Prostate cancer and liquid biopsies: Clinical applications and challenges.

Liquid biopsy has emerged as a valuable and minimally invasive tool for real-time detection of clinically actionable abnormalities across various cancer types. Its applicability is particularly compelling in the realm of prostate cancer, where novel therapeutic agents, including those targeting DNA repair systems, are under development. Despite these advancements, challenges persist in effectively screening for prostate cancer, enhancing risk stratification, and determining optimal approaches for treating advanced disease. Consequently, there is a pressing need for improved biomarkers to aid clinicians in decision-making within these contexts. Cell-free DNA and extracellular vesicle analysis have demonstrated promise in diagnosis, prognostication, assessment of treatment responses, and identification of emerging mechanisms of resistance. Nevertheless, obstacles must be addressed before liquid biopsies can be integrated into routine clinical practice. These challenges encompass preanalytical considerations such as sample collection and storage, methods of extracellular vesicle isolation and enrichment, and the need for enhanced interpretation of generated sequencing data. This review provides a comprehensive overview of current clinical opportunities in managing prostate cancer through blood-based liquid biopsy, highlighting the progress made, and acknowledging the challenges that remain. Additionally, we discuss the next steps required for the effective implementation of liquid biopsies in guiding personalized treatment strategies for prostate cancer.

Multicomponent Intervention for Overactive Bladder in Women: A Randomized Clinical Trial.

Importance: Although the cognitive components of behavioral therapy for overactive bladder (OAB) are widely recognized, there is a lack of studies evaluating the effectiveness of multicomponent interventions that include cognitive components as a treatment for OAB. Objective: To examine the efficacy of a multicomponent intervention in improving health-related quality of life (HRQOL) for women with moderate to severe OAB. Design, Setting, and Participants: This multicenter, open-label, randomized clinical trial was conducted in Japan among women aged 20 to 80 years who had moderate to severe OAB. Participants were recruited from 4 institutions between January 16, 2020, and December 31, 2022, through self-referral via advertisement or referral from the participating institutions. Interventions: Participants were randomized 1:1 by minimization algorithm using an internet-based central cloud system to four 30-minute weekly sessions of a multicomponent intervention or waiting list. Both groups continued to receive baseline treatment throughout the study period. Main Outcomes and Measures: The primary outcome was the least-squares mean changes from baseline through week 13 in HRQOL total scores of the OAB questionnaire between 2 groups. Secondary outcomes included OAB symptom score and frequency volume chart. Results: A total of 79 women were randomized to either the intervention group (39 participants; mean [SD] age, 63.5 [14.6] years) or the waiting list control group (40 participants; mean [SD] age, 63.5 [12.9] years). One participant from each group dropped out from the allocated intervention, while 5 participants in the intervention group and 2 in the control group dropped out from the primary outcome assessment at week 13. Thirty-six participants (92.3%) in the intervention group and 35 (87.5%) in the control group had moderate OAB. The change in HRQOL total score from baseline to week 13 was 23.9 points (95% CI, 18.4-29.5 points) in the intervention group and 11.3 points (95% CI, 6.2-16.4 points) in the waiting list group, a significant difference of 12.6 points (95% CI, 6.6-18.6 points; P < .001). Similar superiority of the intervention was confirmed for frequency of micturition and urgency but not for OAB symptom score. Conclusions and Relevance: These findings demonstrate that a multicomponent intervention improves HRQOL for women with moderate to severe OAB and suggest that the cognitive component may be an effective treatment option for women with OAB. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000038513.

Effects of thienopyridine class antiplatelets on bleeding outcomes following robot-assisted radical prostatectomy.

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.

Renal cell carcinoma with multiple bone metastases effectively treated by a combination of tyrosine kinase inhibitor, robot-assisted partial nephrectomy, and metastasectomy.

Key Clinical Message: Maintaining a disease-free status for a long time in cases of renal cell carcinoma with multiple bone metastases and repeated recurrences is challenging. What matters most in the multidisciplinary approach is the treatment strategy. Although this is a case where multidisciplinary treatment resulted in long-term CR during the TKI era, the treatment strategy is still relevant now that treatment options have increased. Abstract: Recent advances in medications, such as immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), have improved metastatic renal cell carcinoma (mRCC) outcomes. We report a case of mRCC with bone metastasis that was successfully treated using a multidisciplinary approach. Here, we present a case of a 56-year-old man with left renal cancer and large and painful bone metastases at the 11th thoracic vertebrae (Th11). Therefore, a metastasectomy of Th11 was performed. Systemic treatment with TKI, robot-assisted partial nephrectomy, and metastasectomy were then administered. No recurrence was observed in >2 years. Long-term disease-free survival with the TKI-era multidisciplinary approach in a patient with mRCC remains significant when considering treatment sequences, especially now that drug treatment options-including ICIs-have increased. Treatment strategy and indication and timing of resection of the primary lesion and metastasectomy should be carefully considered in each case.

Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. METHODS: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). RESULTS: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. CONCLUSION: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

Impact of prostate position-based image-guidance in intensity-modulated radiation therapy for localized prostate cancer.

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.

Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

Removal characteristics of presepsin by operating conditions and hemofilter.

Presepsin, which is used as a biomarker for sepsis, is thought to be removed by dialysis, but the actual removal properties of dialysis are unknown. We investigated the presepsin removal properties of continuous hemodiafiltration using the high concentration of presepsin from human plasma drained by plasma exchange. Each solution in plasma exchange was connected to a continuous hemodiafiltration blood circuit and circulated at 4 conditions. The results show that presepsin was confirmed to be removed more efficiently in hemofiltration than in hemodialysis. In addition, when using a polymethylmethacrylate hemofilter for continuous hemodiafiltration, the lowest presepsin concentration is on the filtrate side, suggesting that the main removal mechanism is adsorption. Since presepsin has a molecular weight of 13,000, its removal efficiency is high by hemofiltration as per principle. In addition, since the main adsorption principle of polymethylmethacrylate hemofilter is hydrophobic bond, presepsin is considered to be adsorbed. Since presepsin is metabolized in the kidney, it is elevated in renal failure. In this paper, we confirmed that presepsin is eliminated by continuous hemodiafiltration not only in the kidney. Depending on the timing of presepsin measurement, there is a risk of missing the diagnosis of sepsis. Kidney function and continuous hemodiafiltration should be checked when measuring presepsin.

Current trends in the promising immune checkpoint inhibition and radiotherapy combination for locally advanced and metastatic urothelial carcinoma.

Locally advanced and metastatic urothelial carcinoma (UC) remains a challenging malignancy, though several novel therapeutic drugs have been developed in recent years. Over the past decade, immune checkpoint inhibitors (ICI) have shifted the paradigm of therapeutic strategies for UC; however, only a limited number of patients respond to ICI. Since radiotherapy (RT) is widely known to induce systemic immune activation, it may boost the efficacy of ICI. Conversely, RT also causes exhaustion of cytotoxic T cells, and the activation and recruitment of immunosuppressive cells; ICI may help overcome these immunosuppressive effects. Therefore, the combination of ICI and RT has attracted attention in recent years. The therapeutic benefits of this combination therapy and its optimal regimen have not yet been determined through prospective studies. Therefore, this review article aimed to provide an overview of the current preclinical and clinical studies that illustrate the underlying mechanisms and explore the optimization of the RT regimen along with the ICI and RT combination sequence. We also analyzed ongoing prospective studies on ICI and RT combination therapies for metastatic UC. We noted that the tumor response to ICI and RT combination seemingly differs among cancer types. Thus, our findings highlight the need for well-designed prospective trials to determine the optimal combination of ICI and RT for locally advanced and metastatic UC.

Discovery of lipid profiles in plasma-derived extracellular vesicles as biomarkers for breast cancer diagnosis.

Lipids are a major component of extracellular vesicles; however, their significance in tumorigenesis and progression has not been well elucidated. As we previously found that lipid profiles drastically changed in breast tumors upon progression, we hypothesized that lipid profiles of plasma-derived extracellular vesicles could be utilized as breast cancer biomarkers. Here, we adopted modified sucrose cushion ultracentrifugation to isolate plasma-derived extracellular vesicles from breast cancer (n = 105), benign (n = 11), and healthy individuals (n = 43) in two independent cohorts (n = 126 and n = 33) and conducted targeted lipidomic analysis. We established a breast cancer diagnostic model comprising three lipids that showed favorable performance with the area under the receiver operating characteristic curve of 0.759, 0.743, and 0.804 in the training, internal validation, and external test sets, respectively. Moreover, we identified several lipids that could effectively discriminate breast cancer progression and subtypes: phosphatidylethanolamines and phosphatidylserines were relatively higher in Stage III, whereas phosphatidylcholines and sphingomyelins were higher in Stage IV; phosphatidylcholines and ceramides were correspondingly concentrated in HER2-positive patients, while lysophosphatidylcholines and polyunsaturated triglycerides were concentrated in the triple-negative breast cancer subtype. Lipid profiling of plasma-derived extracellular vesicles is a non-invasive and promising approach for diagnosing, staging, and subtyping breast cancer.

Sexual function using the EORTC QLQ-TC26 in testicular cancer survivors: A multi-institutional, cross-sectional study.

OBJECTIVE: To evaluate sexual function after treatment using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Testicular Cancer 26 (EORTC QLQ-TC26) questionnaire in Japanese testicular cancer (TC) survivors in a multi-institutional, cross-sectional study. METHODS: This study enrolled TC survivors who visited any of eight high-volume institutions in Japan from 2018 to 2019. After obtaining informed consent, participants completed the EORTC QLQ-TC26 questionnaires. We evaluated sexual function after treatment for TC using the EORTC QLQ-TC26 and analyzed the impact of treatment on sexual function in TC survivors. RESULTS: A total of 567 TC survivors responded to the EORTC QLQ-TC26. Median age at the time of response was 43 years (interquartile range [IQR] 35-51 years), and median follow-up period after treatment was 5.2 years (IQR 2.2-10.0 years). Sexual function, particularly ejaculatory function, was significantly lower after post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) than after Surveillance or Chemotherapy groups (p < 0.05). In the PC-RPLND group, nerve-sparing procedure preserved postoperative ejaculatory function after RPLND compared with the non-nerve-sparing and offered improved ejaculatory function with time. On multivariate analysis, RPLND was a significant predictor of post-treatment ejaculatory dysfunction, particularly without nerve-sparing (odds ratio 3.0, 95% CI 1.2-7.7, p < 0.05). In addition, TC survivors with nerve-sparing RPLND had higher sexual activity than those without. CONCLUSION: This survey of the EORTC QLQ-TC26 showed that sexual function and activity in TC survivors after RPLND was reduced in the absence of nerve-sparing techniques.

Nomogram Predicting Locally Advanced Prostate Cancer in Patients with Clinically Organ-Confined Disease Who Underwent Robot-Assisted Radical Prostatectomy: A Retrospective Multicenter Cohort Study in Japan (The MSUG94 Group).

PURPOSE: We created a clinically applicable nomogram to predict locally advanced prostate cancer using preoperative parameters and performed external validation using an external independent validation cohort. PATIENTS AND METHODS: From a retrospective multicenter cohort study of 3622 Japanese patients with prostate cancer who underwent robot-assisted radical prostatectomy at ten institutions, the patients were divided into two groups (MSUG cohort and validation cohort). Locally advanced prostate cancer was defined as pathological T stage ≥ 3a. A multivariable logistic regression model was used to identify factors strongly associated with locally advanced prostate cancer. Bootstrap area under the curve was calculated to assess the internal validity of the prediction model. A nomogram was created as a practical application of the prediction model, and a web application was released to predict the probability of locally advanced prostate cancer. RESULTS: A total of 2530 and 427 patients in the MSUG and validation cohorts, respectively, met the criteria for this study. On multivariable analysis, initial prostate-specific antigen, prostate volume, number of cancer-positive and cancer-negative biopsy cores, biopsy grade group, and clinical T stage were independent predictors of locally advanced prostate cancer. The nomogram predicting locally advanced prostate cancer was demonstrated (area under the curve 0.72). Using a nomogram cutoff of 0.26, 464 of 1162 patients (39.9%) could be correctly diagnosed with pT3, and 2311 of 2524 patients (91.6%) could avoid underdiagnosis. CONCLUSIONS: We developed a clinically applicable nomogram with external validation to predict the probability of locally advanced prostate cancer in patients undergoing robot-assisted radical prostatectomy.

The Roles of Extracellular Vesicles in the Progression of Renal Cell Carcinoma and Their Potential for Future Clinical Application.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is thought to originate from renal tubular epithelial cells. Extracellular vesicles (EVs) are nanosized lipid bilayer vesicles that are secreted into extracellular spaces by nearly all cell types, including cancer cells and non-cancerous cells. EVs are involved in multiple steps of RCC progression, such as local invasion, host immune modulation, drug resistance, and metastasis. Therefore, EVs secreted from RCC are attracting rapidly increasing attention from researchers. In this review, we highlight the mechanism by which RCC-derived EVs lead to disease progression as well as the potential and challenges related to the clinical implications of EV-based diagnostics and therapeutics.

Efficacy and Tolerability of Second-line Pembrolizumab With Radiation Therapy in Advanced Urothelial Carcinoma.

BACKGROUND/AIM: Considering the limited data available on immune checkpoint inhibitors and radiation combination therapy in advanced urothelial carcinoma, this study evaluated the survival benefit and associated toxicity of adding radiation therapy to second-line pembrolizumab. PATIENTS AND METHODS: We retrospectively examined 24 consecutive patients with advanced bladder or upper urinary tract urothelial carcinoma and for whom second-line pembrolizumab was initiated between August 2018 and October 2021 in combination with radiation therapy (with curative intent in 12 patients, and palliative intent in 12 patients). Their survival outcomes and toxicities were compared with those of propensity-score-matched cohorts from a Japanese multicenter study with similar characteristics who received pembrolizumab monotherapy. RESULTS: The median follow-up periods after pembrolizumab initiation were 15 months for the curative cohort and 4 months for the palliative cohort. The median overall survival was 27.7 months for the curative cohort and 4.8 months for the palliative cohort. Compared with the matched pembrolizumab monotherapy cohort, overall survival was better among the curative cohort although not statistically significant (p=0.13), but similar between the palliative and matched pembrolizumab monotherapy cohorts (p=0.44). There was no difference in the incidence of grade ≥2 adverse events between the combination and monotherapy cohorts, irrespective of the intent of radiation therapy. CONCLUSION: The combination of radiation therapy and pembrolizumab can be performed with a clinically acceptable safety profile, and the addition of radiation therapy to immune checkpoint inhibitors may improve survival outcome after pembrolizumab treatment in cases where the intent of radiation therapy is curative.

Extracellular vesicles secreted from bone metastatic renal cell carcinoma promote angiogenesis and endothelial gap formation in bone marrow in a time-dependent manner in a preclinical mouse model.

Introduction: Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation. Materials and methods: We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo. Results: Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs. Conclusion: EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.

Thermal strain is greater in the late afternoon than morning during exercise in the gym without airflow and air conditioning on a clear summer day.

Introduction: There are no reports examining the time-of-day effect on team training sessions in the gym without airflow and air conditioning on thermal strain in the summer heat. We investigated this effect during badminton training sessions on a clear summer day. Methods: Nine male high school badminton players (Mean ± SD; age 17.1 ± 0.6 y, height 171 ± 4 cm, body mass 59 ± 7 kg) completed two 2.5-h badminton training sessions in the gym without airflow and air conditioning. The training sessions were started at 0900 h (AM) and 1600 h (PM) on separate days in August. Skin temperatures (chest, triceps, thigh, calf), infrared tympanic temperature, heart rate, thermal sensation and rating of perceived exertion were recorded at rest and at regular intervals during the sessions. Results: Indoor and outdoor environmental heat stress progressively increased in AM and decreased in PM during the sessions. Ambient temperature (AM 30.1 ± 0.9°C; PM 33.2 ± 1.0°C: P < 0.001) and wet-bulb globe temperature (AM 28.1 ± 0.5°C; PM 30.0 ± 0.9°C: P = 0.001) during the sessions in the gym were higher in PM than AM. Mean skin temperature (AM 34.2 ± 1.0°C; PM 34.7 ± 0.7°C: P < 0.001), infrared tympanic temperature (AM 37.8 ± 0.5°C; PM 38.1 ± 0.4°C: P = 0.001) and thermal sensation (AM 2.7 ± 1.4; PM 3.3 ± 1.0: P < 0.001) during the sessions were higher in PM than AM. Body heat storage (AM 159 ± 30 W·m-2; PM 193 ± 30 W·m-2: P < 0.05) was greater in PM than AM. There were no time-of-day differences in the average heart rate (AM 75 ± 4% age-predicted maximal heart rate; PM 76 ± 5 age-predicted maximal heart rate: P = 0.534), body mass loss (AM 0.6 ± 0.3 kg; PM 0.8 ± 0.2°C: P = 0.079), the volume of water ingested (AM 1.5 ± 0.1 L; PM 1.6 ± 0.3 L: P = 0.447) and rating of perceived exertion (AM 16 ± 2; PM 16 ± 3: P = 0.281). Conclusions: This study indicates greater thermal strain in PM trial than in AM trial during team training sessions in the gym without airflow and air conditioning on a clear summer day. Therefore, athletes and coaches of indoor sports should perceive that athletes may be exposed to a greater risk for thermal strain in the late afternoon from 1600 h than in the morning from 0900 h during the sessions in the gym under these conditions.