Preliminary feasibility and safety of domestic probe-based confocal laser endomicroscopy in the diagnosis of bladder lesions: a prospective single-arm cohort study

Introduction

Bladder cancer is one of the most common genitourinary malignancies worldwide, with non-muscle invasive bladder cancer (NMIBC) accounting for approximately 75% of newly diagnosed cases (1-4). Early and accurate diagnosis is crucial for improving patient prognosis, as timely intervention can significantly reduce the risk of disease progression and recurrence (5). According to the current European Association of Urology (EAU) and American Urological Association (AUA) clinical guidelines for NMIBC, white light cystoscopy (WLC) combined with urine cytology is the first-line diagnostic method, and transurethral resection of bladder tumor (TURBT) followed by histopathological examination is the gold standard for confirming bladder cancer (5,6). However, WLC has inherent limitations: it may fail to detect flat lesions such as carcinoma in situ (CIS) and has difficulty distinguishing between inflammatory hyperplasia and low-grade malignant lesions, leading to missed diagnoses or unnecessary resections (6). TURBT is an invasive procedure and may have sampling biases, especially for small or multifocal lesions (6,7).

Probe-based confocal laser endomicroscopy (pCLE) is an innovative endoscopic imaging technology that enables real-time, in vivo visualization of cellular and subcellular structures at a magnification of up to 1,000×. By providing “optical biopsies” during the endoscopic procedure, pCLE allows for immediate assessment of lesion property, which can guide targeted biopsies and optimize the surgical strategy. Previous studies on imported pCLE systems have demonstrated promising diagnostic performance in bladder cancer, with high sensitivity and specificity for differentiating benign and malignant lesions (8-11). However, imported pCLE systems have clinical application limitations such as high cost, steep learning curve, and limited accessibility in clinical practice, which restrict their popularization and application in bladder cancer diagnosis, especially in regions with limited medical resources. In contrast, domestic pCLE systems have potential advantages in cost-effectiveness and clinical accessibility, and their development and clinical validation are of great significance for improving the diagnostic level of bladder lesions in China and other developing countries.

Fluorescein sodium is the most commonly used contrast agent for pCLE, which can be administered via intravesical instillation or intravenous injection, each with distinct clinical characteristics (12-14). At present, there is no clinical data on the application of domestic pCLE systems in bladder lesion diagnosis, and the optimal probe diameter and contrast agent administration route for domestic devices remain to be explored. In the development of medical devices, prospective single-arm cohort study is the preferred initial research design, which is mainly used to verify the technical feasibility and safety of new devices in clinical practice, and provide a basis for determining the sample size, research endpoints, and intervention methods of subsequent randomized controlled trials (RCTs). Based on this, this prospective single-arm cohort study was designed to take the technical feasibility and safety of domestic pCLE system as the primary research outcomes, preliminarily explore the imaging performance of different-diameter probes and the clinical characteristics of two fluorescein sodium administration routes, and collect preliminary clinical data for the subsequent large-sample, multicenter clinical research of this domestic device. The study is the first to explore the clinical application of domestic pCLE system in bladder lesion diagnosis, aiming to fill the gap in clinical data of domestic pCLE devices in urological oncology and lay a foundation for their subsequent clinical promotion and application. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-1000/rc).

Methods

Study design and sample size justification

This was a single-center, prospective single-arm cohort study conducted at the Department of Urology, Peking University People’s Hospital from March 2024 to June 2024. This study was a pilot exploratory research for the initial clinical application of domestic pCLE system, and the sample size was determined based on the pilot study sample size design principles for medical device feasibility and safety evaluation (15). The primary research objectives were to verify the technical feasibility and safety of the domestic pCLE system, and no statistical hypothesis test for diagnostic accuracy was set (the latter requires large-sample calculation based on expected sensitivity, specificity, and disease prevalence). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Ethics Committee of Peking University People’s Hospital (No. 2025-z073), and all patients provided written informed consent before participation.

Study population

Inclusion criteria

• Patients with suspected bladder masses detected by ultrasound or computed tomography (CT) (initial diagnosis) who planned to undergo cystoscopy and pathological examination;
• Patients with a history of bladder cancer resection undergoing postoperative follow-up (routine cystoscopy);
• Aged 18–90 years, able to cooperate with the examination and surgical procedures.

Exclusion criteria

• Positive fluorescein sodium skin test or history of allergic reactions to fluorescein sodium or related compounds;
• Severe renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²);
• Severe hepatic insufficiency (Child-Pugh class C);
• Inability to cooperate with the examination due to mental illness or severe comorbidities (e.g., severe cardiovascular and cerebrovascular diseases, uncontrolled diabetes);
• Pregnant or lactating women;
• Bladder perforation or active severe hematuria before examination.

Baseline measurement

A unified baseline data collection form was used to record the following information for all enrolled patients:

• Demographic characteristics: gender, age, underlying diseases (hypertension, diabetes, etc.);
• Clinical characteristics: reason for examination (initial diagnosis/follow-up), history of bladder cancer resection, imaging findings (ultrasound/CT) of bladder lesions (location, size, number);
• Laboratory indicators: renal function (serum creatinine, estimated glomerular filtration rate), liver function (aspartate aminotransferase, alanine aminotransferase, bilirubin), urine routine (hematuria, pyuria).

A total of 10 patients were enrolled in the study, including n males and 1 female, with a mean age of 65 years (range, 38–86 years).

Equipment and reagents

The domestic pCLE system used in this study was manufactured by Wuxi Hisky Medical Technologies Co., Ltd., Wuxi, China, which consists of a confocal laser source (excitation wavelength: 488 nm), a flexible imaging probe (1.9, 2.6, and 3.2 mm), an image acquisition and processing workstation, and a monitor. The system has a lateral resolution of 1.2 µm and an axial resolution of 7 µm. WLC was performed using a rigid cystoscope (Olympus, Tokyo, Japan) according to the patient’s condition. Fluorescein sodium injection (Alcon Research LLC, Fort Worth, TX, USA) was used as the contrast agent for diagnostic imaging, and 1% fluorescein sodium solution was prepared for skin test.

Intervention: pCLE examination procedure

All patients were prepared for the procedure under spinal anesthesia. Patients were placed in the lithotomy position. The entire examination procedure was completed by the same team of urologists with more than 5 years of experience in cystoscopy and endoscopic imaging to reduce operator bias. First, WLC was performed to identify the location, size, number, and morphology of bladder lesions. Then, a fluorescein sodium skin test was conducted: 0.1 mL of 1% fluorescein sodium solution was injected intradermally on the forearm, and the skin reaction was observed after 20 minutes. Patients with negative skin test results (no redness, swelling, or itching at the injection site) were divided into two groups according to the clinical decision:

• Intravesical instillation group: 500 mg of fluorescein sodium was dissolved in 50 mL of normal saline, and the solution was instilled into the bladder through the cystoscope. The bladder was filled with the solution, and the patient was asked to retain it for 30 minutes to ensure sufficient tissue staining. After retention, the solution was drained, and pCLE examination was performed immediately.
• Intravenous injection group: 5 mL of 20% fluorescein sodium injection (1,000 mg) was injected intravenously through the antecubital vein at a slow rate (over 2–3 minutes). pCLE examination was started 5 minutes after the completion of injection.

During pCLE examination, the imaging probe was inserted through the working channel of the cystoscope and placed in contact with the surface of the lesion. The probe was moved gently to scan the lesion and the surrounding normal tissue. Images and videos were continuously acquired at a frame rate of 12 frames per second, and representative images were saved for subsequent analysis. Probes of different diameters (1.9, 2.6, and 3.2 mm) were tested in each patient to compare the imaging quality and maneuverability.

Post-examination treatment: TURBT or biopsy was performed for all patients after pCLE examination, and the resected tissue specimens were sent for histopathological examination.

Outcome measures

Primary outcomes (feasibility and safety)

Feasibility: defined as the technical completion rate of pCLE examination, i.e., the proportion of patients who successfully completed the entire pCLE examination process (including lesion scanning, image/video acquisition, and quality meeting the analysis requirements) among all enrolled patients.

Safety: evaluated by recording all adverse reactions related to pCLE examination or fluorescein sodium during and within 72 hours after the procedure, and the adverse reactions were graded according to the Clavien-Dindo classification system [grade 0: no adverse reaction; grade I: mild adverse reaction, no clinical intervention required; grade II: moderate adverse reaction, requiring pharmacological intervention; grade III: severe adverse reaction, requiring surgical/endoscopic/interventional treatment; grade IV: life-threatening adverse reaction, requiring intensive care unit (ICU) treatment; grade V: death].

Secondary outcomes

Imaging performance of probes: evaluated by two senior urologists (blinded to clinical data) for the imaging quality (clarity of cellular/tissue structures) and maneuverability (ease of reaching lesions in different bladder parts) of 1.9, 2.6, and 3.2 mm probes, with a 4-point scoring system (1: poor; 2: fair; 3: good; 4: excellent).

Clinical characteristics of two fluorescein sodium administration routes: operation time (from contrast agent administration to the end of pCLE examination), interference degree to the subsequent TURBT surgical field [0: no interference; 1: mild interference (lesion margin visualization affected but no impact on operation completion); 2: severe interference (operation unable to be completed)].

Preliminary pCLE imaging features: descriptive analysis of the cellular and tissue structural characteristics of normal bladder mucosa, benign lesions, and different grades of malignant lesions based on pCLE images, with histopathological examination as the gold standard.

Pathological examination

After pCLE examination, transurethral resection of the bladder lesion or biopsy was performed for all patients. The resected tissue specimens were fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned, stained with hematoxylin-eosin (HE), and examined by a senior pathologist with more than 10 years of experience in urinary pathology. Pathological classification was based on the 2022 World Health Organization (WHO) classification of urinary tract tumors, including high-grade urothelial carcinoma, low-grade urothelial carcinoma, benign lesions after CIS surgery, and papillary urothelial neoplasm of low malignant potential (PUNLMP).

Statistical analysis

Statistical analysis was performed using SPSS 26.0 software (IBM Corp., Armonk, NY, USA). Since this was a pilot feasibility study with a small sample size, only descriptive statistics were used, and no inferential statistical analysis was performed. Continuous variables were expressed as mean ± standard deviation (SD) or median (range), and categorical variables were expressed as frequencies and percentages. Imaging quality and maneuverability scores of probes were expressed as median [interquartile range (IQR)].

Results

Baseline characteristics of the study cohort

The baseline demographic and clinical characteristics of the 10 enrolled patients are summarized in Table 1. The cohort had a mean age of 65.0±15.2 years, 9 males (90.0%) and 1 female (10.0%), with 4 cases (40.0%) of hypertension and 4 cases (40.0%) of diabetes. Nine cases (90.0%) were for initial diagnosis of bladder masses and 1 case (10.0%) was for postoperative follow-up of bladder cancer. Lesions were distributed in the bladder trigone (4 cases, 40.0%), lateral wall (3 cases, 30.0%), dome (2 cases, 20.0%) and multiple sites (1 case, 10.0%), with a median lesion diameter of 1.5 cm (range, 0.5–3.0 cm) and 5 cases (50.0%) of single lesion, 5 cases (50.0%) of multiple lesions (≥2). All patients had normal renal and hepatic function except one with mild renal impairment.

Primary outcomes: feasibility and safety

Feasibility: all 10 enrolled patients successfully completed the entire pCLE examination process, including lesion scanning, image/video acquisition (quality meeting the analysis requirements), with a technical completion rate of 100% (feasibility rate =100%).

Safety: no adverse reactions related to pCLE examination or fluorescein sodium were observed during and within 72 hours after the procedure (Clavien-Dindo grade 0). Transient yellowish-green urine occurred in all 4 patients in the intravenous injection group, which was a non-clinically significant reaction without the need for pharmacological or interventional treatment, and resolved spontaneously within 24–36 hours. No anaphylactic reactions, skin rashes, nausea, vomiting, renal or liver function impairment were found in any patient.

Secondary outcomes: probe imaging performance and fluorescein sodium administration routes

Imaging performance of different-diameter probes

The 2.6 mm probe had the optimal comprehensive performance, with a median imaging quality score of 4 (IQR, 4–4) and a median maneuverability score of 4 (IQR, 3–4). The 1.9 mm probe had poor imaging quality (median score =2; IQR, 1–2) due to its small size leading to limited resolution, while the 3.2 mm probe had excellent imaging quality (median score =4; IQR, 4–4) but poor maneuverability (median score =2; IQR, 1–2), especially difficult to reach lesions in narrow anatomical areas such as the bladder neck and lateral wall angles.

Clinical characteristics of two fluorescein sodium administration routes

Six patients were assigned to the intravesical instillation group and 4 to the intravenous injection group. The intravesical instillation group had a longer operation time (median =45 minutes; range, 30–60 minutes) with 0 cases of surgical field interference (0/6) during subsequent TURBT. The intravenous injection group had a significantly shorter operation time (median =7 minutes; range, 5–10 minutes), but 2 cases (50.0%) of mild surgical field interference (interference degree =1) (lesion margin visualization was slightly affected, but the TURBT operation was successfully completed without additional intervention). All patients in both groups achieved clear contrast enhancement of bladder lesions for pCLE imaging.

Pathological results

Histopathological examination results (gold standard) showed: 5 cases (50.0%) of high-grade urothelial carcinoma, 3 cases (30.0%) of low-grade urothelial carcinoma, 1 case (10.0%) of benign lesions after CIS surgery, and 1 case (10.0%) of PUNLMP. Among the 5 cases of high-grade urothelial carcinoma, 1 patient with multiple lesions (≥5 lesions) distributed in the bladder trigone, bladder neck, lateral wall, and dome underwent radical cystectomy, and the remaining 9 patients underwent TURBT (surgical specimens were consistent with preoperative biopsy results).

Preliminary descriptive pCLE imaging features of bladder tissues

Due to the small sample size, only preliminary descriptive analysis of pCLE imaging features was performed (no quantitative diagnostic accuracy calculation), and the typical pCLE features of different bladder tissues observed in this study were as follows (Figure 1):

• Normal bladder mucosa: polygonal superficial umbrella cells with clear boundaries, uniform size, and regular arrangement; subepithelial capillaries with clear lumens and uniform distribution (Figure 1A);
• Benign lesions after CIS surgery: slight cell hyperplasia or disorganization, but no obvious cellular pleomorphism; no papillary structures or fibrovascular cores; clear cell boundaries (Figure 1B);
• Low-grade urothelial carcinoma: well-formed papillary structures with distinct fibrovascular cores; cells are relatively uniform in size and shape, with slightly increased nuclear-cytoplasmic ratio; cell arrangement is relatively regular (Figure 1C);
• High-grade urothelial carcinoma: disordered cell arrangement; obvious cellular pleomorphism with large and hyperchromatic nuclei; unclear cell boundaries; disorganized or absent papillary structures; irregular distribution of capillaries (Figure 1D);
• PUNLMP: papillary structures with fibrovascular cores; cells are almost similar to normal urothelial cells, with minimal nuclear atypia (Figure 1E).

Figure 1 Representative images of domestic pCLE imaging. (A) Normal bladder mucosa; (B) benign lesions after CIS surgery; (C) low-grade urothelial carcinoma; (D) high-grade urothelial carcinoma; (E) PUNLMP. CIS, carcinoma in situ; pCLE, probe-based confocal laser endomicroscopy; PUNLMP, papillary urothelial neoplasm of low malignant potential.

Discussion

This single-center prospective single-arm cohort study is the first to verify the technical feasibility and safety of a domestic pCLE system in the diagnosis of bladder lesions, with a 100% technical completion rate and no Clavien-Dindo grade ≥I adverse reactions in 10 enrolled patients. As a pilot exploratory study for the initial clinical application of domestic medical devices, the results provide important preliminary clinical data for the subsequent development and large-sample research of this domestic pCLE system. The following key findings are discussed in combination with the current clinical status and study limitations.

Feasibility and safety: core outcomes of pilot medical device research

The primary research objective of this study was to verify the technical feasibility and safety of the domestic pCLE system, which is the core endpoint of the initial clinical evaluation of new medical devices (15). The 100% technical completion rate indicates that the domestic pCLE system has good technical operability in clinical practice, and the probe can be effectively combined with conventional cystoscopy to complete the scanning of bladder lesions in different anatomical parts (trigone, lateral wall, dome, etc.). The safety results showed no adverse reactions related to the device or contrast agent, which is consistent with the safety profile of imported pCLE systems reported in previous studies (16,17). The transient yellowish-green urine in the intravenous injection group is a known physiological reaction of fluorescein sodium (renal excretion), without clinical intervention, which further confirms the safety of fluorescein sodium in bladder lesion diagnosis with pCLE.

Notably, this study used the Clavien-Dindo classification system to standardize the grading of adverse reactions, which is a universal standard for clinical research adverse reaction evaluation and makes the safety results more comparable and credible. The excellent feasibility and safety results lay a solid foundation for the subsequent large-sample, multicenter clinical research of this domestic pCLE system.

Probe selection and fluorescein sodium administration route: clinical practical guidance

The choice of probe diameter is crucial for the imaging performance of pCLE, and the balance between imaging quality and maneuverability is the key to clinical application (18). This study found that the 2.6 mm probe had the optimal comprehensive performance, which is consistent with the research results of Adams et al. (17) on pCLE probes for urinary tract imaging. The 1.9 mm probe had poor imaging quality due to insufficient resolution, which may lead to the inability to clearly identify cellular details, while the 3.2 mm probe had poor maneuverability and was difficult to reach lesions in narrow anatomical areas such as the bladder neck and lateral wall angles—this finding provides direct practical guidance for the clinical application of this domestic pCLE system, and the 2.6 mm probe is recommended as the first choice for subsequent clinical research and application.

For the two fluorescein sodium administration routes, both can achieve clear contrast enhancement for pCLE imaging, but have their own clinical characteristics. Intravesical instillation has no interference to the subsequent TURBT surgical field, which is suitable for patients who need immediate tumor resection after pCLE diagnosis; however, the long operation time (30–60 minutes) may increase patient discomfort and the risk of bladder irritation. Intravenous injection has the advantage of short operation time (5–10 minutes) and high examination efficiency, which is suitable for patients who only need diagnostic evaluation of bladder lesions; but 50% of cases have mild interference to the visualization of TURBT lesion margins (without affecting operation completion). This finding is consistent with the clinical characteristics of fluorescein sodium administration routes reported in previous studies (12-14), and provides a reference for the clinical selection of contrast agent administration routes for domestic pCLE systems.

Preliminary pCLE imaging features: no quantitative diagnostic accuracy calculation

This study observed preliminary distinguishable pCLE imaging features between normal bladder mucosa, benign lesions, and different grades of malignant lesions, which is consistent with the imaging features of imported pCLE systems reported in previous studies (8-11). However, due to the extremely small sample size (only 10 cases, including only 1 case of benign lesions and 1 case of PUNLMP), the number of non-malignant cases is far less than the statistical requirement for diagnostic accuracy calculation (the marginal error of sensitivity and specificity is extremely high, leading to clinically unreliable results). Therefore, this study only performed descriptive analysis of imaging features and did not calculate any quantitative diagnostic accuracy indicators (sensitivity, specificity, accuracy), which is a key improvement to avoid misleading clinical interpretation of the results. The preliminary imaging features observed in this study need to be verified and supplemented in subsequent large-sample studies with sufficient numbers of benign and malignant lesions of different types and grades.

Critical study limitations

This study is a pilot exploratory research with several unavoidable critical limitations, which must be fully recognized and explained, and the research conclusions must be strictly limited within the scope of the study design:

• Extremely small sample size: only 10 patients were enrolled, and no inferential statistical analysis was performed. The results can only verify the technical feasibility and safety of the domestic pCLE system in a small sample, and cannot be generalized to the whole clinical population, nor can any conclusion on the diagnostic efficacy of the system be drawn.
• Single-center design: the study was conducted in a single tertiary hospital, and the enrolled patients have relatively homogeneous clinical characteristics, which may lead to selection bias. The feasibility and safety results need to be verified in multicenter studies with different levels of medical institutions and more diverse patient populations.
• Lack of randomization and control group: the patients were divided into two fluorescein sodium administration groups according to clinical decision, without randomization, which may lead to selection bias. In addition, there is no control group (e.g., imported pCLE system or WLC), so it is impossible to directly compare the clinical advantages of the domestic pCLE system with existing diagnostic methods.
• Lack of long-term follow-up: this study only evaluated the short-term feasibility and safety of the domestic pCLE system, and did not conduct long-term follow-up to assess the value of the system in bladder cancer recurrence monitoring and prognosis evaluation, which is an important clinical application direction of pCLE and needs to be explored in subsequent studies.
• User dependence of pCLE: pCLE imaging interpretation has a steep learning curve and is highly user-dependent (8-11). Although this study was completed by the same experienced urological team, the lack of a unified imaging interpretation standard and inter-observer consistency analysis is a limitation, which needs to be improved in subsequent large-sample studies.

Future research directions

Based on the results and limitations of this pilot study, the following future research directions for the domestic pCLE system are proposed:

• Conduct large-sample (calculated based on diagnostic accuracy research requirements) multicenter prospective cohort studies to verify the preliminary imaging features of the domestic pCLE system and evaluate its diagnostic efficacy (sensitivity, specificity, accuracy) for bladder lesions;
• Design RCT studies to compare the diagnostic performance of the domestic pCLE system with imported pCLE systems and conventional WLC, and further explore the optimal contrast agent administration route and probe application scheme;
• Establish a unified domestic pCLE imaging interpretation standard for bladder lesions and conduct inter-observer and intra-observer consistency analysis to reduce user dependence;
• Conduct long-term follow-up studies to evaluate the clinical value of the domestic pCLE system in bladder cancer recurrence monitoring, prognosis evaluation, and guiding individual treatment;
• Explore the application of the domestic pCLE system in the diagnosis of other urological lesions (e.g., ureteral, renal pelvic lesions) to expand its clinical application scope.

Conclusions

In this single-center prospective single-arm cohort pilot study, the domestic pCLE system demonstrated excellent technical feasibility (100% technical completion rate) and good safety (no Clavien-Dindo grade ≥ I adverse reactions) in the diagnosis of bladder lesions. The 2.6 mm probe has the optimal comprehensive imaging performance and is the preferred probe for clinical application; intravesical instillation and intravenous injection of fluorescein sodium have their own clinical characteristics, which can be selected according to the patient’s clinical needs. The study observed preliminary distinguishable pCLE imaging features of different bladder tissues, but due to the small sample size, no conclusion on the diagnostic accuracy of the domestic pCLE system can be drawn.

Larger-sample, multicenter prospective cohort studies and RCTs with sufficient statistical power are urgently needed to verify the preliminary imaging features, evaluate the diagnostic efficacy, and explore the optimal clinical application scheme of this domestic pCLE system. The results of this pilot study lay a solid preliminary clinical foundation for the subsequent research and clinical promotion of domestic pCLE systems in the field of urological oncology.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-1000/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-1000/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-1000/prf

Funding: This study was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0525700), the National Key Research and Development Program of China (No. 2018YFA0902802), the Beijing Municipal Science &Technology Commission (No. Z191100006619010), and the National Natural Science Foundation of China (No. 81802533).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-1000/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was approved by the Institutional Ethics Committee of Peking University People’s Hospital (No. 2025-z073), and all patients provided written informed consent before participation.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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