraterone acetate or enzalutamide), docetaxel, and/or cabazitaxel. We evaluated the treatment sequence for mCRPC and the effect of sequence patterns on overall survival. Results The median age was 71 years. A total of 35 patients received ART-ART, 33 received ART-docetaxel, 68 received docetaxel-ART, and 10 received docetaxel-cabazitaxel sequences. The most prescribed treatment sequence was docetaxel-ART (47%), followed by ART-ART (24%). Overall survival calculated from the initial diagnosis reached 83, 57, 79, and 37 months in the ART-ART, ART-docetaxel, docetaxel-ART, and docetaxel-cabazitaxel, respectively. Multivariate Cox regression analyses showed no significant difference in overall survival between the first-line ART (n = 68) and first-line docetaxel (n = 78) therapies (hazard ratio [HR], 0.84; P = .530), between the ART-ART (n = 35) and docetaxel-mixed (n = 111) sequences (HR, 0.82; P = .650), and between the first-line abiraterone (n = 32) and first-line enzalutamide (n = 36) sequences (HR, 1.58; P = .384). Conclusion The most prescribed treatment sequence was docetaxel followed by ART. No significant difference was observed in overall survival among the treatment sequences in real-world practice.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

The effect of concomitant steroid use on the antibody response to a SARS-CoV-2 vaccine in patients with prostate cancer (PC) remains unknown. We aimed to evaluate the rates of antispike immunoglobulin G (IgG) antibody response to the BNT162b2 mRNA vaccine in patients with PC using steroids.This cross-sectional study conducted from June 21, 2021 to January 5, 2022 included 215 patients with PC who received the second dose of the BNT162b2 mRNA vaccine at least 7 days before the measurement of titers of IgG antibodies against the receptor-binding domain of SARS-CoV-2 spike (S) protein. We compared the rate of anti-SARS-CoV-2 S IgG ≥15 U/mL between patients with or without concomitant steroid use.Of 215, we identified 33 patients who had concomitant steroid use. Of these, 12 and 21 patients were metastatic castration-sensitive PC and castration-resistant PC (CRPC), respectively. Patients with concomitant steroid use had a significantly lower rate of antibody titer ≥15 U/mL than those without steroid use (82% vs. 95%, P = 0.021). Patients with CRPC with concomitant steroid use (n =21) also had a lower rate of antibody titer ≥15 U/mL (71%) than those without steroid use (93%, P = 0.051), although this was not statistically different. Increased number of systemic treatments administered after diagnosis of CRPC (3 lines or more) were significantly associated with antibody titers15 U/mL (97% vs. 77%, P0.001).The humoral response to the BNT162b2 mRNA vaccine was significantly lower in patients with concomitant steroid use. Anti-SARS-CoV-2 S antibody titers were affected by CRPC status, the accumulation of post-CRPC treatments, and steroid use.

To evaluate the effect of 6-cycle completion and earlier use of radium-233 dichloride (Ra223) on the prognosis of patients with metastatic castration-resistant prostate cancer (mCRPC).We retrospectively evaluated 75 patients with bone metastases-predominant mCRPC who were treated with Ra223 between August 2016 and August 2021. The primary purpose of the study was to assess the effect of Ra223 completion (6 cycles) on patient prognosis, and the secondary purpose was to investigate factors associated with Ra223 incompletion (fewer than 6 cycles) and overall survival.The median age of the patients was 72 years. The median number of Ra223 administrations was 6 (interquartile range, 5-6), and the median Ra223 completion rate was 75%. The median time from mCRPC diagnosis to Ra223 administration was 17 months, and the median number of prior treatments was 2. Multivariable analysis indicated that unfavorable performance status (0), prostate-specific antigen (PSA) level10 ng/ml, extension of bone metastasis score 3 to 4, and Ra223 incompletion were significantly associated with poor overall survival. In addition, EOD 3 to 4 and 3 or more prior CRPC treatments were significantly associated with Ra223 incompletion.Six-cycle completion and earlier administration of Ra233 are potentially associated with favorable survival. Unfavorable factors (EOD 3-4 and ≥3 prior treatments) were significantly associated with Ra223 incompletion.

Background The clinical diagnosis of urothelial carcinoma (UC) relies on invasive methods in patients with hematuria. Although more sensitive and noninvasive screening methods are required, a specific serum biomarker for UC is lacking. Objective To examine whether serum glycan-based biomarkers can be applied to UC detection. Design, setting, and participants Between April 1994 and June 2016, serum N -glycan concentrations were retrospectively measured in 212 patients with UC before treatment (UC group) and 212 pair-matched controls using glycoblotting and mass spectrometry. Outcome measurements and statistical analysis N -glycan levels were compared between the groups using receiver operating characteristic curves to select candidate N -glycans. We created an N -glycan score based on the combination of candidate N -glycans. The specificity and sensitivity of the candidate N -glycan score were evaluated using receiver operating characteristic curves. Results and limitations The N -glycan score was calculated using six N -glycans ( m/z 1566, m/z 1687, m/z 1769, m/z 1871, m/z 2011, and m/z 2337) that were significantly associated with UC. The median N -glycan score was significantly higher in the UC group than in the pair-matched control group (5.0 vs 1.0, p N -glycan score correctly classified UC patients with a sensitivity, specificity, and area under the curve of 93%, 81%, and 0.95, respectively. The limitations of our study included its retrospective nature and nonclinical setting. Conclusions Serum N -glycan content has the potential to be a specific and sensitive novel serum biomarker that may improve the accuracy of the detection for UC and reduce unnecessary invasive screening. Validation of this test in a large-scale prospective study is needed. Patient summary Combination of serum N -glycan ( N -glycan score) is a novel serum marker for urothelial carcinoma that is expressed by 93% of patients and thus is far more sensitive than classic urine cytology. Validation in a large patient cohort is needed.

Background Paraganglioma (extra-adrenal pheochromocytoma) of the bladder is a very rare disease, accounting for 0.06% of all bladder tumors. Optimal management of bladder paraganglioma before kidney transplantation is unknown. We report a case of partial cystectomy for urinary bladder paraganglioma before living kidney transplantation. Case Presentation A 59-year-old man with a 27-year history of hemodialysis was referred to our department for further examination of a bladder tumor detected during pre-transplantation testing. Cystoscopy revealed a submucosal tumor on the right side of the bladder. The patient experienced a hypertensive crisis during transurethral resection of the bladder tumor. Endocrinologic and pathologic examinations confirmed the diagnosis of paraganglioma in the urinary bladder. A partial cystectomy was performed before kidney transplantation. Nine months after partial cystectomy, the patient underwent AB0-incompatible living kidney transplantation from his spouse. No disease recurrence or graft rejection was observed 12 months after the transplantation. Conclusions To our knowledge, this is the 1st report on the management of paraganglioma in the urinary bladder before living kidney transplantation. Kidney transplantation after partial cystectomy is an option that may be considered in patients with paraganglioma of the urinary bladder, with careful observations of bladder function and vesicoureteral reflux to the grafts.

Purpose Pre-emptive kidney transplantation (PKT) is expected to improve graft and cardiovascular event-free survival compared with standard kidney transplantation. Aortic calcification is reported to be closely associated with renal dysfunction and cardiovascular events; however, its implication in PKT recipients remains incompletely explored. This aim of this study was to evaluate whether PKT confers a protective effect on aortic calcification, renal function, graft survival, and cardiovascular event-free survival. Methods One hundred adult patients who underwent renal transplantation between January 1996 and March 2016 at Hirosaki University Hospital and Oyokyo Kidney Research Institute were included. Among them, 19 underwent PKT and 81 patients underwent pretransplant dialysis. We retrospectively compared pretransplant and post-transplant aortic calcification index (ACI), renal function (estimated glomerular filtration rate [eGFR]), and graft and cardiovascular event-free survivals between the 2 groups. Results The median age of this cohort was 45 years. Preoperative ACI was significantly lower in PKT recipients. There were no significant differences between the 2 groups regarding postoperative eGFR, graft survival, and cardiovascular event-free survival. However, the ACI progression rate (ΔACI/y) was significantly lower in PKT recipients than in those who underwent pretransplant dialysis. Higher ACI was significantly associated with poor cardiovascular event-free survival. Conclusions PKT is beneficial in that it contributes to the slow progression of after transplantation. Although we could not observe significant differences in graft and cardiovascular event-free survivals between the 2 groups, slow progression of aortic calcification showed a potential to decrease cardiovascular events in PKT recipients during long-term follow-up.

The number of cycles of platinum-based first-line chemotherapy associated with the maximum tumor response in patients with advanced urothelial carcinoma is not yet established. We investigated the association between the number of cycles and the maximum radiological response of first-line chemotherapy.We retrospectively evaluated 167 patients with advanced urothelial carcinoma treated with platinum-based first-line chemotherapy between May 2003 and December 2020. The primary outcome was estimating the number of cycles associated with the maximum radiological response and progression disease rate within the 6 cycles. The radiological response was evaluated by the RECIST v1.1. The secondary outcomes included the difference in radiological response rate and the impact on overall survival between the cisplatin-based and carboplatin-based regimens.The maximum radiological response was -22% at Cycles 2. It was significantly decreased at Cycles 4 (-15%) compared with Cycles 2 (P0.001). The progression disease rate within the first 2, 4, and 6 cycles were 21% and 63%, and 84%, respectively. Radiological response was no significant difference between the cisplatin-based and carboplatin-based regimens. However, it was significantly decreased in the carboplatin-based regimen at Cycles 4 (-17%) compared with Cycles 2 (-22%; P = 0.004). Background-adjusted overall survival was not significantly different in between the cisplatin-based and carboplatin-based regimens (hazard rate 1.27; P = 0.337).The maximum radiological response was -22% at Cycles 2. The radiological response was significantly different between Cycle 2 and 4. More than half of patients had disease progression within the first 4 cycles.

As a major component of the extracellular matrix, hyaluronan (HA) plays an important role in defining the biochemical and biophysical properties of tissues. In light of the extremely rapid turnover of HA and the impact of this turnover on HA biology, elucidating the molecular mechanisms underlying HA catabolism is key to understanding the in vivo functions of this unique polysaccharide. Here, we show that TMEM2, a recently identified cell surface hyaluronidase, plays an essential role in systemic HA turnover. Employing induced global Tmem2 knockout mice (Tmem2iKO), we determined the effects of Tmem2 ablation not only on the accumulation of HA in bodily fluids and organs, but also on the process of HA degradation in vivo. Within 3 weeks of tamoxifen-induced Tmem2 ablation, Tmem2iKO mice exhibit pronounced accumulation of HA in circulating blood and various organs, reaching levels as high as 40-fold above levels observed in control mice. Experiments using lymphatic and vascular injection of fluorescent HA tracers demonstrate that ongoing HA degradation in the lymphatic system and the liver is significantly impaired in Tmem2iKO mice. We also show that Tmem2 is strongly expressed in endothelial cells in the subcapsular sinus of lymph nodes and in the liver sinusoid, two primary sites implicated in systemic HA turnover. Our results establish TMEM2 as a physiologically relevant hyaluronidase with an essential role in systemic HA catabolism in vivo, acting primarily on the surface of endothelial cells in the lymph nodes and liver.

Summary Background Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. Methods In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov, number NCT02387996, and is completed. Follow-up is still ongoing. Findings Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0–24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9–39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5–32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5–23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3–4 treatment-related adverse events occurred in 48 (18%) of 270 patients—most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). Interpretation Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. Funding Bristol-Myers Squibb.

Objectives To evaluate the impact of symptomatic recurrence on oncological outcomes in patients with primary high-risk non-muscle invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumor (TURBT). Materials and Methods We retrospectively evaluated 428 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. Of the 428 patients, 140 had experienced recurrence at any site and were divided into 2 groups: patients who had experienced recurrence detected by the surveillance (asymptomatic group) and patients who had experienced recurrence detected by a symptom-driven investigation (symptomatic group). Background-adjusted multivariable analyses with the inverse probability of treatment weighting method were performed to evaluate the impact of symptomatic recurrence on cancer-specific survival and overall survival after first recurrence in patients who had experienced recurrence. Moreover, multivariable analysis was performed to identify predictive factors of symptomatic recurrence in the entire cohort. Results Median age and follow-up periods were 72 (interquartile range [IQR] 64–79) years and 55 (IQR 29–96) months, respectively. Of the 140 patients who experienced recurrence, 106 (76%) were diagnosed by the surveillance (asymptomatic group) and 34 (24%) were diagnosed by a symptom-driven investigation (symptomatic group). In the background-adjusted multivariable analyses with the inverse probability of treatment weighting model, symptomatic recurrence was significantly associated with shorter cancer-specific survival along with shorter overall survival after first recurrence. In the multivariable analysis, only tumor grade was selected as a significant predictive factor of symptomatic recurrence after TURBT. Conclusions Symptomatic recurrence was significantly associated with poor oncological outcomes in patients with primary high-risk NMIBC. Patients with grade 3 tumors may require more intensive surveillance after TURBT.

Objectives To investigate the impact of chronic kidney disease (CKD) on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who underwent adjuvant induction bacillus Calmette-Guerin (BCG) therapy after transurethral resection of bladder tumor (TURBT). Materials and Methods We conducted a multi-institutional retrospective study assessing 209 patients with high-risk NMIBC who underwent TURBT and subsequent adjuvant induction BCG therapy from December 1998 to April 2019. Patients were divided into 2 groups: those with preoperative estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m2 (non-CKD group), and those with eGFR Results Median age and follow-up period after TURBT were 72 years and 45 months, respectively. Of 209 patients, 71 (34%) were diagnosed with CKD before TURBT. Background-adjusted multivariate analyses with the IPTW method indicated that CKD was significantly associated with shorter intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. In the Fine-Gray competing risk regression model, CKD showed significantly higher probabilities of intravesical recurrence and MIBC progression, with an adjusted subdistribution hazard ratio of 1.886 (95% confidence interval 1.069–3.330, P = 0.028) and 3.740 (95% confidence interval 1.060–13.20, P = 0.040), respectively. Conclusions CKD presents a risk factor of poor oncological outcomes in patients with high-risk NMIBC who underwent adjuvant induction BCG therapy after TURBT.

To determine how frailty and comorbidities affect surgical contraindication in patients with localized prostate cancer (CaP).We evaluated the effects of frailty in 479 patients with localized CaP who were treated with robot-assisted radical prostatectomy (RARP), or radiotherapy (RT) eligible for surgery (RT-nonfrail), or those with RT ineligible for surgery due to frailty or comorbidity (RT-frail) from February 2017 to April 2020. We retrospectively compared the geriatric 8 screening (G8) scores between patients with surgical indications (RARP and RT-nonfrail groups) and those with surgical contraindications (RT-frail group). The effect of G8 score in the RT-frail groups was investigated using multivariate logistic regression analysis. We developed and validated a nomogram for surgical contraindication in patients with localized CaP.The median age of patients was 70 years. There were 256, 60, and 163 patients in the RARP, RT-nonfrail, and RT-frail, respectively. The G8 score in the RARP and RT-nonfrail groups was significantly higher than in the RT-frail group (15 vs. 14, respectively, P0.001). Age, comorbidities (cerebrocardiovascular disease or chronic respiratory disease), and G8 score were significantly associated with the RT-frail group. The nomogram showed that the area under the curve was 0.872 and 0.923 in the training and validation sets, respectively. The cutoff for surgical contraindication was39.5%.The G8 score and comorbidities have a significant effect on surgical contraindication in patients with localized CaP.

Objectives We aimed to evaluate the effect of frailty on health-related quality-of-life (HRQOL) and lower urinary symptoms (LUTS) following robot-assisted radical prostatectomy (RARP) in patients with prostate cancer (CaP). Materials and Methods We longitudinally evaluated geriatric 8 (G8), HRQOL, and LUTS for 12 months in 118 patients with RARP from January 2017 to April 2020. Patients were divided into frail (G8 ≤14) and nonfrail (G8 >14) groups. We compared the effect of frailty on HRQOL and LUTS between the frail and nonfrail groups before and 12 months after RARP. Results The median age of patients was 68 years. The number of patients in the frail and nonfrail groups were 41 and 77, respectively. No significant difference in patients’ background was observed between the groups, except for the presence of cardiovascular disease (22% vs. 7.8%, P = 0.041). There was no significant difference in HRQOLs and LUTS between the groups at baseline. Similarly, HRQOLs, LUTS, and pad-free continence rates were not significantly different between the groups at 12 months after RARP. In the nonfrail group, LUTS at 12 months following RARP significantly improved compared to those at the baseline, but it did not significantly improve in the frail group. Multivariable logistic regression analysis demonstrated that frailty was not significantly associated with LUTS worsening. Conclusions Frailty was not significantly associated with the worsening of HRQOL, LUTS, and pad-free continence rates in patients treated with RARP.

Introduction To avoid over-treatment of early stage prostate cancer (PCa), predictive biomarkers for PCa aggressiveness which can be obtained during pre-treatment evaluation are essential. Core 2 β-1, 6- N -acetylglucosaminyl-transferase-1 (GCNT1) is a key enzyme that forms core 2 branched O -glycans, the expression of which is associated with aggressive potential of prostate cancer. We examined whether GCNT1 expression in prostate biopsy specimen can predict cancer recurrence after radical prostatectomy for the patients with with PCa. We then investigated molecular background for aggressive malignant potential mediated by GCNT1 expression. Methods Paraffin-embedded PCa biopsy specimens were immunohisto-chemically tested for GCNT1 expression using an anti-GCNT1 monoclonal antibody. We also examined the role of GCNT1 in PCa progression using cell lines which express high or low levels of GCNT1. Results GCNT1 expression correlated with D′ Amico's recurrence risk classification. The GCNT1-positive rate in organ confined PCa was significantly lower than that in PCa with extra-prostatic extension. GCNT1-negative tumors were associated with significantly better prostate-specific antigen (PSA)-free survival compared with GCNT1-positive tumors. Multivariate analysis revealed that GCNT1 expression status was an independent risk factor for PSA recurrence after radical prostatectomy. Subsequent basic study revealed that GCNT1-over-expressing cells produced a significantly larger amount of growth factors when co-cultured with prostate stromal cells compared with GCNT1-knocked down cells and formed larger tumors. Conclusions GCNT1 expression in prostate biopsy specimen is a significant and independent predictor of recurrence after radical prostatectomy, which can be used in pre-treatment decision making for the patient. Further validation study is necessary to establish clinical implication of GCNT1 in management of PCa.

Objectives To validate the substratification of high-risk in the European Association of Urology (EAU) guidelines and to develop the simplified substratification to improve usefulness and predictive accuracy on oncological outcomes in patients with primary high-risk nonmuscle-invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumor (TURBT). Materials and methods We retrospectively evaluated 428 patients with primary high-risk NMIBC who underwent TURBT from November 1993 to April 2019. First, the efficacy of the EAU highest-risk on intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival was evaluated with univariate analyses. Second, we developed our simplified substratification based on multivariate analysis for intravesical RFS (lower- and higher-risk). We compared predictive accuracy on oncological outcomes using the receiver operating characteristic curve between the EAU and the simplified substratifications. Results Median age and median follow-up periods were 72 years and 51 months, respectively. The EAU highest-risk was not associated with shorter intravesical RFS and MIBC-free survival (P = 0.054 and P = 0.350, respectively). In multivariate analysis, tumor size, grade 3, and chronic kidney disease were significantly associated with shorter intravesical RFS, and we developed the simplified substratification including those 3 factors. Of 428 patients, 89 (21%) were substratified into the simplified higher-risk. The predictive accuracy of the simplified substratification on intravesical recurrence, MIBC and metastasis progression, and cancer-specific mortality was significantly superior to the EAU substratification. Conclusion Our simplified substratification might contribute to improving predictive accuracy on intravesical recurrence, MIBC and metastasis progression, and cancer-specific mortality in patients with primary high-risk NMIBC who underwent TURBT.

Objectives To evaluate the impact of preoperative chronic kidney disease (CKD) on the prognosis of patients with primary non–muscle-invasive bladder cancer (NMIBC) who underwent transurethral resection of bladder tumor (TURBT). Materials and methods We retrospectively evaluated 434 patients with primary NMIBC who underwent TURBT from November 1993 to April 2019. The patients were divided into 2 groups: patients with preoperative estimated glomerular filtration rate ≥60 ml/min/1.73 m2 (non-CKD group) and Results The median age and median follow-up period were 72 years and 51 months, respectively. Of 434 patients, 141 (32%) were diagnosed with CKD before TURBT. In background-adjusted multivariate analyses, CKD was an independent risk factor for those oncological outcomes, except for UUT recurrence. The predictive accuracy of CKD plus risk factors in the European Organization for Research and Treatment of Cancer scoring system on oncological outcomes was significantly improved compared with those risk factors alone, except for UUT recurrence. Conclusion Preoperative CKD was a risk factor and might improve predictive accuracy on poor prognosis in patients with primary NMIBC who underwent TURBT.

To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up-regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis.

Background Urothelial carcinomas of ureter grafts in renal transplant patients are rare. Here we report our experience with a case of BK virus–associated urothelial carcinoma in a ureter graft. Case Report A 47-year-old man developed chronic renal failure secondary to diabetes mellitus and started maintenance hemodialysis in September 2007. Two months later, the patient received a renal transplant from his 70-year-old mother. The patient developed BK virus–associated nephropathy 1 year after transplantation and presented with a decline in renal function and hydronephrosis in the transplanted kidney 4 years 6 months after transplantation. Cystoscopy and retrograde pyelography revealed an irregular filling defect in the ureter graft. Cytologic diagnosis of his urine revealed a high-grade urothelial carcinoma. Computerized tomography showed a cT2 ureteral tumor and no involvement of other organs. The patient subsequently underwent a transplant nephroureterectomy with bladder cuff resection. Histopathologic findings revealed a high-grade urothelial carcinoma, pT2, in the ureter graft with SV40-positive staining. The patient was closely observed without adjuvant chemotherapy therapy and remained disease free 1 year after surgery. Renal transplant recipients with BK virus infection are at high risk of developing urologic malignancies. Close attention is necessary to diagnose post-transplantation urologica malignancies as early as possible.

We determined if the serum N-glycan profile can be used as a diagnostic marker of antibody-mediated rejection (ABMR) in living donor kidney transplant (LKTx) recipients. Glycoblotting, combined with mass spectrometry, was used to retrospectively examine N-glycan levels in the postoperative sera of 197 LKTx recipients of whom 16 recipients had ABMR with or without T-cell-mediated rejection (TCMR), 40 recipients had TCMR, and 141 recipients had no adverse events. Multivariate discriminant analysis for prediction of ABMR was performed by inputting an ABMR event as an explanatory variable and sex, age, and serum N-glycan level as objective variables. The N-glycan score was calculated by multiplying the level of candidate objective variables by objective function values. The ABMR predictive performance of the N-glycan score was assessed by receiver operator characteristic curve and Kaplan–Meier curve analyses. The N-glycan score discriminated ABMR with 81.25% sensitivity, 87.85% specificity, and an area under the curve (AUC) of 0.892 that was far superior to that of preformed donor-specific antibody status (AUC, 0.761). Recipients with N-glycan-positive scores >0.8770 had significantly shorter ABMR survival than that of recipients with N-glycan-negative scores. Although the limitations of our study includ its small sample size and retrospective nature, the serum N-glycan score may contribute to prediction of ABMR.

Aims The objectives of this study were to investigate the clinical and oncological outcomes of patients with malignant tumors of the urinary bladder undergoing minimum incision endoscopic radical cystectomy (MIE-RC). Methods Between August 2005 and June 2011, 130 consecutive patients at Hirosaki University Hospital underwent MIE-RC and bilateral lymphadenectomy for malignant tumors of the urinary bladder. We retrospectively studied all 130 patients. MIE-RC was performed through a 7-cm suprapubic midline incision. A 30° laparoscope was conveniently positioned on the head side of the patients, for precise observation and monitoring. Results The median operative time for all procedures, including MIE-RC, bilateral pelvic lymphadenectomy and urinary diversion was 266 min. The median estimated blood loss was 1260 mL. None of the patients had positive surgical margins. The post-operative median follow-up period was 32.8 months. The 5-year overall and disease-free survival rates were 91.6% and 87.0%, respectively. Conclusions Our experience with MIE-RC appears to be favorable with acceptable operative and oncological outcomes.

Aims The objective of this study was to investigate the clinical and oncological outcomes of prostatectomy patients undergoing minimum incision endoscopic radical prostatectomy (MIE-RP). Methods Between September 2005 and May 2010, 541 patients underwent MIE-RP with bilateral lymphadenectomy for clinically localized prostate cancer at Hirosaki University Hospital. The present retrospective study enrolled 375 patients who had not received neoadjuvant or adjuvant therapy. MIE-RP was performed through a 6-cm suprapubic midline incision. A 30° laparoscope was conveniently positioned on the head side of the patient for precise observation and monitoring. Results The median operating time was 119 min, and the estimated blood loss was 900 ml. The most frequent perioperative complication was leakage from the vesicourethral anastomosis (6.7%), and rectal injury occurred in 1.0%. Overall, 31.2% of the patients had a positive surgical margin, including 11.1% with pT2, 52.9% with pT3 and 100% with pT4 diseases. The post-operative median follow-up period was 40.5 months (range, 2–56.5 months). The 5-year PSA-free survival rate was 71.6%. In multivariate analysis, high-risk patients (according to the D'Amico risk criteria), pathological T stage and positive surgical margins were identified as independent predictors of PSA-free survival. The limitations of this study included a retrospective study, relatively short follow-up period and single-institution nature of the study. Conclusions MIE-RP is a safe and minimally invasive procedure that may represent a reliable alternative to laparoscopic and robotic-assisted RP.