Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer

Response to reviewers

Dear Editor,

Please find below our answers to each reviewers’ questions and comments regarding the manuscript of our latest article entitled ‘Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center’. We are grateful to have the opportunity to submit this new and corrected version of the manuscript. Although we are fully aware that our study does not provide an absolute proof that robotic-assisted laparoscopy is superior to conventional laparoscopy to perform complex procedures, we are confident that our results will at the very least give new insights on this matter in the particular setting of an enhanced recovery program. We advocate that this study be seen as a kind of experience sharing well supported by figures. Our impression is that the use of robotic-assisted laparoscopy allows us to perform increasingly complex procedures while maintaining acceptable length of hospitalization and complication rates. Awareness of the respective profitability of conventional laparoscopy and robotic-assisted laparoscopy could allow surgeons to make an educated decision for the surgical route they will use for their patients.

Sincerely yours,

The Authors

Editor’s comments

PONE-D-20-01006

Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center

PLOS ONE

Dear Dr. Netter,

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.

We would appreciate receiving your revised manuscript by Apr 05 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

- A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

- An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Antonio Simone Laganà, M.D., Ph.D.

Academic Editor

PLOS ONE

 

Additional Editor Comments (if provided):

The topic of the manuscript is interesting. Nevertheless, the reviewers raised several concerns: considering this point, I invite authors to perform the required major revisions.

In addition, authors may consider the following comments:

- In light of the advanced techniques to detect early stage disease, to date it is mandatory to consider even the possibility of fertility-sparing approaches in order to preserve reproductive potential of women affected by gynecological cancers. I invite authors to discuss this point, referring to: PMID: 28868252; PMID: 28840513; PMID: 28188573.

- The management of women affected by gynecological cancers needs a particular attention even to the preservation of an appropriate quality of life and sexual function, which risk to be severely impaired by surgical/chemo/radio treatments. I would discuss this point, at least briefly, referring to: PMID: 28625095; PMID: 28275393.

Response to the Editor: Editor is right, fertility preservation is now one of the major challenges in the management of women’s cancers. Our unit always discuss these issues for women of reproductive age and we consistently refer these patients to a fertility specialist prior to surgery. Obviously, it is always difficult to address the vast variety of topics linked to the field of gynecological cancers. Nevertheless, we acknowledge that this interesting point was missing from the discussion section. We modified the paragraph regarding the limitations of our study in the discussion:

Original sentence: Furthermore, we have not reported data on estimated blood loss, post-operative pain or oncological outcomes, as our report focused on the main objectives of the ERP (morbidity and length of stay).

Modified Sentence: Furthermore, our study focused mainly on the LPO which is the easiest way to assess the efficiency of an ERP. However, it does not render the whole complexity of the treatment of gynecological cancers. Indeed, we have not reported data on the oncological outcomes such as the relapse-free survival. The long-term quality of life is also missing from our reported data. In particular, we did not report any data on the fertility preservation which is strongly linked to the well-being of young patients suffering from gynecological cancers [27–31]. Thus, we cannot formally conclude on the profitability of each surgical approach, and can only describe the elements that we use to decide which MIS technique will be used.

27. Chiofalo B, Palmara V, Laganà AS, Triolo O, Vitale SG, Conway F, et al. Fertility Sparing Strategies in Patients Affected by Placental Site Trophoblastic Tumor. Curr Treat Options Oncol. 2017;18: 58. doi:10.1007/s11864-017-0502-0

28. Laganà AS, La Rosa VL, Rapisarda AMC, Platania A, Vitale SG. Psychological impact of fertility preservation techniques in women with gynaecological cancer. Ecancermedicalscience. 2017;11: ed62. doi:10.3332/ecancer.2017.ed62

29. Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. The Importance of Fertility Preservation Counseling in Patients with Gynecologic Cancer. J Reprod Infertil. 2017;18: 261–263.

30. Vitale SG, Rossetti D, Tropea A, Biondi A, Laganà AS. Fertility sparing surgery for stage IA type I and G2 endometrial cancer in reproductive-aged patients: evidence-based approach and future perspectives. Updat Surg. 2017;69: 29–34. doi:10.1007/s13304-017-0419-y

31. Vitale SG, La Rosa VL, Rapisarda AMC, Laganà AS. Fertility preservation in women with gynaecologic cancer: the impact on quality of life and psychological well-being. Hum Fertil Camb Engl. 2018;21: 35–38. doi:10.1080/14647273.2017.1339365

Journal Requirements

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

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 http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

We ensured that our manuscript meets PLOS ONE’s style requirements, including for file naming.

2. Please include your IRB/ethics committee approval number in your ethics statement. The number provided currently (NCT03950011) is a ClinicalTrials.gov identifier. Thank you for your attention to this request.

We added our IRB in the materials and methods section (RAAC-IPC-2016-011)

3. In your Methods section, please provide additional information about the participant recruitment method and the demographic details of your participants. Please ensure you have provided sufficient details to replicate the analyses such as: a) the recruitment date range (month and year), b) a description of how participants were recruited, and c) descriptions of where participants were recruited and where the research took place.

We ensured that we provided the aforementioned details:

a) The recruitment date range was already written: “study from January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) to September 2018.”

b and c) We modified the description of our recruitment methods:

Original sentence: All the patients who followed the ERP signed an informed consent form and the study was approved by our ethical committee

Modified sentence: All women over 18 years of age who required gynecologic surgery at the Institut Paoli-Calmette during the study period followed our ERP. They were informed of the study during their first consultation and were asked to provide written consent for the storage and use of their data. The study was approved by our ethical committee.

4. Thank you for stating the following in the Competing Interests section:

"I have read the journal's policy and the authors of this manuscript have the following competing interests:

Eric Lambaudie and Gilles Houvenaeghel are proctors for Intuitive Surgical.

Other authors have nothing to disclose."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests). If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

We included our updated Competing Interests statement in our cover letter: “We have read the journal's policy and the authors of this manuscript have the following competing interests: Eric Lambaudie and Gilles Houvenaeghel are proctors for Intuitive Surgical. Other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

5. Please ensure that you refer to Figure 3 in your text as, if accepted, production will need this reference to link the reader to the figure.

We ensured that we referred to Figure 3 in the manuscript: “The percentage of procedures performed using RAL over time is presented in Figure 3.”

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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

We included captions for our Supporting Information files at the end of the manuscript before the references:

Supporting information

S1 Dataset. Clinical and surgical data.

 

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: No

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

Reviewer #1: Yes

Reviewer #2: Yes

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: 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: No

 

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: PONE-D-20-01006

In this article the authors tried to compare the characteristics of procedures for gynecologic cancers conducted with laparoscopy or robotic-assisted laparoscopy. Results showed that expert surgeons from the center preferentially choose robotic-assisted laparoscopy to perform complex gynecologic oncological procedures. The topic of this manuscript is interesting and falls within the scope of the journal. Moreover, the study methodology is well described, and the results are precisely presented.

We thank Reviewer #1 for his kind remarks.

Reviewer #2: I was pleased to revise the manuscript entitled “Choosing the appropriate minimally-invasive approach to treat gynecologic cancers in the context of an enhanced recovery program: insights from a comprehensive cancer center” (Manuscript Number: PONE-D-20-01006).

The study was approved by the local Institutional Review Board and written informed consent was obtained from all patients enrolled in this study.

In general, this manuscript was aimed to compare the characteristics of procedures for gynecologic cancers conducted with conventional laparoscopy (CL) or robotic-assisted laparoscopy (RAL) in the context of an enhanced recovery program (ERP). In my honest opinion, the topic is interesting enough to attract the readers’ attention. Nevertheless, there are different methodological limits that impede conclusions. The manuscript presents different limits as reported below:

1. All the text needs a language revision by a native English speaker person, in order to improve its readability.

At your request, we had the manuscript proofread by AJE scholar, we attach the certificate to the submission.

2. I would suggest checking the use of abbreviation, which should be reported in the extended form at the first use both in the abstract and manuscript and avoid abbreviation explanation.

Abbreviations:

CL = conventional laparoscopy

RAL = robotic-assisted laparoscopy

ERP = enhanced recovery program

LPO = post-operative length of hospitalization

MIS = minimally invasive surgery

We checked the use of abbreviation throughout the manuscript and did the required corrections.

3. Abstract. Based on the abstract it is unclear the role of enhanced recovery program in the manuscript.

We agree with Reviewer #2 this was insufficiently explained in the abstract. We modified accordingly:

Original sentence: This is a secondary analysis of prospectively collected data at a comprehensive cancer center between 2016 and 2018. We included patients that underwent minimally-invasive surgery for gynecological cancers.

Modified sentence: This is a secondary analysis of prospectively collected data from a cohort study conducted between 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and 2018. We included patients that underwent minimally-invasive surgery for gynecological cancers and followed our ERP.

4. Methods. I would suggest better clarifying the inclusion and exclusion criteria. Both for the prospective study and both for the population included in the analysis. It is unclear who was collected in the database.

Reviewer #2 is right, our recruitment method was insufficiently explained. We actually conducted a secondary analysis of prospectively collected data (as mentioned in the abstract) from a prospective cohort study in which every patient undergoing surgery for a gynecological cancer is included within the framework of our ERP since January 2016. We modified the “study design” section accordingly:

Original sentences: We conducted a prospective observational study from January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) to September 2018. All the patients who followed the ERP signed an informed consent form and the study was approved by our ethical committee

Modified sentences: This was a secondary analysis of prospectively collected data from a cohort study conducted between January 2016 (when the ERP was first implemented at the Institut Paoli-Calmettes, a comprehensive cancer center in France) and September 2018. All women over 18 years of age who required gynecologic surgery at the Institut Paoli-Calmette during the study period followed our ERP. They were informed of the study during their first consultation and were asked to provide written consent for the storage and use of their data. The study was approved by our ethical committee

Original sentence: Consecutive patients undergoing minimally invasive procedures (hysterectomy and/or pelvic or para-aortic lymphadenectomy), either by RAL or CL, for gynecologic cancers (cervical, endometrial or ovarian cancer) were identified.

Modified sentence: Consecutive patients undergoing minimally invasive procedures (hysterectomy and/or pelvic or para-aortic lymphadenectomy), either by RAL or CL, for gynecologic cancers (cervical, endometrial or ovarian cancer) were identified. We excluded patients who underwent surgery for benign indications and patients for whom a laparotomy was indicated.

5. The results are a description of the population underwent minimally invasive surgery for gynecologic oncological disease at the Institut Paoli-Calmettes. The comparison between CL and RAL is strongly limited by the differences between women underwent one or the other surgical technique based primarily on the surgeon choice, which is based on the patient characteristics and required surgical procedure. More than a description of population characteristics is not possible considering these differences. The logistic regression shows this point, clarifying that other factors instead of the minimally invasive approach are actually cause of the observed differences.

Reviewer #2 is right. Our study is only a description of our current surgical practice and an attempt to determine if it is efficient in the context of our ERP. Our conclusion is that the surgeons from our unit preferentially choose RAL over CL to perform more complex procedures. Although this conclusion is well supported by our results, we acknowledge that we were somehow too liberal when suggesting in the discussion that RAL was superior to CL too perform complex procedure. Therefore we tried to attenuate the interpretation of our results throughout the manuscript to clarify that we cannot conclude on the superiority of one route or the other for complex procedures.

Abstract:

Original sentence: The logistic regression analysis that adjusted for predictors of prolonged hospitalization suggested that the use of RAL reduced the likelihood of a LPO > 3 days (Adjusted OR = 0.573 [0.236–1.388]; p = 0.217).

Modified sentence: The logistic regression analysis that adjusted for predictors of prolonged hospitalization revealed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO > 3 days (Adjusted OR = 0.573 [0.236–1.388]; p = 0.217).

Original sentence: This seems to be efficient, in the context of our ERP, to maintain acceptable LPO and complication rate even for more complex procedures.

Modified sentence: More studies are needed to determine whether this strategy is efficient to manage complex procedures in the framework of an ERP.

Discussion:

Original paragraph: Although their choice is more intuitive and experienced-based than properly supported by scientific evidences, it seems to comply with the objectives of our ERP. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL reducing the likelihood of a LPO superior to 3 days. Conversely, when used for isolated procedures RAL significantly increases the LPO compared to CL. The operative time for isolated procedures was, however, similar for the two approaches, suggesting that the increased LPO is attributable to other features of RAL, such as the number and width of incisions. For combined procedures, there was a non-significant statistical trend in favor of RAL reducing LPO. Operative time was also decreased for combined procedures performed by RAL. Subgroup analysis of total hysterectomies with pelvic lymphadenectomies showed a significant reduction of LPO for RAL compared to CL. The number of observations for the other combined procedures were too low to draw any reliable conclusions.

Modified paragraph: As a consequence, the two groups (RAL and CL) are too different to allow a reliable comparison. This prevents us from firmly concluding on the influence of this strategy of choosing the surgical route on the LPO. Despite this major impediment, our study gives us a hint on the value of RAL to manage complex patients and procedures. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO superior to 3 days. Without statistical adjustment, the only subgroup that showed a significant reduction of LPO for RAL compared to CL was the total hysterectomies with pelvic lymphadenectomies subgroup. The number of observations for the other combined procedures were too low to draw any reliable conclusions. Conversely, when used for isolated procedures RAL seems to be significantly associated with an increased LPO compared to CL. These results brought together, while broadly limited by the weak comparability of the groups, seem to support the fact that RAL is more profitable when used for more complex procedures and patients. The interpretation of the operative time is subject to the same limitations since we cannot take into account all the possible confounders related to the differences between the two populations. The operative time was decreased for combined procedures performed by RAL. For isolated procedures it was, however, similar for the two approaches, suggesting that the increased LPO in this subgroup could be attributable to other features of RAL (such as the number and width of incisions). or to other confounders (age, BMI).

Conclusion

Sentence deleted: This seems to be efficient, in the context of our ERP, to maintain acceptable LPO and complication rate even for more complex procedures.

6. Discussion. Lines 218-223. This interpretation is unclear, particularly about the compliance with ERP. No comparison between before and after the introduction of ERP is provided. The results of logistic regression show how the observed differences between the two population are not related to the surgical approach but to other confounders.

Reviwer #2 is right, with this study design we cannot conclude on whether RAL is of any help for our ERP. We modified accordingly:

Original sentence: Although their choice is more intuitive and experienced-based than properly supported by scientific evidences, it seems to comply with the objectives of our ERP. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL reducing the likelihood of a LPO superior to 3 days.

Modified sentence: As a consequence, the two groups (RAL and CL) are too different to allow a reliable comparison. This prevents us from firmly concluding on the influence of this strategy of choosing the surgical route on the LPO. Despite this major impediment, our study gives us a hint on the value of RAL to manage complex patients and procedures. Indeed, the results of the logistic regression analysis taking into account predictors of a prolonged hospitalization showed a non-statistically significant trend in favor of RAL being associated to a reduced likelihood of a LPO superior to 3 days.

7. The interpretation of operative time is questionable if not corrected for all the possible confounders related to the difference between the two population.

This is absolutely true, however, our results show that isolated procedures were performed with similar operative time with RAL and CL despite the population of the RAL group presenting more elements of surgical complexity (BMI, age…). Similarly, for combined procedures, the operative time is inferior with RAL than with CL despite these elements. Nevertheless, we cannot rule out other confounders that are not reported in this article. For that reason, we tried to attenuate the interpretation of our results:

Orginal sentence: The operative time for isolated procedures was, however, similar for the two approaches, suggesting that the increased LPO is attributable to other features of RAL, such as the number and width of incisions. For combined procedures, there was a non-significant statistical trend in favor of RAL reducing LPO. Operative time was also decreased for combined procedures performed by RAL.

Modified sentence: The interpretation of the operative time is subject to the same limitations since we cannot take into account all the possible confounders related to the differences between the two populations. The operative time was decreased for combined procedures performed by RAL. For isolated procedures it was, however, similar for the two approaches, suggesting that the increased LPO in this subgroup could be attributable to other features of RAL, (such as the number and width of incisions). or to other confounders (age, BMI).

8. Line 259. Why should the observational design be a weakness?

Reviewer #2 is obviously right. The observational design of this study complies well with our main objective which was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit in the context of an ERP. We simply deleted this sentence:

Deleted sentence: The observational nature of the present study is its main weakness.

9. Study limits should be improved and better reported.

We agree with reviewer #2, the limits were insufficiently discussed. We already addressed some of the concerns regarding the comparability of the patients by answering to the comment #5. On the advice of the Editor, we also added a paragraph on fertility preservation. We acknowledge that we need to improve our limitation paragraph with the comments of Reviewer #2:

Original paragraph: Surgical approaches have clearly been chosen by surgeons with the a priori belief of a better profitability of RAL for more complex procedures. As a consequence, the low number of observations for combined procedures performed by CL prevented us from determining whether there is a significant difference in LPO between the two approaches in this subgroup of interest. Furthermore, we have not reported data on estimated blood loss, post-operative pain or oncological outcomes, as our report focused on the main objectives of the ERP (morbidity and length of stay).

Modified paragraph: Our primary objective was to describe and compare the characteristics of procedures for gynecologic cancers that were performed with either CL or RAL in our unit. Although we determined that surgeons from our unit preferentially choose to use RAL to perform complex procedures, two major impediments prevented us from concluding whether this strategy is effective to reduce the LPO. Firstly, surgical approaches have clearly been chosen by surgeons with the a priori belief of a better profitability of RAL for more complex procedures and patients. As a consequence, we obtained two groups with very different features which make it difficult to compare outcomes. We have attempted to overcome this bias by conducting a subgroup analysis and a logistic regression analysis. These analyses must be interpreted with the utmost precaution and cannot provide sufficient evidence to recommend one surgical approach or the other regardless of complexity. Secondly, our study population presents a high degree of heterogeneity since it includes patients suffering from different gynecological cancers. We chose to conduct our subgroup analysis by regrouping patients who underwent similar procedures rather than regrouping patients with the same cancer localization. Although this method is suitable for analyzing the surgical complexity, it does not account the specific difficulties associated with the surgical treatment of each cancer. Furthermore, our study focused mainly on the LPO which is the easiest way to assess the efficiency of an ERP. However, it does not render the whole complexity of the treatment of gynecological cancers. Indeed, we have not reported data on the oncological outcomes such as the relapse-free survival. The long-term quality of life is also missing from our reported data. In particular, we did not report any data on the fertility preservation which is strongly linked to the well-being of young patients suffering from gynecological cancers [27–31]. Thus, we cannot formally conclude on the profitability of each surgical approach, and can only describe the elements that we use to decide which MIS technique will be used. Finally, the reproducibility of our findings is limited to MIS expert centers where surgeons have advanced skills both for RAL and CL.

 

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: No

Attachments

Attachment

Submitted filename: Response to Reviewers.docx