Real-world prostate-specific antigen response and progression to castration-resistant prostate cancer among men with metastatic castration-sensitive prostate cancer treated with apalutamide: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

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.

Comparative assessment of disease recurrence after transurethral resection of non-muscle-invasive bladder cancer with and without a photodynamic diagnosis using 5-aminolevulinic acid: a propensity score-matching analysis.

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.

Differences in oncological benefits from second transurethral resection between white-light initial surgery and photodynamic diagnosis-guided initial surgery for primary high-risk non-muscle invasive bladder cancer.

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.

Photodynamic diagnosis-assisted transurethral resection of bladder tumor for high-risk non-muscle invasive bladder cancer improves intravesical recurrence-free survival (BRIGHT study).

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.

Impact on Japanese healthcare economics of photodynamic diagnosis-assisted transurethral resection of bladder tumor for non-muscle invasive bladder cancer: A multicenter retrospective cohort study.

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.

The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle-invasive bladder cancer: a single-arm phase II study.

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.

Real-world analysis of apalutamide-associated skin adverse events in Japanese patients with advanced prostate cancer: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

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.

Bladder cancer prospective cohort study on high-risk non-muscle invasive bladder cancer after photodynamic diagnosis-assisted transurethral resection of the bladder tumor (BRIGHT study).

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.

Serotonin neurons in the median raphe nucleus bidirectionally regulate somatic signs of nicotine withdrawal in mice.

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.

Formation Mechanism and Toxicological Significance of Biogenic Mercury Selenide Nanoparticles in Human Hepatoma HepG2 Cells.

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 (Na2SeO3) on inorganic Hg (Hg2+) 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 Na2SeO3 and Hg2+ 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 Hg2+ was ameliorated by the simultaneous exposure to Na2SeO3 even before the formation of insoluble HgSe nanoparticles. Our data confirmed for the first time that HepG2 cells can circumvent the toxicity of Hg2+ through the direct interaction of Hg2+ 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.

Self-learning hybrid Monte Carlo method for isothermal-isobaric ensemble: Application to liquid silica.

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.

Qualitative analysis of actual Standard for Exchange of Nonclinical Data (SEND) datasets for Data Domains: Proposition from Japan Pharmaceutical Manufacturers Association SEND Taskforce Team on standardization of nonclinical data.

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.

A Validation Study of the National Database of Health Insurance Claims and Specific Health Checkups of Japan Regarding the Annual Number of Tooth Extractions Performed Across the Entire Japanese Population.

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.

Electroconvulsive Therapy While Receiving OralAnticoagulation for Deep Venous Thrombosis:Report on Eight Cases and a Review of theLiterature.

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.

Impact of divergent differentiation in urothelial carcinoma on oncological outcome in patients with T1 high-grade bladder cancer.

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 Efficacy of Trimodal Chemoradiotherapy with Cisplatin as a Bladder-Preserving Strategy for the Treatment of Muscle-Invasive Bladder Cancer.

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.

Diagnostic accuracy of magnification endoscopy with acetic acid enhancement and narrow-band imaging in gastric mucosal neoplasms.

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.

Clinical significance of a second-line chemotherapy regimen with paclitaxel, ifosfamide and nedaplatin for metastatic urothelial carcinoma after failure of cisplatin-based chemotherapy.

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.

BUBR1 overexpression predicts disease-specific survival after nephroureterectomy in patients with upper tract urothelial carcinoma.

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.

Risk stratification using Bmi-1 and Snail expression is a useful prognostic tool for patients with upper tract urothelial carcinoma.

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.