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Abstract Real-world data on health-related quality of life (HRQoL) in advanced urothelial carcinoma (aUC) receiving immune checkpoint inhibitors (ICIs) are limited. This study included 42 patients with aUC who received second-line or later pembrolizumab (n = 19), maintenance avelumab followed by first-line chemotherapy (n = 13), or adjuvant nivolumab after radical surgery (n = 10). Time-course changes in the domains and scales related to HRQoL were evaluated using the EORTC QLQ-C30, FACT-G, and SF-8 questionnaires during ICI therapy. Anchor-based approaches for minimally important differences were determined as ‘improved’, ‘stable’, and ‘deteriorated’. We found significant improvements after the start of pembrolizumab treatment on many scales. Almost none of the scales changed significantly in the avelumab and nivolumab groups. Approximately 80% of the pembrolizumab group had deteriorated social/family well-being in FACT-G. Approximately 60% of the patients in the avelumab group had deteriorated general health and vitality in SF-8. In the nivolumab group, none of the scales deteriorated in > 50% of the patients. Deterioration of physical function in the SF-8 was associated with occurrence of treatment-related adverse events ≥ grade 2 during ICI therapy (P = 0.013). Our findings demonstrated that majority of patients with aUC who received ICI therapy had a stable HRQoL, which was consistent with evidence from clinical trials.

Abstract Objective The objective of this study is to validate the predictive ability of the 2021 European Association of Urology (EAU) risk model compared to that of existing risk models, including the 2019 EAU model and risk scoring tables of the European Organization for Research and Treatment of Cancer, Club Urologico Espanol de Tratamiento Oncologico, and Japanese Nishinihon Uro‐oncology Extensive Collaboration Group. Patients and methods This retrospective multi‐institutional database study included two cohorts—3024 patients receiving intravesical bacillus Calmette–Guerin (BCG) treatment (BCG cohort) and 789 patients not receiving BCG treatment (non‐BCG cohort). The Kaplan–Meier estimate and log‐rank test were used to visualize and compare oncological survival outcomes after transurethral surgery among the risk groups. Harrell's concordance index (C‐index) was used to evaluate the predictive ability of the models. Results We observed a risk shift from the 2019 EAU risk grouping to the 2021 EAU risk grouping in a substantial number of patients. For progression, the C‐index of the 2021 EAU model was significantly higher than that of the 2019 EAU model in both the BCG (0.617 vs. 0.572; P = 0.011) and non‐BCG (0.718 vs. 0.560; P

Unresectable, metastatic, advanced urothelial carcinoma (aUC) is an aggressive disease and is treated with platinum-containing first-line chemotherapy, followed by immune checkpoint inhibitors and antibody–drug conjugates. Response to first-line chemotherapy is a vital priority in sequential treatment strategies because a better response to first-line chemotherapy is associated with a better response to subsequent therapies. Gemcitabine plus carboplatin chemotherapy is conventionally recommended for cisplatin-ineligible patients. This multicenter, single-arm prospective trial will investigate whether dose-dense methotrexate, vinblastine, doxorubicin, and carboplatin (DD-MVACarbo) chemotherapy is superior to gemcitabine plus carboplatin chemotherapy in terms of efficacy in platinum-naïve, cisplatin-ineligible patients with aUC. After screening and registration, a total of 46 patients will be treated with this novel chemotherapy regimen. The primary endpoint is the objective response rate. The secondary endpoints include disease control rate, patient-reported outcomes, and adverse events. No evidence of this novel intervention is available as of July 2024. The results are expected to change the standard of care and improve the management of patients with aUC.

Background. Photodynamic diagnosis-assisted transurethral resection of bladder tumors (PDD-TURBT) enhances detection of elusive lesions compared to standard white light-transurethral resection of bladder tumors (WL-TURBT). If minimal light exposure during PDD-TURBT induces the accumulation of reactive oxygen species (ROS), potentially resulting in phototoxicity in small lesions, apoptosis may be triggered in residual small tumors, allowing them to escape resection. We investigated the hypothesis of a potential photodynamic therapeutic effect during PDD-TURBT. Methods and Materials. Our study, conducted between January 2016 and December 2020 at Nara Medical University Hospital, focused on a specific emphasis on ROS production. Immunohistochemical analysis for thymidine glycol and Nε-hexanoyl-lysine was performed on 69 patients who underwent 5-aminolevulinic acid-mediated PDD-TURBT and 28 patients who underwent WL-TURBT. Additionally, we incrementally applied the minimal irradiation energy to T24 and UM-UC-3 cells treated with 5-aminolevulinic acid using instruments similar to those used in PDD-TURBT and evaluated intracellular ROS production and phototoxicity. Results. Immunohistochemical analysis revealed a significant increase in production of thymidine glycol and Nε-hexanoyl-lysine within the PDD-TURBT group. In T24 and UM-UC-3 cells treated with 5-aminolevulinic acid and light exposure, immunofluorescent staining demonstrated a dose-dependent increase in intracellular ROS production. In addition, higher irradiation energy levels were associated with a greater increase in ROS production and phototoxicity, as well as more significant decrease in mitochondrial membrane potential. Conclusion. Although the irradiation energy used in PDD-TURBT did not reach the levels commonly used in photodynamic therapy, our findings support the presence of a potential cytotoxic effect on bladder lesions during PDD-TURBT.

Background. Although routine surveillance imaging to examine upper urinary tract urothelial cancer recurrence during follow-up of nonmuscle invasive bladder cancer is recommended, its necessity remains invalidated. A single-institute long-term follow-up cohort study to evaluate the clinical impact of routine surveillance imaging and identify risk factors for upper urinary tract urothelial cancer recurrence after nonmuscle invasive bladder cancer treatment was conducted. Methods and Materials. A retrospective chart review of 864 patients with primary nonmuscle invasive bladder cancer who underwent initial transurethral resection of bladder tumor between 1980 and 2020 was conducted. The opportunities to diagnose its recurrence were examined. Moreover, oncological outcomes included upper urinary tract urothelial cancer recurrence-free survival and overall survival. Results. Of 864 patients, 19 (2.2%) experienced upper urinary tract urothelial cancer recurrence. Among 19 patients, recurrence was detected through routine imaging in 12 (63.2%), cystoscopy in 2 (10.5%), urine cytology in 2 (10.5%), and presence of gross hematuria in 1 (5.3%). All patients had high- or highest-risk NMIBC at diagnosis of primary nonmuscle invasive bladder cancer. On multivariate Fine-Gray proportional regression analyses, a tumor size of ≥30 mm and carcinoma in situ were independently associated with short upper urinary tract urothelial cancer recurrence-free survival (P=0.040 and 0.0089, respectively). Conclusion. Most patients experiencing upper urinary tract urothelial cancer recurrence were diagnosed by routine surveillance imaging, suggesting its clinical importance, especially for patients with nonmuscle invasive bladder cancer accompanied by a tumor size of ≥30 mm and carcinoma in situ.

Enfortumab vedotin (EV), a nectin-4-directed antibody conjugated to monomethyl auristatin E (MMAE), has been approved for patients with advanced urothelial carcinoma (aUC) previously treated with platinum-based chemotherapy and immune inhibitors. Taxane agents and MMAE share antitumor mechanisms through microtubule disruption, thus raising a notable concern regarding cross-resistance between these drugs. This case report describes two patients with taxane-based chemotherapy-refractory aUC who responded well to EV. A 71-year-old man (case 1) with pT3N0M0 renal pelvic UC showed a partial response to EV in metastatic lesions of the bilateral lungs and right pelvic lymph nodes after three cycles of paclitaxel plus gemcitabine chemotherapy. A 53-year-old man (case 2) with cT3bN2M0 bladder UC underwent platinum-based neoadjuvant chemotherapy and the following radial cystectomy (ypTis ypN0). He developed bilateral lung metastases and showed a complete response to EV in the metastatic lesions after 20 cycles of paclitaxel plus nedaplatin chemotherapy. Our experience of two cases demonstrated that tumor response to EV can be expected in patients with taxane-refractory aUC.

Abstract Background Tenascin-C (TN-C) is an extracellular matrix glycoprotein related to tissue inflammation. Our previous retrospective study conducted in 2016 revealed that the serum tenascin-C level was higher in patients with Kawasaki disease (KD) who were resistant to intravenous immunoglobulin (IVIG) and developed coronary artery lesions (CALs). The present study is a prospective cohort study to assess if the serum level of tenascin-C could be used as a novel biomarker to predict the risk of resistance to initial treatment for high-risk patients. Methods A total of 380 KD patients were registered and provided serum samples for tenascin-C measurement before commencing their initial treatment. Patients who did not meet the inclusion criteria were excluded from analysis; of the 181 remaining subjects, there were 144 low-risk patients (Kobayashi score: ≤4 points) and 37 high-risk patients (Kobayashi score: ≥5 points). The initial treatments for low-risk patients and high-risk patients were conventional therapy (IVIG with aspirin) and prednisolone combination therapy, respectively. The patient clinical and laboratory data, including the serum tenascin-C level, were compared between initial treatment responders and non-responders. Results In the low-risk patients, there was no significant difference in the median levels of serum tenascin-C between the initial therapy responders and non-responders. However, in the high-risk patients, the median serum tenascin-C level in initial therapy non-responders was significantly higher than that in initial therapy responders (175.8 ng/ml vs 117.6 ng/ml). Conclusions Serum tenascin-C could be a biomarker for predicting the risk of high-risk patients being non-responsive to steroid combination therapy. Trial registration This study was a prospective cohort study. It was approved by the ethics committee of each institute and performed in accordance with the Declaration of Helsinki.

Abstract Background To explore possible solutions to overcome chronic Bacillus Calmette–Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG). Methods This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000–2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven−/eight-dose iBCG (Group C), 60 (2.2%) received seven−/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan–Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed. Results RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P

Abstract Background Abnormalities in the number of vessels can be found for both the umbilical artery and vein. We sometimes encounter cases of a decreased number of umbilical cord vessels, such as a single umbilical artery. In contrast, there may be an increase from three to four vessels within the umbilical cord. A supernumerary umbilical vein is particularly very rare, and it is generally found in combination with congenital anomalies. We report a case of a partial supernumerary umbilical vein. Case presentation The previous pregnancy of a 37-year-old healthy Japanese woman (gravida 2, para 1) had been uncomplicated, and the resulting child was alive and well. Prenatal examination at 36 weeks of gestation revealed the coexistence of a four-vessel part and a normal three-vessel part of the umbilical cord. A healthy female neonate weighing 2726 g was born at 38 weeks of gestation. The umbilical cord measured 40 cm in length; the four-vessel part continued to a distance of 18 cm from the surface of the infant’s body, and the remaining umbilical cord comprised three vessels. On histological examination, the fetal side of the umbilical cord had two arteries and two veins, and the placental side had two arteries and one vein. Isolated supernumerary umbilical veins tend to be overlooked. We consider that it is important to evaluate the number of umbilical cord vessels in the second trimester using ultrasound combined with color Doppler in at least three sites: the insertion sites on both the fetal abdomen and placenta, and the free loop of the umbilical cord. Conclusions Prenatal diagnosis of isolated supernumerary umbilical cord vessels tends to be overlooked. However, supernumerary vessels of the umbilical can be associated with fetal congenital anomalies. The number of vessels within the umbilical cord must be examined because the detection of such abnormalities may lead to the prenatal diagnosis of other congenital anomalies.

MazF is an endoribonucleolytic toxin that cleaves intracellular RNAs in sequence-specific manners. It is liberated in bacterial cells in response to environmental changes and is suggested to contribute to bacterial survival by inducing translational regulation. Thus, determining the cleavage specificity provides insights into the physiological functions of MazF orthologues. Nitrospira, detected in a wide range of environments, is thought to have evolved the ability to cope with their surroundings. To investigate the molecular mechanism of its environmental adaption, a MazF module from Nitrospira strain ND1, which was isolated from the activated sludge of a wastewater treatment plant, is examined in this study. By combining a massive parallel sequencing method and fluorometric assay, we detected that this functional RNA-cleaving toxin specifically recognizes the AACU, AACG, and AAUU motifs. Additionally, statistical analysis suggested that this enzyme regulates various specific functions in order to resist environmental stresses.

The recent eighth tumor-node-metastasis (TMN) staging system classifies renal cell carcinoma (RCC) with perirenal fat invasion (PFI), renal sinus fat invasion (SFI), or renal vein invasion (RVI) as stage pT3a. However, limited data are available on whether these sites have similar prognostic value or recurrence rate. We investigated the recurrence rate based on tumor size, pathological invasion sites including urinary collecting system invasion (UCSI), and clinically detected renal vein thrombus (cd-RVT) with pT3aN0M0 RCC. We retrospectively reviewed 91 patients with pT3aN0M0 RCC who underwent surgical treatment. Patients with tumor size > 7 cm, UCSI, three invasive sites (PFI + SFI + RVI), and cd-RVT showed a significant correlation with high recurrence rates (hazard ration (HR) 2.98, p = 0.013; HR 8.86, p < 0.0001; HR 14.28, p = 0.0008; and HR 4.08, p = 0.0074, respectively). In the multivariate analysis, tumor size of >7 cm, the presence of UCSI, and cd-RVT were the independent predictors of recurrence (HR 3.39, p = 0.043, HR 7.31, p = 0.01, HR 5.06, p = 0.018, respectively). In pT3a RCC, tumor size (7 cm cut-off), UCSI, and cd-RVT may help to provide an early diagnosis of recurrence.

Toxin-antitoxin (TA) systems are implicated in prokaryotic stress adaptation. Previously, bioinformatics analysis predicted that such systems are abundant in some slowly growing chemolithotrophs; e.g., Nitrosomonas europaea. Nevertheless, the molecular functions of these stress-response modules remain largely unclear, limiting insight regarding their physiological roles. Herein, we show that one of the putative MazF family members, encoded at the ALW85_RS04820 locus, constitutes a functional toxin that engenders a TA pair with its cognate MazE antitoxin. The coordinate application of a specialised RNA-Seq and a fluorescence quenching technique clarified that a unique triplet, UGG, serves as the determinant for MazF cleavage. Notably, statistical analysis predicted that two transcripts, which are unique in the autotroph, comprise the prime targets of the MazF endoribonuclease: hydroxylamine dehydrogenase (hao), which is essential for ammonia oxidation, and a large subunit of ribulose 1,5-bisphosphate carboxylase/oxygenase (rbcL), which plays an important role in carbon assimilation. Given that N. europaea obtains energy and reductants via ammonia oxidation and the carbon for its growth from carbon dioxide, the chemolithotroph might use the MazF endoribonuclease to modulate its translation profile and subsequent biochemical reactions.

Hepatitis C virus (HCV) is an important etiological agent of severe liver diseases, including cirrhosis and hepatocellular carcinoma. The HCV genome encodes nonstructural protein 3 (NS3) helicase, which is a potential anti-HCV drug target because its enzymatic activity is essential for viral replication. Some anthracyclines are known to be NS3 helicase inhibitors and have a hydroxyanthraquinone moiety in their structures; mitoxantrone, a hydroxyanthraquinone analogue, is also known to inhibit NS3 helicase. Therefore, we hypothesized that the hydroxyanthraquinone moiety alone could also inhibit NS3 helicase. Here, we performed a structure–activity relationship study on a series of hydroxyanthraquinones by using a fluorescence-based helicase assay. Hydroxyanthraquinones inhibited NS3 helicase with IC50 values in the micromolar range. The inhibitory activity varied depending on the number and position of the phenolic hydroxyl groups, and among different hydroxyanthraquinones examined, 1,4,5,8-tetrahydroxyanthraquinone strongly inhibited NS3 helicase with an IC50 value of 6 µM. Furthermore, hypericin and sennidin A, which both have two hydroxyanthraquinone-like moieties, were found to exert even stronger inhibition with IC50 values of 3 and 0.8 µM, respectively. These results indicate that the hydroxyanthraquinone moiety can inhibit NS3 helicase and suggest that several key chemical structures are important for the inhibition.

The detection of carcinoma in situ (CIS) is essential for the management of high-risk non-muscle invasive bladder cancers. Here, we focused on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) combined with photodynamic diagnosis (PDD) for the detection of CIS. A total of 45 patients undergoing pre-surgical DCE-MRI and PDD-assisted endoscopic surgery accompanied by biopsies of the eight segmentations were analyzed. Immunohistochemical analysis of the biopsies revealed hypervascularity of CIS lesions, a cause of strong submucosal contrast-enhancement. It was found that 56 (16.2%) of 344 biopsies had pathologically proven CIS. In the DCE-MRI, the overall sensitivity and specificity for detecting CIS were 48.2% and 81.9%, respectively. We set out two different combinations of PDD and DCE-MRI for detecting CIS. Combination 1 was positive when either the PDD or DCE-MRI were test-positive. Combination 2 was positive only when both PDD and DCE-MRI were test-positive. The overall sensitivity of combinations 1 and 2 were 75.0% and 37.5%, respectively (McNemar test, vs PDD alone; p = 0.041 and p < 0.001, respectively). However, the specificity was 74.0% and 91.7%, respectively (vs PDD alone; both p < 0.001). Our future goal is to establish ‘MRI-PDD fusion transurethral resction of the bladder tumor (TURBT), which could be an effective therapeutic and diagnostic approach in the clinical management of high-risk disease.

Under environmental stress, microbes are known to alter their translation patterns using sequence-specific endoribonucleases that we call RNA interferases. However, there has been limited insight regarding which RNAs are specifically cleaved by these RNA interferases, hence their physiological functions remain unknown. In the current study, we developed a novel method to effectively identify cleavage specificities with massive parallel sequencing. This approach uses artificially designed RNAs composed of diverse sequences, which do not form extensive secondary structures, and it correctly identified the cleavage sequence of a well-characterized Escherichia coli RNA interferase, MazF, as ACA. In addition, we also determined that an uncharacterized MazF homologue isolated from Pseudomonas putida specifically recognizes the unique triplet, UAC. Using a real-time fluorescence resonance energy transfer assay, the UAC triplet was further proved to be essential for cleavage in P. putida MazF. These results highlight an effective method to determine cleavage specificity of RNA interferases.

Nitrosomonas europaea carries numerous toxin-antitoxin systems. However, despite the abundant representation in its chromosome, studies have not surveyed the underlying molecular functions in detail, and their biological roles remain enigmatic. In the present study, we found that a chromosomally-encoded MazF family member, predicted at the locus NE1181, is a functional toxin endoribonuclease, and constitutes a toxin-antitoxin system, together with its cognate antitoxin, MazE. Massive parallel sequencing provided strong evidence that this toxin endoribonuclease exhibits RNA cleavage activity, primarily against the AAU triplet. This sequence-specificity was supported by the results of fluorometric assays. Our results indicate that N. europaea alters the translation profile and regulates its growth using the MazF family of endoribonuclease under certain stressful conditions.