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Objectives: To determine the effects of prophylactic urethrectomy (PU) on oncological and perioperative outcomes in patients with bladder cancer (BC) undergoing radical cystectomy (RC). Methods: This retrospective study analyzed data on 1976 evaluable patients with BC who underwent RC. Patients were drawn from 36 institutions within the Japanese Urological Oncology Group. Oncological outcomes were compared using restricted mean survival times (RMSTs) based on inverse probability of treatment weighting (IPTW)‐adjusted Kaplan–Meier curves for non‐urinary tract recurrence‐free survival (NUTRFS), cancer‐specific survival (CSS), and overall survival (OS). Interaction terms within IPTW‐adjusted Cox regression models were examined to assess the heterogeneity of treatment effect based on the risk of urethral recurrence (UR). The association between PU, estimated blood loss (EBL), and the incidence of severe postoperative surgical complications (SPSCs) (Clavien‐Dindo grade 3 or higher) was analyzed. Results: Of 1976 patients, 1448 (73.3%) received PU. IPTW adjustment was used to balance baseline characteristics between the treatment groups. Within the 107‐month window of patient monitoring, PU showed no survival benefits (NUTRFS difference: 0.2 months [95% confidence interval: −6.8 to 7.3]; CSS, 1.2 [−4.9 to 7.3]; OS, 0 [−6.5 to 6.5]). No significant interactions were observed with factors associated with UR, and PU was associated with unfavorable perioperative outcomes (EBL, 1179 mL vs. 983 mL; SPSC, 14.6% vs. 7.0%). Conclusions: This study showed that (1) PU was not associated with survival in patients with BC undergoing RC, regardless of UR‐associated factors, and (2) PU was associated with unfavorable perioperative outcomes. [ABSTRACT FROM AUTHOR]

Objective: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC. Patients and methods: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non‐urinary tract recurrence‐free survival (NUTR‐FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer. Results: At median follow‐up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR‐FS were observed when TUR specimens were classified as pure‐urothelial carcinoma (UC), subtypes, DD, or non‐UC. Among 2449 patients diagnosed with pure‐UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre‐RC neutrophil–lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively). Conclusion: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre‐RC neutrophil–lymphocyte ratio and pathological stage were independent prognostic factors for OS. [ABSTRACT FROM AUTHOR]

Objectives: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre‐enfortumab vedotin era, many patients could not receive third‐line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real‐world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third‐line treatment. Methods: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort. Results: At the median follow‐up of 28.5 months, the median overall survival from first‐line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second‐ and third‐line treatment. Notably, 52% had their treatment terminated before the opportunity for third‐line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil‐to‐lymphocyte ratio (≥3), and low body mass index (<21 kg/m2) at the start of first‐line treatment were independent risk factors for not proceeding to third‐line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three. Conclusions: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects. [ABSTRACT FROM AUTHOR]

Background and Objectives: Our aim was to clarify the oncological outcomes of the two different approaches to laparoscopic nephroureterectomies (LNUs) in Japan, and to examine whether there were any significant differences between the transperitoneal approach and the retroperitoneal approach. Materials and Methods: We retrospectively evaluated patients who underwent an LNU for upper tract urothelial carcinoma (UTUC) from January 2013 to December 2022. We identified 52 patients who underwent a transperitoneal LNU (tLNU) and 93 who underwent a retroperitoneal LNU (rLNU). We adopted age, smoking, and pT-stage matching, and 43 patients were classified in each group. We investigated the time from surgery to recurrence (RFS: recurrence-free survival), the time to death (OS: overall survival), and the time to non-urothelial-tract recurrence-free survival (NUTRFS). A Cox regression analysis was performed to evaluate the risk factors that influenced recurrence. Results: There were no significant differences in the RFS, OS, and NUTRFS between the two matched groups. In the multivariate Cox regression analysis, the pT stage (pT3≥ vs. pT2≤) had an HR = 2.09 and a p = 0.01, and was an independent prognostic risk factor regarding cancer recurrence. Conclusions: There were no significant differences in the oncological outcomes between the tLNU and rLNU groups. It is suggested that the transperitoneal approach should be selected for LNUs. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusion Trial registration The high rate of delayed bleeding after colorectal endoscopic submucosal dissection (ESD) in patients undergoing anticoagulant therapy remains a problem. Whether prophylactic clip closure reduces the rate of delayed bleeding in these patients is unclear. This study aimed to evaluate the efficacy of prophylactic clip closure in patients receiving anticoagulants.This multicenter prospective interventional trial was conducted at nine referral centers in Japan. Patients regularly taking anticoagulants, including warfarin potassium or direct oral anticoagulants, and undergoing ESD for colorectal neoplasms were enrolled. The discontinuation of anticoagulants was minimized according to recent guidelines. After the ESD, post‐ESD ulcers were prophylactically closed using endoclips. The primary end‐point was the incidence of delayed bleeding. The sample size was 45 lesions, and prophylactic clip closure was considered effective when the upper limit of the 90% confidence interval (CI) for delayed bleeding did not exceed 20%.Forty‐five lesions were used, and three were excluded. Complete closure was achieved in 41/42 lesions (97.6%). The overall delayed bleeding rate was low, at 4.9% (2/41; 90% [CI] 0.8–14.5), which was significantly lower than that at the prespecified threshold of 20% (P = 0.007). The median closure procedure time was 17 min, and the median number of clips was nine. No massive delayed bleeding requiring transfusion, interventional radiology, or surgery was observed, and no thromboembolic events were observed.Prophylactic clip closure may reduce the risk of delayed bleeding following colorectal ESD in patients receiving anticoagulants.UMIN Clinical Trial Registry (UMIN000036734). [ABSTRACT FROM AUTHOR]

Treatment options for urothelial carcinoma were limited until the emergence of immune checkpoint inhibitors, and even now, the prognosis of metastatic disease is poor compared with the other two major genitourinary cancers, renal cell carcinoma and prostate cancer. Despite the increasing use of immune checkpoint inhibitors in the sequential treatment of urothelial carcinoma, conflicting results from similar randomized clinical trials call into question the efficacy of this treatment. In addition, physicians must be aware of the clinical characteristics of immune checkpoint inhibitors, including immune‐related adverse events, pseudo‐ and hyperprogression. This review summarizes the conflicting results of recent clinical trials and provides insights into the role of immune checkpoint inhibitors in the treatment of urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Arsenic is a known carcinogen for the human urinary bladder. The present study explored aberrant DNA methylation in rat bladder carcinogenesis induced by dimethylarsinic acid (DMAV), a primary arsenic metabolite. Genome-wide DNA methylation and microarray gene expression analyses of DMAV-induced rat urothelial carcinoma (UC) and the urothelium of rats treated with DMAV for 4 weeks identified 40 genes that were both hypermethylated and downregulated in DMAV-induced rat urothelial carcinoma. Notably, four of these genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMAV. Furthermore, CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Our findings highlight the significance of aberrant DNA methylation in DMAV-induced bladder carcinogenesis, implying early-stage arsenic-induced methylation changes. Arsenic is a known human urinary bladder carcinogen. While arsenic is known to cause aberrant DNA methylation, the mechanism of arsenic-triggered bladder carcinogenesis is not fully understood. The goal of this study was to identify aberrant DNA methylation in rat bladder urothelial carcinoma (UC) induced by dimethylarsinic acid (DMAV), a major organic metabolite of arsenic. We performed genome-wide DNA methylation and microarray gene expression analyses of DMAV-induced rat UCs and the urothelium of rats treated for 4 weeks with DMAV. We identified 40 genes that were both hypermethylated and downregulated in DMAV-induced rat UCs. Notably, four genes (CPXM1, OPCML, TBX20, and KCND3) also showed reduced expression in the bladder urothelium after 4 weeks of exposure to DMAV. We also found that CPXM1 is aberrantly methylated and downregulated in human bladder cancers and human bladder cancer cells. Genes with aberrant DNA methylation and downregulated expression in DMAV-exposed bladder urothelium and in DMAV-induced UCs in rats, suggest that these alterations occurred in the early stages of arsenic-induced bladder carcinogenesis. Further study to evaluate the functions of these genes will advance our understanding of the role of aberrant DNA methylation in arsenic bladder carcinogenesis, and will also facilitate the identification of new therapeutic targets for arsenic-related bladder cancers. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy (RT) has recently been highlighted as a partner of immune checkpoint inhibitors. The advantages of RT include activation of lymphocytes while it potentially recruits immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). This study aimed to investigate the mechanism of overcoming treatment resistance in immunologically cold tumours by combining RT and MDSC-targeted therapy. Methods: The abscopal effects of irradiation were evaluated using MB49 and cisplatin-resistant MB49R mouse bladder cancer cells, with a focus on the frequency of immune cells and programmed cell death-ligand 1 (PD-L1) expression in a xenograft model. Results: MB49R was immunologically cold compared to parental MB49 as indicated by the fewer CD8+ T cells and lower PD-L1 expression. Polymorphonuclear MDSCs increased in both MB49 and MB49R abscopal tumours, whereas the infiltration of CD8+ T cells increased only in MB49 but not in MB49R tumours. Interestingly, PD-L1 expression was not elevated in abscopal tumours. Finally, blocking MDSC in combination with RT remarkably reduced the growth of both MB49 and MB49R abscopal tumours regardless of the changes in the frequency of infiltrating CD8+ T cells. Conclusions: The combination of RT and MDSC-targeted therapy could overcome treatment resistance in immunologically cold tumours. [ABSTRACT FROM AUTHOR]

Background and Aim: Cold snare polypectomy is commonly performed to remove small colorectal polyps. Accidental resection of carcinomas during this procedure has been reported. Herein, we aimed to clarify the clinicopathological features and clinical course of colorectal carcinomas resected by cold snare polypectomy. Methods: This multicenter retrospective cohort study was conducted at 10 Japanese healthcare centers. Of the colorectal lesions resected by cold snare polypectomy between April 2016 and March 2020, lesions pathologically diagnosed as carcinoma were reviewed. Centralized histology (based on the Vienna classification) and endoscopic reviews were performed. The study endpoints were endoscopic features and clinical outcomes of cold snare polypectomy‐resected colorectal carcinomas (Vienna category ≥4.2). Results: We reviewed 74 of the 70 693 lesions resected by cold snare polypectomy. After a central pathological review, 68 lesions were diagnosed as carcinomas. The Japan Narrow‐band imaging Expert Team (JNET) classification type 2B, lesion size ≥6 mm, and multinodular morphology were the significant endoscopic predictors of carcinoma resected by cold snare polypectomy. No adverse events related to the procedure occurred. Sixty‐three lesions were diagnosed as carcinomas within the mucosal layer, and 34 were curative resections. Of the five carcinoma lesions with submucosal invasion, additional surgery revealed remnant cancer tissues in one lesion. No local or metastatic recurrence was observed during follow‐up. Conclusions: Although most of the carcinomas resected by cold snare polypectomy were within the mucosal layer, few lesions invading the submucosa were identified. Careful pre‐procedural endoscopic evaluation, especially focusing on the JNET classification and multinodular morphology, is recommended. [ABSTRACT FROM AUTHOR]

We have succeeded in in situ synthesis of gold nanoparticles (Au NPs) on the interior surfaces of red blood cell ghosts (RBCGs) with a cytoskeleton chemically conjugated to a gold-binding peptide. The Au NP-deposited RBCG with the peptide exhibits enhanced catalytic reactivity for the reduction of 4-nitrophenol due to the uniform distribution of the Au NPs on the inner surface and the coverage of the Au NPs surface with the peptide. [ABSTRACT FROM AUTHOR]

Carbonic anhydrases (CAs) play an important role in maintaining pH homeostasis. We previously demonstrated that overexpression of CA2 was associated with invasion and progression of urothelial carcinoma (UC) in humans. The purpose of the present study was to evaluate the effects of the CA inhibitor acetazolamide (Ace) on N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN)‐induced bladder carcinogenesis in mice and explore the function of CA2 in muscle invasion by UC. Male mice were treated with 0.025% (experiment 1) or 0.05% BBN (experiment 2) in their drinking water for 10 weeks, then treated with cisplatin (Cis), Ace, or Cis plus Ace for 12 weeks. In experiment 1, the overall incidence of BBN‐induced UCs was significantly decreased in the BBN→Ace and BBN→Cis+Ace groups. In experiment 2, the overall incidence of BBN‐induced UCs was significantly decreased in the BBN→Cis+Ace group, and the incidence of muscle invasive UC was significantly decreased in both the BBN→Ace and the BBN→Cis+Ace groups. We also show that overexpression of CA2 by human UC cells T24 and UMUC3 significantly increased their migration and invasion capabilities, and that Ace significantly inhibited migration and invasion by CA2‐overexpressing T24 and UMUC3 cells. These data demonstrate a functional association of CA2 with UC development and progression, confirming the association of CA2 with UC that we had shown previously by immunohistochemical analysis of human UC specimens and proteome analysis of BBN‐induced UC in rats. Our finding that inhibition of CA2 inhibits UC development and muscle invasion also directly confirms that CA2 is a potential therapeutic target for bladder cancers. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo‐resistant urothelial carcinoma (UC). Patients and Methods: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM). Results: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68–1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non‐squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15–0.90; P = 0.023) compared to patients with PUC. Conclusions: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo‐resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC. [ABSTRACT FROM AUTHOR]