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Background: In Japan, the authorized period (2-4 h) between oral administration of 5-aminolevulinic acid hydrochloride (5-ALA) and transurethral resection for non-muscle invasive bladder cancer (NMIBC) may restrict photodynamic diagnosis (PDD) usage. Therefore, this prospective, single-arm, phase III study aimed to evaluate the diagnostic accuracy and safety of PDD at an extended administration period (4-8 h)., Methods: From January 2022 to May 2023, 161 patients with NMIBC were enrolled from eight hospitals. The primary endpoint was the blue light (BL) sensitivity of pathologically positive biopsies. The secondary endpoints were a comparison of the specificity and positive and negative prediction rates under BL and white light (WL) conditions., Results: A total of 1242 specimens comprising 337 histological NMIBC specimens were analyzed. BL-sensitivity was 95.3%. Its lower limit of 95% confidence interval (92.4-97.3%) exceeded the threshold (70%) of non-inferiority to authorized usage. Sensitivity and specificity were significantly higher and lower for BL than those for WL (95.3% vs. 61.1%, P < 0.001; 52.7% vs. 95.2%, P < 0.001), respectively. The positive and negative predictive rates were significantly lower and higher for BL than those for WL (42.9% vs. 82.7%, P < 0.001; 96.8% vs. 86.8%, P < 0.001), respectively. Of the 145 patients receiving 5-ALA, 136 (93.8%) and 75 (51.7%) experienced 377 adverse events and 95 adverse reactions, respectively, most of which were grade 1 or 2., Conclusion: For extended period, the efficacy of PDD for NMIBC was similar to that of authorized period, in terms of higher sensitivity and lower specificity compared with WL, and the safety was acceptable., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Avelumab and pembrolizumab are administered after platinum-based chemotherapy for the treatment of metastatic urothelial carcinoma. We explored the prognostic factors and risk scores for predicting the outcomes of metastatic or unresectable urothelial carcinoma at the start of treatment with immune checkpoint inhibitors., Methods: This retrospective study included patients with metastatic or unresectable urothelial carcinoma treated with avelumab or pembrolizumab after platinum-based chemotherapy between January 2017 and December 2022. Prognostic factors, including patient and tumor characteristics and blood data at the initiation of immune checkpoint inhibitor therapy, were examined., Results: This study included 36 and 207 patients treated with avelumab and pembrolizumab, respectively, for metastatic or unresectable urothelial carcinoma. Eastern Cooperative Oncology Group performance status, presence of visceral metastases, platelet-to-lymphocyte ratio and lactate dehydrogenase levels were independent prognostic factors for predicting overall survival. The median overall survival of patients in the risk-score model was 58.5 months (score zero), 27.9 months (one), 13.1 months (two) and 3.9 months (three or higher). The C-index for overall survival was 0.718 for the newly developed risk score compared with 0.679 for the Bellmunt score and 0.703 for the Bellmunt-C-reactive protein score. Additionally, the C-index for overall survival using the immune prognostic index derived from lactate dehydrogenase and the platelet-to-lymphocyte ratio was 0.646 compared with 0.615 for the Lung Immune Prognostic Index., Conclusions: A risk score that includes the platelet-to-lymphocyte ratio and lactate dehydrogenase may serve as a useful model for predicting prognosis following the initiation of immune checkpoint inhibitors in patients with metastatic or unresectable urothelial carcinoma., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: In cases of metastatic and unresectable urothelial carcinoma with no disease progression after 4 cycles of chemotherapy, including platinum agents, treatment options include continuation of chemotherapy or switching to maintenance therapy with avelumab. This study compared the treatment outcomes of avelumab maintenance therapy with those of pembrolizumab in urothelial carcinoma using propensity score matching., Patients and Methods: Between January 2017 and December 2022, 243 patients with metastatic and unresectable urothelial carcinoma were treated with either avelumab or pembrolizumab at the Yamaguchi University Hospital and its affiliated institutions. We retrospectively compared the oncological outcomes and adverse events by aligning patient characteristics and treatment backgrounds using propensity score matching., Results: The analysis compared 36 cases receiving avelumab maintenance therapy after chemotherapy to 49 cases where patients, after receiving 4 courses of chemotherapy including platinum-based agents without disease progression, were subsequently administered pembrolizumab as a second-line treatment following disease progression. Using propensity score matching, 27 cases from each group were selected for comparison. From the initiation of prechemotherapy to disease progression on immune checkpoint inhibitors, the median progression-free survival was 20.7 and 23.3 months in the avelumab and pembrolizumab groups, respectively, with no statistically significant difference observed (P = .358). However, avelumab tended to have a lower rate of high-dose glucocorticoid treatment compared to pembrolizumab., Conclusion: Progression-free survival was similar for avelumab maintenance therapy and the sequence of continued chemotherapy followed by pembrolizumab after no disease progression at four chemotherapy courses. Avelumab may require less high-dose glucocorticoid treatment, potentially enhancing safety., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) using oral 5-aminolevulinic acid hydrochloride reduced residual tumors in high-risk non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD-TURBT for intravesical recurrence after a second transurethral resection for high-risk NMIBC., Methods: High-risk NMIBC patients initially treated with PDD-TURBT (PDD group) were prospectively registered between 2018 and 2020. High-risk patients with NMIBC who were initially treated with white-light TURBT (WL group) were retrospectively registered. Intravesical recurrence-free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis., Results: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25-0.77). In subgroup analysis, PDD-TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14-0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16-0.86), and no postoperative intravesical Bacillus Calmette-Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13-0.58)., Conclusions: PDD-TURBT may reduce short-term intravesical recurrence in patients with high-risk NMIBC., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Background: The diagnostic accuracy of cystoscopy varies according to the knowledge and experience of the performing physician. In this study, we evaluated the difference in cystoscopic gaze location patterns between medical students and urologists and assessed the differences in their eye movements when simultaneously observing conventional cystoscopic images and images with lesions detected by artificial intelligence (AI). Methodology: Eye-tracking measurements were performed, and observation patterns of participants (24 medical students and 10 urologists) viewing images from routine cystoscopic videos were analyzed. The cystoscopic video was captured preoperatively in a case of initial-onset noninvasive bladder cancer with three low-lying papillary tumors in the posterior, anterior, and neck areas (urothelial carcinoma, high grade, and pTa). The viewpoint coordinates and stop times during observation were obtained using a noncontact type of gaze tracking and gaze measurement system for screen-based gaze tracking. In addition, observation patterns of medical students and urologists during parallel observation of conventional cystoscopic videos and AI-assisted lesion detection videos were compared. Results: Compared with medical students, urologists exhibited a significantly higher degree of stationary gaze entropy when viewing cystoscopic images ( p  < 0.05), suggesting that urologists with expertise in identifying lesions efficiently observed a broader range of bladder mucosal surfaces on the screen, presumably with the conscious intent of identifying pathologic changes. When the participants observed conventional and AI-assisted lesion detection images side by side, contrary to urologists, medical students showed a higher proportion of attention directed toward AI-detected lesion images. Conclusion: Eye-tracking measurements during cystoscopic image assessment revealed that experienced specialists efficiently observed a wide range of video screens during cystoscopy. In addition, this study revealed how lesion images detected by AI are viewed. Observation patterns of observers' gaze may have implications for assessing and improving proficiency and serving educational purposes. To the best of our knowledge, this is the first study to utilize eye tracking in cystoscopy. University of Tsukuba Hospital, clinical research reference number R02-122.

Objectives: The aim of this study was to compare clinical outcomes between patients receiving second TUR after initial white-light transurethral resection of bladder tumor (WL-TURBT) and initial photodynamic diagnosis (PDD)-assisted TURBT., Methods: A total of 1007 patients were divided into four groups based on the treatment pattern: WL-TURBT with second TUR (161 patients, WL-second group) or without second TUR (540 patients, WL-alone group) and PDD-TURBT with second TUR (112 patients, PDD-second group) or without second TUR (194 patients, PDD-alone group). Oncologic outcomes (bladder cancer recurrence, progression, urothelial cancer-specific mortality) and rates of residual tumor and risk stratification of non-muscle-invasive bladder cancer (NMIBC) after second TUR were evaluated., Results: After propensity score-matching 121 patients were included each in the WL-alone and WL-second groups, and 63 patients each in the PDD-alone and PDD-second groups. In the WL group, the second TUR was significantly associated with improved progression-free (p = 0.012) and urothelial cancer-specific free survival (p = 0.011), but not with recurrence-free survival (p = 0.93). Patients initially treated with PDD-TURBT, and with a tumor diameter <30 mm and multifocality had a relatively high benefit from second TUR. The rates of residual tumor and risk stratification of NMIBC did not significantly differ between WL-TURBT and PDD-TURBT groups., Conclusions: Our findings suggested that a second TUR could be omitted after an initial PDD-TURBT in selected patients with high-risk NMIBC., (© 2024 The Japanese Urological Association.)

Background/aim: Hair-follicle keratinocytes contain high levels of cysteine, which is derived from methionine, rapidly proliferate, and form the hair shaft. The high proliferation rate of hair-follicle keratinocytes resembles that of aggressive cancer cells. In the present study, we determined the effect of a methionine-deficient diet on hair loss (alopecia) in mice with or without homocysteine supplementation., Materials and Methods: Mice were fed a normal rodent diet (2020X, ENVIGO) (Group 1); a methionine-choline-deficient diet (TD.90262, ENVIGO) (Group 2); a methionine-choline-deficient diet with a 10 mg/kg/day supply of homocysteine administered by intra-peritoneal (i.p.) injection for 2 weeks (Group 3). In Group 2, mice were fed a methionine-choline-deficient diet for an additional 2 weeks but with 10 mg/kg/day of i.p. l-homocysteine and the mice were observed for two additional weeks. Subsequently, the mice were fed a standard diet that included methionine. Hair loss was monitored by photography., Results: After 14 days, hair loss was observed in Group 2 mice on a methionine-restricted diet but not in Group 3 mice on the methionine-restricted diet which received i.p. homocysteine. In Group 2, at 2 weeks after methionine restriction, hair loss was not rescued by homocysteine supplementation. However, after restoration of methionine in the diet, hair growth resumed. Thus, after 2 weeks of methionine restriction, only methionine restored hair loss, not homocysteine., Conclusion: Hair maintenance requires methionine in the diet. Future experiments will determine the effects of methionine restriction on hair-follicle stem cells., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Colorectal cancer (CRC) is the third-leading cause of death in the world. Although the prognosis has improved due to improvement of chemotherapy, metastatic CRC is still a recalcitrant disease, with a 5-year survival of only 13%. Irinotecan (IRN) is used as first-line chemotherapy for patients with unresectable CRC. However, there are severe side effects, such as neutropenia and diarrhea, which are dose-limiting. We have previously shown that methionine restriction (MR), effected by recombinant methioninase (rMETase), lowered the effective dose of IRN of colon-cancer cells in vitro. The aim of the present study was to evaluate the efficacy of the combination of low-dose IRN and MR on colon-cancer in nude mice., Materials and Methods: HCT-116 colon-cancer cells were cultured and subcutaneously injected into the flank of nude mice. After the tumor size reached approximately 100 mm 3 , 18 mice were randomized into three groups; Group 1: untreated control on a normal diet; Group 2: high-dose IRN on a normal diet (2 mg/kg, i.p.); Group 3: low-dose IRN (1 mg/kg i.p.) on MR effected by a methionine-depleted diet., Results: There was no significant difference between the control mice and the mice treated with high-dose IRN, without MR. However, low-dose IRN combined with MR was significantly more effective than the control and arrested colon-cancer growth (p=0.03). Body weight loss was reversible in the mice treated by low-dose IRN combined with MR., Conclusion: The combination of low-dose IRN and MR acted synergistically in arresting HCT-116 colon-cancer grown in nude mice. The present study indicates the MR has the potential to reduce the effective dose of IRN in the clinic., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Japanese men receiving apalutamide often experience skin-adverse events (AEs), possibly requiring treatment interruption or dose reduction. However, concerns have arisen regarding the impact of these adjustments on the efficacy of apalutamide. Our study evaluated the efficacy, safety, and persistence of apalutamide in men with metastatic castration-sensitive prostate cancer (mCSPC)., Methods: We retrospectively reviewed the medical records of 108 men with mCSPC from 14 Japanese institutions. The primary outcomes were the efficacy of apalutamide: prostate-specific antigen (PSA) response (50%, 90% and < 0.2 decline) and progression to castration-resistant prostate cancer (CRPC). The secondary outcomes were the skin-AE and compliance of apalutamide., Results: PSA50%, PSA90% and PSA < 0.2 declines were observed in 89.8, 84.3 and 65.7%, and the median time to CRPC progression was not reached. PSA < 0.2 decline and an initial full dose of apalutamide were significantly associated with a longer time to CRPC. The most common AE was skin-AE (50.9%), and there was no association between the occurrence of skin-AE and the time to CRPC (P = 0.72). The median apalutamide persistence was 29 months, which was longer in the initial full dose recipients than in the reduced dose recipients. The dosage is reduced in about 60% of patients within the first year of treatment in the initial full dose recipients., Conclusions: Our findings indicate the effectiveness of apalutamide in Japanese men with mCSPC, despite a substantial portion requiring dose reduction within a year among the initial full dose recipients., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Among patients with non-muscle-invasive bladder cancer (NMIBC), systematic reviews showed lower recurrence rate in patients treated with photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) than with white-light (WL) TURBT. However, the result is not consistent between clinical trials and the significance of preoperatively available factors in disease recurrence after PDD-TURBT remains unclear., Methods: The present study retrospectively analyzed 1174 NMIBC patients who underwent TURBT and were followed up for ≥ 6 months. Among 1174 patients, 385 and 789 underwent PDD-TURBT with oral 5-aminolevulinic acid (the PDD group) and WL-TURBT (the WL group), respectively. Recurrence-free survival (RFS) was compared between the PDD and WL groups before and after propensity score matching, and the impact of several baseline parameters on RFS between the 2 groups was investigated after matching., Results: Before propensity score matching, RFS was significantly longer in the PDD group than in the WL group (P = 0.006). After matching, 383 patients were included in both groups, and RFS was significantly longer in the PDD group than in the WL group (P < 0.001). In the cohort after matching, RFS between the two groups was compared in each subgroup classified according to baseline parameters, including age, sex, history of previous or concomitant upper urinary tract urothelial carcinoma, preoperative urinary cytology, tumor multiplicity, and tumor size, and significantly longer RFS was observed in the PDD group in all subgroups, except for the patients with tumors ≥ 30 mm (P = 0.21)., Conclusion: These results suggest that PDD-TURBT prolongs RFS in NMIBC patients, except for those with tumors ≥ 30 mm., (© 2023. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

We evaluated the usable specimen thickness of Si for lattice imaging on a transmission electron microscopy (TEM) instrument operating at 300 kV and equipped with a complementary metal-oxide-semiconductor camera by using an original reference material (RM) and comparing the lattice images obtained from Si patterns of the RM with various thicknesses. Lattice images of the {111} planes of crystalline Si are successfully observed for patterns with thicknesses of up to 508 nm. However, the contrast of these lattice fringes at a thickness of 508 nm is not distinct, even when recorded using a longer exposure time (5.0 s) than that required to obtain lattice images of patterns with thicknesses of 316 nm or less (0.5 s). Based on these results, we conclude that the practical thickness of crystalline Si specimens for accurate structural analysis and TEM magnification calibration via lattice imaging is less than approximately 500 nm under the experimental conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Objectives: Bladder cancer, especially non-muscle invasive bladder cancer (NMIBC), is one of the most costly cancers owing to its long-term management. Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) reduces the risk of intravesical recurrence. However, its impact on healthcare economics in Japan remains unclear. We evaluated the comprehensive medical costs of Japanese healthcare economics regarding PDD-TURBT., Methods: This large-scale, multicenter, retrospective study included a dataset of 1531 patients who were diagnosed with primary NMIBC who underwent initial TURBT between April 2006 and June 2021. A one-to-one propensity-score matching analysis was used for an unbiased comparison based on postTURBT follow-up periods. The total medical costs, including hospitalization, surgical procedures for TURBT and salvage radical cystectomy, adjuvant intravesical therapies, and follow-up examinations, were compared between white light (WL)-TURBT and PDD-TURBT groups., Results: After propensity-score matching, 468 patients each of WL- and PDD-TURBT groups were matched. Total costs were 510 337 128 and 514 659 328 ¥ in WL- and PDD-TURBT groups, respectively. The costs of adjuvant intravesical therapies, follow-up examinations, and salvage radical cystectomy in PDD-TURBT group were equivalent to or lower than those in WL-TURBT group. Furthermore, total costs of high- and highest-risk NMIBC in PDD-TURBT group were either equivalent or lower compared to those in WL-TURBT group., Conclusions: The total costs associated with PDD-TURBT were higher compared to WL-TURBT, while there is the potential of PDD-TURBT to reduce the burden on healthcare economics in limited cases., (© 2023 The Japanese Urological Association.)

The first sharp diffraction peak (FSDP) in the total structure factor has long been regarded as a characteristic feature of medium-range order (MRO) in amorphous materials with a polyhedron network, and its underlying structural origin is a subject of ongoing debate. In this study, we utilized machine learning molecular dynamics (MLMD) simulations to explore the origin of FSDP in two typical high-density silica glasses: silica glass under pressure and permanently densified glass. Our MLMD simulations accurately reproduce the structural properties of high-density silica glasses observed in experiments, including changes in the FSDP intensity depending on the compression temperature. By analyzing the simulated silica glass structures, we uncover the structural origin responsible for the changes in the MRO at high density in terms of the periodicity between the ring centers and the shape of the rings. The reduction or enhancement of MRO in the high-density silica glasses can be attributed to how the rings deform under compression., (© 2023. The Author(s).)

Background/aim: In osteosarcoma, lung metastasis is a major cause of cancer-related death, as the 5-year survival rate for patients with metastases is approximately only 20-30%. To develop improved therapeutic strategies against lung-metastatic osteosarcoma, an experimental lung-tumor-implantation mouse model is needed for basic research. In the present study, we developed a precise and facile endotracheal lung-tumor-implantation technique., Materials and Methods: For establishment of the lung-tumor-implantation mouse model of metastatic osteosarcoma, 5 mice were used. A 15-mm longitudinal incision was made in the center of the neck to expose the salivary glands. The salivary glands were then split, exposing the trachea covered by the sternohyoid muscles. The trachea was then clearly exposed by cutting the sternohyoid muscles longitudinally. A 22 G gavage needle was tilted slightly toward the left side of the mouse and inserted from the oral cavity into the bronchus, with confirmation of the position of the tip of the gavage needle visualized through the tracheal wall, followed by injection of 0.5% crystal violet to first confirm the accuracy of endotracheal injection in the lung. A 143B-GFP cell suspension (2.0×10 6 cells/50 μl PBS) was then injected endotracheally in other mice., Results: The procedure, including anesthesia and suturing, took approximately 10 minutes. The left lobe of the lung, in which crystal violet was injected endotracheally, was stained in 3 out of 3 mice (100%). 143B-GFP-osteosarcoma tumors were detected with GFP fluorescence in the left lobe of the lung in 3 out of 4 mice (75%), 5 weeks after endotracheal injection. One mouse died 4 weeks after 143B-GFP-cell implantation., Conclusion: This novel technique of establishing tumors in the lung via endotracheal injection of cancer cells is precise and facile and can be used widely, since neither a surgical microscope nor X-ray imaging are needed., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The development of a novel therapy to overcome primary and acquired resistance to abiraterone is an unmet need. This study aimed to evaluate the efficacy and safety of adding 5α-reductase inhibitor dutasteride to abiraterone, explore proof of concept, and identify candidates suitable for combination therapy. This phase II, single-arm, and open-label study enrolled second-generation antiandrogen- and chemotherapy-naïve patients with castration-resistant prostate cancer. Patients received abiraterone and prednisolone for 4 weeks, followed by adding dutasteride. The primary end point was a 50% prostate-specific antigen response rate. Serum concentrations of abiraterone and its metabolites as well as HSD3B1 and SRD5A2 genotypes were measured. The association between drug metabolism and genotypes and their impact on the efficacy of combination therapy were assessed. Among 21 patients, 18 (85.7%) achieved ≥50% PSA reduction. Median time to treatment failure was not reached during the median follow-up of 15.4 months. No patients experienced grade ≥3 adverse events. Although dutasteride reduced serum 3-keto-5α-abiraterone concentrations, higher serum 3-keto-5α-abiraterone concentrations on combination therapy were associated with a shorter time to treatment failure. HSD3B1 and SRD5A2 genotypes were associated with serum Δ4-abiraterone and 3-keto-5α-abiraterone concentrations before adding dutasteride, respectively. Time to treatment failure was longer in patients with homozygous wild-type HSD3B1, but comparable between those with the SRD5A2 genotype. The promising outcomes of this study warrant further investigation of combination therapy in a randomized trial. Stratification by HSD3B1 and SRD5A2 genetic profiles might identify patients suitable for combination therapy., (© 2022 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Patient selection for transurethral resection of the bladder tumor using photodynamic diagnosis (PDD-TURBT) with oral 5-aminolevulinic acid (5-ALA) hydrochloride for non-muscle-invasive bladder cancer (NMIBC) is still unclear as to the best balance of risks (adverse events including hypotension) and benefits (reduction of intravesical recurrence)., Methods: This single-center retrospective study between April 2013 and March 2022, compared the intravesical recurrence-free survival between patients who underwent PDD-TURBT and WL-TURBT using propensity score matching., Results: A total of 222 patients who underwent PDD-TURBT and 177 patients who underwent WL-TURBT for NMIBC were included. Propensity score matching was used to compare intravesical recurrence-free survival in 119 NMIBC patients in the both treatment groups. The intravesical recurrence-free survival within 500 days was significantly higher in the PDD-TURBT group than in the WL-TURBT group (P = 0.039; hazard ratio [HR] 0.48 [0.23-0.98]). Subgroup analysis showed that PDD-TURBT contributed to the reduction of short-term intravesical recurrence in patients aged < 75 years (P = 0.02; HR 0.22 [0.06-0.79]) and primary disease (P = 0.038; HR 0.35 [0.13-0.94]). Hypotension with a systolic blood pressure of < 80 mmHg was observed in 79 patients (35.6%) during PDD-TURBT surgery. In particular, age ≥75 years and general anesthesia were independent prognostic factors for predicting intraoperative hypotension., Conclusions: PDD-TURBT reduced short-term intravesical recurrence in NMIBC, whereas a higher frequency of hypotension was found in patients aged ≥ 75 years. These results suggest that the risks and benefits of PDD-TURBT are well balanced in younger patients (< 75 years) and those with primary disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: The objective of this work is to evaluate the additional oncological benefit of photodynamic diagnosis (PDD) using blue-light cystoscopy in transurethral resection (TURBT) for primary non-muscle-invasive bladder cancer (NMIBC) based on the International Bladder Cancer Group (IBCG)-defined progression and the subsequent pathological pathways., Patients and Methods: We reviewed 1578 consecutive primary NMIBC patients undergoing white-light TURBT (WL-TURBT) or PDD-TURBT during 2006-2020. One-to-one propensity score-matching was performed using multivariable logistic regression to obtain balanced groups. IBCG-defined progression of NMIBC included stage-up and grade-up as well as conventional definitions such as the development of muscle-invasive BC or metastatic disease. Nine oncological endpoints were evaluated. Sankey diagrams were generated to visualize follow-up pathological pathways after the initial TURBT., Results: Comparison of event-free survival between the matched groups revealed that PDD use decreased the bladder cancer recurrence risk and IBCG-defined progression risk, whereas no significant difference was noted in conventionally defined progression. This was attributable to a reduced risk of stage-up, from Ta to T1, and grade-up. Sankey diagrams of the matched groups showed that patients with primary Ta low-grade tumour and first-recurrence Ta low-grade tumour did not have bladder recurrence or progression, while some of those in the WL-TURBT group developed recurrence after treatment., Conclusions: The multiple survival analysis demonstrated that the risk of IBCG-defined progression was significantly decreased by PDD use in NMIBC patients. Sankey diagrams revealed possible differences in pathological pathways after the initial TURBT between the two groups, demonstrating that repeated recurrence could be prevented by PDD use., Competing Interests: The authors disclose no potential conflicts of interest., (© 2023 The Authors. BJUI Compass published by John Wiley & Sons Ltd on behalf of BJU International Company.)

Tellurium (Te) is an industrially useful element but causes environmental contamination. The formation of biogenic Te nanorods (Te-BgNRs) in plants is one of the Te detoxification pathways associated with the phytoremediation of Te because Te-BgNRs contain low-toxicity Te at high densities. In this study, we investigated the mechanism of Te-BgNR formation in a common unicellular green alga, Chlamydomonas reinhardtii, on the basis of elemental analysis by inductively coupled plasma mass spectrometry (ICP-MS). After exposure to 1000 μM sodium tellurate (Na2TeO4) for 2 weeks, the alga accumulated 65.2 fg of Te per cell, and 55.8% of which was present in an insoluble form. Electron microscopic observations revealed that the insoluble Te was rod-shaped elemental Te, i.e. Te-BgNRs, and had a highly crystalline nanostructure. We determined the Te contents in Te-BgNRs by single-particle ICP-MS analysis and found that these nanorods were formed at tellurate exposure concentrations of 100 to 1000 μM. In contrast, soluble Te compounds were found in algal cells even at exposure concentrations lower than 100 μM. These findings suggest that the algal cells initially metabolized tellurate to form soluble Te compounds, and excess tellurate that could not be metabolized was then transformed to Te-BgNRs, which are less toxic than tellurate. Our findings provide a novel approach to Te remediation through the formation of BgNRs in C. reinhardtii., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer; however, a substantial number of patients with muscle-invasive bladder cancer are not appropriate candidates to radical cystectomy due to co-morbidities or anxiety regarding bladder preservation. Trimodal bladder-sparing therapy is an intelligent and attractive treatment option for such patients. We established a novel treatment strategy using trimodal treatment with gemcitabine and cisplatin., Methods: Patients diagnosed with muscle-invasive bladder cancer by transurethral resection of bladder tumor and who wished for bladder preservation were recruited. The regimens were gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 in day 1 and concomitant irradiation 1.8 Gy/Fr, five fractions per week. Irradiation was administered to the true pelvis up to 36 Gy and was then boosted to the entire bladder until a total of 54 Gy. Transurethral resection of bladder tumor was also performed after chemoradiotherapy to evaluate pathological response to treatment. We evaluated treatment efficacy and survival, safety of chemoradiotherapy with gemcitabine and cisplatin., Results: Thirty-eight patients were enrolled, and three patients were excluded. Pathological complete response after chemoradiotherapy was observed in 31 patients, and the 5-year bladder-intact metastasis-free survival rate was 76%. The 5-year cancer-specific and overall survival rates for chemoradiotherapy were 85 and 75%, respectively, which were not significantly different from those for radical cystectomy (73 and 71%, respectively). Grade 3/4 adverse events included neutropenia (63%), anemia (18%) and thrombocytopenia (37%); however, treatment-related deaths were not observed., Conclusions: Chemoradiotherapy using gemcitabine and cisplatin for muscle-invasive bladder cancer is effective for local cancer control and shows no significant difference in oncological prognosis compared with radical cystectomy., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Variation in the (220) lattice spacing of Si due to specimen processing for transmission electron microscopy (TEM) was experimentally evaluated by comparing the measured lattice spacings of crystalline specimens processed by crushing, mechanical polishing only, and combined mechanical and Ar ion polishing. Although distinct variation in the (220) lattice spacing between the Si specimens processed by crushing and by mechanical polishing only is not observed, the (220) lattice spacing of specimens prepared by combined mechanical and Ar ion polishing imply increasing tendency with increasing Ar ion beam irradiation time. Moreover, the (220) lattice spacing measured from the outermost region of the specimen edge tends to be approximately 3% to 5% larger than that measured from the inner region, irrespective of the processing method. These results demonstrate that differences in the processing conditions of Si specimens and in the measurement location of the Si lattice spacing can be major component of the measurement uncertainty in sub-nanometer metrology using TEM with magnification calibration by the Si lattice spacing. When attempting to apply the lattice spacing of Si as a reference with traceability to the International System of Units for TEM magnification calibration in sub-nanometer metrology, the results suggest that the effect of specimen processing on variation in the lattice spacing is not negligible., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Apalutamide-associated skin adverse events are more common in the Japanese than in the global population. However, limited clinical data have hampered further understanding. This real-world study investigated the clinical characteristics of skin adverse events in patients with advanced prostate cancer., Methods: We retrospectively reviewed 119 patient records from 16 institutions in Japan. Skin adverse events were graded according to the Common Terminology Criteria for Adverse Events (v5.0). The incidence and characteristics of skin adverse events (along with the clinical risk factors for their incidence, worsening, and recurrence) were evaluated., Results: Fifty-five patients (46.2%) experienced skin adverse events. The median times to the incidence and remission of skin adverse events were 62 and 30 days, respectively. Grade 3 skin adverse events were observed in 15 patients (12.6%). The median time from the first incidence to apalutamide interruption was significantly longer in patients with progression to grade 3 skin adverse events than in those without such a progression (8 vs. 0 days, p = 0.005). Skin adverse events were observed in 45.2% of patients who resumed apalutamide treatment (median treatment interruption time: 31.5 days). Sixteen patients (13.4%) permanently discontinued apalutamide due to skin adverse events. No significant clinical risk factors for the incidence, worsening and recurrence of apalutamide-associated skin adverse events were observed., Conclusions: Nearly half of the Japanese patients in this study experienced skin adverse events following apalutamide administration. The time to apalutamide discontinuation after the incidence of skin adverse events was positively correlated with the worsening of these events., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Radium is refocused from the viewpoint of an environmental pollutant and cancer therapy using alpha particles, where it mainly exists as a hydrated ion. We investigated the radium hydration structure and the dynamics of water molecules by extended X-ray absorption fine structure (EXAFS) spectroscopy and ab initio molecular dynamics (AIMD) simulation. The EXAFS experiment showed that the coordination number and average distance between radium ion and the oxygen atoms in the first hydration shell are 9.2 ± 1.9 and 2.87 ± 0.06 Å, respectively. They are consistent with those obtained from the AIMD simulations, 8.4 and 2.88 Å. The AIMD simulations also revealed that the water molecules in the first hydration shell of radium are less structured and more mobile than those of barium, which is an analogous element of radium. Our results indicate that radium can be more labile than barium in terms of interactions with water., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Objectives: Transurethral resection of bladder tumor with photodynamic diagnosis has been reported to result in lower residual tumor and intravesical recurrence rates in non-muscle invasive bladder cancer. We aimed to evaluate the usefulness of photodynamic diagnosis-transurethral resection of bladder tumor combined with oral 5-aminolevulinic acid hydrochloride for high-risk non-muscle invasive bladder cancer., Methods: High-risk non-muscle invasive bladder cancer patients with an initial photodynamic diagnosis-transurethral resection of bladder tumor (photodynamic diagnosis group) were prospectively registered between 2018 to 2020. High-risk non-muscle invasive bladder cancer cases with a history of initial white-light transurethral resection of bladder tumor (white-light group) were retrospectively registered. Propensity score-matching analysis was used to compare residual tumor rates, and factors that could predict residual tumors at the first transurethral resection of bladder tumor were evaluated., Results: Analyses were conducted with 177 and 306 cases in the photodynamic diagnosis and white-light groups, respectively. The residual tumor rates in the photodynamic diagnosis and white-light groups were 25.7% and 47.3%, respectively. Factor analysis for predicting residual tumors in the photodynamic diagnosis group showed that the residual tumor rate was significantly higher in cases with a current/past smoking history, multiple tumors, and pT1/pTis. When each factor was set as a risk level of 1, cases with a total risk score ≤1 showed a significantly lower residual tumor rate than cases with a total risk score ≥2 (8.3% vs 33.3%, odds ratio 5.46 [1.81-22.28])., Conclusions: In high-risk non-muscle invasive bladder cancer cases, the odds of a residual tumor after initial photodynamic diagnosis-transurethral resection of bladder tumor were 0.39-fold that of the odds of those after initial white-light transurethral resection of bladder tumor. A risk stratification model could be used to omit the second transurethral resection of bladder tumor in 27% of the cases., (© 2022 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)

Predicting materials properties of nuclear fuel compounds is a challenging task in materials science. Their thermodynamical behaviors around and above the operational temperature are essential for the design of nuclear reactors. However, they are not easy to measure, because the target temperature range is too high to perform various standard experiments safely and accurately. Moreover, theoretical methods such as first-principles calculations also suffer from the computational limitations in calculating thermodynamical properties due to their high calculation-costs and complicated electronic structures stemming from f-orbital occupations of valence electrons in actinide elements. Here, we demonstrate, for the first time, machine-learning molecular-dynamics to theoretically explore high-temperature thermodynamical properties of a nuclear fuel material, thorium dioxide. The target compound satisfies first-principles calculation accuracy because f-electron occupation coincidentally diminishes and the scheme meets sampling sufficiency because it works at the computational cost of classical molecular-dynamics levels. We prepare a set of training data using first-principles molecular dynamics with small number of atoms, which cannot directly evaluate thermodynamical properties but captures essential atomistic dynamics at the high temperature range. Then, we construct a machine-learning molecular-dynamics potential and carry out large-scale molecular-dynamics calculations. Consequently, we successfully access two kinds of thermodynamic phase transitions, namely the melting and the anomalous [Formula: see text] transition induced by large diffusions of oxygen atoms. Furthermore, we quantitatively reproduce various experimental data in the best agreement manner by selecting a density functional scheme known as SCAN. Our results suggest that the present scale-up simulation-scheme using machine-learning techniques opens up a new pathway on theoretical studies of not only nuclear fuel compounds, but also a variety of similar materials that contain both heavy and light elements, like thorium dioxide., (© 2022. The Author(s).)

Background: More than 10 years have passed since the first nationwide study on the reasons for tooth extraction in Japan. In the present study, we conducted the second nationwide survey to update the previous data., Methods: This was a descriptive study. A sample population consisting of 5,250 dentists was selected by systematic random sampling using the 2018 membership directory of the Japan Dental Association. The reason for each permanent tooth extraction was documented by each dentist during a period of 1 week from June 4 to June 10, 2018. A questionnaire was provided for documentation. Reasons for tooth extraction were categorised into 6 groups as follows: caries, periodontal disease, fracture, orthodontics, impacted teeth, and others., Results: A total of 2345 identified dentists responded to the questionnaire (recovery rate: 44.8%). Information on 7809 extracted teeth from 6398 patients was obtained. Periodontal disease was the main reason for tooth extraction for both sexes (men: 40.4%, women: 34.9%). Caries accounted for 30.2% of tooth extractions among men and 29.0% among women. Periodontal disease was predominant in the groups older than 55 years of age. Dental fracture accounted for 16.8% of tooth extractions among men and 19.2% among women., Conclusions: Caries and periodontal disease are still the main reasons for tooth extraction in Japan. Moreover, dentists should note that fractures accounted for approximately one-fifth of permanent tooth extractions after the age of 45 years., Competing Interests: Conflict of Interest None disclosed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

It is widely recognized that the toxicity of mercury (Hg) is attenuated by the simultaneous administration of selenium (Se) compounds in various organisms. In this study, we revealed the mechanisms underlying the antagonistic effect of sodium selenite (Na 2 SeO 3 ) on inorganic Hg (Hg 2+ ) toxicity in human hepatoma HepG2 cells. Observations by transmission electron microscopy indicated that HgSe (tiemannite) granules of up to 100 nm in diameter were accumulated in lysosomal-like structures in the cells. The HgSe granules were composed of a number of HgSe nanoparticles, each measuring less than 10 nm in diameter. No accumulation of HgSe nanoparticles in lysosomes was observed in the cells exposed to chemically synthesized HgSe nanoparticles. This suggests that intracellular HgSe nanoparticles were biologically generated from Na 2 SeO 3 and Hg 2+ ions transported into the cells and were not derived from HgSe nanoparticles formed in the extracellular fluid. Approximately 85% of biogenic HgSe remained in the cells at 72 h post culturing, indicating that biogenic HgSe was hardly excreted from the cells. Moreover, the cytotoxicity of Hg 2+ was ameliorated by the simultaneous exposure to Na 2 SeO 3 even before the formation of insoluble HgSe nanoparticles. Our data confirmed for the first time that HepG2 cells can circumvent the toxicity of Hg 2+ through the direct interaction of Hg 2+ with a reduced form of Se (selenide) to form HgSe nanoparticles via a Hg-Se soluble complex in the cells. Biogenic HgSe nanoparticles are considered the ultimate metabolite in the Hg detoxification process.

This report describes a validation study of data in the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) obtained by nationwide surveys on tooth extractions. The following 3 data sources on tooth extractions in Japan were compared: (1) the Nationwide Survey of the Reasons for Permanent Tooth Extractions in Japan (a previous survey conducted by the present authors); (2) the Statistics on Medical Care Activities in Public Health Insurance; and (3) the 4th NDB Open Data Japan. Source 1 was a nationwide survey conducted in 2018; sources 2 and 3 comprised data that are freely available for use by the public. In Source 1, 2,345 of 5,250 dentists approached responded to the questionnaire (recovery rate: 44.8%). The number of extracted teeth among younger age groups (aged 25-50 years) reported in Source 1 was lower than that in the other two sources. In contrast, the number of extracted teeth among older age groups reported in Source 1 was higher than that reported in the other two sources. However, when stratified by age group, all differences across the 3 sources regarding the mean annual number of tooth extractions were <0.05 teeth/year. The present results suggest that the NDB is a reliable resource for data on tooth extractions performed across the entire Japanese population.

Diabetes mellitus is closely related to oral health. We aimed to determine the relationship between diabetes mellitus and tooth extraction due to periodontal disease and dental caries. Japan's second nationwide survey data collected from 4 June to 10 June 2018 was used to identify reasons for tooth extraction among patients aged > 40 years. General dentists collected information on patients who underwent tooth extraction procedures, and the presence of diabetes mellitus was determined through interviews. Multivariable logistic regression was performed to investigate the relationship between diabetes mellitus and the reasons for tooth extraction, including periodontal disease and dental caries. In total, 2345 dentists responded to the survey (response rate 44.8%). We analyzed data on 4625 extracted teeth from 3750 patients (1815 males and 1935 females). Among patients with self-reported diabetes mellitus, 55.4% had extractions due to periodontal disease compared to 46.7% of such extractions among those without self-reported diabetes mellitus. Self-reported diabetes mellitus was significantly associated with tooth extraction due to periodontal disease. No significant differences were observed in dental caries according to self-reported diabetes mellitus status. This study provides further evidence of a significant association between diabetes mellitus and tooth extraction due to periodontal disease.

Coral microbial flora has been attracting attention because of their potential to protect corals from environmental stresses or pathogens. Although coral-associated bacteria are considered to be acquired from seawater, little is known about the relationships between microbial composition in corals and its surrounding seawater. Here, we tested several methods to identify coral-associated bacteria in coral and its surrounding seawater to detect specific types of Ruegeria species, some of which exhibit growth inhibition activities against the coral pathogen Vibrio coralliilyticus. We first isolated coral-associated bacteria from the reef-building coral Galaxea fascicularis collected at Sesoko Island, Okinawa, Japan, via random colony picking, which showed the existence of varieties of bacteria including Ruegeria species. Using newly constructed primers for colony PCR, several Ruegeria species were successfully isolated from G. fascicularis and seawater. We further investigated the seawater microbiome in association with the distance from coral reefs. By seasonal sampling, it was suggested that the seawater microbiome is more affected by seasonality than the distance from coral reefs. These methods and results may contribute to investigating and understanding the relationships between the presence of corals and microbial diversity in seawater, in addition to the efficient isolation of specific bacterial species from coral or its surrounding seawater., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Self-learning hybrid Monte Carlo (SLHMC) is a first-principles simulation that allows for exact ensemble generation on potential energy surfaces based on density functional theory. The statistical sampling can be accelerated with the assistance of smart trial moves by machine learning potentials. In the first report [Nagai et al., Phys. Rev. B 102, 041124(R) (2020)], the SLHMC approach was introduced for the simplest case of canonical sampling. We herein extend this idea to isothermal-isobaric ensembles to enable general applications for soft materials and liquids with large volume fluctuation. As a demonstration, the isothermal-isobaric SLHMC method was used to study the vibrational structure of liquid silica at temperatures close to the melting point, whereby the slow diffusive motion is beyond the time scale of first-principles molecular dynamics. It was found that the static structure factor thus computed from first-principles agrees quite well with the high-energy x-ray data.

In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Standard for Exchange of Nonclinical Data (SEND) has been adopted by the US FDA, which has required pharmaceutical companies who are developing new drugs for the US market to implement SEND. The Japan Pharmaceutical Manufacturers Association (JPMA) SEND Taskforce Team responded to this situation by starting a project to better understand the contents of SEND datasets. The project focused on domains generally included in the SEND domains for single- and repeat-dose general toxicology studies, and surveyed what kind of information are populated in which domains and in what way. The qualitative analysis of the results indicated that variations exist based on whether or not an individual variable was populated and on how the variable was populated. The Taskforce Team recommends reducing variations not only in the SEND datasets but also in the descriptions in the study protocol and/or final study report. Reduction of such variations should lead to higher quality datasets with powerful and increased searchability so that accumulated SEND datasets should become more valuable. These efforts would provide regulatory agencies with easier review of SEND datasets, which contributes to efficient development of new drug candidates., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Biosynthesis of Te nanoparticles may occur in higher plants exposed to Te, as reported on microorganisms. However, unambiguous observations of the biogenic nanoparticles (BgNPs) of Te in plants are lacking. Hence, in this study, we investigated the formation of insoluble BgNPs of Te in garlic (Allium sativum) as a model plant., Method: We performed elemental analysis based on inductively coupled plasma-mass spectrometry (ICP-MS) technique, and obtained Te concentration and distribution in various parts of garlic. In addition, insoluble Te particles were detected by fast time-resolved ICP-MS. Direct observation of the insoluble Te particle was also conducted by scanning electron microscope (SEM) and transmission electron microscope (TEM)., Results: A part of the roots and clove from Te-exposed garlic showed black coloration. Te concentrations in the black-colored parts were significantly increased compared with the non-colored parts. Transient signals of Te unique to nanoparticles were detected from the insoluble fractions of the black-colored parts. Finally, rod-shaped biogenic Te nanoparticles consisting of highly crystalline elemental Te was observed by SEM and TEM., Conclusion: Our data provide new insights to the metabolic pathway of Te in higher plants for the formation of insoluble biogenic nanoparticles, which is extremely important for the detoxification of Te., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Purpose: The aim of this study was to determine the significance of the membranous urethral length (MUL), including the thickness of the urethral sphincter, for recovery from postoperative stress urinary incontinence (SUI) following holmium laser enucleation of the prostate (HoLEP)., Methods: We analyzed 78 patients who underwent HoLEP between June 2013 and September 2018, all of whom preoperatively received magnetic resonance imaging. MUL was measured using sagittal T2-weighted fast spin-echo images. The clinical and anatomical factors associated with MUL were evaluated. The recovery time of urinary incontinence was compared between patients with a long MUL (≥14 mm) and a short MUL (<14 mm). SUI included both stress and mixed urinary incontinence. Continence was defined as complete dryness., Results: The median MUL in patients without incontinence at 1 month postoperatively was significantly longer than the MUL in patients with incontinence (15.3 mm vs. 12.7 mm, P<0.001). The continence rates at 1 month after HoLEP in patients with longer MULs and shorter MULs were 80.4% and 30.0%, respectively. The recovery time of urinary incontinence in patients with longer MULs (≥14 mm) was significantly shorter than that in patients with shorter MULs (<14 mm) (log-rank test, P=0.001). After 6 months, the continence rates in patients with longer MULs and shorter MULs were similar (97%). MUL was significantly correlated with the recovery period of urinary incontinence (r=-0.459, P<0.001)., Conclusion: MUL was useful for predicting early recovery from urinary incontinence following HoLEP. This study provides evidence that postoperative urinary incontinence following a transurethral procedure for benign prostatic hyperplasia was associated with anatomical factors. A long MUL was associated with better tolerance to urinary sphincter damage by the transurethral procedure.

Background and study aims  Magnification endoscopy with narrow-band imaging (NBIME) and NBIME with acetic acid enhancement (A-NBIME) enable visualization of the vascular and microstructural patterns of colorectal polyp. We compared the diagnostic accuracy and reproducibility of white light endoscopy (WLE), NBIME, and A-NBIME for predictive histologic diagnosis. Patients and methods  Consecutive colorectal polyps (N = 628; 38 hyperplasias, 488 adenomas, 72 M-SM1 cancers, and 30 SM2 cancers) were photographed with WLE, NBIME, and A-NBIME. Endoscopic images were independently reviewed by three experts, according to the traditional criteria for WLE, the Japan NBI Expert Team classification for NBIME, and pit pattern classification for A-NBIME to compare diagnostic accuracy and interobserver diagnostic agreement among modalities. Results  The specificity (95 % confidence interval) of hyperplasia and SM2 cancer with WLE were 98.2 % (96.8 %-99.1%) and 99.4 % (98.5 %-99.9 %), respectively, showing high accuracy for endoscopic resection without magnifying observation. Diagnostic accuracy of WLE, NBIME, and A-NBIME was 80.8 % (77.4 %-83.8 %), 79.3 % (75.9 %-82.4 %), and 86.1 % (83.2 %-88.7 %), respectively, showing the highest accuracy for A-NBIME among modalities ( P  < .05). NBIME showed a lower PPV for M-SM1 cancer ( P  < .05), as with WLE ( P  = .08) compared to A-NBIME. Fleiss's kappa values for WLE, NBIME, and A-NBIME diagnosis were 0.43 (0.39 - 0.46), 0.52 (0.49 - 0.56) and 0.65 (0.62 - 0.69), respectively, showing insufficient reproducibility of WLE and superiority of A-NBIME among modalities. Conclusion  WLE showed high accuracy for endoscopic resection of colorectal polyps in expert diagnosis. NBIME demonstrated a higher diagnostic reproducibility than WLE. A-NBIME showed possible superiority among modalities in both diagnostic accuracy and reproducibility., Competing Interests: Competing interests The authors declare that they have no conflict of interest.

Background: Electroconvulsive therapy (ECT) is indicated for critical psychiatric conditions, which themselves constitute a risk for deep venous thrombosis (DVT) owing to prolonged immobility, dehydration, and venous stasis., Objective: We describe challenging instances of ECT implementation while taking direct oral anticoagulants (DOACs)., Method: We report on 8 patients receiving DOACs for DVT who were successfully treated with ECT at the University of Yamanashi Hospital. We also provide a literature review on this topic., Results: There were 6 female patients (the average age was 60.9+/-13.4 y.o.) and diagnoses included major depression, bipolar depression and schizophrenia. DOACs were edoxaban for 4 patients, rivaroxaban for 2, and apixaban for 2. A total of 92 ECT sessions were cautiously and safely completed in collaboration with multidisciplinary medical professionals without problematic adverse events, such as bleeding. A literature search found one case series of warfarin but currently available evidence is confined to sporadic case reports regarding ECT and DOACs for DVT. These reports were represented by successful implementation of ECT to patients receiving treatment with anticoagulants for DVT or thromboembolism. Ours is the first of a successful treatment with ECT while taking apixaban or edoxaban., Conclusion: A clinical dilemma is that ECT is indicated for critical conditions that are likely to predispose patients to developing DVT. Paucity of data clearly highlights the need for more studies to support a contention that ECT, when carefully performed in consultation with other medical experts, is a viable treatment for those with DVT receiving oral anticoagulants., (Copyright © 2018 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Oral healthcare systems (OHCS) are designed to maintain the health and function through Communication (Health promotion and education), Prevention, Assessment and Diagnosis, and Treatment. The complexity of these OHCS functions for the ageing are described utilizing the spectrum of dependency of the Seattle Care Pathway framework. Barriers and disparities which challenge the development of OHCS for the ageing can be universal but often vary between developed and developing countries. Recognizing that oral diseases are largely preventable, strategies to improve OHCS must be targeted locally, nationally, and internationally at oral health policy, education, research, and clinical care., (© 2017 FDI World Dental Federation.)

Objective: T1 high-grade bladder cancer has a poor prognosis compared with other non-muscle-invasive bladder cancers. We investigated the clinical outcomes among patients with T1 high-grade bladder cancer to identify factors related to cancer recurrence and disease progression., Methods: We retrospectively reviewed the data of 148 patients who were diagnosed with T1 high-grade bladder cancer by transurethral resection from January 2001 to February 2015 at our institution. Clinicopathological factors were analyzed using univariate and multivariate analyses., Results: The median age and follow-up duration were 72 years and 45.4 months, respectively. Sixty-two patients (41.9%) had recurrence, 28 (18.9%) experienced progression and 13 (8.8%) died of bladder cancer. In the multivariate analysis, divergent differentiation was an independent factor related to recurrence (P = 0.0096, hazard ratio = 2.5), whereas a non-papillary tumor shape, divergent differentiation and presence of a residual tumor at the time of the second transurethral resection were independent factors related to progression (P = 0.0349, hazard ratio = 3.8; P = 0.0074, hazard ratio = 6.8 and P = 0.0449, hazard ratio = 4.1, respectively). There were no independent factors related to cancer-specific mortality. Divergent differentiation was the only independent factor associated with both recurrence and progression. In addition, patients with divergent differentiation had significantly worse recurrence-free survival and progression-free survival rates than did patients without divergent differentiation (log-rank P = 0.0009 and P = 0.0019, respectively)., Conclusions: In this study, the presence of divergent differentiation was related to worse oncological outcomes in patients with T1 high-grade bladder cancer. Patients with divergent differentiation may require stringent follow-up and early cystectomy after recurrence to improve oncological outcomes., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Introduction: Open radical cystectomy (ORC) is currently the standard treatment for muscle-invasive bladder cancer (MIBC) without metastasis, while many patients with MIBC are not always appropriate candidates due to multiple comorbidities. To evaluate the bladder-preservation strategy, we compared the results with those obtained by ORC., Patients and Methods: We retrospectively analyzed the data of 50 patients with MIBC treated by trimodal chemoradiotherapy with cisplatin (CDDP-radiation [CDDP-R]). Transurethral resection of the bladder tumor (TURBT) was performed before treatment to confirm pathological stage ≥T2. Extensive TURBT was performed after chemoradiotherapy to evaluate the pathological response to treatment. We compared the survival outcomes of our CDDP-R with those of ORC (retrospective cohort, n = 205) by propensity score matching analysis., Results: The 2- and 5-year progression-free survival, bladder-intact survival, cancer-specific survival, and overall survival (OS) rates after treatment were 70.8 and 63.9%, 64.0 and 49.8%, 86.7 and 71.8%, and 84.3 and 64.8%, respectively. The 2- and 5-year OS rates after CDDP-R were 90.5 and 74.3%, respectively, and those after ORC were 71.8 and 59.9%, respectively, indicating a significant survival advantage conferred by CDDP-R over ORC (p < 0.05, HR 0.45, 95% CI 0.21-0.94)., Conclusions: In selected patients, CDDP-R for MIBC may provide comparative oncological outcomes as ORC., (© 2017 S. Karger AG, Basel.)

Objectives: To investigate the expression levels of E-cadherin, Snail, Twist and Bmi-1 in the human upper tract urothelial carcinoma, and to assess whether these factors could be prognostic markers., Methods: Immunohistochemistry was carried out to determine the expression of E-cadherin, Snail, Twist and Bmi-1 in upper tract urothelial carcinoma samples from 144 patients that underwent total nephroureterectomy between January 1995 and December 2010. The patient population had a median age of 71 years, and comprised 104 men and 40 women, with a median follow-up period of 40 months. The prognostic value of these markers was assessed by univariate and multivariate analysis. A risk stratification analysis was carried out., Results: Snail and Bmi-1 expression predicted worse overall survival (P = 0.0075 and 0.0035), cancer-specific survival (P = 0.0919 and 0.0085) and recurrence-free survival (P = 0.0360 and 0.0817, respectively) compared with tumors that lacked Snail and Bmi-1 expression. Additionally, clinical parameters, grade, stage and lymphovascular invasion correlated with overall survival, cancer-specific survival and recurrence-free survival. Multivariate analysis showed that Bmi-1 expression was among the most significant factors in predicting cancer-specific survival (P = 0.0333). The combination of Snail, Bmi-1 and pathological stage was the most useful prognostic biomarker for upper tract urothelial carcinoma., Conclusion: Risk stratification by epithelial-mesenchymal transition and cancer stem cell-regulated genes, such as Snail and Bmi-1, might be useful prognostic markers for upper tract urothelial carcinoma., (© 2016 The Japanese Urological Association.)

CD44, a major surface receptor for hyaluronic acid, has multiple isoforms and represents a major cancer stem cell marker for various epithelial tumors. CD44 variant 9 (CD44v9) was correlated with recurrence and metastasis in gastric and colon cancer. We examined its role in invasion and as a biomarker for the basal muscle invasive molecular subtype showing worse prognosis, and for tumor progression in high risk (pT1/high grade) non‑muscle invasive bladder cancers (NMIBCs). CD44v9, cytokeratin 5/6 (CK5/6), and cytokeratin 20 (CK20) expression was evaluated by immunohistochemistry in 98 pathologically confirmed specimens (36 muscle and 62 high‑risk non‑muscle) and correlated to clinical outcome. In vitro analysis was performed using two human bladder cancer cell lines (HT1376 and 5637). The CD44v9 high‑expressing group exhibited significantly lower progression‑free and cancer‑specific survival rates in both muscle (P=0.0349 and 0.0382, respectively) and non‑muscle (P=0.0002 and 0.0079) invasive patients. CD44v9 expression was significantly correlated with CK5/6 (P<0.001), colocalizing at the muscle invasion front but distinctly separated from CK20 in non‑muscle invasion. CD44 and CD44v9 siRNA knockdown demonstrated significantly lower Matrigel invasion ability and significantly shorter migration distance (all P<0.01). CD44 and CD44v9 knockdown increased E‑cadherin and decreased N‑cadherin, snail, and slug epithelial‑mesenchymal transition marker protein expression. Thus, higher CD44v9 expression was associated with worse prognosis, likely impacting invasion and migration via the epithelial‑mesenchymal transition. Together, these findings suggest that CD44v9 expression might be a useful predictive biomarker in basal‑type muscle and high-risk NMIBC.

Objective: To date, there are few reliable markers to distinguish tumors with aggressive characteristics in upper tract urothelial carcinoma. The purpose of this study was to identify a biomarker related to genetic instability (chromosomal instability or microsatellite instability) with prognostic value, in patients with upper tract urothelial carcinoma., Methods: Expression of chromosomal instability-related markers (BUBR1, p53, polo-like kinase 1) and microsatellite instability-related markers (mismatch repair proteins, MLH1 and MSH2) were assessed by immunohistochemistry in 100 patients who had radical nephroureterectomy for upper tract urothelial carcinoma. Numerical aberrations of chromosomes 7, 9 and 17 were evaluated by fluorescence in situ hybridization, which allowed an estimation of the degree of chromosomal instability. BUB1B copy number was examined by array-based comparative genomic hybridization in 32 patients with upper tract urothelial carcinoma., Results: BUBR1 status was most significantly correlated with chromosomal instability-related and low mismatch repair parameters, according to the molecular biomarkers examined. Overexpression of BUBR1 is frequently detected in tumors with higher histological grade (P < 0.0001) and is significantly associated with chromosomal instability (P = 0.0071). Array-based comparative genomic hybridization revealed that no tumors (0%) showed BUB1B amplification and gain, indicating that overexpression of BUBR1 was independent of BUB1B copy number. For disease-specific survival, BUBR1 overexpression, lymphovascular invasion, pathological tumor stage, pathological lymph node involvement and low MSH2 expression were significant prognostic factors in univariate analyses. In multivariate analyses, BUBR1 overexpression was an independent prognostic factor for disease-specific survival (P = 0.0483, risk ratio 3.76, 95% confidence interval: 1.01-18.43)., Conclusions: BUBR1 may have significant potential as a biomarker for estimating disease-specific survival in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Cisplatin-based chemotherapy has been commonly used as the first-line chemotherapy for metastatic urothelial carcinoma. However, after failure of the first-line cisplatin-based chemotherapy, there is no established standard second-line chemotherapy. Starting in 2006, paclitaxel, ifosfamide and nedaplatin chemotherapy has been performed as the second-line chemotherapy in our institution. Here, we report the treatment results of paclitaxel, ifosfamide and nedaplatin chemotherapy., Methods: From 2006 to 2015, 33 patients with metastatic urothelial carcinoma were treated with paclitaxel, ifosfamide and nedaplatin chemotherapy after failure of first-line cisplatin-based chemotherapy in our institution. We retrospectively examined the treatment outcome and predictive factors for therapeutic effects of paclitaxel, ifosfamide and nedaplatin. The median age, treatment cycle and follow-up period were 62.5 years, 3 cycles and 10.4 months, respectively., Results: The median overall survival and progression-free survival were 10.4 and 3.5 months, respectively. Complete and partial responses were found in 3 and 7 patients, respectively, with an overall response rate of 30%. All patients developed grade 3-4 neutropenia, but there was no treatment-related death. In multivariate analysis, the only prognostic factor for progression-free survival was 24-hour urinary creatinine clearance., Conclusions: A paclitaxel, ifosfamide and nedaplatin regimen as second-line chemotherapy for metastatic urothelial carcinoma was effective and tolerable. Moreover, paclitaxel, ifosfamide and nedaplatin chemotherapy may be more effective in patients with satisfactory renal function., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Study Aims: Magnification endoscopy with narrow-band imaging (NBIME) and NBIME with acetic acid enhancement (A-NBIME) visualize the capillary and microstructure patterns of the gastric mucosal surface, respectively. This study aimed to compare the diagnostic accuracy and interobserver agreement for white-light endoscopy (WLE), NBIME, and A-NBIME in the different histologic types of gastric mucosal neoplasm., Patients and Methods: Consecutive gastric neoplasms (n = 220; 49 adenomas, 144 differentiated adenocarcinomas, and 27 undifferentiated adenocarcinomas) were photographed with WLE, NBIME, and A-NBIME. Macroscopic patterns using WLE, capillary patterns using NBIME, and microstructure patterns using A-NBIME were respectively classified into type M1/M2/M3, type C1/C2/C3/C4, and type S1/S2/S3, as the indicators of adenoma, differentiated adenocarcinoma, and undifferentiated adenocarcinoma (Type C4, unevaluable because of capillary invisibility), according to the previously reported classifications. Endoscopic images were independently reviewed by three experts and three non-experts. Diagnostic accuracy and interobserver diagnostic agreement were compared among the modalities., Results: Kappa values (95 % confidence interval [CI]) for WLE, NBIME, and A-NBIME diagnosis were 0.36 (0.33 - 0.39), 0.58 (0.54 - 0.61), and 0.62 (0.55 - 0.68) for experts and 0.31 (0.29 - 0.33), 0.36 (0.34 - 0.38), and 0.52 (0.48 - 0.56) for non-experts, showing good reproducibility of A-NBIME diagnosis regardless of proficiency. All experts and non-experts diagnosed the histologic types statistically more accurately with A-NBIME than with WLE and NBIME (P < 0.05). Overall the "experts-agreed" diagnostic accuracy (95 %CI) was 75.5 % (70.0 - 81.0) for WLE vs. 74.1 % (67.6 - 80.6) for NBIME vs. 90.5 % (86.7 - 94.1) for A-NBIME (P < 0.05). WLE and NBIME were insufficient to predict the diagnosis of adenomas and undifferentiated adenocarcinomas., Conclusion: A-NBIME showed statistically significantly higher diagnostic accuracy for gastric mucosal neoplasms, with good reproducibility, compared with WLE and NBIME, which provided similar lower accuracy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and Goals: Pit pattern (PP) analysis of colorectal neoplasms using magnification chromoendoscopy with crystal violet (CV-MCE) is useful for predicting histologic features, but it is time consuming. Capillary pattern analysis by magnification endoscopy with narrow-band imaging (NBIME) is a useful and simpler procedure, but its diagnostic accuracy may be inferior to CV-MCE. NBIME with acetic acid enhancement (A-NBIME) is effective for rapid visualization of gastric mucosal microstructures. We performed a prospective study to compare the diagnostic reliability and feasibility of A-NBIME and CV-MCE in PP diagnosis of colorectal neoplasms., Study: The present study consisted of 3 protocols: Study-1 assessed 56 colorectal lesions photographed with A-NBIME and CV-MCE, and the endoscopic images were reviewed by 3 experts to compare the diagnostic concordance; study-2 assessed 202 colorectal lesions photographed with A-NBIME in 116 consecutive patients and the correlation between PP and histologic findings; study-3 randomly allocated 100 patients with colorectal lesions equally to A-NBIME and CV-MCE, and compared the procedure time and visible ratio of PP., Results: The κ value for interobserver agreement for A-NBIME and CV-MCE was 0.71 (0.66 to 0.75) and 0.80 (0.75 to 0.85), respectively. Intraobserver agreement between modalities for each reviewer was 0.79 (0.70 to 0.88), 0.80 (0.71 to 0.90), and 0.74 (0.67 to 0.82). Non-neoplastic polyps and massively invasive submucosal adenocarcinomas were statistically related to type II and type VI-H/VN. The procedure time was statistically shorter with A-NBIME than with CV-MCE (31 vs. 81 s), and the visible ratio of PP was equivalent (98.9% vs. 98.3%)., Conclusions: A-NBIME is comparable with CV-MCE in PP diagnosis of colorectal neoplasms and is a simpler technique.

We constructed a regulation system for DNA secondary structure formation of G-rich sequences using a designed PNA peptide exhibiting an on-to-off switching functionality, depending on the protease activity. This study introduces the new concept of a simple and powerful system for regulating quadruplex-related important biological events.

To investigate the adrenal toxicity of a novel inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase, compound X (CX), histopathological examinations, fat staining, adrenal cholesterol measurement, blood biochemistry, plasma corticosterone and ACTH measurement, ACTH-stimulation assay, and adrenal gene-expression analyses were done in rats in repeated-dose studies (experiment 1: 0, 3, 10, 30 and 150mg/kg for 4, 8, 15 and 28 days; experiment 2: 0, 3, 10,30 and 150mg/kg for 28 days; experiment 3: 0, 10, 30, 100 and 300mg/kg for 28 days). CX induced morphologic changes such as vacuolation and hypertrophy in the zona fasciculata (ZF) at ≥10mg/kg, and eosinophilic changes in the ZF at 150mg/kg. Vacuolation decreased in a dose-dependent manner and was replaced by eosinophilic changes. Inflammatory and fibrous changes were observed at ≥30mg/kg. These changes were expressed at early stages of dosing and were not exacerbated by extension of the administration period. Oil-red-O/Filipin staining showed depletion of cholesterol ester in dose-dependent manner and enabled adrenal cholesterol measurement. Filipin staining also revealed vacuoles to be composed of cholesterol esters. No significant changes were observed during the dosing period of CX for plasma corticosterone and ACTH levels. Gene-expression analyses showed up-regulation of Star and Abca1 mRNA levels at 300mg/kg. In conclusion, CX induced adrenal toxicity, but CX did not influence adrenocortical functions, and exacerbation of adrenal toxicities by extension of the administration period was not observed. Up-regulation of genes related to the transport of FC, such as Star and Abca1, were observed in CX groups, and these genes may be involved in the maintenance of adrenal structure and function in rats given CX., (Copyright © 2013 Elsevier GmbH. All rights reserved.)