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Systematic Review
Revised

Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis

[version 3; peer review: 1 approved, 2 approved with reservations]
PUBLISHED 10 Aug 2020
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Background and Aim
Mitomycin-C is a potent agent that plays an important role in tissue healing and scar formation. This study aims to investigate the efficacy of Mitomycin-C in treating anterior urethral stricture after internal urethrotomy.
Methods
Studies evaluating efficacy of mitomycin-c for anterior urethral stricture post urethrotomy were searched using Pubmed, Scopus, Sciencedirect, MEDLINE, and Cochrane Reviews as directory databases. The search was done in March 15th 2020. Terms being used in the searching process were “mitomycin-c” or “mitomycin”, “urethral stricture”, “urethral stenosis”, “internal urethrotomy”, “optical urethrotomy” and its synonyms. Every study with the design of retrospective or prospective clinical study being done in human subject was included. Study appraisal conducted in accordance to Oxford University Center for Evidence-Based Medicine. The conclusion of each study was summarized and the calculation of random effects from every study was conducted in meta-analysis. Random effects model is chosen because small number of studies and quite different.
Results
Three studies involving 311patients were included in this review, all of them reported less recurrence of in patients treated with mitomycin-c post urethrotomy (p<0.001). Risk ratio of all studies was 0.41 with 95% confidence interval (0.25-0.68).  
Conclusion
Mitomycin-C has the potential of efficacy in treating anterior urethral stricture post internal urethrotomy. Relatively few numbers of studies may impact in the strength of this review and further studies need to be done.

Keywords

mitomycin-c, urethral stricture, internal urethrotomy

Revised Amendments from Version 2

Several changes have been made. In the methods section: inclusion and exclusion criteria has been restructured, study selection, data extraction, and risk of bias assessment have also been added. In results section: study flow diagram has been changed according to PRISMA guide, risk of bias, and result of side effects have been added. In  Discussion: the first four paragraph has been deleted, risk of bias has been discussed, heterogeneity has been discussed, definition recurrence has been mentioned.

See the authors' detailed response to the review by Laetitia M. O. de Kort
See the authors' detailed response to the review by Farhad Shokraneh

Background

Urethral stricture often impairs quality of life and may result in a large economic burden1. There are several procedures available for treating this condition, ranging from minimally invasive procedures like internal optical urethrotomy (IOU) to invasive procedure such as urethroplasty, with or without grafting, and tissue engineering2. However, despite the methods available, urethral stricture often recurs. Several manipulations have been tried to prevent urethral stricture, such as indwelling catheter insertion, urethral calibration procedure, and home self-catheterization. Unfortunately, repeated instrumentation can cause scar formation. Moreover, it can also complicate subsequent reconstruction, which can lead to several complications3,4. On the other hand, there have been several studies evaluating the effects of antifibrotic drugs such as glucocorticoid and mitomycin-C on urethral strictures. Mitomycin-C is an agent that has the potential to inhibit mitosis, fibroblast proliferation, formation of blood vessels, and synthesis of protein and collagen. This agent plays role in tissue healing process and scar formation by reducing the release of matrix proteins by inhibiting proliferative fibroblasts5.

To our knowledge, there have not been any systematic reviews or meta-analyses regarding the efficacy of mitomycin-C in treating anterior urethral stricture post internal urethrotomy. Thus, the present study aims to investigate the efficacy of mitomycin-C in treating anterior urethral stricture post internal urethrotomy. We hope that by conducting this review and analysis, a definite conclusion regarding the efficacy of such treatment could be achieved.

Methods

This systematic review was conducted based on guidelines from the Oxford University Center for Evidence-Based Medicine6. Our present study aims to determine whether mitomycin-C provide better efficacy compared to controls (without mitomycin-C) in adult patients with anterior urethral stricture after internal urethrotomy.

Inclusion and exclusion criteria

Inclusion criteria were (1) Study type: RCT (Randomized Control Trial) until March 15th 2020; (2) Intervention and comparator: internal urethrotomy with addition Mitomycin-C vs internal urethrotomy without Mitomycin-C; (3) Patients: humans with anterior urethral stricture; (4) Primary outcome: efficacy of Mitomycin-C administration, determined by risk ratio; and (5) Secondary outcome: side effects from Mitomycin-C administration. Exclusion criteria were (1) Animal study; (2) case reports); (3) case series; (4) book chapters; and (5) editorials.

Search strategy

To find suitable studies to be included in this review, we used PubMed, Scopus, ScienceDirect, MEDLINE, and Cochrane Reviews as directory databases. We used combination of keywords “((((((mitomycin c[MeSH Terms]) OR mitomycin[MeSH Terms]) OR mitomycin c)) AND ((((((((((((((((urethral stricture[MeSH Terms]) OR urethral strictures[MeSH Terms]) OR stricture, urethral[MeSH Terms]) OR strictures, urethral[MeSH Terms]) OR urethral stenosis[MeSH Terms]) OR urethral stenoses[MeSH Terms]) OR stenosis, urethral[MeSH Terms]) OR stenoses, urethral[MeSH Terms]) OR urethral stricture) OR urethral strictures) OR stricture, urethral) OR strictures, urethral) OR urethral stenosis) OR urethral stenoses) OR stenosis, urethral) OR stenoses, urethral)) AND “urethra/surgery”[MeSH Terms]) AND Humans[Mesh]”. We also used term “human” as limiting term to exclude every study that was not conducted on human subjects.

Study selection and data extraction

A single reviewer screened the articles based on the titles, abstracts, and full text. Then, the data on author, publication year, details of studies subjects, details of studies intervention, and results are extracted.

Risk of bias sssessment

Another single reviewer assessed the risk of bias using the Cochrane Risk of Bias Tool, which include random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Every domain was judged with 3 levels (low risk, unclear risk, and high risk).

Analysis and concluding the review

We evaluated the study using appraisal worksheet for randomized clinical trial from Oxford University Center for Evidence-Based Medicine to stratify the risk of bias6. Using Revman 5.3 software, recurrence number from all selected studies were analyzed. Data were analyzed using forest plots with calculation of random effects. It was also done using Revman 5.3 to show relative risk/risk ratio for recurrence rate variable dan p-value. We summarized the conclusion of each study at the table along with its appraisal. We decided to use random effects model since the small amount of study and the difference between them.

Results

Literature search

Searching process (searching strategy showed in Figure 1) by using five databases found 49 study articles. There were 13 articles eliminated after screening for duplication. The remained 36 articles were reduced to seven articles after title and abstract screening, leaving seven full text articles to be reviewed. Based on study design, we eliminated three articles, leaving four articles to be summarized in systematic review and meta-analysis.

b3875861-3365-427f-b988-fb27177aca11_figure1.gif

Figure 1. Study flow diagram.

Study characteristics and quality assessment

Four selected studies were conducted in 2007, 2015, 2016, and 20192,4,7,8. All studies evaluated the effectivity of mitomycin-C given after internal urethrotomy for anterior urethral stricture. From these selected articles, three evaluated the usage of submucosal injection of mitomycin-C for anterior urethral stricture after urethrotomy. How mitomycin-C was injected differed in every study. Mazdak et al.4 study used 0,1 mg of Mitomycin-C in 2 ml of distilled water injected in four quadrants, Ali et al.2 study used 0,1% Mitomycin-C injected in three quadrants, and Islam et al.7 study used 0,1 mg in 2 ml of distilled water in two quadrants. Moradi et al.8 study evaluated intraluminal injection of Mitomycin-C in hydrogel base, consisting of 0.8 mg Mitomycin-C with 1cc water and propylene glycol to PF-127 poloxamer. The hydrogel base was injected through a small feeding tube to reach the site of stricture. All studies applied mitomycin-C after internal urethrotomy procedure and were conducted in populations with different age means. Each of studies’ quality was assessed using guide from Oxford University Center for Evidence-Based Medicine; this is explained in Table 1 and Table 2.

Table 1. Characteristics of subjects in included studies.

StudiesAverage age (year)Pre-intervention
stricture site
Procedure
of internal
urethrotomy
Clinical featureCause of injury
MMC
group
Control
group
MMC
Group
Control
group
Urinary
retention
Bladder
Outlet
Obstruction
AzotemiaUrosepsisMitomycin-C
Group
Control
group
Moradi
et al.,
20168
54.55
±
21.25
53.75 ±
24.75
Anterior urethral
stricture
Trans-urethral
incision at
12 o’clock
via cold knife
urethrotomy
N/AN/A
Ali et al.,
20152
37.31
± 10.1
40.1 ± 11.4Bulbar
urethra:
84.6%
Penile
urethra:
15.4%
Bulbar
urethra:
78.1%
Penile
urethra:
21.9%
Internal Optic
urethrotomy
Mitomycin-C groupRoad traffic:
59%
Iatrogenic:
30.8%
Straddle:
9%
Infective: 1.3%
Road traffic:
71.2%
Iatrogenic:
21.9%
Straddle: 6.8%
Infective: -
70.5%16.6%10.2%2.5%
Control group
57.5%31.5%9.5%1.3%
Mazdak
et al.,
20074
29.8
(15–70)
29.2 (11–66)Anterior urethral
stricture
Trans- urethral
incision at
12 o’clock
via cold knife
urethrotomy
N/AStraddle injury or other blunt
perineal trauma
Islam
et al.,
20197
49.43
± 8.10
48.98±7.20Anterior urethral
stricture
Internal Optic
Urethrotomy
N/AIdiopathic, lichen sclerosus,
urethritis, or unknown

[i] MMC, mitomycin C.

Table 2. Summary and appraisal of the selected articles.

StudiesLoESample
size
Methods of
mitomycin-
C
application
Timing of
mitomycin-
C
application
Follow
up
end-
point
ValidityImportanceApplicability
Randomized
allocation
Similarity
of group
Equal
Treatment
Minimal
Loss to
Follow-
up
BlindingRelevanceFeasibilityBenefit
Overweight
the Harm
Moradi
et al.,
20168
1b40Intraluminal
injection
of 0.8 mg
mitomycin-C
+ propylene
glycol
through
indwelling
catheter
After Internal
Urethrotomy
12
months
Not statedYesYesYesNot statedRR = 0.20
ARR = 0.40
RRR = 0.80
NNT = 2.5
UnsureYesYes
Ali et al.,
20152
1b180Submucosal
injection
of 0.1%
mitomycin-
C at three
quadrants
(1, 11, &
12 o’clock
position)
using TLA
needle
After Internal
Urethrotomy
18 monthsYesNoYesYesNot statedRR = 0.38
ARR = 0.23
RRR = 0.62
NNT = 4.35
UnsureYesYes
Mazdak
et al.,
20074
1b40Submucosal
injection
of 0.1 mg
mitomycin-
C in four
quadrants
(1,5,7, &
11 o’clock
position)
using
22- Gauze
cystoscopic
needle
Before
Internal
Urethrotomy
6
months
Not statedYesYes YesNot statedRR = 0.20
ARR = 0.40
RRR = 0.80
NNT = 2.5
UnsureYesYes
Islam
et al.,
20197
1b80Submucosal
injection
of 0.1 mg
Mitomycin-
C in two
quadrants
(11 & 1
o’clock)
using
21-gauge
cystoscopic
needle
After
internal
Urethrotomy
6 monthsYesYesYesYesNot statedRR = 0.62
ARR = 0.25
RRR = 0.38
NNT = 4
UnsureYesYes

[i] LoE, level of evidence; RR relative risk; ARR, absolute risk reduction; RRR, relative risk reduction; NNT, number needed to treat.

Outcome measures

We included the studies in which recurrence was defined by a patient having obstructive symptoms, obvious stricture at retrograde urethrography, or uroflowmetry with maximum flow rate less than 12 mL/s, and stricture was measured using retrograde urethrogram or ultrasonography of the urethra. The outcome that measured was recurrence rate (percentage).

Risk of Bias

The summary of the risk bias assessment can be found in Figure 2. All of the studies stated that they have undergone randomization. But only Ali et al. and Islam et al. mentioned the randomization method. A common problem with all the studies included in this review is that there was no clear concealment and blinding statement. All of the studies are completed and have relatively small loss to follow-up rates. Mazdak et al. didn’t mentioned recurrence criteria resulting high risk in selective reporting, but other studies mentioned2,4,7,8.

b3875861-3365-427f-b988-fb27177aca11_figure2.gif

Figure 2. Risk of Bias Summary.

Results and heterogeneity of the studies

All selected articles stated that Mitomycin-C had a significant effect on preventing or delaying urethral stricture recurrence post internal urethrotomy. All studies reported that the time-based recurrence rates in the two groups differed, where lower recurrence rates were found in the group given Mitomycin-C2,4,7,8. From study characteristic that is quite different and small number of studies, we choose to use random-effects model in forest plot showed in Figure 3. This forest plot suggests that there were significant differences between cases and control group. It showed from risk ratio is 0.41 with 95% confidence interval of 0.25 until 0.68, with p value <0.05. As for side effects are reported minimal and insignificant2,8.

b3875861-3365-427f-b988-fb27177aca11_figure3.gif

Figure 3. Forest plot for recurrence rate.

Test for heterogeneity Tau-square = 0.09; chi-square = 4.78; df = 3; p-value = 0.19; I-squared = 37%.

Discussion

All the studies included in this review treated the two groups equally and had relatively small loss-to-follow-up rates. A common problem with all the studies included in this review is that there was no clear blinding statement. Mazdak et al.4 and Moradi et al.8 study stated that their studies are randomized. But, the randomization procedure was not stated in the study method. On the other hand, although Ali et al.2 had randomized its subjects, age characteristics in the two groups were significantly different. Mazdak et al.4 also didn’t mentioned recurrence criteria, which could result in high risk bias. There was also a relevant study by Azzawi et al.9 that matches our inclusion criteria. But we are unable to access the full text, so we decide to exclude it. As for heterogeneity, from the calculation might not be important difference (I2=27%, p = 0.19). But the small number of studies, that calculation may not work well. From the studies we could notice the difference in age and methods in administering Mitomycin-C, those difference might add up the heterogeneity.

All studies support the use of mitomycin-C to prevent or delay anterior urethral stricture after internal urethrotomy, which in this review defined by a patient having obstructive symptoms, obvious stricture at retrograde urethrography, or uroflowmetry with maximum flow rate less than 12 mL/s, and every stricture in this review are all primary stricture.. This was confirmed by a less rate of recurrence rate in Mitomycin-C patients2,4,8; we found that those who had Mitomycin-C administered had lower incidence of recurrence during one year and 18 months of follow up (RR = 0.32, P < 0.001). This was also confirmed by a series of cases by Farrell et al.10, Farrell et al.11, and Sourial et al.12 Mazdak et al.4 injected mitomycin-C into the urethral submucosa and reported that patients with mitomycin-C injection had lower rates of stricture recurrence. Opposing this study, some researchers proposed that submucosal injection could increase the complication rate and reduce the duration of the effective dose within the tissue, which yielded a scientific discussion13. Ayyildiz et al.14 assessed the efficacy of Mitomycin-C for preventing urethral scar by applying the agent topically to the traumatized region in rats. They concluded that mitomycin-C applied locally reduced fibrosis significantly in a dose-independent manner.

Although all studies support the use of Mitomycin-C to prevent or delay post urethrotomy urethral stricture and the side effects reported in the studies reviewed are minimal, in Ali et al.2 and Moradi et al.8 are insignificant, but Mazdak et al.4 and Islam et al.7 didn’t asses any side effects, the results of this review need to be followed up with caution. The limitation of this study can be seen from only a few studies that discuss this topic. Some of the existing studies are not enough to be generalized to a wider population, given that selected studies were carried out in Iran and Pakistan2,4,7,8. Therefore their application needs to be carried out wisely and cautiously. Research related to this in the future can still be done with different populations.

Due to short period of follow up time in all studies, some authors2,4 concluded that the study of Mitomycin-C needed firm results regarding long term success. Mazdak et al.4 added that stricture may recur within two years after internal urethrotomy.

Conclusion

Mitomycin-C could be used as a potential additional treatment for anterior urethral strictures after internal urethrotomy. However, further studies are required to investigate the safety and efficacy of this method for treating anterior urethral strictures, as only a limited number of studies presently exist.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Open Science Framework: PRISMA checklist for ‘Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis’. https://doi.org/10.17605/OSF.IO/APU9B15.

The updated PRISMA checklist is available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

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how to cite this article
Irdam GA, Wahyudi I and Andy A. Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.12688/f1000research.19704.3)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 3
VERSION 3
PUBLISHED 10 Aug 2020
Revised
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5
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Reviewer Report 16 Jan 2023
Muhammet İrfan Dönmez, Istanbul University, Istanbul, Turkey 
Approved with Reservations
VIEWS 5
In this study, the authors aimed to investigate the efficacy of Mitomycin-C in adult patients with anterior urethral stricture after internal urethrotomy. Three studies involving 311 patients were included and a systematic review was conducted. However, I do have some ... Continue reading
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CITE
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Dönmez Mİ. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.28494.r157926)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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9
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Reviewer Report 18 Aug 2020
Laetitia M. O. de Kort, University Medical Centre Utrecht, Utrecht, The Netherlands 
Approved
VIEWS 9
I am satisfied ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
de Kort LMO. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.28494.r69072)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 2
VERSION 2
PUBLISHED 03 Jun 2020
Revised
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Reviewer Report 29 Jun 2020
Farhad Shokraneh, King's College London, London, UK 
Approved with Reservations
VIEWS 39
I thank the authors for applying a few of my suggestions:
  • Running an update search and adding one of my suggested studies;
     
  • Changing the Fixed-Effect Model to Random-Effects Model (Effects not
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Shokraneh F. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.26186.r64256)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 10 Aug 2020
    Andy Andy, Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, 10430, Indonesia
    10 Aug 2020
    Author Response
    Thank you for your feedback, I really appreciate it. As for the method section and other feedbacks we’ll be revising it. As for the journal database, we have changed from ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 10 Aug 2020
    Andy Andy, Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, 10430, Indonesia
    10 Aug 2020
    Author Response
    Thank you for your feedback, I really appreciate it. As for the method section and other feedbacks we’ll be revising it. As for the journal database, we have changed from ... Continue reading
Views
26
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Reviewer Report 18 Jun 2020
Laetitia M. O. de Kort, University Medical Centre Utrecht, Utrecht, The Netherlands 
Approved with Reservations
VIEWS 26
My comments:
  • The length of the stricture is important indeed and should not be
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
de Kort LMO. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.26186.r64255)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 10 Aug 2020
    Andy Andy, Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, 10430, Indonesia
    10 Aug 2020
    Author Response
    Thank you for the feedback again. We really appreciate it. For the length of stricture after critical reading over the references, only Mazdak et al compare the length of the ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 10 Aug 2020
    Andy Andy, Department of Urology, Faculty of Medicine, Universitas Indonesia, Jakarta Pusat, 10430, Indonesia
    10 Aug 2020
    Author Response
    Thank you for the feedback again. We really appreciate it. For the length of stricture after critical reading over the references, only Mazdak et al compare the length of the ... Continue reading
Version 1
VERSION 1
PUBLISHED 08 Aug 2019
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Reviewer Report 17 Feb 2020
Farhad Shokraneh, King's College London, London, UK 
Not Approved
VIEWS 43
The authors have conducted the first systematic review to answer this research question. It is a valuable effort.
 
Abstract
  1. EBSCOhost and Ovid are not databases. They are search interfaces or search engines for
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Shokraneh F. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.21610.r59109)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 03 Jun 2020
    Andy Andy, Indonesia University, Urology Department, Indonesia
    03 Jun 2020
    Author Response
    Thank you for the feedback, we have revised according to most of your comments. Update also has been implemented. As for contacting the authors for N/A in tables, we have ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 03 Jun 2020
    Andy Andy, Indonesia University, Urology Department, Indonesia
    03 Jun 2020
    Author Response
    Thank you for the feedback, we have revised according to most of your comments. Update also has been implemented. As for contacting the authors for N/A in tables, we have ... Continue reading
Views
28
Cite
Reviewer Report 03 Feb 2020
Laetitia M. O. de Kort, University Medical Centre Utrecht, Utrecht, The Netherlands 
Approved with Reservations
VIEWS 28
The subject of this review is interesting and relevant to clinical practice. The review is well written. I have some comments:
  • The literature search was until September 2018. Why is an update missing?
     
... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
de Kort LMO. Reviewer Report For: Efficacy of mitomycin-C on anterior urethral stricture after internal urethrotomy: A systematic review and meta-analysis [version 3; peer review: 1 approved, 2 approved with reservations]. F1000Research 2020, 8:1390 (https://doi.org/10.5256/f1000research.21610.r59108)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 03 Apr 2020
    Andy Andy, Indonesia University, Urology Department, Indonesia
    03 Apr 2020
    Author Response
    Thank you for your review. We have revised our publication according to your comments and we will upload it as soon as possible. But some comments I would like to ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 03 Apr 2020
    Andy Andy, Indonesia University, Urology Department, Indonesia
    03 Apr 2020
    Author Response
    Thank you for your review. We have revised our publication according to your comments and we will upload it as soon as possible. But some comments I would like to ... Continue reading

Comments on this article Comments (0)

Version 3
VERSION 3 PUBLISHED 08 Aug 2019
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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