
==== Front
PLoS One
PLoS One
plos
PLOS ONE
1932-6203
Public Library of Science San Francisco, CA USA

10.1371/journal.pone.0305240
PONE-D-24-20978
Research Article
Biology and Life Sciences
Bioengineering
Biotechnology
Medical Devices and Equipment
Catheters
Engineering and Technology
Bioengineering
Biotechnology
Medical Devices and Equipment
Catheters
Medicine and Health Sciences
Medical Devices and Equipment
Catheters
Medicine and Health Sciences
Surgical and Invasive Medical Procedures
Medicine and Health Sciences
Epidemiology
Medical Risk Factors
Cancer Risk Factors
Medicine and Health Sciences
Oncology
Cancer Risk Factors
Medicine and Health Sciences
Urology
Genitourinary Cancers
Bladder Cancer
Medicine and Health Sciences
Oncology
Cancers and Neoplasms
Genitourinary Tract Tumors
Bladder Cancer
Biology and Life Sciences
Anatomy
Lymphatic System
Lymph Nodes
Medicine and Health Sciences
Anatomy
Lymphatic System
Lymph Nodes
Medicine and Health Sciences
Endocrinology
Endocrine Disorders
Diabetes Mellitus
Medicine and Health Sciences
Medical Conditions
Metabolic Disorders
Diabetes Mellitus
Medicine and Health Sciences
Clinical Medicine
Signs and Symptoms
Edema
Research and Analysis Methods
Mathematical and Statistical Techniques
Statistical Methods
Regression Analysis
Physical Sciences
Mathematics
Statistics
Statistical Methods
Regression Analysis
Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancer
Lymphatic embolization after radical cystectomy
https://orcid.org/0009-0005-5075-1843
Shin Yoo Sub Conceptualization Data curation Formal analysis Investigation Writing – original draft Writing – review & editing 1
Han Kichang Investigation Validation 2
Lee Jongsoo Validation Writing – original draft 1
Han Hyun Ho Methodology Validation 1
Jang Won Sik Conceptualization Methodology 1
Kim Gyoung Min Project administration Writing – review & editing 2 *
https://orcid.org/0000-0002-4184-8468
Heo Ji Eun Conceptualization Project administration Writing – original draft Writing – review & editing 1 *
1 Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
2 Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
Zahir Mazyar Editor
Keck Hospital of USC, UNITED STATES OF AMERICA
Competing Interests: The authors have declared that no competing interests exist.

* E-mail: heoji87@yuhs.ac (JEH); gyoungmin@yuhs.ac (GMK)
24 9 2024
2024
19 9 e03052404 6 2024
8 9 2024
© 2024 Shin et al
2024
Shin et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background and objective

Although radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the standard treatment of muscle invasive bladder cancer, it may cause lymphatic leakage. Recent studies describe lymphatic embolization (LE) as an option to manage post-operative lymphatic leakage. Hence, this study evaluated the outcome of LE in patients receiving RC and analyzed factors associated with outcomes.

Methods

This was a retrospective analysis of patients who underwent LE after RC for bladder cancer between August 2017 and June 2023. The data was assessed for analysis at January 2024. The patients were divided into a clinical success group and a clinical failure group. Clinical failure was defined as the following: 1) those who required drainage catheter placement >7 days after LE, 2) those who needed re-intervention before catheter removal, and 3) those who experienced adverse events associated with LE. Logistic regression analysis was performed to identify the factors associated with outcomes of LE.

Key findings and limitations

We analyzed 45 patients who underwent LE after RC. Twenty-eight (62.2%) patients were identified as clinically successful. Four patients required re-embolization, but none required more than two sessions of intervention. Three patients experienced lymphatic complications after LE. In multivariable analysis, maximal daily drainage volume of >1,000 mL/day (odds ratio [OR] = 4.729, 95% confidence interval [CI]: 1.018–21.974, p = 0.047) and diabetes mellitus (DM) (OR = 4.571, 95% CI: 1.128–18.510, p = 0.033) were factors associated with LE outcome.

Conclusions and clinical implications

Our results suggest LE as a potentially effective procedure for controlling post-operative lymphatic leaks after RC, with few minor side effects. Patients exceeding a daily drainage of 1,000mL/day or with a medical history of DM have a higher risk for re-intervention and clinical failure after LE.

The author(s) received no specific funding for this work. Data AvailabilityAs this study covers an extremely specific population, our data set is potentially identifying patient information even after proper de-identification. Still, our data can be shared upon request. Contact for our data can be made through the institutional review board (Yonsei-IRB, irb@yuhs.ac).
Data Availability

As this study covers an extremely specific population, our data set is potentially identifying patient information even after proper de-identification. Still, our data can be shared upon request. Contact for our data can be made through the institutional review board (Yonsei-IRB, irb@yuhs.ac).
==== Body
pmcIntroduction

Pelvic lymphatic leakage is a well-recognized postoperative complication after pelvic surgery. In most cases, these leaks resolve spontaneously because the rate of fluid leakage does not exceed the rate of absorption by the peritoneum. However, in cases of massive leakage, patients may require extended placement of post-operative drainage catheters, which can delay their overall recovery and initiation of adjuvant therapy. Additionally, excessive fluid build-up from these leaks can lead to the formation of lymphocele, resulting in secondary complications, e.g., infections, pain, and deep vein thrombosis [1].

For well-contained lymphatic fluid collections such as lymphoceles, percutaneous drainage and sclerotherapy using ethanol injection are effective. Injected ethanol has been proposed to cause fibrosis of the lymphatic channels, sealing leakage points [2, 3]. Early postoperative leakage, however, often occurs as a spill into the pelvic space, making it unsuitable for sclerotherapy [4]. Consequently, lymphatic embolization (LE) has garnered attention as an effective alternative to sclerotherapy. Not only is LE suitable for controlling early spillages, but it is also more effective than ethanol sclerotherapy in controlling leaks [5, 6].

Although LE has generally been considered safe and effective in multiple retrospective studies, no studies have focused on a single disease entity or type of surgery [4–7]. Pelvic surgery encompasses a wide range of urological, gynecological, and gastrointestinal surgeries, each with distinct patterns of nodal metastasis and surgical protocols.

Patients with muscle-invasive bladder cancer are frequently treated using radical cystectomy (RC) with bilateral pelvic lymph node dissection (PLND) [8]. Although the ideal extent of dissection has not been defined, the SWOG 1011 trial recently confirmed lower mortality and morbidity using a standard PLND template than that with an extended approach, without compromising overall patient survival [9]. Lymphatic complications may occur in up to 3–11% of patients, with an increased incidence in patients who undergo a wide PLND template or extraperitoneal approach [10–15]. However, the management of post-RC lymphatic leaks and/or lymphoceles is not well-defined. Only few case reports are available, each describing a different treatment approach [16, 17]. Such lymphatic complications can impede perioperative recovery and delay future treatment. Therefore, this study aimed to assess the efficacy of LE and identify the risk factors associated with successful outcomes of LE for lymphatic leakage after RC.

Materials and methods

Ethics statements

This study was approved by the Institutional Review Board (IRB) of Yonsei University Hospital (IRB number: 4-2023-0766). The requirement for informed consent was waived by the IRB owing to the non-invasive and retrospective study design. Data was provided to the authors after de-identifying all personal information of participants.

Study design and population

We reviewed a single-institution database in January 2024 to identify patients who underwent LE after RC and PLND for bladder cancer between August 2017 and June 2023. All RC was performed with a curative intent. To ensure the inclusion of cases specific to early postoperative lymphatic leakage, the following criteria were applied: 1) lymphocele present prior to LE, 2) presence of idiopathic lymphatic leaks unrelated to PLND, and 3) postoperative leaks related to surgical procedures in anatomical regions outside the pelvis. To maintain the homogeneity of the cohort, we excluded patients with pathological reports describing conditions other than urothelial carcinoma. We defined the primary outcome of the study as the rate of clinical success of LE. Secondary outcomes included risk factors associated with LE and complications associated with the procedure.

Lymphatic leakage was confirmed when radiographic evidence of leakage was found in lymphangiography. Lymphangiography and LE was consulted in patients who continued to experience daily catheter drainage exceeding 500 mL/day for >5 days despite receiving conservative care. Conservative management included low-fat diet with medium-chain triglycerides (MCTs) and protein supplementation. Secondary causes of fluid collection such as infection, postoperative bleeding, and urine leakage were excluded prior to consultation. Consequently, we only included patients whose drainage fluid exhibited a grossly clear, odorless character, negative culture results, and creatinine levels consistent with their serum levels. Simultaneous LE following lymphangiography was performed when radiographic evidence of lymphatic leakage was found.

Radical cystectomy and pelvic lymph node dissection procedure

Prior to surgery, patients received thorough consultation on the surgical approach and type of urinary diversion. Open RC was performed in an extraperitoneal fashion, and robotic RC was performed intraperitoneally using a multiport robotic system. All patients received a bilateral PLND using a standard template, dissecting the external iliac, internal iliac, and obturator lymph nodes. All lymph nodes were dissected proximal to the common iliac bifurcation, above the circumflex iliac vein and medial to the genitofemoral nerve. Bilateral iliac arteries, iliac veins and obturator nerves were skeletonized during PLND. Bipolar cauterization was used to seal visible leakage sites after PLND, with or without applying metal clips based on the surgeons’ preference. A drainage catheter was placed in the pelvic space before closing the incision, and a post-operative abdominal X-ray was filmed, which confirmed its correct position.

Lymphangiography, LE procedure

Two experienced interventional radiologists performed the LE procedure. Both inguinal lymph nodes (LNs) were punctured using a 3.5-cm long 25-gauge fine needle under ultrasound guidance. Lymphangiography was performed by manually injecting ethiodized oil (Lipiodol; Guerbet, LLC) into the LNs at an injection rate of 0.2–0.5 mL per minute until opacification of the pelvic lymphatic system was observed. Following the identification of lymphatic leakage, 5% dextrose water was injected into the LN before embolization to avoid premature polymerization. LE was performed by injecting a mixture of N-butyl cyanoacrylate and ethiodized oil at a ratio of 1:1–1:4 into the LNs, which provided afferent lymphatic flow to the leakage sites (Fig 1). When there was a LN closer to the leakage site than the initially accessed LN, that closest upstream LN was additionally punctured and embolization was performed there.

10.1371/journal.pone.0305240.g001 Fig 1 Successful clinical outcome in a 67-year-old man.

Daily catheter drainage was increasing up to 1600 mL/day. Lymphatic embolization was performed on postoperative day 5. Leakage of Lipiodol into the pelvic cavity was noted (arrowheads) bilaterally on nodal lymphangiography. Embolization was performed by injecting a mixture of N-butyl cyanoacrylate and Lipiodol into the lymph nodes (arrows) at a ratio of 1:3. The amount of drainage decreased to 32 mL/day at 2 days after procedure, and the drainage catheter was removed.

Data collection

We collected the following data: the daily drain output before and after LE, patient age at the time of the procedure, body mass index, sex, medical history, surgical approach, type of urinary diversion, estimated blood loss (EBL), and pathological results. Lymph node density was calculated as the percentage of positive lymph nodes from the total number of nodes dissected during PLND ([number of positive nodes/number of total dissected nodes] *100).

All patients received imaging studies and out-patient follow-ups based on the National comprehensive cancer network bladder cancer guideline (version 4.2024) [18]. Image studies and out-patient records within 6 months after LE were reviewed for LE associated complications.

After LE, patients were categorized into clinical success and failure groups. Although the definition of clinical success varied upon different studies, we applied a unique and stringent for defining clinical success [5, 6]. Patients were included in the failure group if they met any of the following criteria: 1) drainage catheter placement required > 7 days post-LE, 2) re-intervention required prior to catheter removal, and 3) occurrence of adverse events associated with LE, e.g., lower extremity edema found on computed tomography (CT) within 6 months of post-LE follow-up. There was no consistent timing for drainage catheter removal among the patients, as the timing was determined by the surgeon in charge of the patient; however, drainage removal was frequently indicated when daily drainage was < 300 mL per day. Re-intervention was defined as the requirement for more than one session of LE prior to drainage catheter removal.

Statistical analysis

Comparative analysis was conducted using the Fisher exact test; linear-by-linear association analysis was used to analyze categorical variables, and the Mann–Whitney test was used to analyze continuous variables. Additionally, logistic regression analysis was performed to identify the risk factors for clinical failure. The level of significance was set at p<0.05. The cutoff value for drainage volume used in logistic regression was set in reference to previous studies [19, 20]. All statistical analyses were performed using SPSS (version 26.0; IBM Corp., Armonk, NY, USA).

Results

A total of 491 patients underwent RC during the study period, of whom 55 subsequently underwent LE. Ten patients were excluded from this study for the following reasons: non-urothelial cancer origin (n = 6), LE after drainage catheter removal (n = 2), non-procedure-related mortality (n = 1), or incomplete clinical data (n = 1) (Fig 2). In total, 45 patients were included in our analysis.

10.1371/journal.pone.0305240.g002 Fig 2 Summary of patient selection and results of lymphatic embolization for lymphatic leakages.

Table 1 shows the clinical characteristics of patients in the success and failure groups. Among the 45 patients included in this study, 28 (62.2%) were categorized into the success group. Diabetes Mellitus (DM) was more prevalent in the clinical failure group (21.4% and 52.9%, p = 0.050). Other demographic variables were not significantly different between the two groups. Moreover, the surgical approach (p = 0.144), urinary diversion type (p = 0.341), and EBL (p = 0.927) did not differ between the groups. The median number of dissected LNs were 16.5 (12.3–24.5) and 19.0 (14.5–25.5) in the success and failure groups, respectively (p = 0.331). with both groups representing similar frequencies of nodal metastasis (42.9% and 41.2%, respectively; p = 1.000). Distant metastasis was found only in the success group (17.9% vs. 0%, p = 0.140).

10.1371/journal.pone.0305240.t001 Table 1 Patients’ characteristics.

Characteristics	Success (n = 28)	Failurea (n = 17)	P value	
Age (y)	73.0 (69.3–77.0)	74.0 (68.0–80.0)	0.972	
Body mass index (kg/m2)	24.5 (22.7–25.5)	23.4 (21.1–25.8)	0.223	
Sex			0.547	
    Male	27 (96.4%)	15 (88.2%)		
    Female	1 (3.6%)	2 (11.8%)		
Medical history				
    Hypertension	15 (53.6%)	8 (47.1%)	0.763	
    Diabetes mellitus	6 (21.4%)	9 (52.9%)	0.050	
    ASA			0.381	
    1	1 (3.6%)	0 (0%)		
    2	6 (21.4%)	7 (41.2%)		
    3	21 (75%)	10 (58.8%)		
Surgical approach			0.144	
    Open	27 (96.4%)	14 (82.4%)		
    Robotic	1 (3.6%)	3 (17.6%)		
Urinary diversion			0.341	
    Ureterocutaneostomy	9 (32.1%)	5 (29.4%)		
    Ileal conduit	18 (64.3%)	9 (52.9%)		
    Neobladder	1 (3.6%)	3 (17.6%)		
Estimated blood loss (mL)	600.0
(462.5–1000.0)	600.0
(300.0–1100.0)	0.927	
T stage			0.537	
    ≤T2	10 (35.7%)	8 (47.1%)		
    >T2	18 (64.3%)	9 (52.9%)		
N stage			1.000	
    N0	16 (57.1%)	10 (58.8%)		
    ≥N1	12 (42.9%)	7 (41.2%)		
M stage			0.140	
    M0	23 (82.1%)	17 (100%)		
    M1	5 (17.9%)	0 (0%)		
Variant histology	11 (64.7%)	6 (35.3%)	1.000	
Positive surgical margin	5 (17.9%)	2 (11.8%)	0.693	
Total number of dissected LN (n)	16.5 (12.3–24.5)	19.0 (14.5–25.5)	0.331	
LN density (%)	0.0 (0.0–18.3)	12.0 (9.0–26.0)	0.979	
Average catheter drainage (mL/d)	487.8
(380.6–601.4)	613.0
(474.5–833.0)	0.058	
Maximum catheter drainage (mL/d)	750.0
(583.5–1039.8)	1014.0
(693.5–1525.0)	0.050	
Duration from operation to LE (d)	7.0 (6.0–9.75)	7.0 (7.0–11.0)	0.271	
Day from LE to drain removal (d)	4.0 (2.0–5.0)	8.0 (5.5–12.0)	<0.001	
Day to discharge after LE (d)	4.0 (3.0–7.8)	12.0 (9.0–26.0)	<0.001	
ASA = American society of anesthesiologists physical status classification, LE = Lymphatic embolization; LN = lymph node. Data are expressed median (interquartile range) or N (%).

a) Failure defined as: 1) Requiring reintervention, 2) > 1 week to drainage catheter removal post lymphatic embolization, 3) lymphatic complications.

The average daily drainage volumes were 487.8 mL/day and 613.0 mL/day in the success and failure groups, respectively (p = 0.058). The maximum daily drainage was significantly higher in the failure group than in the success group (750.0 mL/day vs. 1014.0 mL/day, p = 0.050). Fig 3 depicts the median drainage volume of the clinical success and failure group, from 5 days prior to LE to 5 days post-LE. An overall decrease in volume after LE is observed in both groups. 24 of 28 (85.7%) clinical success group removed their drain within 5 days after LE, and 4 out of 17 (23.5%) clinical failure group removed their drain within 5 days after LE.

10.1371/journal.pone.0305240.g003 Fig 3 Median daily drainage volume of patients from 5 days prior to LE to 5 days after LE.

A) Median daily drainage volume in clinical success group. B) Median daily drainage volume in clinical failure group.

Among the 17 (37.8%) patients classified in the failure group, 4 required re-embolization due to recurrent lymphatic leakage, and 10 either failed to have their drainage catheter removed prior to discharge or received delayed removal of their drains (Table 2). Of the 4 patients requiring re-embolization, all successfully removed their catheter after their second session. Three patients presented lower extremity edema after LE. All edemas were self-resolved during out-patient follow-up. Five patients were found with incidental, asymptomatic lymphoceles after LE through routine follow-up abdominal CT. None required additional drainage. Lymphoceles were located either in the lower quadrant of the abdomen or the pelvic space, and the median size of the lymphocele was 4.0 cm. Although the largest lymphocele reached up to 10.0 cm, no complications or symptoms were found.

10.1371/journal.pone.0305240.t002 Table 2 Clinical outcomes of lymphatic embolization.

Outcomes	No. of events (%)	
Reintervention	4 (8.9%)	
Catheter Removal		
    Success (≤ 1 week)	35 (77.8%)	
    Delayed (> 1 week)	9 (20.0%)	
    Failure	1 (2.2%)	
Intervention related complication		
    None	42 (93.3%)	
    Lower extremity edema	3 (6.7%)	
Non-lymphatic complicationa		
    Gastrointestinal	4 (8.9%)	
    Pulmonary	2 (4.4%)	
    Wound complication	2 (4.4%)	
    Anastomosis stricture	2 (4.4%)	
    Anastomosis leakage	1 (2.2%)	
Clinical success		
    Success	28 (62.2%)	
    Failure	17 (37.8%)	
Follow up imaging		
    Asymptomatic lymphocele	5 (8.9%)	
    Complicated lymphocele	0 (0%)	
a) complications greater Clavien-dindo classification grade 3 were recorded

The results of the logistic regression analysis of the clinical outcomes of LE are presented in Table 3. Multivariate analysis demonstrated that maximal daily drainage volume of >1,000 mL/day (odds ratio [OR] = 4.729, 95% confidence interval [CI]: 1.018–21.974, p = 0.047) and diabetes mellitus (DM) (OR = 4.571, 95% CI: 1.128–18.510, p = 0.033) were significantly associated with clinical failure of LE. Nodal stage of disease (OR = 0.933, 95% CI: 0.275–3.168, p = 0.912) nor lymph node density (cut-off≥20%) (OR = 0.923, 95% CI: 0.225–3.780, p = 0.911) was not associated with clinical outcome.

10.1371/journal.pone.0305240.t003 Table 3 Logistic regression analysis of risk factors associated with clinical outcome.

1. Univariate analysis		
Variables	OR (95% CI)	P value	
Sex	3.60 (0.30–43.08)	0.312	
Age (≥75 years)	0.56 (0.10–3.16)	0.511	
Body mass index (kg/m2)	2.67 (0.74–9.60)	0.133	
Medical history			
    Hypertension	0.77 (0.23–2.58)	0.672	
    Diabetes Mellitus	4.13 (1.11–15.32)	0.034	
Average catheter drainage (≥500mL/d)	3.25 (0.85–12.45)	0.085	
Maximum catheter drainage (≥1000mL/d)	4.20 (1.00–17.60)	0.050	
Surgical approach	5.40 (0.44–66.67)	0.188	
T stage (≥T2)	0.63 (0.18–2.13)	0.453	
N stage (≥N1)	0.93 (0.28–3.17)	0.912	
Variant histology	0.84 (0.24–2.95)	0.789	
Positive surgical margin	0.61 (0.16–3.58)	0.587	
Lymph node density (≥20%)	0.92 (0.23–3.78)	0.911	
2. Multivariate analysis			
Variables	OR (95% CI)	P value	
Diabetes Mellitus	4.57 (1.13–18.51)	0.033	
Maximum catheter drainage (≥1000mL/d)	4.73 (1.02–21.97)	0.047	
OR = odds ratio, CI = Confidence interval

Discussion

While previous investigations of LE have included heterogeneous patient groups with pelvic lymphatic leakage, our study marks the first attempt to explore LE exclusively in patients with bladder cancer undergoing RC. Of the 45 cases, 35(77.8%) patients underwent successful drainage removal within a week after LE, and all but 1 patient had their drain removed before discharge. While minor side effect (leg edema) was observed, no major adverse events were observed during the 6-month follow-up. Thus, our study demonstrates that LE is an effective and safe procedure for refractory lymphatic leakage in patients after RC.

Conservative management has traditionally been the primary approach for managing lymphatic leakage. Leibovitch et al. proposed an algorithm starting with MCT diets, followed by the addition of total parental nutrition or somatostatin analogs [21]. In parallel with the aforementioned study, early investigations proceeded to surgical intervention only after the failure of dietary and medical management [22, 23]. However, conservative management often requires prolonged drainage catheter placement, which not only affects the patient’s quality of life and prolongs hospitalization, but also increases the risk of secondary infection. Therefore, the advent of LE has enabled early intervention for refractory leaks, resulting in quicker resolution of lymphatic leakage and thus improving patient quality of life and complications associated with the leak.

Early studies have shown the efficacy and safety of LE for postoperative lymphatic leakage [1, 24–26]. However, initial impact was limited as early studies focused on the feasibility and technical aspect of the procedure. Recent investigations have attempted to compare LE with sclerotherapy; Kim et al. showed not only improved clinical success rates in LE compared with sclerotherapy, but also a reduced number of sessions in patients receiving LE [5]. A comparison by Seyferth et al. showed similar results, with earlier resolution of leakage in the LE group than in the sclerotherapy group [6]. Further, Lee et al. analyzed the risk factors for successful LE in 71 patients [4]. Their research revealed that old age and a larger drainage volume before LE (>1,500 mL/day) were associated with clinical failure.

In this study, we found that a maximum preprocedural drainage volume >1,000 mL/day was an independent predictor of LE failure. The average drainage volume showed a similar trend, although this did not reach statistical significance. Our results are consistent with those of a previous study that demonstrated that daily drainage of >500 mL/day negatively affects the clinical success of therapeutic lymphangiography [27]. Although the exact causality linking drainage volume to embolization remains uncertain, it is conceivable that a large drainage volume correlates with multiple leakage sites or severe lymphatic injury.

The absence of universal guidelines for managing lymphatic leakage underscores the clinical challenges that practitioners face. Balancing decisions between early intervention and conservative management remains pivotal for the treatment of patients with lymphatic leakage. Some studies have advocated an early surgical approach when preoperative leakage exceeds 1,000–1,500 mL/day, as larger drainage volumes are more resistant to conservative treatment than smaller drainage volumes [28–30]. Our study extended this paradigm to LE, suggesting the potential for early intervention in patients with large drainage volumes. Still, high risk patients with a high drainage volume or underlying DM should be informed of the increased risk of clinical failure.

Our study reported a lower success rate than that reported in previous research on LE (62.2% vs. 80–100%) [4, 6, 7, 26]. We attribute this difference to our re-defined criteria for clinical success. Prior studies on LE have defined clinical success on the basis of drain removal without recurrence. However, this definition overstates the importance of LE, given that lymphatic leakage can be self-limiting and may not always require intervention [19]. Consequently, we adopted a more comprehensive criterion by including only patients who had a procedure-to-drainage removal interval within 7 days, while excluding those requiring re-intervention or experiencing adverse events. When the definition of clinical success described in previous studies was applied, only one of the 45 patients failed to have their drainage catheter removed prior to discharge, yielding a success rate of 97.8% [4, 6, 7, 26].

DM is a well-known risk factor for lymphatic vascular integrity, as it disrupts the lymphatic endothelium and inhibits lymphangiogenesis [31–33]. Therefore, it was not surprising that DM also negatively influenced the success of LE in our study. Patients with bladder cancer are already predisposed to poor lymphatic vessel integrity, as they are predominantly diagnosed at an older age than are patients with other cancers. Patients are most commonly diagnosed in their 70s, with >55% of initial diagnoses occurring after 70 years of age [34, 35]. Age-related changes in lymphatic vessels include the degeneration of vascular walls and decreased contractility, which may contribute to increased permeability to lymphatic fluid [36, 37]. DM, therefore, may have worsened the already compromised lymphatic vessels, acting as a confounding risk for the success of LE.

This study has some limitations. The retrospective nature and small sample size introduced inherent bias. Moreover, as there is currently no consensus on the timing of intervention and drainage catheter removal, these decisions are made individually by the surgeon or hospitalist in charge of the patient’s postoperative care. Nevertheless, our study is unique in that it is the first to investigate the efficacy of LE for a single disease. Therefore, we considered specific pathological factors and surgical methodologies in our analyses, which were not possible to consider in a heterogeneous patient group. Our study could further illustrate the characteristics of lymphatic leakage in bladder cancer, which has been poorly characterized in the past. Future prospective studies with larger cohorts and longer follow-up periods are warranted to define clear indications for LE and drainage catheter removal.

Conclusions

Our results demonstrate LE as a potentially safe and effective intervention for refractory lymphatic leakage after RC. However, patients with underlying DM and patients with a daily drainage volume of >1,000 mL/day have a higher risk of clinical failure of LE.

10.1371/journal.pone.0305240.r001
Decision Letter 0
Ortner Gernot Academic Editor
© 2024 Gernot Ortner
2024
Gernot Ortner
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
11 Jul 2024

PONE-D-24-20978Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancerPLOS ONE

Dear Dr. Heo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

I suggest to consider the comments of the reviewers to improve the quality of the manuscript with the main focus on methodological details, sub-group analysis and statistics. 

Please submit your revised manuscript by Aug 25 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Gernot Ortner

Academic Editor

PLOS ONE

Journal Requirements:

1. When submitting your revision, we need you to address these additional requirements.

Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

3. Please amend either the abstract on the online submission form (via Edit Submission) or the abstract in the manuscript so that they are identical.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is a retrospective study of 45 patients who underwent LE following RCx for BCa. The success rate was 62.2%, and lymphatic complications after LE were noted in three patients. In MVA, maximal daily drainage of >1,000 mL/day and DM were independent factors associated with LE failure.

The paper is well-written with an appropriate methodology and a clear message.

Comments and questions:

Introduction:

1. When discussing LND extent in RCx, it would be beneficial to mention the results of the SWOG 1011 trial.

2. I recommend reporting further details on the management of lymphatic leakage in “bladder cancer” patients instead of presenting general data.

Methods:

1. Were all cystectomies performed with curative intent, or were there any palliative cases?

2. Please add details about LND. What methods were used for ligating the lymphatics (metal clips, bipolar, etc.)? How many drains in which locations were placed after the surgery?

3. Daily drainage < 300 mL/day has been the indication for drain removal. Please comment on this, as it is on the high side.

4. The primary and secondary outcomes should be clearly defined.

Results:

1. Given the number of cases, the continuous variables should be reported as median (IQR or range) instead of mean (SD).

2. Is there any data on baseline comorbidities (e.g., ASA, CCI, ECOG), length of hospital stay, and overall perioperative complications?

3. Among those who responded well to LE, what was the trend of lymphatic drainage before and after embolization?

Discussion:

1. The data reported on line 212 (77.6% successful drain removal) is a bit confusing.

2. Please highlight the pros and cons of LE over conservative management.

3. For those who are at higher risk for LE failure, what is your suggested strategy?

Reviewer #2: Dear Authors,

Thank you for submitting your manuscript. This study presents an interesting analysis of 45 patients who underwent lymphatic embolization after radical cystectomy. I appreciate the opportunity to review it. Below are my comments and suggestions for improvement:

- I would appreciate a more detailed description of the embolization procedure, providing more technical information.

- You only described perioperative variables of the cystectomy. Consider adding other variables, such as the quantity of embolizing fluid injected, etc.

- For the multivariate analysis, why did you set 1000 mL as a cutoff? Is there a study that defines that value as a predictor of lymphatic leakage? You should consider using a discrete value, for example, every 100 mL/day, to understand how the probability of the event increases with each increment.ù

Thank you again for your work and for allowing me to review your manuscript.

Reviewer #3: Shin and colleagues present a retrospective study on the outcome of lymphatic embolization (LE) in patients undergoing RC with PLND (standard PLND template) proximal to the common iliac bifurcation, inferior to the circumflex iliac vein and medial to the genitofemoral nerve. LE was performed if the daily catheter drainage exceeded 500 mL/day for >5 days despite conservative therapy. The authors excluded patients with lymphocele evident on CT before LE.

Patients were stratified by success vs. failure. Failure was defined as: 1) those who required drainage catheter placement >7 days after LE, 2) those who needed re-intervention before catheter removal, and 3) those who experienced adverse events associated with LE. LE was performed by injecting a mixture of N-butyl cyanoacrylate and ethiodized oil at a ratio of 1:1–1:4 into the inguinal LN.

Of 491 patients, 55 patients experienced a lymphocele with LE. 45 patients were included in this study. Of these, 28/45 were in the success group. The mean number of resected LN was 18.89 ± 9.53 and 20.94 ± 10.50 for the success and the failure group, respectively. The mean time from RC to LE was 8.50 ± 3.91 and 13.18 ± 17.22 days for the success and the failure group, respectively. Drainage catheters remained in place significantly longer in the failure group (3.54 ± 1.69 vs. 9.12 ± 5.12).

Secondary interventions in the failure group (n=17) comprised the need for a reintervention/-embolization, prolonged catheter, complications etc.

In the multivariable analysis, maximal daily drainage volume of >1,000 mL/d and diabetes were associated with clinical failure. The scientific English is good.

I have a few points to consider:

• The authors should describe the PLND template in more detail.

• What is the proportion of patients with lymphoceles that underwent LE?

• The authors excluded patients with lymphocele evident on CT before LE. What was the rationale for this?

• The authors state that (page 6, line 106): “Lymphatic leakage was diagnosed when radiographic evidence of leakage was found in lymphangiography“. Did all patients undergo lymphangiography?

• The authors excluded patients with evident lymphoceles on CT before LE. Why were those patients excluded? Why were not all patients included that underwent LE?

• The size and extent of the lymphoceles are poorly characterized. Please elaborate.

• How was correct catheter placement during drainage of the lymphocele verified?

• I suggest revising the statistics of the paper, adhering to the statistical outcome reporting guidelines provided by major urological journals

• How were the complications assessed? Was there a standardized approach?

• The confidence intervals in the multivariable analysis are incredibly large.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes.

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0305240.r002
Author response to Decision Letter 0
Submission Version1
12 Aug 2024

Reviewer #1:

We would like to thank you for your thorough evaluation of our paper. We revised our paper after reviewing your recommendations for revision:

1. Introduction: When discussing LND extent in RCx, it would be beneficial to mention the results of the SWOG 1011 trial.

We added the SWOG 1011 trial information in our introduction, line 81-84.

2. Introduction: I recommend reporting further details on the management of lymphatic leakage in “bladder cancer” patients instead of presenting general data.

We definitely agree with your comment. Despite lymphatic complications frequently occurring up to ~10% in RC patients, not much research has been conducted on the disease course of lymphatic leakages specific to RC. We therefore believe that our study is one of the first to identify lymphatic leaks specifically related to bladder cancer. We elaborated the management of leakage specific to bladder cancer in line 84-87.

3. Methods: Were all cystectomies performed with curative intent, or were there any palliative cases?

Yes, all radical cystectomies were performed with curative intent without any palliative cases. We have specified it in line 101-102.

4. Methods: Please add details about LND. What methods were used for ligating the lymphatics (metal clips, bipolar, etc.)? How many drains in which locations were placed after the surgery?

Thank you for the suggestion. We included the information regarding the methods used to seal the lymphatics in line 128-130.

5. Methods: Daily drainage < 300 mL/day has been the indication for drain removal. Please comment on this, as it is on the high side.

As mentioned in line 168-171, the timing of catheter removal was dependent on the surgeon in charge of the patient. 300mL/day was the common indication for drainage catheter removal in our hospital. We have rephrased the paragraph for clarity.

6. Methods: The primary and secondary outcomes should be clearly defined.

We clarified our primary and secondary outcomes in 108-110. Thank you for the suggestion.

7. Results: Given the number of cases, the continuous variables should be reported as median (IQR or range) instead of mean (SD).

The following changes have been made in Table 1 and results.

8. Results: Is there any data on baseline comorbidities (e.g., ASA, CCI, ECOG), length of hospital stay, and overall perioperative complications?

Thank you for the suggestion. We added details of ASA in Table 1. CCI and ECOG were not recorded during hospital stay. We also added the frequency of non-lymphatic peri-operative complications in Table 2. Clavien-dindo grade 3 or higher was counted in the analysis, as grade 1 and 2 complications were extremely frequent after RC.

9. Results: Among those who responded well to LE, what was the trend of lymphatic drainage before and after embolization?

We have added Figure 3 to better illustrate this trend. Both the clinical success and clinical failure group showed a visible decline in drainage volume after LE. However, pre-procedural drainage volume was higher in the clinical failure group, and the clinical success group had more patients who removed their drains, while only a few patients in the clinical success group removed their drain within 5 days after LE (85.7% vs 23.5%). We have added this detail in Figure 3 and line 210-214.

10. Discussion: The data reported on line 212 (77.6% successful drain removal) is a bit confusing.

Thank you for pointing this out. We rephrased the statement (line 246-248), to clarify that 77.8% of patients successfully removed their catheter within a week after LE.

11. Discussion: Please highlight the pros and cons of LE over conservative management:

We have added the role of LE compared to conservative management in line 255-260. We hope this helps clarify the pros and cons of LE.

11. Discussion: For those who are at higher risk for LE failure, what is your suggested strategy?

Refractory lymphatic leakage is difficult to manage. We suggest an early intervention for the high risk patients, as these patients would not respond well to conservative management. Although these patients also are at a higher risk of failure to LE, drainage volume still decreases significantly after LE (as shown in the added figure from question 9). We have further clarified this in out discussion (line 284-286). 

#Reviewer 2:

1. I would appreciate a more detailed description of the embolization procedure, providing more technical information.

We described the LE process in further detail in line 134-144. Thank you for the suggestion

2. You only described perioperative variables of the cystectomy. Consider adding other variables, such as the quantity of embolizing fluid injected, etc.

Thank you for your suggestion. However, the quantity of embolizing fluid has not been recorded in our medical record and thus could not be evaluated. Still, we believe that procedure related risks would be minimal as all leaks were visually sealed during embolization.

3. For the multivariate analysis, why did you set 1000 mL as a cutoff? Is there a study that defines that value as a predictor of lymphatic leakage? You should consider using a discrete value, for example, every 100 mL/day, to understand how the probability of the event increases with each increment.

Thank you for the suggestion. We set 1,000mL/day as our cutoff value, as few previous studies illustrate drainage volume of 1,000 – 1,500 mL/day as a cutoff for surgical intervention. As mentioned in the manuscript there is no clearly defined volume for intervention in lymphatic leaks, and we believe that our study could approaching a cutoff value set for surgical management would be the proper starting point. We clarified this in our manuscript (line 177-179).

#Reviewer 3:

1. The authors should describe the PLND template in more detail.

Thank you for the suggestion. We described the PLND template in more detail, which is outlined in line 124-128 of the manuscript.

2. What is the proportion of patients with lymphoceles that underwent LE?

Thank you for pointing this out. As specified in our selection criteria, we intentionally excluded patients who underwent LE due to lymphoceles (line 103-105). First of all, we wished to focus on early leaks, which has few unique characteristics from lymphoceles (outlined in line 69-75). Moreover, most of the patients who presented with symptomatic lymphoceles were treated with sclerotherapy, thus did not undergo LE.

3. The authors state that (page 6, line 106): “Lymphatic leakage was diagnosed when radiographic evidence of leakage was found in lymphangiography“. Did all patients undergo lymphangiography?

Thank you for your question. Lymphangiography was used during all LE procedures to visualize leaks from the lymphatic vessel. Patients suspected of lymphatic leakage, and those who agreed on LE therefore underwent lymphangiography. When leaks were visualized, we could diagnose post-operative lymphatic leakage, and undergo LE. Patients without leaks shown in lymphangiography, although not included in the study, would not undergo LE. We clarified our manuscript accordingly (Line 111-114).

4. The authors excluded patients with evident lymphoceles on CT before LE. Why were those patients excluded? Why were not all patients included that underwent LE?

As specified in our selection criteria, we intentionally excluded patients who underwent LE due to lymphoceles. The main purpose of the study is to evaluate LE in early post-operative leaks. We further clarified our exclusion criteria to avoid any confusion (line 103-105). Thank you.

5. The size and extent of the lymphoceles are poorly characterized. Please elaborate.

Thank you pointing out. We described the characteristics of the lymphoceles that were found in 5 of our patients in line 225-229.

6. How was correct catheter placement during drainage of the lymphocele verified?

Thank you for pointing this out. A drainage catheter was placed in the pelvic space before closing the incision, and a post-operative abdominal x-ray was filmed, which confirmed its correct position. We added this description in line 130-132.

7. I suggest revising the statistics of the paper, adhering to the statistical outcome reporting guidelines provided by major urological journals

Thank you for pointing this out. We made adjusted corrections to our table.

8. How were the complications assessed? Was there a standardized approach?

All patients received imaging studies and out-patient follow-ups based on the National comprehensive cancer network bladder cancer guideline (version 4.2024). Image studies and out-patient records within 6 months after LE were reviewed for LE associated complications. We illustrated this in line 160-163.

9. The confidence intervals in the multivariable analysis are incredibly large.

Thank you pointing this out. We do acknowledge this as our limitation, and is mostly due to our small sample size. However, LE is yet an emerging therapy and our sample size is still one of the largest to be published. We believe that future studies with larger sample sizes would provide a clearer result.

Attachment Submitted filename: Response to Reviewers.docx

10.1371/journal.pone.0305240.r003
Decision Letter 1
Zahir Mazyar Academic Editor
© 2024 Mazyar Zahir
2024
Mazyar Zahir
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
29 Aug 2024

PONE-D-24-20978R1Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancerPLOS ONE

Dear Dr. Heo,

Thank you for submitting the revised version of your manuscript to PLOS ONE. After careful consideration and in light of the reviewers' comments, we feel that your manuscript has merit to get published but requires some minute alterations prior to publication. Therefore, we invite you to submit a revised version of the manuscript that addresses these points raised.

Please submit your revised manuscript by Oct 13 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Mazyar Zahir, MD 

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

1. I believe that, given the small sample size and multiple limitations of the study, the conclusions drawn may overemphasize the benefits of lymphatic embolization (LE). I suggest revising the conclusion section of both the abstract and the main manuscript body ( line 323) to clarify that your findings are only suggestive of a possible effectiveness of LE in controlling post-operative lymphatic leaks after radical cystectomy.

2. The very high rate of clinical failure in the robotic surgical group warrants further elaboration. It appears that 3 out of 4 patients (75%) in this group experienced LE failure. This might suggest that the surgical team is less experienced with robot-assisted radical cystectomy (RARC) and typically performs surgeries in an open radical cystectomy (ORC) manner, potentially leading to more lymphatic manipulation and leaks (indicating a learning curve effect).

3. Another issue lies with the type of urinary diversion (UD). It was observed that 14 out of 45 patients (31.1%) underwent ureterocutaneostomy (UC), a simple UD associated with a much lower risk of lymphatic injury. However, UC is not commonly utilized in developed Western countries. This represents another limitation of your study, particularly in terms of the generalizability of your findings.

4. The definition of clinical success needs to be properly referenced.

5. I encourage the respected authors to undertake a thorough linguistic and grammatical revision of the manuscript, ideally in collaboration with a native English-speaking physician. Several sentences do not clearly convey their intended meaning. For example, the sentence in lines 271-272, "Here, we found that a maximal preprocedural drainage volume exceeding 1,000 mL/day was an independent predictor of LE success," implies that a higher preprocedural drainage volume correlates with higher success, whereas the opposite is true. The term "success" should be changed to "failure" here.

Additional lines requiring significant grammatical and linguistic revisions include lines 71-75, 81-86, 103-108, 164-172, 183-185, and 294-300.

6. Lines 84-86 and 89-90 discuss similar concepts regarding the prevalence of lymphatic complications. I recommend removing one of these sections to improve the flow of the introduction. The introduction is generally good but needs a comprehensive grammatical and linguistic revision.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I would like to thank the authors for addressing all the comments appropriately. I have no further comments.

Reviewer #2: Dear Authors,

Thank you for submitting your revised manuscript. I appreciate the opportunity to review it after your improvements. I don’t have further comments on this paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Bignante Gabriele

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0305240.r004
Author response to Decision Letter 1
Submission Version2
7 Sep 2024

Response to the editor:

We would like to thank you for evaluating our manuscript and providing feedback to improve our paper. Here are our responses to your suggestion.

1. I believe that, given the small sample size and multiple limitations of the study, the conclusions drawn may overemphasize the benefits of lymphatic embolization (LE). I suggest revising the conclusion section of both the abstract and the main manuscript body (line 323) to clarify that your findings are only suggestive of a possible effectiveness of LE in controlling post-operative lymphatic leaks after radical cystectomy.

Thank you for your suggestion. We made the following changes in line 56-57 and line 322-323.

2. The very high rate of clinical failure in the robotic surgical group warrants further elaboration. It appears that 3 out of 4 patients (75%) in this group experienced LE failure. This might suggest that the surgical team is less experienced with robot-assisted radical cystectomy (RARC) and typically performs surgeries in an open radical cystectomy (ORC) manner, potentially leading to more lymphatic manipulation and leaks (indicating a learning curve effect).

We appreciate your response and concern regarding the high rate of clinical failure in RARC. RARC is becoming increasingly common in our practice, and is showing promising results in our institution as well. Unfortunately, this is a single-arm study with only 4 patients who received RARC. Thus, a direct comparison between ORC and RARC is difficult. When enough LE cases are collected, we would be able to attempt a study with a control group (conservative management or sclerotherapy vs LE), which would better elucidate the whether ORC or RARC might take a role in the clinical success of LE. Thank you.

3. Another issue lies with the type of urinary diversion (UD). It was observed that 14 out of 45 patients (31.1%) underwent ureterocutaneostomy (UC), a simple UD associated with a much lower risk of lymphatic injury. However, UC is not commonly utilized in developed Western countries. This represents another limitation of your study, particularly in terms of the generalizability of your findings.

Thank you for pointing out the high incidence of UC in our study. UC is carefully considered in patients with severe bowel conditions (IBD, radiation, bowel adhesions, etc.) in our institution, and avoided whenever possible. As a tertiary institution in Korea, patients with complicated bowel conditions are often referred specifically for the choice of UD in MIBC, therefore resulting in a higher rate of UC compared to ICUD or neobladders.

However, as lymphatic leakage is a complication associated with PLND rather than UD, we believe that the standard PLND template applied in all patients would support the generalizability of our study.

4. The definition of clinical success needs to be properly referenced.

In this study, we defined clinical success according to timing of drain catheter removal, re-intervention or post-procedural complications. This is unique to our study, and allows our study to truly represent patients who are at a higher risk of undesirable results after LE (further illustrated in line 290-299). We have further elucidated this is our Methods section (line 164-166). Thank you for the feedback.

5. I encourage the respected authors to undertake a thorough linguistic and grammatical revision of the manuscript, ideally in collaboration with a native English-speaking physician. Several sentences do not clearly convey their intended meaning. For example, the sentence in lines 271-272, "Here, we found that a maximal preprocedural drainage volume exceeding 1,000 mL/day was an independent predictor of LE success," implies that a higher preprocedural drainage volume correlates with higher success, whereas the opposite is true. The term "success" should be changed to "failure" here.

Additional lines requiring significant grammatical and linguistic revisions include lines 71-75, 81-86, 103-108, 164-172, 183-185, and 294-300.

Thank you for pointing out this issue. We went through a full revision of the manuscript to improve our linguistic errors accordingly.

6. Lines 84-86 and 89-90 discuss similar concepts regarding the prevalence of lymphatic complications. I recommend removing one of these sections to improve the flow of the introduction. The introduction is generally good but needs a comprehensive grammatical and linguistic revision.

We made the according change in our introduction (line 85-87), and also went through a thorough linguistic revision. Thank you for your suggestion.

Attachment Submitted filename: Response to Reviewers.docx

10.1371/journal.pone.0305240.r005
Decision Letter 2
Zahir Mazyar Academic Editor
© 2024 Mazyar Zahir
2024
Mazyar Zahir
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
9 Sep 2024

Lymphatic embolization for early post-operative lymphatic leakage after radical cystectomy for bladder cancer

PONE-D-24-20978R2

Dear Dr. Heo,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Mazyar Zahir, MD

Academic Editor

PLOS ONE

10.1371/journal.pone.0305240.r006
Acceptance letter
Zahir Mazyar Academic Editor
© 2024 Mazyar Zahir
2024
Mazyar Zahir
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
15 Sep 2024

PONE-D-24-20978R2

PLOS ONE

Dear Dr. Heo,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Mazyar Zahir

Academic Editor

PLOS ONE
==== Refs
References

1 Keskin MS , Argun OB , Obek C , Tufek I , Tuna MB , Mourmouris P , et al . The incidence and sequela of lymphocele formation after robot-assisted extended pelvic lymph node dissection. BJU Int. 2016;118 (1 ):127–31. doi: 10.1111/bju.13425 26800257
2 Hur S , Jun H , Jeong YS . Novel interventional radiological management for lymphatic leakages after gynecologic surgery: lymphangiography and embolization. Gland Surg. 2021;10 (3 ):1260–7. doi: 10.21037/gs-2019-ursoc-10 33842273
3 Mahrer A , Ramchandani P , Trerotola SO , Shlansky-Goldberg RD , Itkin M . Sclerotherapy in the management of postoperative lymphocele. J Vasc Interv Radiol. 2010;21 (7 ):1050–3. doi: 10.1016/j.jvir.2010.03.014 20537556
4 Lee K , Chang SJ , Won JH , Kwon Y , Kim SH , Kim JE , et al . Intranodal Lymphangiography and Embolization for the Treatment of Early Postoperative Lymphatic Leaks after Pelvic Surgery. J Vasc Interv Radiol. 2023;34 (4 ):591–91. doi: 10.1016/j.jvir.2022.12.020 36526076
5 Kim SW , Hur S , Kim SY , Cho JY , Kwak C , Kim HS , et al . The Efficacy of Lymph Node Embolization Using N-Butyl Cyanoacrylate Compared to Ethanol Sclerotherapy in the Management of Symptomatic Lymphorrhea after Pelvic Surgery. J Vasc Interv Radiol. 2019;30 (2 ):195–202 e1. doi: 10.1016/j.jvir.2018.09.038 30717950
6 Seyferth ER , Itkin M , Nadolski GJ . Intranodal Glue Embolization for Postoperative Lymphatic Leaks in the Groin and Pelvis: Comparison with Sclerotherapy. J Vasc Interv Radiol. 2023;34 (4 ):600–6. doi: 10.1016/j.jvir.2022.12.031 36563935
7 Moussa AM , Camacho JC , Maybody M , Gonzalez-Aguirre AJ , Ridouani F , Kim D , et al . Percutaneous Lymphatic Embolization as Primary Management of Pelvic and Retroperitoneal Iatrogenic Lymphoceles. J Vasc Interv Radiol. 2021;32 (11 ):1529–35. doi: 10.1016/j.jvir.2021.07.022 34363941
8 Perera M , McGrath S , Sengupta S , Crozier J , Bolton D , Lawrentschuk N . Pelvic lymph node dissection during radical cystectomy for muscle-invasive bladder cancer. Nat Rev Urol. 2018;15 (11 ):686–92. doi: 10.1038/s41585-018-0066-1 30104615
9 Lerner SP TC , Svatek RS , Daneshmand S , Pohar K , Skinner E , et al . SWOG S1011–subgroup analysis of the phase III surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer. Journal of Urology. 2023;;211 (5S2 ):e2.
10 Gschwend JE , Heck MM , Lehmann J , Rubben H , Albers P , Wolff JM , et al . Extended Versus Limited Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Survival Results from a Prospective, Randomized Trial. Eur Urol. 2019;75 (4 ):604–11. doi: 10.1016/j.eururo.2018.09.047 30337060
11 You C , Li Q , Yang Y , Qing L , Liu S , Wang Y , et al . Extraperitoneal Versus Intraperitoneal Radical Cystectomy for Bladder Cancer: A Systematic Review and Meta-Analysis. Ann Surg Oncol. 2023;30 (9 ):5932–41. doi: 10.1245/s10434-023-13744-5 37344747
12 Hirobe M , Tanaka T , Shindo T , Ichihara K , Hotta H , Takahashi A , et al . Complications within 90 days after radical cystectomy for bladder cancer: results of a multicenter prospective study in Japan. Int J Clin Oncol. 2018;23 (4 ):734–41.
13 Katsimperis S , Tzelves L , Tandogdu Z , Ta A , Geraghty R , Bellos T , et al . Complications After Radical Cystectomy: A Systematic Review and Meta-analysis of Randomized Controlled Trials with a Meta-regression Analysis. Eur Urol Focus. 2023. doi: 10.1016/j.euf.2023.05.002 37246124
14 Kim SH , Yu A , Jung JH , Lee YJ , Lee ES . Incidence and risk factors of 30-day early and 90-day late morbidity and mortality of radical cystectomy during a 13-year follow-up: a comparative propensity-score matched analysis of complications between neobladder and ileal conduit. Jpn J Clin Oncol. 2014;44 (7 ):677–85. doi: 10.1093/jjco/hyu051 24791782
15 Maibom SL , Joensen UN , Poulsen AM , Kehlet H , Brasso K , Roder MA . Short-term morbidity and mortality following radical cystectomy: a systematic review. BMJ Open. 2021;11 (4 ):e043266. doi: 10.1136/bmjopen-2020-043266 33853799
16 Kallappan S , Manickam R , Nachimuthu S , Ganesapandi T . Unusual lymphocele following radical cystectomy with orthotopic neobladder. Indian J Urol. 2019;35 (2 ):168–9. doi: 10.4103/iju.IJU_284_18 31000926
17 Onishi Y , Moribata Y , Shimizu H , Shimizu K , Sano T , Kobayashi T , et al . Intranodal Lymphangiography during Surgical Repair of Pelvic Lymphorrhea after Radical Cystectomy. Case Rep Urol. 2021;2021 :7822422. doi: 10.1155/2021/7822422 34327035
18 Network NCC . Bladder cancer (version 4.2024) [Available from: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf.
19 Lv S , Wang Q , Zhao W , Han L , Wang Q , Batchu N , et al . A review of the postoperative lymphatic leakage. Oncotarget. 2017;8 (40 ):69062–75. doi: 10.18632/oncotarget.17297 28978181
20 Kariya S , Yamamoto S , Nakatani M , Ono Y , Maruyama T , Tanigawa N . The role of lymphatic interventional radiology for postoperative lymphorrhea. Int J Gastrointest Interv. 2022;11 (4 ):186–91.
21 Leibovitch I , Mor Y , Golomb J , Ramon J . The diagnosis and management of postoperative chylous ascites. J Urol. 2002;167 (2 Pt 1 ):449–57. doi: 10.1016/S0022-5347(01)69064-5 11792897
22 Kim HY , Kim JW , Kim SH , Kim YT , Kim JH . An analysis of the risk factors and management of lymphocele after pelvic lymphadenectomy in patients with gynecologic malignancies. Cancer Res Treat. 2004;36 (6 ):377–83. doi: 10.4143/crt.2004.36.6.377 20368832
23 Evans JG , Spiess PE , Kamat AM , Wood CG , Hernandez M , Pettaway CA , et al . Chylous ascites after post-chemotherapy retroperitoneal lymph node dissection: review of the M. D. Anderson experience. J Urol. 2006;176 (4 Pt 1 ):1463–7. doi: 10.1016/j.juro.2006.06.016 16952661
24 Baek Y , Won JH , Kong TW , Paek J , Chang SJ , Ryu HS , et al . Lymphatic Leak Occurring After Surgical Lymph Node Dissection: A Preliminary Study Assessing the Feasibility and Outcome of Lymphatic Embolization. Cardiovasc Intervent Radiol. 2016;39 (12 ):1728–35. doi: 10.1007/s00270-016-1435-x 27485266
25 Smolock AR , Nadolski G , Itkin M . Intranodal Glue Embolization for the Management of Postsurgical Groin Lymphocele and Lymphorrhea. J Vasc Interv Radiol. 2018;29 (10 ):1462–5. doi: 10.1016/j.jvir.2018.04.020 30217746
26 Chu HH , Shin JH , Kim JW , Noh SY , Yang WJ , Park S . Lymphangiography and Lymphatic Embolization for the Management of Pelvic Lymphocele After Radical Prostatectomy in Prostatic Cancer. Cardiovasc Intervent Radiol. 2019;42 (6 ):873–9. doi: 10.1007/s00270-019-02209-6 30919025
27 Alejandre-Lafont E , Krompiec C , Rau WS , Krombach GA . Effectiveness of therapeutic lymphography on lymphatic leakage. Acta Radiol. 2011;52 (3 ):305–11. doi: 10.1258/ar.2010.090356 21498367
28 Selle JG , Snyder WH 3rd , Schreiber JT . Chylothorax: indications for surgery. Ann Surg. 1973;177 (2 ):245–9. doi: 10.1097/00000658-197302000-00022 4698540
29 Liu Y , Pan C , Tang JY , Chen J , Zhou M , Ye QD . What is the result: chylous leakage following extensive radical surgery of neuroblastoma. World J Pediatr. 2012;8 (2 ):151–5. doi: 10.1007/s12519-011-0296-2 21633857
30 Ji W , Wang J , Song B , Zheng K , Ma H , Nadaf A , et al . Cause analysis and therapeutic methods of chylous leakage after pancreaticoduodenectomy. Saudi Med J. 2014;35 (11 ):1396–9. 25399220
31 Scallan JP , Hill MA , Davis MJ . Lymphatic vascular integrity is disrupted in type 2 diabetes due to impaired nitric oxide signalling. Cardiovasc Res. 2015;107 (1 ):89–97. doi: 10.1093/cvr/cvv117 25852084
32 Jiang X , Tian W , Nicolls MR , Rockson SG . The Lymphatic System in Obesity, Insulin Resistance, and Cardiovascular Diseases. Front Physiol. 2019;10 :1402. doi: 10.3389/fphys.2019.01402 31798464
33 Li Y , Liu Y , Liu S , Gao M , Wang W , Chen K , et al . Diabetic vascular diseases: molecular mechanisms and therapeutic strategies. Signal Transduct Target Ther. 2023;8 (1 ):152. doi: 10.1038/s41392-023-01400-z 37037849
34 Saginala K , Barsouk A , Aluru JS , Rawla P , Padala SA , Barsouk A . Epidemiology of Bladder Cancer. Med Sci (Basel). 2020;8 (1 ). doi: 10.3390/medsci8010015 32183076
35 Fang W , Yang ZY , Chen TY , Shen XF , Zhang C . Ethnicity and survival in bladder cancer: a population-based study based on the SEER database. J Transl Med. 2020;18 (1 ):145. doi: 10.1186/s12967-020-02308-w 32228610
36 Shang T , Liang J , Kapron CM , Liu J . Pathophysiology of aged lymphatic vessels. Aging (Albany NY). 2019;11 (16 ):6602–13. doi: 10.18632/aging.102213 31461408
37 Gonzalez-Loyola A , Petrova TV . Development and aging of the lymphatic vascular system. Adv Drug Deliv Rev. 2021;169 :63–78. doi: 10.1016/j.addr.2020.12.005 33316347
