Search Results (89)

Intravesical Bacillus Calmette–Guérin (iBCG) immunotherapy is the standard adjuvant treatment of non-muscle-invasive bladder cancer (NMIBC). Among the potential complications, cases of mycotic aneurysms and acute respiratory distress syndrome (ARDS) are rare but can be life-threatening. Because prior reports have not included whole-genome sequencing (WGS) of clinical Mycobacterium bovis BCG (M. bovis BCG) isolates to assess whether the infecting strain acquires mutations in vivo, we performed WGS in a severe disseminated iBCG-related infection. A 72-year-old man with bladder cancer underwent iBCG instillation. Twelve months after the final instillation, the patient developed an abdominal aortic aneurysm, which was detected and treated with endovascular aneurysm repair (EVAR). Two months later, the patient presented with fever, abdominal pain, and septic shock. Contrast-enhanced computed tomography (CT) and ¹⁸F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) showed rapid aneurysm enlargement. Ziehl–Neelsen staining and PCR of aortic material identified M. bovis BCG. Direct PCR on BAL fluid and urine was negative; however, BAL and urine culture subsequently grew M. bovis BCG, and PCR performed on the culture isolate confirmed M. bovis BCG. Despite combined antituberculosis triplet therapy (isoniazid, rifampicin, and ethambutol), the patient developed ARDS, which gradually improved after surgical management. WGS (with >96% genome coverage) showed the isolate was highly concordant with the vaccine strain and lacked additional virulence-associated mutations, including in esxM. This case illustrates that severe systemic iBCG-related complications can occur without detectable in vivo acquisition of virulence-enhancing mutations; however, interpretation is limited by the single-case design and the absence of host genetic susceptibility testing. Our findings underscore the need for prolonged vigilance regarding late-onset vascular and pulmonary complications after iBCG, and highlight the importance of early multidisciplinary management. Full article

Background/Objectives: Systemic immunotherapy, previously used mainly for advanced urothelial carcinoma, now plays an important role in the treatment of non-muscle invasive bladder cancer (NMIBC), either alone or combined with intravesical BCG instillations. Methods: We conducted a collaborative, comprehensive review to summarize the key evidence and future perspectives on therapeutic intensification strategies involving immune checkpoint inhibitors in NMIBC. A total of 51 references published between 2000 and 2025 were included. Results: Four phase II studies evaluated pembrolizumab, atezolizumab, durvalumab, and cetrelimab as monotherapy in 28 to 132 BCG-unresponsive NMIBC patients. They reported complete response rates ranging from 12% to 43% after 3 to 12 months of treatment, with a durable response rate ranging from 49% to 57.4% at 12 months. To improve these results, a phase II trial launched this year tests a new systemic combination targeting both the PD-1/PD-L1 axis and the emerging HLA-E/NKG2A pathway. Regarding BCG-naïve high-risk (HR) NMIBC, four phase III studies are evaluating BCG instillations combined with systemic immunotherapy: sasanlimab (CREST), durvalumab (POTOMAC), atezolizumab (ALBAN), and pembrolizumab (KEYNOTE-676), with significant results reported for the CREST and POTOMAC trials. The key challenge remains selecting patients most likely to benefit from this combination therapy while avoiding overtreatment. Identifying predictive biomarkers of tumor aggressiveness and response to immunotherapy also represents a major future challenge. Conclusions: Therapeutic intensification using systemic immunotherapy applies to both BCG-unresponsive NMIBC, with a new target pathway (HLA-E/NKG2A), and BCG-naïve HR NMIBC, where the combination of BCG instillations and immunotherapy represents a major breakthrough. Full article

Background/Objectives: Intravesical Bacillus Calmette–Guérin (BCG) is the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), but treatment-related urinary toxicity may compromise quality of life (QoL) and adherence. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been linked to oncologic outcomes in bladder cancer, but its association with urinary symptom burden during BCG therapy remains unclear. We aimed to assess whether baseline NLR is associated with early deterioration in urinary symptoms and urinary QoL following BCG induction. Methods: This prospective study included male patients with NMIBC treated with intravesical BCG. Baseline demographics, comorbidities, laboratory parameters, and urinary symptoms were recorded. Patients were stratified into two groups according to baseline NLR (<3 vs. ≥3). Urinary outcomes were assessed at baseline and 8 weeks using the International Prostate Symptom Score (IPSS) and the IPSS-related QoL item. Univariable and multivariable linear regression analyses were performed. Results: A total of 96 patients were analyzed. Median baseline NLR was 2.6 (IQR: 2.1–3.8). Patients with NLR ≥ 3 (n = 34) and NLR < 3 (n = 62) had comparable baseline characteristics and urinary scores. At 8 weeks, patients with NLR ≥ 3 experienced a greater worsening of urinary symptoms (median IPSS 24 vs. 21, p = 0.02; median change +5 vs. +2, p = 0.01) and QoL (median 5 vs. 4, p = 0.03). Univariable regression confirmed the association of NLR ≥ 3 with worse QoL (β = +0.74; p = 0.003) and higher IPSS (β = +2.20; p = 0.021). Modeled as a continuous variable, each one-unit increase in NLR corresponded to a +0.20 worsening in QoL (p = 0.008). In the multivariable analyses adjusted for baseline IPSS and concomitant CIS, NLR remained independently associated with QoL decline. Conclusions: Baseline NLR was independently associated with worsening urinary symptoms and QoL during BCG induction in NMIBC patients. NLR may represent a simple and accessible biomarker for early risk stratification during BCG induction, warranting validation in larger, longer-term prospective trials. Full article

Background/Objectives: Bladder pain syndrome (BPS), or painful bladder syndrome (PBS)/interstitial cystitis (IC), is a chronic inflammatory condition characterized by symptoms like pain, urgency, urinary incontinence, and sometimes urinary retention, which significantly affect patients’ quality of life. The etiology of PBS/IC remains unclear and may be multifactorial, with no definitive treatment currently available. The challenge lies in finding new therapeutic strategies. Various intravesical treatments, such as heparin, hyaluronic acid, and botulinum toxin, are commonly used for PBS/IC. In this study, we aimed to evaluate the anti-inflammatory effects of intravesical Vessilen^® (a new formulation consisting of 2% adelmidrol and 0.1% sodium hyaluronate) in patients with IC/PBS or other bladder disorders. Methods: This was a pilot study conducted at a tertiary-level urogynecology center. Two validated questionnaires were administered to patients before and after treatment: the Visual Analogue Scale (VAS) and the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS Long Form). The Patient Global Impression (PGI) scale was used to assess symptom severity. Results: Among the 25 patients who completed six weekly instillations, a significant decrease in bladder symptoms was observed, as indicated by both the ICIQ-FLUTS scale (89.3 vs. 61.3; p = 0.021) and VAS score (4.4 vs. 2.6; p < 0.001). Additionally, 80% of patients reported symptom improvement (PGI-I score ≤ 3). Conclusions: Intravesical Vessilen^® (adelmidrol + sodium hyaluronate) appears to be an innovative therapeutic approach for PBS/IC and other chronic inflammatory bladder disorders due to its anti-inflammatory and antinociceptive properties. Full article

Several studies showed that the incidence of Alzheimer’s disease (AD) is significantly lower in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical bacillus Calmette–Guérin (BCG) instillations compared to treatment by alternative methods. Hypothetically, failure to clear misfolded and aggregated proteins (i.e., beta-amyloid) in AD brains and peripheral blood mononuclear cells (PBMCs) implicates BCG in upgrading the unfolded protein response (UPR). To test this hypothesis, pre- versus post-BCG PBMC proteins of the UPR pathway were compared in six NMIBC patients by capillary immunoelectrophoresis on an Abby instrument. PERK, the endoplasmic reticulum (ER) resident kinase, a stress-activated sensor, and its substrate alpha component of the eIF2 translation factor (eIF2a) complex inactivation were considered as potentially proapoptotic via a downstream proapoptotic transcription factor only if persistently high. GAPDH, a glycolytic marker of innate immunocyte training by BCG, and eight other UPR proteins were considered antiapoptotic. Summation of antiapoptotic %change scores per patient showed that the older the age, the lower the antiapoptotic %change. Higher antiapoptotic scores were observed upon a longer time from BCG treatment (with the exception of the patient in her ninth decade of life). Studies with more individuals could substantiate that BCG enhances the antiapoptotic aggregate-clearance effect of the UPR in PBMCs of NMIBC patients, which hypothetically protects brain cells against AD. Full article

OnabotulinumtoxinA is an FDA-approved treatment for adults with overactive bladder (OAB) who have an inadequate response to, or are intolerant of, oral pharmacotherapies including anticholinergics or beta-3 agonists. However, procedural practices of onabotulinumtoxinA intradetrusor injection vary among practitioners and can affect patient experience. To address this, a panel of six high-volume intravesical onabotulinumtoxinA providers with 100 years of combined experience convened to discuss the best office practices when treating patients with OAB. These key best practices include counseling patients on available OAB therapies, including onabotulinumtoxinA, at the initial consultation in accordance with established AUA and SUFU guidelines in a way that is easily understood. An office setting is preferred over a hospital or surgery center when performing the procedure. Staff involvement, from scheduling to post-procedure, is essential for establishing the relationships necessary to optimize patient experience and encourage compliance and retreatment. Experts generally recommend using a viscous lidocaine bladder instillation for an anesthetic 15 min prior to the reconstitution of onabotulinumtoxinA with 5 to 10 mL of normal saline. A range of one to 20 injection sites is acceptable, with a smaller number preferred. Starting in the lower bladder, experts recommend using a slower speed of injection to improve distribution and decrease patient discomfort. Subsequent treatments should be regularly scheduled at six-month intervals with the option of re-treating earlier if symptoms return, but no sooner than 12 weeks. For office intravesical onabotulinumtoxinA procedures, optimization of the patient experience by the physician and their staff, starting with the initial visit through the post-treatment follow-up, is key to long-term patient compliance. Full article

Introduction: Recently, alpha-emitting radionuclides like astatine-211 have offered promising results in clinical development. Non-muscle-invasive bladder cancer (NMIBC) presents a need for novel therapies. One promising approach is radioimmunotherapy targeting Carbonic Anhydrase IX (CA-IX), which is supported by preclinical and clinical evidence. The aim of our preclinical and clinical studies was to evaluate the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) for future use in NMIBC patient care. Methods: The anti-CA-IX antibody, girentuximab (TLX250), was labeled with lutetium-177 and astatine-211 for in vitro studies. Affinity constant measurements of [²¹¹At]At-girentuximab in RT-112 cells were taken, and toxicity evaluations were conducted in vitro and in healthy mice. Additionally, a clinical proof-of-concept study, PERTINENCE, that used [⁸⁹Zr]Zr-girentuximab for PET/CT imaging in bladder cancer patients was conducted. Results: The measurement of the affinity constant of [²¹¹At]At-girentuximab in RT112 cells revealed high binding affinity and significant cytotoxicity compared to [177Lu]Lu-girentuximab. Biodistribution studies in healthy mice indicated low systemic radioactivity uptake, and a bladder post-instillation examination showed no abnormalities in bladder mucosa, suggesting safety. In the PERTINENCE study, which involved patients with NMIBC tumors expressing CA-IX, [⁸⁹Zr]Zr-girentuximab PET/CT showed no extravesical leakage. Wall bladder uptake spots correlated with recurrence or inflammatory reaction. A dosimetric study suggested the potential efficacy and favorable safety profile of intravesical alpha therapy with the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) in NMIBC treatment. Conclusions: Preclinical and clinical data demonstrate the promising therapeutic role of ²¹¹At-targeted alpha agents in NMIBC, and the [²¹¹At]At-anti-CA-IX antibody (ATO-101™) could fulfill this role. A phase I FIH clinical trial is in preparation, and results are expected within the next years. Full article

Background: While Bacillus Calmette-Guérin (BCG) remains the first-line therapy for high-risk bladder cancer, 30–40% of patients develop treatment resistance necessitating radical cystectomy, some are not suitable candidates for this procedure. This underscores the critical need for novel therapeutic approaches. Emerging clinical evidence has increasingly supported the therapeutic potential of oncolytic viruses in bladder cancer treatment. Based on this clinical foundation, we investigated the anti-tumor effects of KD01, a novel type 5 recombinant oncolytic adenovirus previously developed by our team engineered to express truncated BID (tBID), in bladder cancer. Methods: The cytotoxic effects and anti-tumor efficacy of KD01 were systematically evaluated across human bladder cancer cell lines, and cell death pathways were investigated by RNA sequencing and validated. Combination therapy studies with cisplatin employed cytotoxic testing. In the final stage, the safety of KD01 bladder instillation was evaluated. Results: KD01 induced bladder cancer cell death through multiple mechanisms, including oncolysis, immunogenic cell death, and mitochondrial apoptosis. At higher doses, KD01 combined with cisplatin synergistically inhibited cancer cell proliferation and induced apoptosis. Additionally, KD01 amplified damage-associated molecular patterns (DAMPs) release and immune activation; the combination with cisplatin further enhanced the process. Safety evaluations showed favorable tolerance to intravesical perfusion with KD01. Conclusions: The dual action of KD01 in directly killing tumor cells and activating anti-tumor immunity underscores its potential as a therapeutic agent. These findings highlight the preclinical efficacy and safety of KD01, informing the design of clinical trials. Full article

Worldwide, urinary tract infections (UTIs) have an increased incidence, especially in women. Recurrent UTIs (rUTIs) appear in less than three months in 80% of the cases, being associated with age, sexual activity, or diabetes mellitus. Antibiotics represent the first line of treatment for rUTIs after the diagnosis based on a positive mid-stream urine (MSU) culture. Alternative therapies including low-dose antibiotic treatment, immunoprophylaxis, cranberry extracts, probiotics, D-mannose, intravesical instillations, methenamine, and estrogens may reduce the recurrence of UTIs in female patients. Multimodal therapy seems to be the future in preventing and treating rUTIs. The main aim of this narrative review is to present the actual therapeutic challenges and the most efficient prophylaxis options in women diagnosed with rUTIs. Full article

Background/Objectives: Lower urinary tract symptoms (LUTs) are commonly reported complications of intravesical Bacillus Calmette–Guerin (BCG) instillation for non-muscle invasive bladder cancer; however, there is limited characterization of the severity of the symptoms. We aim to explore the progression of LUTs with BCG treatment for bladder cancer. Methods: Patients were given the Overactive Bladder Questionnaire Short Form (OAB-q SF) to complete prior to their weekly BCG instillation during their primary six-week induction course. Mean symptom scores were compared for weeks 2 through 6 to baseline scores (week 1) utilizing two-sample tests. Subgroup analysis was conducted to identify cohorts at increased risk for urinary symptom progression. Simple linear regression was performed to determine the change in mean symptom scores over time. Results: A total of 60 patients completed the full six-week induction course and completed the required questionaries. Intravesical BCG administration was associated with no significant change in scores across either the symptom bothers or HFQL surveys, which were taken independently or in aggregate. No statistically significant differences in symptom scores were found between subgroups created based on demographic variables, tumor characteristics, or clinical presentation. Conclusions: Although intravesical BCG may cause acute urinary symptoms, it does not seem to impact a patient’s baseline urinary symptom profile. This is important when counseling patients about the perceived chronic urinary symptom risk associated with BCG treatment. Full article

Background/Objectives: Bladder urothelial carcinoma is a frequent malignant tumor of the urinary system, characterized by its high rates of recurrence and resistance to chemotherapy. This study explored the beneficial effects of overexpressing WW domain-containing oxidoreductase (WWOX) in AY-27 cells encapsulated in an injectable gelatin hydrogel for potential therapeutic applications in bladder cancer. Methods: AY-27 cells were genetically transduced with lentiviruses (LV) to overexpress WWOX (LV-WWOX) and subsequently encapsulated in a gelatin hydrogel. The mechanical properties and morphology of the hydrogels were assessed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The therapeutic efficacy of this approach was evaluated using an F344/AY-27 rat orthotopic bladder cancer model, in which the LV-WWOX-hydrogel (H-LV-WWOX) was administered via intravesical instillation. Results: The gelatin hydrogel formulation demonstrated excellent biocompatibility, stability, and controlled release. In a rat orthotopic model, intravesical instillation of H-LV-WWOX significantly enhanced local immune responses, resulting in notable tumor regression. Compared to the sham-treated group, this approach reduced systemic toxicity and improved overall treatment outcomes. The anticancer effect of WWOX can be attributed to its ability to amplify TNF-α-induced reactive oxygen species (ROS) generation. This ROS-mediated pathway leads to enhanced apoptosis and DNA damage in cancer cells, highlighting the potential mechanism through which WWOX exhibits tumor-suppressive activities. Conclusions: These findings support the therapeutic potential of WWOX overexpression in gelatin hydrogels for bladder cancer treatment and warrant further clinical investigation. Full article

Objectives: The aim of this study was to identify factors that predict recurrence by comparing low-dose and standard-dose Bacillus Calmette-Guérin (BCG) induction therapy in patients with non-muscle invasive bladder cancer (NMIBC). Methods: A total of 273 consecutive NMIBC patients who received low-dose (40 mg) or standard-dose (80 mg) BCG intravesical instillation therapy between January 2004 and December 2023 were analyzed. Recurrence-free survival (RFS) rates were assessed using the Kaplan–Meier method with the log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent predictors of recurrence based on the Club Urológico Español de Tratamiento Oncológico (CUETO) criteria. Results: The log-rank test showed that older age, low BCG dose, number of tumors, and a history of recurrence increased the risk of recurrence significantly. Regarding older patients, recurrence rates were similar between the two dose groups. However, younger patients had significantly lower recurrence rates with standard-dose BCG compared to low-dose BCG. Multiple Cox regression analysis confirmed that older age, low-dose BCG, greater than three tumors, and a history of recurrence were significant predictors of recurrence. Conclusions: In this study, we found that low-dose BCG induction therapy was associated with higher relapse rates compared with standard doses, especially in younger patients. Age-related differences in the immune response to BCG may influence these relapse patterns. Full article

Background: While the clinical application of SII-ONCO-Bacillus Calmette–Guerin (BCG) for non-muscle-invasive bladder cancer (NMIBC) is well established in Greece, there is a lack of real-world data on its effectiveness and safety. This retrospective, observational, multicenter, chart-review study aims to provide real-life data on the effectiveness and safety of SII-ONCO-BCG in patients with intermediate- and high-risk NMIBC. Methods: From January 2016 to December 2023, medical records from six hospital centers were reviewed for adult patients with histologically confirmed stage Ta or T1 NMIBC (with or without carcinoma in situ [CIS]) who received at least one maintenance course of SII-ONCO-BCG after induction. Tumor recurrence and progression were monitored at scheduled time intervals. Primary outcomes included recurrence-free survival (RFS) and progression-free survival (PFS), while adverse events (AEs) constituted secondary outcomes. Results: A total of 162 patients receiving SII-ONCO-BCG were enrolled. Among all patients, 145 (89.5%) patients were men, 88 (54.3%) aged 70 years or older, 103 (63.6%) had T1, 43 (26.5%) Ta, and 21 (12.9%) concurrent CIS. The median follow-up duration was 28.9 months (range, 5–36) and the mean BCG intravesical instillation courses were 13.7 (range, 9–27). After 3-, 2-, and 1-year follow-up, RFS rates of 85.2% (95% CI, 79.7–90.7%), 85.8% (80.4–91.2%), and 87.0% (81.8–92.3%) were observed, respectively. The corresponding 3-, 2-, and 1-year PFS rates were 96.9% (94.2–99.6%), 96.9% (94.2–99.6%), and 97.5% (95.1–99.9%), respectively. During the whole follow-up period, 24 (14.8%) patients experienced at least one AE. Conclusions: This real-world study demonstrates that SII-ONCO-BCG is an effective and safe treatment for patients with intermediate- and high-risk NMIBC. Full article

Loss of the glutathione-S-transferases Theta 2 (Gstt2) expression is associated with an improved response to intravesical Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) patients who receive fewer BCG instillations. To delineate the cause, Gstt2 knockout (KO) and wildtype (WT) C57Bl/6J mice were implanted with tumors before treatment with BCG or saline. RNA was analyzed via single-cell RNA sequencing (scRNA-seq) and real-time polymerase chain reaction (RT-PCR). BCG induced PD-L1 expression in WT mice bladders, while pro-inflammatory TNF-α was upregulated in KO bladders. ScRNA-seq analysis showed that Gstt2 WT mice bladders had a higher proportion of matrix remodeling fibroblasts, M2 macrophages, and neuronal cells. In KO mice, distinct tumor cell types, activated fibroblasts, and M1 macrophages were enriched in the bladders. In WT bladders, the genes expressed supported tumorigenesis and immunosuppressive PD-L1 expression. In contrast, Gstt2 KO bladders expressed genes involved in inflammation, immune activation, and tumor suppression. An 11-gene signature (Hmga2, Peak 1, Kras, Slc2a1, Ankfn1, Ahnak, Cmss1, Fmo5, Gphn, Plec, Gstt2), derived from the scRNA-seq analysis predicted response in NMIBC patients (The Cancer Genome Atlas (TCGA) database). In conclusion, our results indicate that patients with WT Gstt2 may benefit from anti-PD-L1 checkpoint inhibition therapy. Full article

Purpose: Bladder cancer (BC) is a heterogeneous disease with varying outcomes, influenced by disease heterogeneity and variability in treatment and follow-up. Risk groups have been established for non–muscle-invasive BC (NMIBC) to standardize therapy, and several quality control indicators (QCIs) monitor adherence to these risk group-based guidelines. However, controversial results had been obtained regarding the oncological benefits of these QCIs until recent high-quality studies from large registries showed their usefulness. To improve adherence to the European Association of Urology (EAU) Guidelines and benchmark current care in Flemish hospitals within Vlaams Ziekenhuisnetwerk–KU Leuven (VZNKUL), a QCI program for NMIBC was initiated in 2013. This study aims to describe the demographic, clinical, and treatment data of patients enrolled in this program. Participants: The VZNKUL–NMIBC Quality Indicators Program Registry is a prospective cohort including patients treated and followed up with at seven academic and non-academic Flemish hospitals since June 2013. Data collection includes patient characteristics, tumor data, treatment, and oncological outcomes. Findings to date: From June 2013 to December 2020, 4744 transurethral resections of bladder tumors (TURBTs) from 2237 unique patients were analyzed. Most patients (80%) were men with a median age of 73. The median time from diagnosis to TURBT was 19 days. A single tumor was detected in 37% of TURBTs. Tumors larger than 3 cm were found in 20.8% of cases. In 46% of TURBTs, a reTURBT was scheduled according to guidelines. The complication rates were 7.5% and 2.4% for bladder perforation and bleeding, respectively. Postoperative single intravesical instillation of chemotherapy (SIVIC) was administered to 56.9% of 1533 indicated patients with a median time to administration of 4.7 h. Among the cohort, 60.4% had NMIBC, and 9.3% had muscle-invasive BC. Of 972 high-risk patients, 60.7% received adequate BCG induction, while 39.4% received adequate maintenance. After BCG induction ± maintenance, 39.7% were tumor-free, with 17.7% recurrence and 4% progression to muscle-invasive BC. BCG treatment was terminated early for 17% of patients due to intolerance. Early cystectomy was performed for 2.4% of the BCG-naïve patients, and 27.7% of patients with BCG failure underwent a BCG rechallenge. For intermediate-risk patients, 2.1% received adequate BCG, and 23% received intravesical chemotherapy. The median follow-up was 57 months. Five-year recurrence-free, progression-free, cancer-free, overall, and cancer-specific survival rates were 53%, 91.6%, 89%, 70.6%, and 95.6%, respectively, for the NMIBC patients. Of 400 non-metastatic MIBC patients, 217 (54.3%) underwent radical cystectomy (RC), of whom 46% received neoadjuvant chemotherapy, while 18 (4.5%) refused RC, and 74 (18.5%) were considered unfit for the surgery. Future plans: The VZNKUL–NMIBC Quality Indicators Program Registry will continue collecting data to evaluate QCIs and monitor treatment quality, enabling hospitals to benchmark their performance and improve patient care. Additionally, the registry’s real-world data can support research and international collaboration. Trial registration: The study was registered on ClinicalTrials.gov (NCT04167332). Full article