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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]

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]

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]

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]

Objectives: Data on the long‐term outcomes of endoscopic submucosal dissection (ESD) performed in elderly patients with early colorectal cancer (CRC) are limited. We analyzed the prognosis of elderly CRC patients, not only from the viewpoint of treatment curability but also from the patients' baseline physical condition assessed by several indexes. Methods: A retrospective analysis of 729 patients aged ≥75 years who underwent ESD for Tis/T1 CRC in 16 institutions was conducted. The patients were classified into three groups based on curability: curative ESD (Group A, n = 582), non‐curative ESD with additional surgery (Group B, n = 60), and non‐curative ESD without additional surgery (Group C, n = 87). Overall survival (OS) was compared among the groups, and factors associated with reduced OS were investigated. Results: The median follow‐up periods in Groups A, B, and C were 41, 49, and 46 months, respectively (P = 0.62), during which 92 patients died. Two patients (0.3%) in Group A, none (0%) in Group B, and three (3.4%) in Group C died of CRC. Three‐year OS rates in Groups A, B, and C were 93.9%, 96.1%, and 90.1%, respectively, without a significant difference (P = 0.07). Multivariate analysis indicated low (<96.3) geriatric nutritional risk index (GNRI) as the sole independent predictor for reduced OS (hazard ratio 3.37; 95% confidence interval 2.18–5.22; P < 0.0001). Conclusions: Low GNRI, but not the curability attained by ESD, was independently associated with reduced OS in patients with early CRC aged ≥75 years. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab. Methods: This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis. Results: Overall, 391 patients received standard first‐line chemotherapy and pembrolizumab as a second‐line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first‐line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy. Conclusions: Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum‐based first‐line chemotherapy. [ABSTRACT FROM AUTHOR]

Aim: We have previously reported the therapeutic benefits of kamikihito for managing cancer‐related fatigue (CRF) in patients with hormone‐sensitive prostate cancer. Now, due to the routine use of enzalutamide and similar agents for treating castration‐resistant prostate cancer (CRPC), managing enzalutamide‐related fatigue is imperative. Here, we objectively evaluated the effectiveness of kamikihito on fatigue in CRPC patients receiving enzalutamide. Methods: Kamikihito was administered for 12 weeks to 11 patients receiving enzalutamide. We measured the changes in the levels of fatigue (using the Chalder Fatigue Scale (CFS)), depression (using the Center for Epidemiologic Studies Depression Scale (CES‐D)), oxidative stress (by measuring derivatives of reactive oxygen metabolites (d‐ROMs) and biological antioxidant potential (BAP) levels), various cytokines, insomnia (using actigraphy), and in‐vivo metabolites (by metabolomics analysis). Results: Kamikihito improved CFS and CES‐D scores, thus improving fatigue and depression in enzalutamide‐treated patients; however, it did not improve oxidative stress levels. Further, actigraphy showed prolongation of sleeping time, while the levels of various cytokines showed no change. Metabolomics analysis confirmed decrease in lipids and increase in amino acids that correlated with improvement in fatigue. Conclusion: Kamikihito corrected the abnormalities in lipid metabolism, which may have improved the production of amino acids, leading to reduced CRF in CRPC patients receiving enzalutamide. [ABSTRACT FROM AUTHOR]

Background and Aim: Whether Helicobacter pylori eradication prevents metachronous recurrence after endoscopic resection (ER) of early gastric cancer remains controversial. This multicenter retrospective study aimed to evaluate the long‐term (> 5 years) effects of H. pylori eradication by stratifying patients' baseline degrees of atrophic gastritis. Methods: A total of 483 H. pylori‐positive patients who had undergone ER for early gastric cancer were divided into two groups—(i) those having undergone successful H. pylori eradication within 1 year after ER (eradicated group, n = 294) and (ii) those with failed or not attempted H. pylori eradication (non‐eradicated group, n = 189). The cumulative incidences of metachronous gastric cancer between the two groups were compared for all patients, for patients with mild‐to‐moderate atrophic gastritis (n = 182), and for patients with severe atrophic gastritis (n = 301). Results: During a median follow‐up of 5.2 years (range 1.1–14.8), metachronous cancer developed in 52 (17.7%) patients in the eradicated group and in 35 (18.5%) patients in the non‐eradicated group (P = 0.11, log–rank test). In patients with mild‐to‐moderate atrophic gastritis (111 and 71 in the eradicated and non‐eradicated groups, respectively), the cumulative incidence of metachronous cancer was significantly lower in the eradicated group than that in the non‐eradicated group (P = 0.03, log–rank test). However, no significant intergroup difference was observed in patients with severe atrophic gastritis (P = 0.69, log–rank test). Conclusions: Helicobacter pylori eradication had a preventive effect on the development of metachronous gastric cancer in patients with mild‐to‐moderate atrophic gastritis. [ABSTRACT FROM AUTHOR]

Background and Aim: The morphological diagnosis of microvessels on the surface of superficial esophageal squamous cell carcinomas using magnifying endoscopy with narrow‐band imaging is widely used in clinical practice. Nevertheless, inconsistency, even among experts, remains a problem. We constructed a convolutional neural network‐based computer‐aided diagnosis system to classify the microvessels of superficial esophageal squamous cell carcinomas and evaluated its diagnostic performance. Methods: In this retrospective study, a cropped magnifying endoscopy with narrow‐band images from superficial esophageal squamous cell carcinoma lesions was used as the dataset. All images were assessed by three experts, and classified into three classes, Type B1, B2, and B3, based on the Japan Esophagus Society classification. The dataset was divided into training and validation datasets. A convolutional neural network model (ResNeXt‐101) was trained and tuned with the training dataset. To evaluate diagnostic accuracy, the validation dataset was assessed by the computer‐aided diagnosis system and eight endoscopists. Results: In total, 1777 and 747 cropped images (total, 393 lesions) were included in the training and validation datasets, respectively. The diagnosis system took 20.3 s to evaluate the 747 images in the validation dataset. The microvessel classification accuracy of the computer‐aided diagnosis system was 84.2%, which was higher than the average of the eight endoscopists (77.8%, P < 0.001). The area under the receiver operating characteristic curves for diagnosing Type B1, B2, and B3 vessels were 0.969, 0.948, and 0.973, respectively. Conclusions: The computer‐aided diagnosis system showed remarkable performance in the classification of microvessels on superficial esophageal squamous cell carcinomas. [ABSTRACT FROM AUTHOR]

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil‐to‐lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low‐, intermediate‐, and high‐risk groups (discovery cohort) were not yet reached (NYR) (NYR–19.1), 6.8 mo (5.8‐8.9), and 2.3 mo (1.2‐2.6), respectively. The HRs (95% CI) for OS in the low‐ and intermediate‐risk groups vs the high‐risk group were 0.07 (0.04‐0.11) and 0.23 (0.15‐0.37), respectively. The objective response rates for in the low‐, intermediate‐, and high‐risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first‐line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab‐treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design. [ABSTRACT FROM AUTHOR]

Background and Aim: To investigate whether assessment by magnifying narrow‐band imaging (M‐NBI) based on the classification of the Japan Esophageal Society provides additional value to the estimation of the invasion depth of superficial esophageal squamous cell carcinoma (SCC) compared with assessment by white light endoscopy (WLE) alone. Methods: Endoscopic images of 211 consecutive superficial esophageal SCCs resected by endoscopic submucosal dissection were separated into WLE and M‐NBI images. Depth estimation was performed independently by five evaluators using the numerical depth estimation scale (0 = epithelium (EP)/lamina propria (LPM), 1 = EP/LPM > muscularis mucosa (MM)/shallow submucosa (SM1), 2 = MM/SM1 > EP/LPM, 3 = MM/SM1, 4 = MM/SM1 > deep submucosa (SM2), 5 = SM2 > MM/SM1, 6 = SM2), using primarily WLE images (step 1), and subsequently both WLE and M‐NBI images (step 2). The discordance scores, determined by the average of the five evaluators' difference between the estimated score (from 0 to 6) and pathological score (0 for histologically proven EP/LPM, 3 for MM/SM1, and 6 for SM2), were analyzed in steps 1 and 2. Results: The discordance scores significantly decreased in step 2 (0.53 ± 0.06) compared with those in step 1 (0.79 ± 0.07) (P < 0.001). When the discordance score < 1.5 was regarded as a clinically correct diagnosis, the rate of the clinically correct diagnosis significantly increased in step 2 compared with that in step 1 (81% to 91%, P < 0.001). Conclusion: M‐NBI has an additive value for estimating the invasion depth of superficial esophageal SCCs. [ABSTRACT FROM AUTHOR]

Objectives: Endoscopic biopsies for nonampullary duodenal epithelial neoplasms (NADENs) can induce submucosal fibrosis, making endoscopic resection difficult. However, no biopsy‐free method exists to distinguish between NADENs and non‐neoplasms. We developed a diagnostic algorithm for duodenal neoplasms based on magnifying endoscopy findings and evaluated the model's diagnostic ability. Methods: Magnified endoscopic images and duodenal lesion histology were collected consecutively between January 2015 and April 2016. Diagnosticians classified the surface patterns as pit, groove or absent. In cases of nonvisible surface patterns, the vascular pattern was evaluated to determine regularity or irregularity. The correlation between our algorithm (pit‐type or absent with irregular vascular pattern) and the lesion histology were evaluated. Four evaluators, who were blinded to the histology, also classified the endoscopic findings and evaluated the diagnostic performance and interobserver agreement. Results: Endoscopic images of 114 lesions were evaluated (70 NADENs and 44 non‐neoplasms, 31 in the superior and 83 in the descending and horizontal duodenum). Of the NADEN surface patterns, 88% (62/70) were pit‐type, while 79% (35/44) of the non‐neoplasm surface patterns were groove‐type. Our diagnostic algorithm for differentiating NADENs from non‐neoplasms was high (sensitivity 96%, specificity 95%) in the descending and horizontal duodenum. The evaluators' diagnostic performances were also high, and interobserver agreement for the algorithm was good between each diagnostician and evaluator (κ = 0.60–0.76). Conclusion: Diagnostic performance of our algorithm sufficiently enabled eliminating endoscopic biopsies for diagnosing the descending and horizontal duodenum. [ABSTRACT FROM AUTHOR]

Background and Aim: The incidence of post‐endoscopic submucosal dissection (ESD) coagulation syndrome (PECS) can be decreased by closing mucosal defects. However, large mucosal defects after colorectal ESD cannot be closed endoscopically. We established line‐assisted complete clip closure (LACC), a novel technique for large mucosal defects after colorectal ESD. We evaluated the prophylactic efficacy of LACC for preventing PECS. Methods: Sixty‐one consecutive patients on whom LACC after colorectal ESD was attempted from January 2016 to August 2016 were analyzed. After exclusion of patients with incomplete LACC and adverse events during ESD, 57 patients comprised the LACC group. In contrast, 495 patients who did not undergo closure of a mucosal defect comprised the control group. Propensity score matching was used to adjust for patients’ backgrounds. Treatment outcomes were evaluated between the groups. Results: Median resected specimen size in the LACC‐attempted group was 35 mm (range, 20–72 mm), and LACC success rate was 95% (58/61). Median procedure time of LACC was 14 min. In the LACC group, incidence of PECS was only 2%, and no delayed bleeding or perforation occurred. Propensity score matching created 51 matched pairs. Adjusted comparisons between the LACC and control groups showed a lower incidence of PECS (0% vs 12%, respectively; P = 0.03) and shorter hospitalization (5 vs 6 days, respectively; P < 0.001) in the LACC group. Conclusion: This study suggests that LACC can effectively reduce the incidence of PECS, although further large‐scale studies are warranted. [ABSTRACT FROM AUTHOR]

Background and Aim: Colorectal endoscopic submucosal dissection (ESD) remains challenging because of technical difficulties, long procedure time, and high risk of adverse events. To facilitate colorectal ESD, we developed traction‐assisted colorectal ESD using a clip and thread (TAC‐ESD) and conducted a randomized controlled trial to evaluate its efficacy. Methods: Patients with superficial colorectal neoplasms (SCN) ≥20 mm were enrolled and randomly assigned to the conventional‐ESD group or to the TAC‐ESD group. SCN ≤50 mm were treated by two intermediates, and SCN >50 mm were treated by two experts. Primary endpoint was procedure time. Secondary endpoints were TAC‐ESD success rate (sustained application of the clip and thread until the end of the procedure), self‐completion rate by the intermediates, and adverse events. Results: Altogether, 42 SCN were analyzed in each ESD group (conventional and TAC). Procedure time (median [range]) for the TAC‐ESD group was significantly shorter than that for the conventional‐ESD group (40 [11–86] min vs 70 [30–180] min, respectively; P < 0.0001). Success rate of TAC‐ESD was 95% (40/42). The intermediates’ self‐completion rate was significantly higher for the TAC‐ESD group than for the conventional‐ESD group (100% [39/39] vs 90% [36/40], respectively; P = 0.04). Adverse events included one intraoperative perforation in the conventional‐ESD group and one delayed perforation in the TAC‐ESD group. Conclusion: Traction‐assisted colorectal endoscopic submucosal dissection reduced the procedure time and increased the self‐completion rate by the intermediates (UMIN000018612). [ABSTRACT FROM AUTHOR]

Proteins are attractive materials for supramolecular chemistry due to their multifunctionality and self‐organization ability. In this work, we synthesized a diheme compound, in which two iron‐protoporphyrin IX molecules are associated via a linker chain, and introduced it into a de novo designed four‐helix bundle protein with two heme‐binding sites. The protein gradually bound the diheme compound by bis‐histidyl ligation and formed supramolecular polymers. Polymer formation was observed by atomic force microscopy (AFM), which revealed the highly branched, dendritic forms of the fibrous architecture. The present results may open a pathway toward nanowire construction with de novo heme‐proteins. [ABSTRACT FROM AUTHOR]

Objectives: To report the treatment outcomes of patients with extrinsic ureteral obstruction treated with metallic stents and to identify the factors predicting stent failure. Methods: A total of 52 patients with extrinsic ureteral obstruction as a result of malignancy (66 ureters) were treated with metallic stents (Resonance®) and included in the study. The median observation period was 118 days. Results: The median survival time of these patients was 210 days, and the stent patency rate was 86.0% at 6 months and 60.0% at 1 year. Eight (15.4%) patients underwent nephrostomy as a result of stent failure. The occlusion rate of bilateral ureteral obstructed cases was significantly higher than that of unilateral cases. There was no correlation between the preoperative serum creatinine level, causes of ureteral occlusions (compression by tumor, lymph node metastasis, peritoneal dissemination), obstructed site (upper, middle, lower ureter) and stent failure. Conclusions: Metallic stents are excellent in maintaining patency compared with the conventional stents. Therefore, they can be used as first‐line treatment of malignant ureteral obstructions. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy is initially effective for treating patients with advanced prostate cancer; however, the prostate cancer gradually becomes resistant to androgen deprivation therapy, which is termed castration-resistant prostate cancer ( CRPC). Androgen receptor splice variant 7 ( AR-V7), one of the causes of CRPC, is correlated with resistance to a new-generation AR antagonist (enzalutamide) and poor prognosis. Heat shock protein 70 (Hsp70) inhibitor is known to decrease the levels of full-length AR ( AR- FL), but little is known about its effects against CRPC cells expressing AR-V7. In this study, we investigated the effect of the Hsp70 inhibitors quercetin and VER155008 in the prostate cancer cell line LNCaP95 that expresses AR-V7, and explored the mechanism by which Hsp70 regulates AR- FL and AR-V7 expression. Quercetin and VER155008 decreased cell proliferation, increased the proportion of apoptotic cells, and decreased the protein levels of AR- FL and AR-V7. Furthermore, VER155008 decreased AR- FL and AR-V7 mRNA levels. Immunoprecipitation with Hsp70 antibody and mass spectrometry identified Y-box binding protein 1 ( YB-1) as one of the molecules regulating AR- FL and AR-V7 at the transcription level through interaction with Hsp70. VER155008 decreased the phosphorylation of YB-1 and its localization in the nucleus, indicating that the involvement of Hsp70 in AR regulation might be mediated through the activation and nuclear translocation of YB-1. Collectively, these results suggest that Hsp70 inhibitors have potential anti-tumor activity against CRPC by decreasing AR- FL and AR-V7 expression through YB-1 suppression. [ABSTRACT FROM AUTHOR]

Rat bladder cancer is nearly always papillary non-invasive urothelial carcinoma ( UC). To establish an animal model mimicking invasive UC that arises from papillary non-invasive UC in the bladder, male human c-Ha-ras proto-oncogene transgenic rats (Hras128) were treated with 0.05% N-butyl- N-(hydroxybutyl)nitrosameine ( BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate ( PEITC) in their diet as follows: BBN (8 weeks)→ PEITC (8 weeks); PEITC (8 weeks)→ BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→ PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion-associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non-invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non-invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 ( CA2), an overexpressed protein, showed that the relative number of CA2-positive UC was significantly higher for invasive UC compared to non-invasive UC in rats. Moreover, the incidence of CA2-positive cancers was also significantly higher for human muscle-invasive bladder cancer ( MIBC) compared to non- MIBC ( NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion-associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers. [ABSTRACT FROM AUTHOR]

Background and Aim Standard surveillance methods for pharyngeal cancer have not been established. We conducted a randomized controlled trial to investigate the best sedation method for pharyngeal observation using transoral endoscopy. Methods In total, 120 patients who underwent surveillance or diagnostic examinations for esophageal cancer were enrolled and divided equally into three groups (no sedation, midazolam, or pethidine hydrochloride). In the midazolam group, midazolam was given i.v. maintaining a Ramsay score of 3. In the pethidine group, pethidine hydrochloride (35 mg) given i.v. Seven sites in five pharyngeal regions were observed on insertion of the endoscope, and graded (0 = poor, 1 = good). After examination, the five pharyngeal regions were scored using a seven-point scale. Primary endpoint was the total score from the five pharyngeal regions. Secondary endpoints were the proportion of the perfect score using the seven-point scale, discomfort score, and adverse events. Results Mean total scores for the no sedation group, the midazolam group and the pethidine group were 5.7, 5.5, and 6.8, respectively ( P < 0.0001). Proportion of patients with a perfect score for the no sedation group, the midazolam group and the pethidine group were 53%, 35%, and 89%, respectively ( P < 0.0001). The pethidine group had better results than the other two groups. Discomfort score and adverse events were low in the pethidine group. Conclusion Pethidine hydrochloride is a feasible and safe sedation method, and was superior to no sedation and midazolam regarding pharyngeal observation of esophageal cancer patients. [ABSTRACT FROM AUTHOR]

Toward understanding intermolecular interactions governing self-association of proteins, the present study investigated a model protein, myoglobin, using a small-angle X-ray scattering technique. It has been known that removal of the heme makes myoglobin aggregation-prone. The interparticle interferences of the holomyoglobin and the apomyoglobin were compared in terms of the structure factor. Analysis of the structure factor using a model potential of Derjaguin-Laudau-Verwey-Overbeek (DLVO) suggests that the intermolecular interaction potential of apomyoglobin is more attractive than that of holomyoglobin at short range from the protein molecule. [ABSTRACT FROM AUTHOR]

The object of the present study was to identify markers for predicting urinary bladder cancer progression by comparative proteome analysis of bladder cancers and paired normal mucosas. We found that DDX39 was overexpressed in four of six bladder cancers examined compared with respective control tissues. Immunohistochemical analysis using 303 bladder cancer specimens revealed that DDX39 was inversely correlated to p T stage and histological grade progression. The incidence of DDX39high tumors (positive cells ≥50%) was 68.6%, 43.5%, 20.0%, and 5.3% in p Ta, p T1, p Tis, and ≥p T2 tumors, respectively, and 65.2%, 60.7%, and 19.6% in G1, G2, and G3 tumors, respectively. The incidence of DDX39high tumors was significantly lower in p T1 and ≥p T2 compared to p Ta tumors, and also significantly lower in G3 compared to G1 and G2 tumors. Follow-up analysis ( n = 105) revealed that DDX39low tumors (positive cells <50%) were associated with disease progression (hazard ratio 7.485; P = 0.0083). Furthermore, DDX39-knockdown bladder cancer cells increased their invasion ability compared to negative control cells. These results suggest that DDX39 is a suppressor of invasion and loss of its function predicts disease progression in bladder cancers. ( Cancer Sci 2012; 103: 1363-1369) [ABSTRACT FROM AUTHOR]

Type II transmembrane serine proteases (TTSPs) are structurally defined by the presence of a transmembrane domain located near the N-terminus and a C-terminal extracellular serine protease domain. The human TTSP family consists of 17 members. Some members of the family have pivotal functions in development and homeostasis, and are involved in tumorigenesis and viral infections. The activities of TTSPs are regulated by endogenous protease inhibitors. However, protease inhibitors of most TTSPs have not yet been identified. In this study, we investigated the inhibitory effect of hepatocyte growth factor activator inhibitor type 1 (HAI-1), a Kunitz-type serine protease inhibitor, on several members of the TTSP family. We found that the protease activity of a member, TMPRSS13, was inhibited by HAI-1. A detailed analysis revealed that a soluble form of HAI-1 with one Kunitz domain (NK1) more strongly inhibited TMPRSS13 than another soluble form of HAI-1 with two Kunitz domains (NK1LK2). In addition, an in vitro protein binding assay showed that NK1 formed complexes with TMPRSS13, but NK1LK2 did not. TMPRSS13 converted single-chain pro-hepatocyte growth factor (pro-HGF) to a two-chain form in vitro, and the pro-HGF converting activity of TMPRSS13 was inhibited by NK1. The two-chain form of HGF exhibited biological activity, assessed by phosphorylation of the HGF receptor (c-Met) and extracellular signal-regulated kinase, and scattered morphology in human hepatocellular carcinoma cell line HepG2. These results suggest that TMPRSS13 functions as an HGF-converting protease, the activity of which may be regulated by HAI-1. [ABSTRACT FROM AUTHOR]

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The effect of pressure on the heme environment structure of sperm whale and horse heart metcyanomyoglobins was investigated up to 300 MPa by high-pressure 1H NMR spectroscopy. Pressure-induced changes in the distances between the observed protons and the heme iron atom were estimated from changes in the dipolar shift due to the paramagnetic effect on the protons. The changes showed that the heme peripheral structure as a whole was compressed by pressure; the movements of the protons in the heme peripheral residues were in the range of +0.16 to −0.54 Å/300 MPa. One-dimensional compressibilities for the protons, excluding the protons of the distal His residue, were in the range of 1.0 × 10−4 to 6.1 × 10−4/MPa. The movements of the protons induced by pressure correlated well with the distance between the protons and cavities in the protein. The distal His residue (His 64) moved toward the outside of the heme pocket, but remained in the pocket even at 300 MPa. This movement was driven dominantly by a change in the dihedral angle around the Cα-Cβ rotational bond of the residue. Comparative work on horse heart metcyanomyoglobin implied that the conformational change of the His 64 imidazole ring was larger in the horse heart metcyanomyoglobin than in the sperm whale metcyanomyoglobin. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions This study aims to develop a prognostic model that estimates the post‐operative risk of cancer‐specific mortality in patients with bladder cancer who underwent radical cystectomy (RC).We analyzed the data from patients with bladder cancer who had undergone radical cystectomy without receiving adjuvant chemotherapy across 36 institutions in the Japan Urological Oncology Group. The data were randomly split into training (N = 1348) and validation sets (N = 674) in a 2:1 ratio. Twenty‐five variables were analyzed, and a multivariable Cox regression model predicting cancer‐specific mortality was developed and validated. Prognostic scores were categorized into good and poor prognostic groups based on the upper tertile. The performance of the model was compared against the CheckMate 274 risk classification as a reference, which is used for determining the indication of adjuvant nivolumab therapy.The final model incorporated eight variables. In the validation set, it outperformed the CheckMate 274 risk classification with superior time‐dependent area under the curves (5‐year: 0.81 vs. 0.67) and was well‐calibrated. Furthermore, our model reclassified 27.8% of patients categorized as high‐risk by the CheckMate 274 risk classification into the good prognosis group.We developed and validated a prognostic model for patients with bladder cancer who underwent RC. This model will be beneficial in identifying patients with poor prognosis and those who are potential candidates for clinical trials of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background and Aim Methods Results Conclusions Effective treatment of lesions that develop in the irradiated area of head and neck squamous cell carcinoma is a major concern. This study aimed to clarify the efficacy and safety of endoscopic resection for such lesions.Among consecutive patients who underwent endoscopic resection for histologically proven head and neck squamous cell carcinoma between January 2014 and December 2021, those who received definitive radiotherapy/chemoradiotherapy before endoscopic resection were included in this single‐center, retrospective study. Short‐ and long‐term outcomes were evaluated.Among 422 patients who underwent endoscopic resection for 615 lesions, 43 patients with 57 lesions were eligible. All 57 lesions were treated with endoscopic submucosal dissection and en bloc resection was achieved in all lesions. Grade 3 of Common Toxicity Criteria for Adverse Events v5.0 occurred in eight (19%) patients (dysphagia, seven; stricture, three; aspiration pneumonia, two; and pharyngeal necrosis, one [some cases overlapped]), but no grade ≥ 4 events occurred. Enteral nutrition by gastrostomy was temporarily required in two patients owing to dysphagia and laryngeal necrosis. During the median follow‐up of 40 (interquartile range, 29.5–61) months after endoscopic submucosal dissection for the lesions developed in the irradiated area, local recurrence and metachronous lesions developed in two (5%) and nine (21%) patients, respectively. However, total laryngectomies and tracheostomies were avoided in all patients. The 3‐year overall and disease‐specific survivals were 81% (95% confidence interval, 64%–91%) and 94% (95% confidence interval, 79%–99%), respectively.Favorable local control and safety of endoscopic submucosal dissection were demonstrated. [ABSTRACT FROM AUTHOR]

The article offers information on use of the technique Valsalva maneuver to visualize the closed hypopharyngeal space during transoral endoscopy using a novel dedicated mouthpiece in patients with esophageal squamous cell carcinoma (ESCC). It mentions that the Valsalva maneuver improves visibility of hypopharynx, and can be a useful diagnostic procedure for patients at high risk of developing pharyngeal cancer.

Concurrent gastric sarcoidosis and early gastric cancer distinguished by magnifying narrow-band imaging In contrast, the depressed lesion had a clear demarcation line with an irregular microsurface and microvessels, which was highly suspicious for gastric cancer (Fig. c).[2] We endoscopically removed the two lesions (Fig. a). In magnifying narrow-band imaging, the yellowish lesion showed thin and abnormal microvessels with no clear demarcation line (b), whereas the depressed lesion had a clear demarcation line with an irregular microsuface and microvessels (c). gl. [Extracted from the article]

The article presents a case study of a 65-year-old woman with a flat elevated lesion in the superior duodenal angulus, which was diagnosed as adenoma on an endoscopic biopsy 1 year prior. Topics include the lesion showed no progression towards adenocarcinoma. Underwater endoscopic mucosal resection (UEMR) of the lesion was performed. It also concludes that UEMR provides a safe alternative to endoscopic submucosal dissection (ESD) for resecting a duodenal lesion with biopsy scars.

A letter to the editor is presented in response to the article related to colorectal mucosal defect following endoscopic submucosal dissection.

The first-order long period L1, the second-order long period L2 and lamellar crystal thickness lc of isotactic polybutene-1 have been investigated for crystallization in the melt over a wide range (313.2 to 363.2 K) of crystallization temperatures by small-angle X-ray scattering experiments and density measurements. The long period L1 shows a single linear dependence on inverse supercooling. The crystal thickness lc, however, demonstrates two linear dependences on inverse supercooling and a transition from one dependence to the other has been observed around 338.2 K, where lc becomes comparable with the radius of gyration Rg of the samples. [ABSTRACT FROM AUTHOR]

Lateral and end surface free energies of melt-crystallized isotactic polybutene-1 (it-PB1) trigonal and tetragonal crystals have been determined by small-angle X-ray scattering and in situ observation of the crystal growth kinetics. The lateral surface free energy σ of the trigonal phase is about seven times as large as the value σHoff calculated according to Hoffman's equation [Hoffman (1992). Polymer, 33, 2643–2644], while that of the tetragonal phase is roughly in agreement with the estimation. The discrepancy between the values of σ and σHoff for the trigonal phase can be attributed to the loss of conformational entropy of the ethyl side chains of it-PB1. [ABSTRACT FROM AUTHOR]

A new high-pressure phase of the title amino acid (systematic name: 2-ammonio-4-methylpentanoate), C6H13NO2, is reported, with one molecule per asymmetric unit, in contrast to the atmospheric pressure phase, (I), reported by Harding & Howieson [ Acta Cryst. (1976). B 32, 633–634], which has two molecules in the asymmetric unit. The packing consists of a double layer structure, similar to those of (I) and other amino acids with non-polar side chains. [ABSTRACT FROM AUTHOR]