Gastrointestinal Residue Removal Using a Balloon Overtube under Ultrathin Endoscopic Navigation: Ex Vivo and In Vivo Experimental Studies

Round 1

Reviewer 1 Report

In this manuscript, Kozuka K et al. presented “Usefulness of the clip-and-snare method using the pre- looping technique for endoscopic submucosal dissection of gastric neoplasia: A randomized controlled trial”. The content of this study is unique; however, this study had several concerns.

 

Major comments:

1. This method is suitable for removing massive blood clots during endoscopic hemostasis for upper gastrointestinal bleeding. Therefore, I recommend the additional experiment for removing blood clots in vivo and in vitro if you can.

 

2. Use of the ultra-thin endoscope has some advantages for insertion guidance, keep visibility by air insufflation, and confirmation of the residues. Please emphasize them.

 

Minor comments:

1. The visibility of figure 2 was not so high. Please revise it.

Author Response

1）This method is suitable for removing massive blood clots during endoscopic hemostasis for upper gastrointestinal bleeding. Therefore, I recommend the additional experiment for removing blood clots in vivo and in vitro if you can.

Response

Thank you for your valuable comments. As you suggest, we also considered that blood clots would be preferable to experiments related to clinical practice.

We have added the following sentences in the Limitation of the discussion: ‘There was another limitation. While the main purpose of this study was to maintain the operation field by removing blood and foods using our developed device, the clinical effect whether clear operation field contributes to the success rate and procedure time of endoscopic hemostasis remains insufficient evidence. In contrast, unclear operation field is caused by poor preparation and intraoperative bleeding during endoscopic tumor resection. These situations force us to postpone the operation and interrupt the consecutive procedure. Thus, measures to quickly remove the residue and ensure a clear endoscopic field is necessary and meaningful in clinical practice. A clinical study is now scheduled to reveal this proof.

Third, a comparable model of blood clots related to medical procedure was absent in this study. Prior to the start of the study, we considered the introduction of human red blood cell (RBC) products for blood transfusion. In the ex vivo model, because the RBC easily harden in the room air, we could not create individually the same model of blood clots. In the animal model, if inserting human blood into the animal, ethical issues were raised. Consequently, we applied gelatinous jelly as simulated blood clots.’

 

 

2) Use of the ultra-thin endoscope has some advantages for insertion guidance, keep visibility by air insufflation, and confirmation of the residues. Please emphasize them.

Response

Thank you for your valuable comments.

We added the following sentences in the discussion: However, the biopsy forceps applied for achieving continuous suction has a few potential risk of complications such as mucosal injury while no obvious complications appeared in the present study. The maneuver, pushing biopsy forceps on the mucosa, is similar to checking the cushion sign of subepithelial leisons using the forceps. Thus, the maneuver seems less invasive. Without the forceps, the overtube may frequently induce larger mucosal damage because of the suction error. Consequently, the combination of biopsy forceps and ultrathin endoscope is considered an effective tool for suctioning promptly the residue and preventing the mucosal injury by suction errors under direct vision.’

 

 

3) The visibility of figure 2 was not so high. Please revise it.

Response

Thank you for pointing this out. We have inserted a new figure 2.

Reviewer 2 Report

This is an interesting research regarding removal of a large amount of GI residue. And this method is considered to be practical assistance to many endoscopist. However, there are some important concerns.

 

1. An important objective of this study is that a novel device can help in the rapid detection of bleeding sites and hemostasis. However, this study was conducted by simply setting the success rate and procedure time as endpoints. What really matters is the procedure time and success rate of hemostasis. It can be problematic to simply judge that procedure time and suction rate can be applied to hemostasis. If you make a comparable model including the parts related to medical procedure, it will be more convincing comparison. Have you considered this?

 

2. Ultrathin endoscope have very poor image quality and cannot use instruments other than biopsy forcep through force channel. Suction and hemostasis cannot be performed together. If the image quality is poor during hemostasis, it will be difficult to find the lesion, and if the treatment equipment is not used immediately, the time for hemostasis will increase. Have you considered this?

 

3. Conducting and evaluating complications in stable animal experiments can be problematic. Patients with massive residues and needing suction are often not in a stable state and visible state. If you anticipate the situation in such a patient, suction device which has a large diameter and does not have a suction button is relatively difficult to move quickly, and may create additional complications. Have you considered this?

 

4. To prevent complications due to suction, suction was performed with a forcep inserted. However, have you not considered the occurrence of complications caused by forcep? Furthermore, bleeding and perforation may be more likely to occur due to forceps if the patient is moving. Have you considered this?

 

5. Jelly was used instead of blood in ex vivo study. If you predict the situation of ulcer bleeding, you can think of a method to evaluate the suction ability by clotting time using real blood rather than jelly. Have you considered this?

 

6. Why did you choose animals from 11 to 3 month old beagles in the in vivo study? Why did you use 150ml of food jelly?

Author Response

1）An important objective of this study is that a novel device can help in the rapid detection of bleeding sites and hemostasis. However, this study was conducted by simply setting the success rate and procedure time as endpoints. What really matters is the procedure time and success rate of hemostasis. It can be problematic to simply judge that procedure time and suction rate can be applied to hemostasis. If you make a comparable model including the parts related to medical procedure, it will be more convincing comparison. Have you considered this?

Response

I appreciate your important query and understanding for the aim of this study.

According to your suggestion, we have added the following sentences in the Limitation of the discussion: ‘There was another limitation. While the main purpose of this study was to maintain the operation field by removing blood and foods using our developed device, the clinical effect whether clear operation field contributes to the success rate and procedure time of endoscopic hemostasis remains insufficient evidence. In contrast, unclear operation field is caused by poor preparation and intraoperative bleeding during endoscopic tumor resection. These situations force us to postpone the operation and interrupt the consecutive procedure. Thus, measures to quickly remove the residue and ensure a clear endoscopic field is necessary and meaningful in clinical practice. A clinical study is now scheduled to reveal this proof.

Third, a comparable model of blood clots related to medical procedure was absent in this study. Prior to the start of the study, we considered the introduction of human red blood cell (RBC) products for blood transfusion. In the ex vivo model, because the RBC easily harden in the room air, we could not create individually the same model of blood clots. In the animal model, if inserting human blood into the animal, ethical issues were raised. Consequently, we applied gelatinous jelly as simulated blood clots.’

 

 

2) Ultrathin endoscope have very poor image quality and cannot use instruments other than biopsy forceps through force channel. Suction and hemostasis cannot be performed together. If the image quality is poor during hemostasis, it will be difficult to find the lesion, and if the treatment equipment is not used immediately, the time for hemostasis will increase. Have you considered this?

Response

We thank your precise suggestion.

Finally, we added the following sentences in the end of the discussion:

‘To apply this suction method in clinical practice, several issues should be discussed.

Although the old type of ultrathin endoscope which could be used for the animal experiment had relatively poor image quality, newly developed ultrathin endoscopes with high image quality are clinically available. Thus, the image quality of ultrathin endoscope would be not clinically concerned. If the treatment equipment is not used immediately, the procedure time for hemostasis may be prolonged. Therefore, it is more desirable to perform suction and hemostasis simultaneously. A novel hemostatic forceps with 2.3 mm diameter (RAICHO, KANEKA, Osaka, Japan) suitable for the ultrathin endoscopes (FUJIFILM, Tokyo, Japan) with 2.4 mm of scope channel is recently available in clinical practice. Several authors reported that the RAICHO was efficacious for endoscopic hemostasis during endoscopic submucosal dissection using the ultrathin endoscope [18,19]. Accordingly, the simultaneous procedure seems possible. A further study is needed to verify the efficacy.’

 

The following papers are added in the references.

18. Nishiyama, N.; Kobara, H.; Yachida, T.; Mori, H.; Shi, T.; Okano, K.; Masaki, T. Strategy of small-caliber endoscopic submucosal dissection for esophagealneoplasia distal to severe stricture. Endoscopy 2020, 52, E94-E95; DOI: 10.1055/a-1011-3729. 
19. Kikuchi, D.; Tanaka, M.; Nakamura, S.; Nomura, K.; Hayasaka, J.; Ochiai, Y.; Odagiri, H.; Yamashita, S.; Matsui, A.; Hoteya, S. Feasibility of ultrathin endoscope for esophageal endoscopic submucosal dissection. Endosc Int Open. 2021, 9, E606-E609; DOI: 10.1055/a-1352-3805.

 

 

3) Conducting and evaluating complications in stable animal experiments can be problematic. Patients with massive residues and needing suction are often not in a stable state and visible state. If you anticipate the situation in such a patient, suction device which has a large diameter and does not have a suction button is relatively difficult to move quickly, and may create additional complications. Have you considered this?

Response

We added the following sentences in the discussion: ‘When the patient presents with massive bleeding in unstable vital status, the suction device usage should be recommended only under general anesthesia to maintain the safety. Meanwhile, the suction device is originated in the overtube used clinically for enteroscopy, and the tube diameter is same. Thus, the device-associated complications are expected to be low similar to that of enteroscopy use.’

 

 

4) To prevent complications due to suction, suction was performed with a forcep inserted. However, have you not considered the occurrence of complications caused by forcep? Furthermore, bleeding and perforation may be more likely to occur due to forceps if the patient is moving. Have you considered this?

Response

Thank you for your comments.

We added the following sentences in the discussion: ‘The biopsy forceps applied for achieving continuous suction has a few potential risk of complications such as mucosal injury while no obvious complications appeared in the present study. The maneuver, pushing biopsy forceps on the mucosa, is similar to checking the cushion sign of subepthelial leisons using the forceps. Thus, the maneuver seems less invasive. Without the forceps, the overtube may frequently induce larger mucosal damage because of the suction error. Consequently, the combination of biopsy forceps and ultrathin endoscope is considered an effective tool for suctioning promptly the residue and preventing the mucosal injury by suction errors under direct vision.’

 

 

5) Jelly was used instead of blood in ex vivo study. If you predict the situation of ulcer bleeding, you can think of a method to evaluate the suction ability by clotting time using real blood rather than jelly. Have you considered this?

Response

Thank you for your comments.

As we answer for query 1, a model of blood clots related to medical procedure was absent in this study. Prior to the start of the study, we considered the introduction of human red blood cell (RBC) products for blood transfusion. In the ex vivo model, because the RBC easily harden in the room air, we could not create individually the same model of blood clots. In the animal model, if inserting human blood into the animal, ethical issues were raised. Consequently, we applied gelatinous jelly as simulated blood clots.  

 

 

6) Why did you choose animals from 11 to 3 month old beagles in the in vivo study? Why did you use 150ml of food jelly?

Response

Thank you for your comments.

We used 11–13-month-old female beagle dogs, and we confirmed it in the text. A beagle dog is an adult dog when it is 11 months or older, and previous animal studies in the literature are also applied in the similar setting.

We added the following sentences in the ‘2.6. Outcome Measures in the in vivo animal study’.

: ‘Removal was defined as successful when the upper greater curvature folds became visible after suctioning. In our previous experiment, we confirmed that the folds became invisible when the jelly was more than 150 ml. Therefore, we defined the amount of jelly as 150 ml.

Round 2

Reviewer 1 Report

Your revised paper is well written and illustrated because all comments are taking into account.

Author Response

At the recommendation of the academic editor, we have added the beagle animal experimental video in the Supplementary Materials.

 

I thank reviewers for careful reading my manuscript and for your helpful suggestions.

Reviewer 2 Report

Thanks for the detailed response.

 In many countries including Korea, the use of ultrathin endoscopy is still limited. And hemostatic devices through forcep channel are not widely available. In order for this device to be utilized in many contries, it seems that the use of ultrathin endoscopy and hemostatic devices need to be more widely available.

 In patients with massive bleeding and unstable vital status, anesthesia can make the situation worse. So I think it is nearly impossible to use this device in these patients. Then, this device has a limitation that it can be used only in patients with stable status. In order to increase the usability of this device, additional studies that can prove safe use even in unstable status are conducted.

 It would be more convincing that if the study was conducted by adding another viscous simulated residue other than jelly and agar.

 I hope that further clinical studies will proceed well.

Author Response

Thank you for your suggestion.

As for the verification of the safety and clinical indications of our device in patients with unstable general condition, we will conduct clinical studies in the future to clarify this. We will follow your advice and continue to conduct experiments to develop new devices.

 

At the recommendation of the academic editor, we have added the beagle animal experimental video in the Supplementary Materials.

 

I thank reviewers for careful reading my manuscript and for your helpful suggestions.