Percutaneous transhepatic drainage is safe and effective in biliary obstruction-A single-center experience of 599 patients.

BACKGROUND: Historically, surgical bilioenteric bypass was the only treatment option for extrahepatic bile duct obstruction, but with technological advancements, percutaneous transhepatic drainage (PTD) and endoscopic solutions were introduced as a less invasive alternative. Endoscopic methods may lead to a decreasing indication of PTD in the future, but today it is still the standard treatment method, especially in hilar obstructions.
METHODS: In our retrospective data analysis, we assessed technical success rate, reintervention rate, morbidity, mortality, and the learning curve of patients treated with PTD over 12 years in a tertiary referral center.
RESULTS: 599 patients were treated with 615 percutaneous interventions. 94.5% (566/599) technical success rate; 2.7% (16/599) reintervention rate were achieved. 111 minor and 22 major complications occurred including 1 case of death. In perihilar obstruction, cholangitis were significantly more frequent in cases where endoscopic retrograde cholangiopancreatography had also been performed prior to PTD compared to PTD alone, with 39 (18.2%) and 15 (10.5%) occurrences, respectively. DISCUSSION: The results and especially the excellent success rates demonstrate that PTD is safe and effective, and it is appropriate for first choice in the treatment algorithm of perihilar stenosis. Ultimately, we concluded that PTD should be performed in experienced centers to achieve low mortality, morbidity, and high success rates.

Introduction

Obstructive jaundice is a consequence of extrahepatic bile duct obstruction. Historically, surgical bilioenteric bypass was the only solution for this type of obstruction, but with technological advancements, percutaneous transhepatic drainage (PTD) and endoscopic retrograde cholangiography (ERCP) were introduced as less invasive alternatives [1]. Compared with ERCP, PTD is considered as more invasive, since in this intervention, the drain tube has to be punctured through the liver parenchyma, causing more tissue injury. Drain dislocation, drain-related pain or discomfort can affect the patients’ quality of life, which is, of course, not present in endoscopic treatments [2, 3]. These adverse events contribute to that daily routine where ERCP and stent implantation is the first choice as a curative, bridging or palliative treatment for extrahepatic bile duct obstruction. However, several guidelines recommend PTD as the first choice of treatment, especially in hilar obstructions [4, 5]. Nevertheless, the type of intervention should be selected by multidisciplinary teams, based on the disease etiology and the localization of the obstruction. The continuous development of endoscopic ultrasound may lead to a decreasing indication of percutaneous drainage in the future, but today it is still widely accessible and is the standard of care [4], especially considering several scenarios (i.e. Roux-en-Y bilioenteric bypass, Billroth resection, etc.) where endoscopy would be difficult to perform. Adverse events related to percutaneous intervention can reach up to 61%, and mortality to 6% in some reports, but experienced centers can offer better result, for example Robson et al. reported 2% mortality, and Muller et al. reported 28% morbidity [6, 7]. The technical success of the percutaneous intervention is a major advantage, as it can be as high as 94–100% compared to less favorable results of ERCP [2, 8]. In our retrospective data analysis, we asses morbidity and mortality rates, and the learning curve of cases treated over 12 years in a tertiary referral center demonstrating excellent technical success and acceptable complication rates.

Materials and methods

A retrospective data analysis was performed of the results of patients with biliary obstruction treated with PTD between 2007 and 2018 in our tertiary referral center. The study was approved by the Semmelweis University Regional And Institutional Committee of Science and Research Ethics (SE RKEB# 50/2021.). The patient records were accessed via the electronical medical system used by Semmelweis University. The records were fully anonymized at the data analysis, the ethics committee did not required for an informed consent.

Patient population

615 percutaneous biliary interventions were performed in 599 patients with biliary obstruction. The interventions were performed with curative and palliative intention; preoperatively in 98 patients, followed by an operation with curative intention, postoperatively in 63 inoperable patients, and without operation in 436 upfront inoperable patients. The cause of biliary obstruction was diagnosed by radiologic findings (computer tomography, magnetic resonance imaging) and histology. The level of obstruction was determined via percutaneous transhepatic cholangiography (PTC). Perihilar obstructions were classified based on the Bismuth-Corlette (BC) classification. Distal bile duct obstruction was diagnosed between the cystic duct and the level of the pancreas; in case of the postoperative local recurrence of malignancy or anastomotic benign obstruction, no further localization was specified. Disease etiology and stenosis localization results are detailed in Table 1.

Table 1

Patient population of 599 patients.

Patient population	n (total = 599)	%
Age (mean)	65.1 (St.dev 12.07)	-
Sex
Male	315	53%
Female	284	47%
Disease etiology
Pancreatic head malignancy	207	35%
Perihilar malignancy (Klatskin tumor)	183	31%
Common bile duct malignancy	20	3%
Vater papilla malignancy	16	3%
Benign biliary stricture	22	4%
Intrahepatic malignancy	15	3%
Gall bladder malignancy	44	7%
Other malignant disease	92	15%
Localization of the stenosis
Benign anastomotic stricture (in a previous biliodigestive anastomosis) *	5	1%
Intrahepatic	14	2%
Local recurrence of malignancy *	25	4%
Distal bile duct (below the cystic duct)	198	33%
Common bile duct	357	59%
Common bile duct stenosis: Bismuth Corlette Classification
Common bile duct: Bismuth-Corlette type I	202	34%
Common bile duct: Bismuth-Corlette type II	21	4%
Common bile duct: Bismuth-Corlette type IIIa	20	3%
Common bile duct: Bismuth-Corlette type IIIb	24	4%
Common bile duct: Bismuth-Corlette type IV	90	43%
Serum bilirubin (mean)	mean: 365.4 (umol/l) St. dev. 193.6	median: 360 (umol/l)

* no further localization was defined.

n = number of patients.

Technique

The interventions were performed by two physicians. All interventions were carried out with the patient in the supine position. Following premedication with the injection of promethazine (25-50mg), atropine (0.5-1mg), and pethidine (50-100mg), the patient was given local anesthesia consisting of 1% lidocaine at the puncture site. The primary puncture was performed in the 9th–10th intercostal space on the patient’s right side. If left liver lobe decompression was indicated, left-side puncture was performed in the subxiphoid space. Once the Chiba needle (Cook Medical, Bloomington, IN, USA) was in the bile duct, as confirmed with cholangiography, a 0.018-inch wire (Cook Medical) was advanced and the needle was removed. A percutaneous access set (Cook Medical) with two sheaths and a metal cannula was used to introduce a cannula accepting a larger wire suitable for the planned intervention. After the coaxial tip was inserted into the bile duct using the 0.018-inch wire, the two inner components were removed, leaving the outer 4French (F) sheath behind. Cholangiography was performed to determine the obstruction level. A 4F biliary manipulation catheter (Cook Medical) was used to cross the obstructing lesion. The 0.018-inch wire was left in place to preserve the route for security reasons. Finally, an 8.5F or 10.2F drain (Cook Medical) was left behind bridging the stricture. If crossing the obstruction was not possible, an external drain was left in place. The drain was sutured and fixed to the skin with its original kit.

Variables and definitions

Technical success rate, reintervention rate, early complications and learning curves were assessed. Complications were further divided to minor and major groups. Corresponding to the Clavien-Dindo classification, the minor group matched grades I-II, and the major group matched grades III-V. Minor complications were observed, such as pancreatitis, cholangitis, bleeding, hepatic abscess, biloma and drain dislocation. Cholangitis was diagnosed if systemic inflammation, cholestasis, and biliary dilatation were present corresponding to the Tokyo Guidelines of diagnostic criteria of acute cholangitis [9]. The learning curves of the two physicians were assessed based on the internal-external to internal drainage ratio, with the assumption that high internal-external drainage percentage demonstrated the physician being more experienced. Learning curve was also assessed regarding the complication rates over the years.

Statistical analysis

Descriptive statistics (number of events and percentage for categorical variables, and total number, mean, and standard deviation for continuous variables) were obtained using Prism Graphpad and the MS Excel 2016 software. To analyze correlation between categorical variables, Fisher-test (in case of a low number of events) and Chi-squared test were applied. All statistical calculations were done with the IBM-SPSS ver. 25 software (IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.).

Results

Technical success and reintervention rate

The intervention was considered technically successful when internal or external drain could be left in the bile ducts and the final PTC confirmed adequate biliary drainage. Thus, technical success was achieved in 94.5% (566/599) of the patients. In 33 cases, it was technically pointless to drain, as the subsegmental obstruction resulting from the advanced state of the disease could not be resolved with even multiple drainages. The technical success rate was measured in the perihilar subgroup as well: 96.3% (344/357). 16 patients needed reintervention in 30 days due to complications like dislocation (n = 13), drain obliteration (n = 2), or haemobilia (n = 1). The calculated 30-day reintervention rate is 2.7% (16/599).

Complications

Intervention-related early complications were divided into minor and major groups (Table 2). Minor complications were the following: Pancreatitis–defined by the Revised Atlanta Classification–was observed in 7 patients. Bleeding was registered as a complication if red blood cell transfusion was needed. With that consideration, 5 cases of bleeding were registered. Biloma and hepatic abscess were observed in 4 cases, which needed no surgical intervention. 71 patients with cholangitis were registered after the intervention. 63 drain dislocations were noted. Out of these 63 complications, 39 happened within 30 days after the intervention (early dislocation) and 24 happened later than that (late dislocation). From the 39 early dislocation 24 were managed without intervention. In these cases there were different disease courses that did not indicate a reintervention. Such case scenarios were: reposition was managed without true radiological intervention, internal-external drain dislocated to external position, resolution of cholangitis and dilated bile ducts, disease progression or other organ failure.

Table 2

Minor and major complications after percutaneous intervention in 599 patients.

Minor complications (Clavien Dindo I-II)	n	%
Bleeding (transfusion needed)	5	0.01
Cholangitis (after the PTD)	71	12
Early dislocation (managed without intervention)	24	4
Pancreatitis	7	1
Intraabdominal abscess	3	0.5
Intraabdominal biloma	1	0.17
Total	111	19
Major complications (Clavien Dindo III-V)	n	%
Perforation	1	0.17
Bleeding (2 managed with reoperation, 1 with reintervention)	3	0.5
Pancreatitis	1	0.17
Early dislocation and obliteration (managed with reintervention)	15	3
Intraabdominal abscess	1	0.17
Death	1	0.17
Total	22	4

n = number of patients.

Major complications were observed in 22 cases. In 1 case, bile duct perforation with intraabdominal drain dislocation and bile leakage resulted in peritonitis and required operation. In 4 cases, other etiologies (pancreatitis with necrosis, hepatic abscess, and intraabdominal bleeding in two cases) required surgical laparotomy, in 15 cases drain dislocation or obliteration, and 1 case haemobilia was managed with reintervention.

In 1 case, PTD-related small bowel perforation resulted in biliary peritonitis, reoperation and death. The intervention related mortality is 0.17% (1/599).

Complications in the perihilar obstruction subgroup

In this subgroup, we assessed the obstructions classified by BC, mentioned in Table 1. In total, 357 perihilar obstructions were found. Percutaneous intervention was performed after failed ERCP in 214 patients, and 143 PTD without ERCP were done in the mentioned subgroup. Failed ERCP included unsuccessful stent implantation or ineffective drainage. All endoscopic interventions were performed in other institutes. Complication data of percutaneous intervention alone (hilar PTD) and ERCP followed by percutaneous intervention (hilar ERCP+PTD) were analyzed and compared in the hilar obstruction subgroup. 30 minor and 8 major complications were observed in the hilar PTD group, and 39 minor and 12 major complications were found in the hilar ERCP+PTD group (Table 3). The difference between the two groups (hilar ERCP+PTD vs hilar PTD) was statistically not significant (p = 0.557) regarding the total number of complications. We analyzed cholangitis separately as well, as it was the complication with the highest numbers in both subgroups. The other complications were not compared statistically by type because of the low number of events. In the hilar PTD group, 15 cases of cholangitis were observed before and 23 after the intervention. Nevertheless, in the hilar ERCP+PTD group, 39 cases were observed before the percutaneous drainage (between the ERCP and PTD), and 25 after the percutaneous drainage. The number of cholangitis observed before the intervention in the hilar ERCP+PTD subgroup was significantly higher than the other group (p = 0.046), (Fig 1). The numbers of cholangitis observed after the intervention were not different statistically in the subgroups (p = 0.232).

Table 3

Minor and major complications in the hilar PTD group of 143 patients, and the hilar ERCP+PTD group of 214 patients.

Minor complications (Clavien-Dindo I-II)	n (%)–hilar ERCP+PTD		n (%)–hilar PTD group	p
Bleeding	4 (2)		0
Biloma	1 (0.5)		0
Intraabdominal abscess	1 (0.5)		1 (0.7)
Cholangitis (after the PTD)	25 (12)		23 (16)	0.232
Early dislocation (managed without intervention)	8 (4)		1 (0.7)
Pancreatitis	0		5 (3.5)
Total	39 (18)		30 (21)	0.518
Major complications (Clavien-Dindo III-V)	n (%)–hilar ERCP+PTD group		n (%)–hilar PTD group	p
Perforation	1 (0.5)		0
Bleeding (managed with reintervention or reoperation)	2 (0.1)		0
Pancreatitis	0		1 (0.7)
Early dislocation and obliteration (managed with reintervention)	9 (4)		6 (4)
Intraabdominal abscess	0		1 (0.7)
Total	12 (6)		8 (6)	0.996
Major and minor complications		n (%)–hilar ERCP+PTD group	n (%)–hilar PTD group	p
Total		51 (24)	38 (27)	0.557

n = number of patients.

Fig 1

Cholangitis in the hilar PTD group of 143 patients and the hilar ERCP+PTD group of 214 patients before the PTD intervention.

Statistically significant difference. p = 0.046.

Improving results

All interventions were performed by two physicians who were getting more and more experienced through the years. This allowed us to try to measure their improvement with a learning curve. We analyzed the success rates of the percutaneous interventions on an annual basis. External decompression and internal-external decompression were differentiated and counted for every single year in the investigated period. Internal-external decompression was considered as the best experience, being superior to the external method. An annual increase was observed in the number of the internal-external drainage as a result of the physicians getting more and more experienced (Fig 2A). After 203 PTDs, the rate of internal-external/external drainage ratio stabilized above 1.

Fig 2

A—Learning tendency. X axis—years, Y axis—internal-external/external drainage ratio X axis–years. The red dot shows the point where the ratio stabilized above 1 (203 PTDs). B–Learning tendency. X axis–years, Y axis–total number of interventions / total number of complications ratio. The red dot shows the point where between 2011–2012 the internal-external/external ratio stabilized above 1 and the complications started to decrease.

Yearly complication rates were also calculated. A higher peak point has been found during the early years and a decreasing complication rate over the years. This peak corresponds to the early courage of the less experienced interventionists which decreased with the rising experience (Fig 2B). Although this does not follow precisely the learning curve on the other figure but, a major decrease can be observed in the number of complications, approximately between year 2011–2012 (X-axis) where the internal/external ratio stabilized above 1.

Discussion

Obstructive jaundice increases the risk of morbidity and mortality through several pathophysiologic changes [10]. Percutaneous transhepatic biliary drainage is a widely used interventional method to relieve mechanical jaundice regardless of the localization of the obstruction. In this study, we retrospectively analyzed 599 patients with mechanical biliary obstruction receiving percutaneous biliary drain. To the best of our knowledge, this study has the largest patient population in a single center unit in this setting. The high bilirubin levels in our patient population (median serum bilirubin 360 umol/L) indicates the advanced stage of their disease and the low compensatory capability, similar to the study populations in papers published by Sut el al. (median serum bilirubin 397 umol/L) or Robson et al. (median serum bilirubin 201 umol/L) [2, 11].

Despite the low performance status of our study group, we could achieve a high technical success rate (94.5%). In some cases, subsegmental obstructions cause noticeable hyperbilirubinemia, however, these bile ducts are not suitable for percutaneous drainage. Other publications about PTD like Robson et al. published 100% technical success, Garcarek et al. reported 96.2%, Kloek et al. reported 100%. Also, Kloek et al. in the same paper report 81% in endoscopic biliary drainage groups. Walter et al. reported 98% technical success rate after PTD and 78% after endoscopic drainage in 129 patients with Klatskin tumor treated in their study [12]. Vitte et al. published 76% and 86,9% of success in low and high volume endoscopic centers respectively [13]. However, the meta-analysis including the previously mentioned study reports different endoscopic success rates (76–99%) as a result of heterogenous definitions of procedural success [14]. The meta-analysis of Zhao et al. analyzing five retrospective and three randomized controlled trials with a total of 692 participants also reported a trend towards the advantages of PTD over endoscopic drainage from the aspect of technical success (odds ratio (OR), 2.18; 95% CI, 0.73–6.47; P  =  0.16). Another meta-analysis of Tang et al. comparing the two biliary drainage methods in 1030 patients found that PTD was associated with a higher successful rates of palliative relief of cholestasis (RR  =  1.20, 95% CI: 1.10–1.31; P < .0001) [2, 8, 15–18].

The primary goal in biliary obstruction is the resolution of the obstruction and the adequate biliary drainage to relieve imminent cholangitis. Considering that in the majority of the cases PTD happens in an advanced state of the disease, or as a salvage therapy clinical success is hard to interpret. That is why rather technical success was investigated in this study. However, there are several other factors that play an important role in decision making about the technique used to solve the obstruction. Disease etiology, clinical success, quality of life are important in the long term success. However, the literature is not always clear about the best treatment in different disease etiology. The meta-analysis of Huszar et al. found no significant difference between endoscopic, percutaneous or surgical interventions in benign biliary obstructions regardless of the localization, Saluja et al. also found no significant difference between the endoscopic and percutaneous groups in malignant obstructions in the long term patency rates [19]. Quality of life and patient preference are also important knowing that percutaneous drain often needs maintenance, emptying or flushing or internalization of the drain and a painful drain can cause bad patient compliance, besides external drainage results in loss of bile [2, 3, 20]. Not to mention puncture site seeding metastasis which can be also problematic. These factors have to be well considered before making long term therapeutical decisions. Furthermore, complications also play an important role in therapeutical decisions.

In our study population only one patient suffered a lethal complication (0.17%), and only 4% (22/599) of the cases were diagnosed with major complications, which is favorable. After percutaneous interventions, Robson et al. reported 2%, while Mueller et al. reported 0.015% of the interventions resulting in death. Andriulli et al. found 0,33% mortality after ERCP in their systematic review survey including 21 prospective studies and 16.855 patients [2, 21].

Intervention related bowel perforations are major but rare complications thus few studies mention this event. Stapfer et al. and Howard et al. report 0.6–1% of duodenal perforations after ERCP [22, 23]. Only 1 perforation was observed in 261 patient in the largest study reporting perforation after percutaneous intervention [24]. We also had only 1 (0.17%) of this adverse event.

We found 1 severe post PTD pancreatitis (0.17%) in our study group. Andriulli et al. found 3.47% of post ERCP pancreatitis in 16.855 patients in their study. Pancreatic damage was mild in 44.8% in 43.8%; severe in 11.4% of all patients with post-ERCP pancreatitis, or 0.40% of all investigated patients [20]. A study comparing ultrasound and fluoroscopy guided PTD in 195 patients reported no pancreatitis after the PTD [25]. Another meta-analysis about preoperative biliary drainage in hilar cholangiocarcinoma showed that the total incidences of pancreatitis in the endoscopic biliary drainage group was 11.9% (21/157), in contrast to none in the PTD group [26]. This shows a clear advantage of PTD over endoscopic method regarding post-interventional pancreatitis.

The incidence of post-interventional bleeding ranges widely because of differences in definition. In a study conducted by Freeman et al. reported clinically significant hemorrhage in 48 patients (2%) that was, moderate (up to 4 units of blood transfusion were needed) in 22 (0.9%), and severe (i.e., it necessitated the transfusion of 5 or more units of blood, surgery, or angiography) in 12 (0.5%), [27]. In the study already mentioned of Andriulli et. al, bleeding occurred in 226 patients (1.34%, CI 1.16–1.52%); it was moderate in the majority of cases (70.8%), severe in 66 cases, and associated with death in 8 patients; the bleeding-related mortality rate was 3.54% (CI 1.08–6.00%), [20]. Bleeding after PTD is also a well-known complication, given the anatomic location of the intraparenchymal vessels. Nennstiel et al. described 7.7% of bleeding complications after PTD of which only 1 of 252 patients was considered major adverse event [25]. Rivera-Sanfeliz et al. reported higher incidence (8/346) requiring intervention to cease the bleeding [28]. In our presented data we observed 2 major bleedings.

Drain dislocation is a common adverse event as it appears from our data. In Tables 2 and 3 it stands out that it has the second highest number among the major and minor adverse events. ERCP stent migration is a similarly feared complication which can lead to bowel perforation as well. In a meta-analysis comparing percutaneous and endoscopic biliary drainage the total incidence rates of dislocation were 7.7% (12/156), and 18.1% (32/177) respectively. Our combined dislocation rate was 11% (63/599).

Based on these publications there is a slight advantage of percutaneous approach over ERCP regarding the above-mentioned major complications. Although complication data is hard to compare due to patient heterogeneity and the different methodologies applied.

In our study group, 19% (111/599) minor adverse events were observed.

Taking a closer look at our data, we found that in 11%, (63/599) dislocation and in 12%, (71/599) cholangitis is the observed adverse event. Bleeding, pancreatitis, abscess and biloma only occurred in a minority of the cases 3% (16/599).

Our data demonstrates that cholangitis and drain dislodgement are the two most common adverse events after percutaneous drainage, which is in accordance with the data published by Nennstiel et al. and Asadi et al. [7, 29].

Dislocated drain can be the result of bad patient compliance caused by low performance status or pain occurring after the intervention [2, 3]. Nevertheless, percutaneous drainage is not the only factor behind cholangitis. The previously mentioned meta-analysis of Zhao et al. comparing five retrospective studies and three randomized controlled trials reported significantly higher rates of biliary infection after endoscopic intervention than after PTD (OR, 0.59; 95% CI, 0.37–0.93; P  =  .02) [8].

A large proportion (60%) of our patients received PTD only after failed endoscopy. This reflects current practice, since most patients are referred to PTD providing centers with endoscopic stent in situ or after failed ERCP [30, 31]. High pre-interventional cholangitis rates also indicate the supposed adverse event of previous endoscopic intention and raises the question whether ERCP or PTD is the first choice of treatment in obstructive jaundice. Authors attempt to answer this highly debated question in several meta-analyses [32, 33]. The level of bile duct obstruction predicts the suitability of the endoscopic or the percutaneous method. In distal or BC type I-II obstruction, endoscopic intervention is less technically demanding, and is often the first choice in perihilar obstruction. However, in more advanced BC type III-IV obstructions, PTD is more beneficial, as it is less likely to causes cholangitis, as discussed in several guidelines [4, 5, 34]. Therefore, we analyzed the perihilar subgroup in our patient population. The difference between the hilar PTD and hilar ERCP+PTD groups from the perspective of complications was minimal. But only looking at the cholangitis numbers before the percutaneous intervention, we noticed a statistically higher number in the hilar ERCP+PTD group. This suggests that the patients who underwent ERCP before PTD had a higher chance of biliary infection. As the endoscopic procedures were done in other hospitals, during the retrospective data collection data availability was limited regarding the number of patients suffering from cholangitis before the ERCP. Although we do not have the data of patients who successfully underwent ERCP without cholangitis, this result still suggests that in perihilar obstruction, percutaneous access could be less harmful. This suggestion supports the recommendations of the above-mentioned guidelines. Presumably, further randomized controlled trials could clarify the beforementioned suggestions.

Speaking of failed ERCP, it has to be noted that the obstruction which sustain cholangitis was not solved by ERCP and another intervention was urgently needed to save the patient. Better patient selection could improve the rate of failed ERCP-s, indicate adequate primary PTD and solve the obstruction and the cholangitis by itself, or with further conservative treatment.

After failed ERCP, endoscopic-ultrasound-guided biliary drainage (EUSBD) also has to be mentioned. Other authors and guidelines suggest that EUSBD should be preferred over PTD after failed ERCP [35]. However, the benefit of this procedure over the percutaneous intervention treating malignant biliary obstruction is still not clear [36]. The technically demanding EUSBD is still lagging behind the PTD in accessibility, thus PTD remains standard of care in most medical centers [37]. In our patient population, there were no cases with endoscopic-ultrasound-guided biliary drainage prior to PTD.

The most suitable method for the resolution of benign biliary strictures is debated in a meta-analysis published by Huszar et al. [38]. In their data, percutaneous intervention was only superior to using endoscopic single plastic stent, and it is still not clear which is the best minimally invasive technique for the treatment of this etiology. When the obstruction cannot be solved with non-surgical and surgical methods, percutaneous transhepatic drainage combined with corticosteroid injection and balloon dilatation could be an effective treatment choice [39].

In perihilar stenosis, the invasion of the hepatic duct can be crucial from the perspective of operability. This factor is important in surgical planning, especially when liver resection is expected, and the future liver remnant requires preoperative biliary drainage [40, 41]. In this setting, the percutaneous approach is the most effective method for preoperative diagnosis, planning and drainage [39]. PTD is not only beneficial preoperatively, but is also safe and effective intraoperatively in liver and bile duct resections, preventing complications and anastomotic bile leaks [42].

Learning curves are good indicators of gaining experience and improving results [43]. We investigated the rate of internal-external/external drainages believing that internal-external drainage is the better outcome. Higher ratio was considered better. After 203 percutaneous drainages, the ratio stabilized above 1, which translates to the higher rate of internal-external drains. Still, a curve could not be drawn the improvement tendency is clear.

The main limitation of the study is retrospective data collection, the patient composition regarding the many cases with failed ERCP, and the limited data available on the previous endoscopic intervention.

Conclusion

The results and especially the excellent success rates demonstrate that PTD is safe and effective, and it is appropriate for first choice in the treatment algorithm of perihilar stenosis. Ultimately, we concluded that PTD should be performed in experienced centers to achieve low mortality, morbidity, and high success rates.

Raw dataset.

(XLSX)

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9 Jul 2021

PONE-D-21-17286

Percutaneous transhepatic drainage is essential in perihilar biliary obstruction – A single-center experience of 599 patients

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Reviewer #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

**********

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Reviewer #1: Yes

Reviewer #2: 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 analysis of 599 patients who underwent percutaneous transhepatic drainage, evaluating success rate, morbidity and mortality, and learning curve over 12 years.

Table 1 lists the demographics, disease type, and location of lesion. Table 2 lists the major and minor complications. Table 3 lists the complications in the hilar PTD and PTD + ERCP groups. Figure 1 graphs cholangitis in the hilar PTD and ERCP + PTD groups. Figure 2 graphs the learning curve of the interventionalists.

Major Issues:

All ERCPs were done at outside institutions, and so only compares PTD to failed ERCPs. To claim PTD is essential, this would require a comparison to successful ERCP as well.

For Figure 1: From the text it is not clear regarding the timing of the of cholangitis. Is this saying that there is a higher rate of cholangitis after the ERCP, but before the PTD? Or is the cholangitis before both the ERCP and PTD? If you are saying that the cholangitis is after the ERCP, but before the PTD, it is important to state how many of the patients also had cholangitis prior to the ERCP.

I think your conclusions are overstated. You did not compare PTD to ERCP, but compared it to itself and failed ERCP. I think at most you can say that it is safe and effective and is appropriate for first choice in the treatment algorithm. Please consider revising this as well as the title of the manuscript.

Minor Issues:

The formatting of Table 1 can be improved specifically where there are subcategories or lab values.

Table 3, please include p values for the totals that are mentioned in the text.

Please explain more about the complication rate per year as compared to the rate of internal drainage experience curve.

Reviewer #2: Thank you for the opportunity to review this manuscript by Kokas et al. titled “Percutaneous transhepatic drainage is essential in perihilar biliary obstruction – A single center experience of 599 patients.” In this study, the authors retrospectively evaluate their experience performing 615 PTDs in 599 patients over a 12-year period. The number of patients included in this study is impressive. The authors report a technical success rate of 94.5%. Periprocedural mortality occurred in one patient, minor complications in 126 patients (21%), and major complications in 6 patients (1%). Among the 357 patients that underwent PTD for perihiliar biliary obstruction, minor complications developed in 27 patients and major complications in 4 patients. The authors conclude that PTD should be the first choice in the treatment algorithm of perihilar stenosis.

The number of patients included in this manuscript represents the main novelty of the paper; however, the remaining data reported are similar to a number of previously published manuscripts (retrospective studies, randomized controlled trials, systematic reviews and meta-analyses). Additionally, the discussion reads as an editorial with the opinions of the authors and lacks detailed discussion of the literature in context to the current study. I have clarified this further with several comments outlined below:

Major

1. Discussion – the authors advocate for PTD over ERCP; however, the current study does not compare PTD to ERCP. Additionally, the discussion fails to discuss/compare complications after PTD in the context of previously published literature regarding outcomes after ERCP in the setting of biliary obstruction. The discussion broadly approaches this but fails to discuss/compare the two in any granularity. As written, the current manuscript highlights that PTD can be performed safely in biliary obstruction with experienced clinicians.

2. Discussion/Conclusion – The authors conclude that complications rates after PTD are comparable to ERCP and subsequently the authors advocate for PTD as the first choice for perihilar biliary obstruction. (1) The authors study does not compare complications rates between PTD and ERCP. (2) The discussion does not discuss complication rates/types/severity after ERCP in the context of previously published literature. As written, how can the authors make these conclusions?

3. Results – What was the technical success rate among the subgroup of patients that underwent PTD for perihilar biliary obstruction? This appears to be the key point of the manuscript, yet the technical success rate among this subgroup is not reported. As the authors point out, this represents a more technically challenging procedure.

4. Title – “Percutaneous transhepatic drainage is essential in perihilar biliary obstruction” is a strong statement. The title should be revised to avoid “overselling” the study, as this is a retrospective observational report and not a randomized controlled trial (this study does not compare primary PTD to primary ERCP). Additionally, the number of patients listed in the title is not actually the number of patients with perihilar biliary obstruction and should be revised or changed (357 patients had perihilar biliary obstruction).

5. Results – the authors report 63 events where drain dislodgement occurred – these were classified as Clavien-Dindo Grade I or II complications (“minor” by the authors definition). Did none of these patients required a repeat intervention to have the drains replaced? By the authors definition, repeat intervention would be considered a “major” complication (Clavien-Dindo Grade III complications). Can the authors comment on how these 63 patients were managed if they did not require drain replacement? In a previous subsection, the authors state that 16 patients required reintervention in a 30-day period – were these counted as Clavien-Dindo III+ complications? It does not appear they were.

6. Discussion – Should technical success rate be the primary metric in determining approach to biliary drainage for biliary obstruction? Several other factors play an important role in this decision making (i.e., therapeutic success rate, quality of life, durability, etiology/pathology, etc). Can the authors comment on this in their discussion?

7. Results – cholangitis was not included as a “minor” complication after PTD for perihilar biliary obstruction – what is the rationale for excluding this complication, as it clearly his clinical implications?

Minor

1. Abbreviations (manuscript) – All abbreviations should be introduced and written out at first mention, followed by the abbreviated form for the rest of the manuscript.

2. Table 1 – what does the “*” denote?

3. Results – The first paragraph discussing one mortality should be included in the “complications” subsection and not as the first paragraph of the results section.

4. Results (page 9, line 140-141) – The definition of Clavien-Dindo “minor” complication does not need repeating in the results section, as it is defined in the methods.

5. Discussion – Paragraph 1 (a two-sentence paragraph) should be combined with paragraph 2

6. Discussion – throughout the manuscript the authors use the term “percutaneous transhepatic drain” but change to “percutaneous biliary catheter” in the discussion – terminology should remain consistent throughout the manuscript.

7. Discussion (paragraph 2) – the authors introduce new data from their study in the discussion section (median serum bilirubin concentration) – all data should be included in the results section of the manuscript.

8. Results – Procedural mortality was 1/599 – the authors report this as 0.001% - this is actually 0.17%.

**********

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Reviewer #1: Yes: Daniel Milgrom

Reviewer #2: No

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30 Oct 2021

Leonidas G Koniari, MD

Academic Editor

PLOS ONE

Submission Date: 11 august, 2021

Rebuttal letter

PONE-D-21-17286

Percutaneous transhepatic drainage is essential in perihilar biliary obstruction – A single-center experience of 599 patients

Thank you for considering our manuscript for publication. We also appreciate the time and effort you and each of the reviewers have dedicated to providing insightful feedback on ways to strengthen our paper. We have incorporated changes that reflect the detailed suggestions you have graciously provided. We also hope that our edits and the responses we provide below satisfactorily address all the issues and concerns you and the reviewers have noted.

The following document is a point-by-point response to the questions raised by the academic editor, Reviewer #1 and Reviewer #2, respectively. The marked-up manuscript with the changes highlighted will be uploaded separately with the requested raw dataset containing the minimum level of detail necessary to reproduce all numbers reported in the manuscript. We have updated the tables and figures as well, and included one new figure (Fig2. B).

Dear Dr Koniari,

Thank you for considering our manuscript for publication. We understand the questions raised by you and with your help we have improved the quality of the article.

Issue #1: “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 …"

Response: Thank you for the comment. We followed the information provided on the links and revised the styling in order to meet the PLOS ONE style requirements.

Issue # 2: In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Response: We understand the request. The patient record were accessed via the electronical medical system used by the Semmelweis University. The records were fully anonymized at the data analysis, the ethics committee did not required for an informed consent. The anonymized dataset will be available as a supporting information. As most of the patient of the presented study have been already passed away consent for publication of raw data not obtained but dataset is fully anonymous in a manner that can easily be verified by any user of the dataset. Publication of the dataset clearly and obviously presents minimal risk to confidentiality of study participants. It includes no direct identifiers and fewer than three indirect identifiers.

Semmelweis University Regional and institutional committee of science and research ethics contact information:

1091 Budapest, Hungary

Üllői út 93. fsz. 2.

Telefon: 215-7300/53513

Fax: 215-6228/ 53513

e-mail: titkarsag.kutatasetikai-bizottsag@semmelweis-univ.hu

Issue #3: Thank you for stating the following financial disclosure:

" The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

At this time, please address the following queries:

a. Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b. State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c. If any authors received a salary from any of your funders, please state which authors and which funders.

d. If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: The statement - " The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." – was misinterpreted by the authors. The authors received no specific funding for this work, thus this is included in the financial disclosure and the revised cover letter.

Issue #4: We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, 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) and who has imposed them (e.g., an ethics committee). 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 as either Supporting Information files or 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 acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: As you have advised the anonymized data set from this study will be available as a supporting information containing the minimum level of detail necessary to reproduce all numbers reported in the manuscript.

Response to Reviewer #1

Dear Daniel Milgrom MD,

Thank you very much for the review. Your constructive comments revealed some issues what we were unable to see. With your advices, we have revised the manuscript and we hope it will meet your expectations. If there is any further question or suggestion, we are happy to receive it.

Major issue #1: All ERCPs were done at outside institutions, and so only compares PTD to failed ERCPs. To claim PTD is essential, this would require a comparison to successful ERCP as well.

Response:

Thank you for the comment. We agree on your opinion. Our tertiary referral center is a surgical unit where operations and interventional radiological procedures are routinely done. Our unit did not perform ERCP in the investigated period. As a limitation of this retrospective data collection, full data of the ERCPs performed in other units were not available. To narrow the limitations, we softened our conclusions to advocate less PTD over ERCP, and put work into collect more data about previously published literature regarding outcomes after ERCP and PTD results to get a better view from the differences or similarities. (manuscript: p15, line 240-313)

As interventional gastroenterology has been added to our unit recently, we are planning a prospective study comparing ERCP and PTD in the near future.

Major issue #2: For Figure 1: From the text it is not clear regarding the timing of the of cholangitis. Is this saying that there is a higher rate of cholangitis after the ERCP, but before the PTD? Or is the cholangitis before both the ERCP and PTD? If you are saying that the cholangitis is after the ERCP, but before the PTD, it is important to state how many of the patients also had cholangitis prior to the ERCP.

Response:

Thank you for the comment. We agreed on that it was not clear from the text, thus we tried to explain it with more details.

In the hilar ERCP+PTD group 39 cholangitis cases were observed before the percutaneous drainage (between the ERCP and PTD), and 25 after the percutaneous drainage. The endoscopic procedures were done in other hospitals, and during the retrospective data collection data availability was limited about the number of patients suffering from cholangitis before the ERCP.

On the other hand, we consider it important that the obstruction which sustained the cholangitis was not solved by the ERCP and other intervention was urgently needed to save the patient regardless the cholangitis was the consequence of the primary disease or the complication of the failed ERCP. Better patient selection could improve the rate of failed ERCP-s, indicate adequate primary PTD and solve the obstruction and the cholangitis by itself, or with further conservative treatment.

We have included an updated Figure 1 in order to highlight the above mentioned comments, and made some clarification in the text (p11, line 182-183).

Major issue #3: I think your conclusions are overstated. You did not compare PTD to ERCP, but compared it to itself and failed ERCP. I think at most you can say that it is safe and effective and is appropriate for first choice in the treatment algorithm. Please consider revising this as well as the title of the manuscript.

Response: Thank you for the advice. We have changed the conclusion and the title in order to avoid biased point of view and to be more objective about the facts.

• Changed Conclusion:

The results and especially the excellent success rates demonstrate that PTD is safe and effective, and it is appropriate for first choice in the treatment algorithm of perihilar stenosis. Ultimately, we concluded that PTD should be performed in experienced centers to achieve low mortality, morbidity, and high success rates.

• Changed Title:

Percutaneous transhepatic drainage is safe and effective in biliary obstruction – A single-center experience of 599 patients

Minor issue #1: The formatting of Table 1 can be improved specifically where there are subcategories or lab values.

Response: Thank you for the remark, we have corrected and improved Table 1, with highlighted subcategories.(p 10, line 163-165)

Minor issue #2: Table 3, please include p values for the totals that are mentioned in the text.

Response: Thank you for the comment, we have included the p values in Table 3. (p12, line 188-190)

Minor issue #3: Please explain more about the complication rate per year as compared to the rate of internal drainage experience curve.

Response: Thank you for the comment.

We analyzed the total number of complications through the 12 years. A new figure (Fig. 2B) was added, and the original Fig. 2 was renamed as Fig. 2A. A higher peak point has been found during the early years and a decreasing complication rate over the years. This peak corresponds to the early courage of the less experienced interventionists which decreased with the rising experience (Fig. 2B). Although this does not follow precisely the learning curve on the Fig2A but, a major decrease can be observed in the number of complications, approximately between year 2011- 2012 (X-axis) where the internal-external / external ratio stabilized above 1. (p15, line 205-220)

Response to Reviewer #2

Dear Reviewer #2,

We were happy to read your review and in-depth analysis which revealed some question that were left open in the original manuscript. You made clear that some explanations were not complete, and some of our conclusions were inaccurate or biased. We hope that our responses, explanations and the work we put into the revision will meet your expectations.

Major issue #1: Discussion – the authors advocate for PTD over ERCP; however, the current study does not compare PTD to ERCP.

Additionally, the discussion fails to discuss/compare complications after PTD in the context of previously published literature regarding outcomes after ERCP in the setting of biliary obstruction.

The discussion broadly approaches this but fails to discuss/compare the two in any granularity. As written, the current manuscript highlights that PTD can be performed safely in biliary obstruction with experienced clinicians.

Major issue #2: Discussion/Conclusion – The authors conclude that complications rates after PTD are comparable to ERCP and subsequently the authors advocate for PTD as the first choice for perihilar biliary obstruction. (1) The authors study does not compare complications rates between PTD and ERCP. (2) The discussion does not discuss complication rates/types/severity after ERCP in the context of previously published literature. As written, how can the authors make these conclusions?

Response for issues #1 and #2:

Thank you for helping us to see clear the overall picture. We agree on your opinion. Our tertiary referral center is a surgical unit where operations and interventional radiological procedures are routinely done. We did not perform ERCP during the investigated time period. As a limitation of this retrospective data collection, full data of the ERCPs performed in other units were not available. To narrow the limitations, we put more effort into search previously published literature regarding outcomes after ERCP and PTD results to get a better view from the differences or similarities between result of the mentioned interventions. (manuscript: p16, line 236-301)

On the other hand, we moderated our conclusions and suggestions to advocate less PTD over ERCP. We hope our softer conclusions will be less biased. (p16, line 240-313)

As interventional gastroenterology has been added to our unit recently, we are planning a prospective study comparing ERCP and PTD in the near future.

Major issue #3: Results – What was the technical success rate among the subgroup of patients that underwent PTD for perihilar biliary obstruction? This appears to be the key point of the manuscript, yet the technical success rate among this subgroup is not reported. As the authors point out, this represents a more technically challenging procedure.

Response:

Thank you for the relevant question. The technical success rate in the perihilar obstruction subgroup is 96.3% (13/357) which is similarly good as the overall technical success. This result has been also included in the revised manuscript. (p 9, line 137)

Major issue #4: Title – “Percutaneous transhepatic drainage is essential in perihilar biliary obstruction” is a strong statement. The title should be revised to avoid “overselling” the study, as this is a retrospective observational report and not a randomized controlled trial (this study does not compare primary PTD to primary ERCP). Additionally, the number of patients listed in the title is not actually the number of patients with perihilar biliary obstruction and should be revised or changed (357 patients had perihilar biliary obstruction).

Response: We agree on your advice. The changed the title is:

“Percutaneous transhepatic drainage is safe and effective in biliary obstruction – A single-center experience of 599 patients”

Major issue #5: Results – the authors report 63 events where drain dislodgement occurred – these were classified as Clavien-Dindo Grade I or II complications (“minor” by the authors definition). Did none of these patients required a repeat intervention to have the drains replaced? By the authors definition, repeat intervention would be considered a “major” complication (Clavien-Dindo Grade III complications). Can the authors comment on how these 63 patients were managed if they did not require drain replacement? In a previous subsection, the authors state that 16 patients required reintervention in a 30-day period – were these counted as Clavien-Dindo III+ complications? It does not appear they were.

Response: Thank you very much for revealing this issue.

We understand and appreciate your comment. As a result we revised and reconsidered all drain dislocations and reinterventions. Dislocated (or obliterated) drains which needed reintervention were included in the major complication section.

As a final result we have found 63 dislocations (including 2 obliterations): 39 early and 24 late dislocations. From the 39 early cases we have found 15 cases that were managed with radiological reinterventions (13 dislocation 2 obliteration)

In the 24 cases of patients who did not receive reintervention after the PTD dislocation there were different disease courses that did not made the reintervention possible or did not indicate a reintervention. Such case scenarios were: reposition was managed without true radiological intervention, internal-external drain dislocated to external position, resolution of cholangitis after the first PTD, disease progression or other organ failure.

Thus in total we performed 16 reinterventions, due to dislocation or obliteration (n=15), or haemobilia (n=1).

We modified the overall results and the result of the perihilar subgroup (including Table 2 and 3) analysis in accordance to your remark. The corrected Table 3 also includes the correction with cholangitis numbers as you suggested in your response #7. (manuscript: p9, line 150-190)

Major issue #6: Discussion – Should technical success rate be the primary metric in determining approach to biliary drainage for biliary obstruction? Several other factors play an important role in this decision making (i.e., therapeutic success rate, quality of life, durability, etiology/pathology, etc). Can the authors comment on this in their discussion?

Response: Thank you for your suggestion, you have raised an important point. We believe that the primary goal in a biliary obstruction is the resolution of the obstruction and the adequate biliary drainage. Considering that in the majority of the cases PTD happens in an advanced state of the disease, or as a salvage therapy when clinical success is hard to interpret. Not to mention the heterogenous definition of clinical success which makes the comparison even more complicated. That is why we highlighted technical success in our manuscript. Of course there are several other factors that play an important role in decision making not to mention patient preference. We worked on this section, and mentioned your suggestions with more detail in the revised discussion. (manuscript: p18, line 257-277)

Major issue #7: Results – cholangitis was not included as a “minor” complication after PTD for perihilar biliary obstruction – what is the rationale for excluding this complication, as it clearly his clinical implications?

Response: Thank you for the suggestion, we agree on your comment, it should have been included in the minor complications after PTD for perihilar biliary obstructions. We have modified the Table 3 and the result section as well. (p16, line 252-270)

Minor issue #1: Abbreviations (manuscript) – All abbreviations should be introduced and written out at first mention, followed by the abbreviated form for the rest of the manuscript.

Response: Thank you for your advice. The following abbreviations were introduced in the revised manuscript: Percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP,) computer tomography, magnetic resonance imaging.

Minor issue #2: . Table 1 – what does the “*” denote?

Response: It was mistakenly deleted: * no further localization is defined. It has been added to the Table 1 description in the revised manuscript.

Minor issue #3: Results – The first paragraph discussing one mortality should be included in the “complications” subsection and not as the first paragraph of the results section.

Response: We accept the suggestion, it has been included in the complication subsection.

Minor issue #4: Results (page 9, line 140-141) – The definition of Clavien-Dindo “minor” complication does not need repeating in the results section, as it is defined in the methods.

Response: We accept your remark, the repeated Clavien-Dindo minor complication definition has been deleted in the mentioned paragraph.

Minor issue #5: Paragraph 1 (a two-sentence paragraph) should be combined with paragraph 2

Response: Thank you for your advice. We combined the two paragraphs.

Minor issue #6: Discussion – throughout the manuscript the authors use the term “percutaneous transhepatic drain” but change to “percutaneous biliary catheter” in the discussion – terminology should remain consistent throughout the manuscript.

Response: Thank you, we agree on your comment. We have replaced the term [catheter] throughout the paper with [drain] to be more consistent.

Minor issue #7: Discussion (paragraph 2) – the authors introduce new data from their study in the discussion section (median serum bilirubin concentration) – all data should be included in the results section of the manuscript.

Response: Thank you for the remark. Median serum bilirubin concentration has been included in Table 1, results section.

Minor issue #8: Results – Procedural mortality was 1/599 – the authors report this as 0.001% - this is actually 0.17%.

Response: Thank you for the feedback, it has been corrected to 0.17%.

Again, thank you for giving us the opportunity to strengthen our manuscript with your valuable comments and queries. Since all the corrections have been made, we hope the manuscript will now be accepted without any further changes. We have worked hard to incorporate your feedback and hope that these revisions persuade you to accept our submission.

We look forward to hearing from you regarding our submission. We would be glad to respond to any further questions and comments that you may have.

Sincerely,

Ákos Szücs, MD PhD

Corresponding Author

associate professor

deputy head of department,

1st Department of Surgery and Interventional Gastroenterology

Semmelweis University

e-mail: szucs.akos@gmail.com

tel: +36-20-8258916

Submitted filename: Plos Response_to_reviewers.docx

Click here for additional data file.

5 Nov 2021

Percutaneous transhepatic drainage is safe and effective in biliary obstruction - A single-center experience of 599 patients

PONE-D-21-17286R1

Dear Dr. Szücs,

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.

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Leonidas G Koniaris, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

9 Nov 2021

PONE-D-21-17286R1

Percutaneous transhepatic drainage is safe and effective in biliary obstruction - A single-center experience of 599 patients

Dear Dr. Szücs:

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

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.

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on behalf of

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PLOS ONE