Intraoperative Fluorescein Sodium in Pediatric Neurosurgery: A Preliminary Case Series from a Singapore Children’s Hospital

Round 1

Reviewer 1 Report

I would like to thank the Editors for inviting me to review this manuscript. Tan AJL, Low SYY and team have presented their experience of the use of Na-Fl as a neuro-surgical adjunct in pediatric Neuro-Oncology. Overall the study was conducted very well with broad and good representation of patients with different tumors, and the results are presented well.  I have the following comments on the manuscript:

1) In the results section: (106-107)- The numbers do not add up: 15 underwent resection out of which 8 had GTR and 5 had STR. I think the other 2 patients had NTR (which needs to be mentioned in the text).  

2) I am curious about the diffuse midline gliomas (H3-K27M altered)? Where were they located? If in the Pons (the authors say they had 2 tumors in the brainstem), these tumors usually have intact BBB and hence they should not light up with Na-Fl? Also, if they did a stereotactic biopsy- it will be important to whether the biopsy tissue had NA-Fl and how much was it when compared to tissue from other areas? 

3) The authors report 4 cases which were fluorescent negative: 2 cases of suspected radiation induced HGG, one case of cavernoma. What was the other case which was negative?

4) Repetition of lines in 217-218.

5) Line 276- Not sure whether this is a retrospective study? This was a prospective study; However, I acknowledge that the sample size is small.

I congratulate the tam for a job well done.     

Author Response

RESPONSE TO REVIEWER 1

Dear Editor,

The authors would like to submit the revised manuscript titled: ‘Intraoperative fluorescein sodium in pediatric neurosurgery: a preliminary study from a Singapore children’s hospital [neurosci-2165401]’ to be considered for publication in your esteemed journal: NeuroSci.

Reviewer 1:

I would like to thank the Editors for inviting me to review this manuscript. Tan AJL, Low SYY and team have presented their experience of the use of Na-Fl as a neuro-surgical adjunct in pediatric Neuro-Oncology. Overall the study was conducted very well with broad and good representation of patients with different tumors, and the results are presented well.  I have the following comments on the manuscript:

1) In the results section: (106-107)- The numbers do not add up: 15 underwent resection out of which 8 had GTR and 5 had STR. I think the other 2 patients had NTR (which needs to be mentioned in the text).  

We thank Reviewer 1 for pointing this out and apologise for the typo error. The sentence and patient numbers have been amended accordingly. Please see Lines 116 to 117.

 

2) I am curious about the diffuse midline gliomas (H3-K27M altered)? Where were they located? If in the Pons (the authors say they had 2 tumors in the brainstem), these tumors usually have intact BBB and hence they should not light up with Na-Fl? Also, if they did a stereotactic biopsy- it will be important to whether the biopsy tissue had NA-Fl and how much was it when compared to tissue from other areas? 

For the 3 cases that had the diagnosis of ‘diffuse midline glioma (H3K27M-altered), 2 cases were located in the brainstem and the other was in the thalamus. Please see amendment in Table 1. For the brainstem gliomas, our findings for 1 of these cases is congruent with previous publications of Na-Fl being useful for similar cases in this location (References 10 and 18). Please see Lines 152 to 154. The remaining case that Na-Fl did not show fluorescence is highlighted as 1 of the radiation-induced high grade gliomas in Lines 193 to 198. 

The technique to check for Na-Fl fluorescence in stereotactic biopsy cases is adapted from the literature and  has been described by previous studies (References 11, 12 and 13). We amended our methodology for clarity. Please see Lines 89 to 93.

 

3) The authors report 4 cases which were fluorescent negative: 2 cases of suspected radiation induced HGG, one case of cavernoma. What was the other case which was negative?

Once again, we thank Reviewer 1 for pointing this out and apologise our typo error. Please see Lines 126 to 128 for the clarification.

4) Repetition of lines in 217-218.

We have re-checked our manuscript and removed any repetitions within the writing.

5) Line 276- Not sure whether this is a retrospective study? This was a prospective study; However, I acknowledge that the sample size is small.

This is a retrospective study. We apologise for any confusion in our writing. Please see Lines 60 to 61 for the necessary amendments.

I congratulate the tam for a job well done.     

We thank Reviewer 1 for the valuable inputs and encouraging comments for our manuscript. We sincerely hope that our changes and additions will be adequate for the journal’s standards for publication.

 

Regards,

Sharon Low (on behalf of all the authors)

 

Author Response File: Author Response.pdf

Reviewer 2 Report

In this paper, authors conducted a study to determine safety and feasibility of intraoperative Na-Fl use in pediatric brain tumor surgery. No adverse events were registered. They conclude that preliminary findings demonstrate the safe and efficacious use of intraoperative Na-Fl for brain tumors as a neurosurgical adjunct.

The topic is interesting since objective data are still few, and the paper is well written and easy to understand. It partially fits the Topical Collection addressed.

Several methodological issues need to be clarified:

- "preliminary" "safety" "pilot" and "feasibility" study are alternatively used terms in this paper but each of it refers to a kind of study with peculiar methods and goals. Seen the absence of a control group, randomization and cost-effectiveness evaluation, it seems that this study would be better defined as a surgical case series. For further details on non randomised feasibility studies see Lancaster, 2019.

-Adverse effects considered are not specified, except for anaphylaxis.

-Score for Na-Fl fluorescence is not specified. Neither is the number of different neurosurgeons that used it (intra e inter operator variability bias).

-It is stated that use of Na-Fl " did not cause any undue delays" (line128) but no data are provided about surgical timing to prove it.

-It is not clear why this study is addressed to "our local population" (line 53 and often below). Are there specific factors that preclude results generalisation?

Minor errors:

-Table1: Age (months) instead of years;

-Repetition at line 127;

Author Response

RESPONSE TO REVIEWER 2

Dear Editor,

The authors would like to submit the revised manuscript titled: ‘Intraoperative fluorescein sodium in pediatric neurosurgery: a preliminary study from a Singapore children’s hospital [neurosci-2165401]’ to be considered for publication in your esteemed journal: NeuroSci.

Reviewer 1:

In this paper, authors conducted a study to determine safety and feasibility of intraoperative Na-Fl use in pediatric brain tumor surgery. No adverse events were registered. They conclude that preliminary findings demonstrate the safe and efficacious use of intraoperative Na-Fl for brain tumors as a neurosurgical adjunct.

The topic is interesting since objective data are still few, and the paper is well written and easy to understand. It partially fits the Topical Collection addressed.

Several methodological issues need to be clarified:

- "preliminary" "safety" "pilot" and "feasibility" study are alternatively used terms in this paper but each of it refers to a kind of study with peculiar methods and goals. Seen the absence of a control group, randomization and cost-effectiveness evaluation, it seems that this study would be better defined as a surgical case series. For further details on non randomised feasibility studies see Lancaster, 2019.

We thank Reviewer 2 for these useful comments. We have revised the manuscript’s title and removed the said terms in the paper accordingly. Please see Lines 2 to 3 (title), Lines 23 to 24, Lines 55 to 56 and Lines 338 to 339.

 

-Adverse effects considered are not specified, except for anaphylaxis.

Once again, we thank Reviewer 2 for pointing this out. Please see Lines 281 to 292 in the revised manuscript.

-Score for Na-Fl fluorescence is not specified. Neither is the number of different neurosurgeons that used it (intra e inter operator variability bias).

Please see Lines 140 to 141 and Lines 320 to 327 to address these comments.

 

-It is stated that use of Na-Fl " did not cause any undue delays" (line128) but no data are provided about surgical timing to prove it.

Please see Lines 144 to 145 and Lines 331 to 338 to address these comments.

 

-It is not clear why this study is addressed to "our local population" (line 53 and often below). Are there specific factors that preclude results generalisation?

Please see Lines 281 to 292 to address these comments.

 

Minor errors:

-Table1: Age (months) instead of years;

We apologise for this typo error. Table 1 has been corrected accordingly.

 

-Repetition at line 127;

We have re-checked our manuscript and removed any repetitions within the writing.

 

We thank Reviewer 2 for the valuable inputs for our manuscript. We sincerely hope that our changes and additions will be adequate for the journal’s standards for publication.

 

Regards,

Sharon Low (on behalf of all the authors)

 

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors present a retrospective analysis of the role of intraoperative Sodium Fluorescein (SF) in a monocentric, pediatric brain tumors population. The series includes 21 patients with a mean age of 12.1 years old. The dye was intravenously administered at the dose of 2 mg/kg, and surgery was performed by alternating white light and YE560 filter visualization. In 3 cases(14.3%), there was no significant fluorescence detected, but the histopathological diagnosis was of cavernoma (1) and radiation-induced high-grade gliomas (2). In the 31 remaining patients (85.7%) the authors experienced "adequate intraoperative fluorescence". The authors concluded that SF is safe and effective also in the pediatric population.

The current series increases to evaluate the role of SF as intraoperative guidance for brain tumor surgery, also in children. However, I have several issues that must be commented on.

The first one is related to the dose of dye injected. the authors refer that the "standard" dose of SF is 2 mg/kg; whereas according to the literature, different dosages have been employed, the FLUOGLIO and FLUOCERTUM study (refs 3 and 6), as well as other studies report a standard dose of 5 mg/kg weight. Also, recent series focusing only in pediatric brain tumors report a similar dose (see Falco J et al, The role of sodium fluorescein in pediatric supratentorial intra-axial tumor resection: new insights from a monocentric series of 33 consecutive patients. Childs Nerv Syst. 2022 Dec 15. doi: 10.1007/s00381-022-05764-5 AND de Laurentis C, Pediatric Low-Grade Glioma Surgery with Sodium Fluorescein: Efficient Localization for Removal and Association with Intraoperative Pathological Sampling. Diagnostics (Basel). 2022 Nov 23;12(12):2927. doi: 10.3390/diagnostics12122927). The authors should better explain why they decided to use this specific dosage.

Moreover, also the time of injection must be better specified: the time between SF administration and the first YE560 visualization as a pivotal role, considering that some time is necessary to wash out (due to its specific mechanism of action) SF from tissues surrounding the tumor, otherwise false positive results could be obtained. This seems what happened in the case of figure 2 (considering the slight fluorescence into the normal parenchyma around the tumors). I suggest to add, if possible, more explicative figures to better explain the value of SF

Author Response

RESPONSE TO REVIEWER 3

Dear Editor,

The authors would like to submit the revised manuscript titled: ‘Intraoperative fluorescein sodium in pediatric neurosurgery: a preliminary study from a Singapore children’s hospital [neurosci-2165401]’ to be considered for publication in your esteemed journal: NeuroSci.

Reviewer 3:

The authors present a retrospective analysis of the role of intraoperative Sodium Fluorescein (SF) in a monocentric, pediatric brain tumors population. The series includes 21 patients with a mean age of 12.1 years old. The dye was intravenously administered at the dose of 2 mg/kg, and surgery was performed by alternating white light and YE560 filter visualization. In 3 cases(14.3%), there was no significant fluorescence detected, but the histopathological diagnosis was of cavernoma (1) and radiation-induced high-grade gliomas (2). In the 31 remaining patients (85.7%) the authors experienced "adequate intraoperative fluorescence". The authors concluded that SF is safe and effective also in the pediatric population.

The current series increases to evaluate the role of SF as intraoperative guidance for brain tumor surgery, also in children. However, I have several issues that must be commented on.

The first one is related to the dose of dye injected. the authors refer that the "standard" dose of SF is 2 mg/kg; whereas according to the literature, different dosages have been employed, the FLUOGLIO and FLUOCERTUM study (refs 3 and 6), as well as other studies report a standard dose of 5 mg/kg weight. Also, recent series focusing only in pediatric brain tumors report a similar dose (see Falco J et al, The role of sodium fluorescein in pediatric supratentorial intra-axial tumor resection: new insights from a monocentric series of 33 consecutive patients. Childs Nerv Syst. 2022 Dec 15. doi: 10.1007/s00381-022-05764-5 AND de Laurentis C, Pediatric Low-Grade Glioma Surgery with Sodium Fluorescein: Efficient Localization for Removal and Association with Intraoperative Pathological Sampling. Diagnostics (Basel). 2022 Nov 23;12(12):2927. doi: 10.3390/diagnostics12122927). The authors should better explain why they decided to use this specific dosage.

We thank Reviewer 3 for these useful comments. We agree that the word ‘standard’ may seem misleading and have removed it accordingly in the revised manuscript. Please see Line 28. In addition, we have addressed the question of why the dose of 2mg/ kg of Na-Fl is used in our study. Please see Lines 281 to 292.

 

Moreover, also the time of injection must be better specified: the time between SF administration and the first YE560 visualization as a pivotal role, considering that some time is necessary to wash out (due to its specific mechanism of action) SF from tissues surrounding the tumor, otherwise false positive results could be obtained. This seems what happened in the case of figure 2 (considering the slight fluorescence into the normal parenchyma around the tumors). I suggest to add, if possible, more explicative figures to better explain the value of SF

Once again, we thank Reviewer 3 for highlighting this. Please see 321 to 327 and Lines 331 to 338 to address these comments.

 

We thank Reviewer 3 for the valuable inputs and encouraging comments for our manuscript. We sincerely hope that our changes and additions will be adequate for the journal’s standards for publication.

 

Regards,

Sharon Low (on behalf of all the authors)

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

No more suggestions. Accept in present form.

Reviewer 3 Report

The manuscript is now suitable for publication