C-Reactive Protein-Albumin Ratio Predicts Objective Response to Enfortumab Vedotin in Metastatic Urothelial Carcinoma.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate that targets Nectin-4, is used for patients with metastatic urothelial carcinoma who have experienced progression on platinum-based chemotherapy and checkpoint inhibitors. Despite the widespread use of the drug, evidence remains scarce regarding clinical indicators that can predict the response to EV treatment. OBJECTIVE: We aimed to explore the predictive value of clinical indicators derived from peripheral blood tests for treatment responses to EV. METHODS: We utilized records of 109 patients with metastatic urothelial carcinoma treated by EV from our multi-institutional dataset. Receiver operating characteristic curve analyses for predicting objective responses including several indicators from blood examinations, such as C-reactive protein-albumin ratio (CAR), hemoglobin, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and lactate dehydrogenase, were performed. The optimal cutoff points were determined by the Youden index. Logistic regression analyses for achieving objective responses to EV treatment were performed among these indicators. RESULTS: The median age of the cohort was 74 years, and the median follow-up duration was 10 months for the entire group. Median overall survival and progression-free survival from the initiation of EV were 12 and 6 months, respectively. The objective response rate and disease control rate were 48% and 70%, respectively. The receiver operating characteristic curve analysis aimed at predicting the achievement of an objective response to EV showed that the concordant index for the CAR was 0.774, significantly surpassing other indicators such as hemoglobin level, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and serum lactate dehydrogenase. The Youden index identified an optimal cutoff value of 1 for CAR (mg/L for C-reactive protein and g/dL for serum albumin level) in predicting the objective response to EV treatment. Using the cutoff value for the CAR, the cohort was divided into 32 patients (29%) with lower CAR and 77 patients (71%) with higher CAR. The objective response rate was observed to be 84% in the lower CAR group and 32% in the higher CAR group (p < 0.0001). A logistic regression analysis revealed that an Eastern Cooperative Oncology Group Performance Status ≥1 (p = 0.04) and a CAR ≥1 (p < 0.001) were identified as independent predictors for the objective response to EV. CONCLUSIONS: The evaluation of the CAR from a concise blood examination at the initiation of EV could effectively predict the treatment response to EV in patients with metastatic urothelial carcinoma after the progression of platinum-based chemotherapy and checkpoint inhibitors.

Enfortumab vedotin, an antibody-drug conjugate that targets Nectin-4, is currently used for patients with metastatic urothelial carcinoma who no longer respond to checkpoint inhibitors. In the present report, we investigated which clinical indicators can predict achieving an objective response to enfortumab vedotin at the initiation of treatment. Among the blood-based putative indicators, the C-reactive protein-albumin ratio showed the highest value for predicting the treatment response to enfortumab vedotin. As the C-reactive protein-albumin ratio can be easily assessed from blood tests, physicians can consider evaluating it at the start of the EV treatment.

Impacts of a Self-directed Social Resources Study Program on Negative Symptoms and Quality of Life in Schizophrenia Outpatients: A Randomized Controlled Trial.

To clarify whether a self-directed study program on social resources improves negative symptoms, quality of life (QOL), and social participation among outpatients with schizophrenia. Eighty-six participants were randomly divided into intervention and control groups. In addition to the usual day programs, the intervention group participated in a self-directed study program on social resources once a week for eight weeks. The control group participated only in the usual day programs. Negative symptoms and QOL were assessed at baseline and post-intervention using the Positive and Negative Syndrome Scale (PANSS) and the WHO Quality of Life-BREF (WHOQOL-BREF), respectively. Social participation was also assessed. After the intervention, there were no significant differences in the PANSS negative symptoms and WHOQOL-BREF total scores between the two groups. Within-group, PANSS negative symptom scores significantly improved in the intervention group (p < 0.05), but not in the control group. The WHOQOL-BREF physical health subscale scores improved significantly only in the intervention group (p < 0.05). Social participation remained unchanged between the intervention and control groups. The results suggest that a self-directed study program on social resources may be useful for improving negative symptoms and physical QOL in outpatients with schizophrenia. The findings highlight the potential of such interventions to bridge the existing gap in psychosocial rehabilitation strategies for this population.

Effects of different exercise intensities or durations on salivary IgA secretion.

PURPOSE: This study aimed to examine changes in salivary immunoglobulin A (s-IgA) secretion at different intensities or durations of acute exercise. METHODS: Twelve healthy untrained young males were included in randomized crossover trials in Experiment 1 (cycling exercise for 30 min at a work rate equivalent to 35%, 55%, and 75% maximal oxygen uptake [ V ˙ O2max]) and Experiment 2 (cycling exercise at 55% V ˙ O2max intensity for 30, 60, and 90 min). Saliva samples were collected at baseline, immediately after, and 60 min after each exercise. RESULTS: Experiment 1: The percentage change in the s-IgA secretion rate in the 75% V ˙ O2max trial was significantly lower than that in the 55% V ˙ O2max trial immediately after exercise (- 45.7%). The percentage change in the salivary concentration of cortisol, an s-IgA regulating factor, immediately after exercise significantly increased compared to that at baseline in the 75% V ˙ O2max trial (+ 107.6%). A significant negative correlation was observed between the percentage changes in saliva flow rate and salivary cortisol concentration (r = - 0.52, P < 0.01). Experiment 2: The percentage change in the s-IgA secretion rate in the 90-min trial was significantly lower than that in the 30-min trial immediately after exercise (-37.0%). However, the percentage change in salivary cortisol concentration remained the same. CONCLUSION: Our findings suggest that a reduction in s-IgA secretion is induced by exercise intensity of greater than or equal to 75% V ˙ O2max for 30 min or exercise duration of greater than or equal to 90 min at 55% V ˙ O2max in healthy untrained young men.

Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan.

OBJECTIVES: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors. METHODS: The records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan. RESULTS: The median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively. CONCLUSION: PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis.

BACKGROUND & AIMS: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis. METHODS: A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases. RESULTS: AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The ß-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota ß-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site. CONCLUSIONS: PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.

Predictive patterns of lower urinary tract symptoms and bacteriuria in adults with type 2 diabetes.

Background: Numerous studies demonstrated the risk factors for urological complications in patients with diabetes before sodium-glucose co-transporter 2 inhibitor (SGLT2i) became commercially available. This study aimed to comprehensively investigate urological characteristics in patients with type 2 diabetes (T2DM) after SGLT2i became commercially available. Methods: We examined 63 outpatients with T2DM suspected of bacteriuria based on urinary sediment examinations. Urine cultures were performed, and lower urinary tract symptoms (LUTS) were assessed via questionnaires. Patients with bacteriuria were assessed using ultrasonography to measure post-void residual volume (PVR). Utilizing demographic and laboratory data, a random forest algorithm predicted LUTS, bacteriuria, and symptomatic bacteriuria (SB). Results: Thirty-two patients had LUTS and 31 had bacteriuria. High-density lipoprotein cholesterol level was crucial in predicting LUTS, while age was crucial in predicting bacteriuria. In predicting SB among patients with bacteriuria, creatinine level and estimated glomerular filtration rate were crucial. Our models had high predictive accuracy for LUTS (area under the curve [AUC] = 0.846), followed by bacteriuria (AUC = 0.770) and SB (AUC = 0.938) in receiver operating characteristic curve analysis. These predictors were previously reported as risk factors for urological complications. Although SGLT2i use was not an important predictor in our study, all SGLT2i users with bacteriuria had SB and exhibited higher PVR compared to non-SGLT2i users with bacteriuria. Conclusion: This study's random forest model highlighted distinct essential predictors for each urological condition. The predictors were consistent before and after SGLT2i became commercially available. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00687-1.

Effects of mifepristone on adipocyte differentiation in mouse 3T3-L1 cells.

BACKGROUND: Both glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation. METHODS: Mouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice. RESULTS: Mifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues. CONCLUSIONS: Mifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.

Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.

BACKGROUND: Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice. OBJECTIVE: The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients. PATIENTS AND METHODS: A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms. RESULTS: One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4 months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29 months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p = 0.124), PFS (p = 0.936), nor ORR (p = 0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5 months, p = 0.049). For OS, the difference was not statistically significant (27 and 11 months in EV and re-challenging chemotherapy, respectively: p = 0.05). CONCLUSIONS: A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.

Enfortumab vedotin (EV) is an antibody­drug conjugate targeting Nectin-4 and is now utilized for patients with metastatic urothelial carcinoma following treatment with checkpoint inhibitors (CPIs). Until recently, repeating chemotherapy using platinum drugs or continuing CPIs were often the treatments used for these patients. In the present study, we reported real-world treatment outcomes, mainly focusing on EV and repeating chemotherapy. Although the objective responses to the treatments were comparable, the duration of response for patients responding to the treatment was significantly longer in patients treated with EV than in those repeating chemotherapy, resulting in extended survival time with EV treatment.

Significance of the cribriform morphology area ratio for biochemical recurrence in Gleason score 4 + 4 prostate cancer patients following robot-assisted radical prostatectomy.

BACKGROUND: In prostate cancer, histological cribriform patterns are categorized as Gleason pattern 4, and recent studies have indicated that their size and percentage are associated with the risk of biochemical recurrence (BCR). However, these studies included a mixture of cases with various Gleason scores (GSs). We therefore examined the prognostic value of the area and percentage of cribriform patterns in patients with GS 4 + 4 prostate cancer. METHODS: We investigated 108 patients with GS 4 + 4 prostate cancer who underwent robot-assisted radical prostatectomy (RARP). After digitally scanning the hematoxylin and eosin-stained slides, we measured the area of the entire cancer and cribriform patterns. Predictive factors for BCR were explored using log-rank test and Cox proportional hazard model analyses. RESULTS: Sixty-seven (62.0%) patients had a cribriform pattern in RARP specimens, and 32 (29.6%) experienced BCR. The median total cancer area, cribriform pattern area, and percentage of cribriform pattern area (% cribriform) were 427.70 mm2 (interquartile range [IQR], 171.65-688.53 mm2 ), 8.85 mm2 (IQR, 0-98.83 mm2 ), and 2.44% (IQR, 0%-33.70%), respectively. Univariate analyses showed that higher preoperative serum prostate-specific antigen (PSA) levels, positive resection margins, advanced pathological T stage, extraprostatic extension, larger total cancer area, larger cribriform morphology area, and higher % cribriform values were significantly associated with BCR. A multivariate analysis demonstrated that the PSA level (hazard ratio [HR], 1.061; 95% confidence interval [CI], 1.011-1.113; p = 0.017) and % cribriform (HR, 1.018; 95% CI, 1.005-1.031; p = 0.005) were independent predictors of BCR. CONCLUSIONS: An increased % cribriform value was associated with BCR in patients with GS 4 + 4 prostate cancer following RARP.

Exploring Psychiatric Home-Visit Nursing Practices for Patients with Schizophrenia and Hikikomori with a Thematic Analysis.

The phenomenon of some patients with schizophrenia withdrawing and becoming hikikomori needs to be resolved. In some countries, outreach methods are being employed. In Japan, psychiatric home-visit nursing for patients with schizophrenia and hikikomori is being implemented. However, it is not based on sufficient evidence and relies on the experience and intuition of individual nurses. This study explored the underlying themes in the nursing practices of psychiatric home-visit nurses via semi-structured interviews with 10 nurses and a thematic analysis. Nine key themes emerged. Four themes-(i) understanding the patient's world, (ii) supporting the patients as they are, (iii) providing a sense of relief, and (iv) having equal relationships-highlighted the nurses' commitment to respecting patients' individuality while building and sustaining relationships. Two themes-(v) exploring the right timing and (vi) waiting for the appropriate timing-illustrated the nurses' anticipation of proactive patient engagement. Finally, three themes-(vii) working together on things, (viii) continuing care for expanding the patient's world, and (ix) nursing care for the patient's future-underscored the nurses' gradual and methodical approach to working alongside patients. Nursing practices based on these nine themes cultivated meaningful relationships and secured a sense of relief for the patients. Additionally, they awaited patients' proactive engagement and delivered timely support to facilitate positive daily life changes. These findings contribute to the establishment of evidence-based nursing practices for patients with schizophrenia and hikikomori.

Exploring the Potential of Nanogels: From Drug Carriers to Radiopharmaceutical Agents.

Nanogels open up access to a wide range of applications and offer among others hopeful approaches for use in the field of biomedicine. This review provides a brief overview of current developments of nanogels in general, particularly in the fields of drug delivery, therapeutic applications, tissue engineering, and sensor systems. Specifically, cyclodextrin (CD)-based nanogels are important because they have exceptional complexation properties and are highly biocompatible. Nanogels as a whole and CD-based nanogels in particular can be customized in a wide range of sizes and equipped with a desired surface charge as well as containing additional molecules inside and outside, such as dyes, solubility-mediating groups or even biological vector molecules for pharmaceutical targeting. Currently, biological investigations are mainly carried out in vitro, but more and more in vivo applications are gaining importance. Modern molecular imaging methods are increasingly being used for the latter. Due to an extremely high sensitivity and the possibility of obtaining quantitative data on pharmacokinetic and pharmacodynamic properties, nuclear methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) using radiolabeled compounds are particularly suitable here. The use of radiolabeled nanogels for imaging, but also for therapy, is being discussed.

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study.

BACKGROUND: Immune checkpoint inhibitors can cause various immune-related adverse events (irAEs). This study aimed to evaluate the association between the incidence of irAEs and oncological outcomes of metastatic renal cell carcinoma (mRCC) treated with nivolumab plus ipilimumab as first-line therapy. PATIENTS AND METHODS: We retrospectively analyzed data from 69 patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy between September 2018 and September 2021 at 4 institutions. Cox regression analyses were performed to investigate the important factors affecting overall survival (OS) in patients with mRCC treated with nivolumab plus ipilimumab as first-line therapy. RESULTS: During observation with a median follow-up of 9.1 months, the median OS was not reached, while the median progression-free survival was 6.0 months. Patients with irAEs had significantly prolonged OS and progression-free survival than those without irAEs (p = .012 and .002, respectively). Multivariate analysis showed that 3 independent factors, including C-reactive protein (CRP), irAEs, and performance status (PS), were significantly associated with OS (p = .04, .02, and .01, respectively). The patients were subsequently divided into 3 groups as follows: group 1, 20 patients with all 3 independent OS predictors; group 2, 18 patients with irAE predictors alone or 2 positive independent OS predictors (irAEs + CRP or irAEs + PS); group 3, 31 patients with 3 negative independent S predictors. OS varied significantly among the 3 groups (p = .004). CONCLUSION: The appearance of irAEs could predict OS in patients with mRCC treated with nivolumab plus ipilimumab as the first-line therapy.

Comparison of Postoperative Stress Urinary Incontinence between Anteroposterior Dissection and Modified Gilling Method in Holmium Laser Enucleation of the Prostate.

PURPOSE: Few studies have evaluated the usefulness of anteroposterior dissection holmium laser enucleation of the prostate (HoLEP). Thus, this study investigated the incidence of stress urinary incontinence (SUI) after HoLEP and usefulness of anteroposterior dissection HoLEP in preventing postoperative SUI. MATERIALS AND METHODS: In total, 288 patients who underwent HoLEP performed by a single experienced surgeon between May 2014 and September 2021 were enrolled. Furthermore, 134 patients underwent retrograde dissection using the modified Gilling method (surgery 1) and 154 patients underwent anteroposterior dissection HoLEP (surgery 2). The risk factors for SUI, as well as the rates of SUI improvement for the two surgical procedures, were evaluated. RESULTS: Postoperative SUI was observed in 58 (20.1%) of 288 patients, of whom, 48 (82.8%) recovered continence within 6 months. Ten patients (17.2%) required more than 6 months to recover continence. SUI incidence 1 month after HoLEP was 29.9% (40/134 patients) for surgery 1 and 11.7% (18/154 patients) for surgery 2; a statistically significant difference was observed between the two groups (odds ratio [OR], 0.311; 95% confidence interval [CI], 0.168-0.575; p < 0.001). In addition, surgery 2 was significantly associated with early recovery from SUI compared with surgery 1 (stratified hazard ratio, 0.782; 95% CI, 0.615------0.995; p < 0.001). The multivariable analysis demonstrated that only surgical procedure (OR, 0.350; 95%CI, 0.168-0.732; p=0.005) was an independent predictor of SUI.- Conclusion: We reaffirmed that anteroposterior dissection HoLEP is a useful procedure for reducing the risk of postoperative SUI and early recovery of urinary continence.

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

Circulating Plasma Oxytocin Level Is Elevated by High-Intensity Interval Exercise in Men.

PURPOSE: We evaluated whether repeated high-intensity interval exercise (HIIE) influences plasma oxytocin (OT) concentration in healthy men, and, given that OT is mainly synthesized in the hypothalamus, we assessed the concentration difference between the arterial (OT ART ) versus the internal jugular venous OT concentration (OT IJV ). Additionally, we hypothesized that an increase in cerebral OT release and the circulating concentration would be augmented by repeated HIIE. METHODS: Fourteen healthy men (age = 24 ± 2 yr; mean ± SD) performed two identical bouts of HIIE. These HIIE bouts included a warm-up at 50%-60% maximal workload ( Wmax ) for 5 min followed by four bouts of exercise at 80%-90% Wmax for 4 min interspersed by exercise at 50%-60% Wmax for 3 min. The HIIE bouts were separated by 60 min of rest. OT was evaluated in blood through radial artery and internal jugular vein catheterization. RESULTS: Both HIIE bouts increased both OT ART (median [IQR], from 3.9 [3.4-5.4] to 5.3 [4.4-6.3] ng·mL -1 in the first HIIE, P < 0.01) and OT IJV (from 4.6 [3.4-4.8] to 5.9 [4.3-8.2] ng·mL -1 , P < 0.01), but OT ART-IJV was unaffected (from -0.24 [-1.16 to 1.08] to 0.04 [-0.88 to 0.78] ng·mL -1 , P = 1.00). The increased OT levels were similar in the first and second HIIE bouts (OT ARTP = 0.25, OT IJVP = 0.36). CONCLUSIONS: Despite no change in the cerebral OT release via the internal jugular vein, circulating OT increases during HIIE regardless of the accumulated exercise volume, indicating that OT may play role as one of the exerkines.

The lactate response to a second bout of exercise is not reduced in a concurrent lower-limb exercise program.

We aimed to evaluate the blood lactate level in response to two bouts of exercise. First, we hypothesized that blood lactate elevation in response to moderate-intensity aerobic exercise (MIAE) would be lower at the end of the second bout of MIAE than the first bout of MIAE. In this context, we also hypothesized that lactate accumulation at the end of resistance exercise (RE) would be reduced if MIAE is performed before RE (i.e., concurrent exercise; CE). If so, we hypothesized that the order of the CE (i.e., RE + MIAE vs. MIAE + RE) influences blood lactate kinetics. To test the hypotheses, forty-three healthy men participated in three studies. In study 1, 20 men (age 21 ± 2 years) performed two bouts of a 20-min MIAE separated by a 20-min rest interval. In study 2, 11 men (age 22 ± 1 years) performed RE only and CE (MIAE + RE; ARCE) with a 20-min rest interval in a crossover design. In study 3, 12 men (age 21 ± 2 years) performed both CEs, which were ARCE and RE + MIAE (RACE), with a 20-min rest interval in a crossover design. We measured blood lactate before and at the end of each exercise session. In study 1, the blood lactate response to the second bout of MIAE was lower than that of the first bout (P < 0.001, r = 0.68). However, the blood lactate response to the ARCE trial was not lower than the response to the RE trial in study 2 (P = 0.475, r = 0.22). The results of study 3 showed that the RACE and ARCE trials induced a similar lactate response (MIAE P = 0.423, r = 0.28; RE P = 0.766, d = 0.03). These observations indicate that whereas lactate accumulation might be diminished by a second bout of MIAE, a different type of exercise (i.e., aerobic/resistance) did not result in a diminished lactate accumulation in response to a second bout of exercise.

The Effect of Contrast Water Therapy on Dehydration during Endurance Training Camps in Moderate-Altitude Environments.

The effects of contrast water therapy (CWT) on dehydration at moderate altitudes during training camps remain unknown. We hypothesized that CWT reduces dehydration resulting from training at moderate altitudes and improves performance, akin to conditions at sea level. A 13-day endurance training camp was held at a moderate altitude of 1100 m and included 22 university athletes, who were divided into two groups (CWT group, n = 12; control (CON) group, n = 10). The sample size was calculated based on an α level of 0.05, power (1 ß) of 0.8, and effect size of 0.25 based on two-way ANOVA. Longitudinal changes over 13 days were compared using a two-group comparison model. Additionally, 16 athletes participated in an additional performance verification analysis. Subjective fatigue, body mass, and water content (total body water (TBW), extracellular water (ECW), and intracellular water) were measured using bioimpedance analysis every morning, and the titin N-terminal fragment in urine (UTF) was measured as an index of muscle damage. For performance verification, 10 consecutive jump performances (with the reactive strength index (RSI) as an indicator) were evaluated as neuromuscular function indices. The results indicated that the UTF did not significantly differ between the two groups. Moreover, the ECW/TBW values, indicative of dehydration, on days 4 and 5 in the CWT group were significantly lower than those in the CON group. However, there was no significant difference in RSI between the two groups. Therefore, although CWT reduces dehydration in the early stages of the training camp, it may not affect performance.

Essential amino acid supplements ingestion has a positive effect on executive function after moderate-intensity aerobic exercise.

Aerobic exercise acutely improves cognitive function (e.g., executive function (EF); memory recognition (MR)) and increases circulating brain-derived neurotrophic factor (BDNF). In addition, branched-chain amino acids (BCAA) ingestion acutely shortens the choice reaction time and increases brain BDNF. We examined whether the ingestion of essential amino acid (EAA) supplements (mainly composed of BCAA) would positively impact on cognitive function and circulating BDNF after moderate-intensity aerobic exercise. Twenty-two healthy young men received either an EAA supplements or the placebo (PL) 30 min before undergoing aerobic exercise. The participants performed a cycling exercise at 60% of peak oxygen uptake for 30 min. EF after aerobic exercise was better after the EAA treatment than after the PL treatment (P = 0.02). MR (P = 0.38 for response accuracy; P = 0.15 for reaction time) and circulating BDNF (P = 0.59) were not altered by EAA supplements. EF improvement was correlated with increases in some amino acids (leucine, isoleucine, valine, lysine, phenylalanine; all Ps < 0.05) that are potential substrates for synthesizing neurotransmitters in the brain. These results suggest that EAA supplements ingestion had a positive effect on EF after moderate-intensity aerobic exercise, while MR and BDNF were not altered.

Nephron-sparing ureteroscopic surgery vs. radical nephroureterectomy: comparable survival-outcomes in upper tract urothelial carcinoma.

PURPOSE: This study investigates the utility of ureteroscopic surgery (URS) as an alternative to radical nephroureterectomy (RNU) in managing upper tract urothelial carcinoma (UTUC), with a focus on survival outcomes and re-evaluation of current the European Association of Urology guidelines criteria. METHODS: We conducted a retrospective, multi-institutional review of 143 UTUC patients treated with URS (n = 35) or RNU (n = 108). Clinicopathological factors were analyzed, and survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional-hazards models. RESULTS: The median follow-up period was 27 months. Overall survival (OS) and radiographic progression-free survival (rPFS) were comparable between the URS and RNU groups (OS: HR 2.42, 95% CI 0.63-9.28, P = 0.0579; rPFS: HR 1.82, 95% CI 0.60-5.47, P = 0.1641). URS conferred superior renal function preservation. In patients characterized by factors such as radiographically invisible lesions, negative cytology, pTa stage, low-grade tumors, and multiple lesions, the OS outcomes with URS were comparable to those with RNU as follows: radiographically invisible lesions (P = 0.5768), negative cytology (P = 0.7626), pTa stage (P = 0.6694), low-grade tumors (P = 0.9870), and multiple lesions (P = 0.8586). CONCLUSION: URS offers survival outcomes similar to RNU, along with better renal function preservation, especially in low-risk UTUC patients. These findings underscore the urgency of re-evaluating the current EAU guidelines and encourage further research into determining the ideal patient selection for URS in UTUC treatment.