The Role of Stereotactic Frame-Based Biopsy for Brainstem Tumors in the Era of Molecular-Based Diagnosis and Treatment Decisions

Round 1

Reviewer 1 Report

The authors analyze their experience with stereotactic frame-based brainstem biopsy. This is a chapter of paramount importance in neuroncology and requires the best medical skills.

Frame based biopsy is going to be replaced by the frame-less technique: nevertheless, the lessons from frame-based  series are precious to obtain fast and reliable results.

This is a retrospective analysis of an interesting surgical series of stereotactic frame-based brainstem biopsies.

The authors, reporting their findings in 22 patients, conclude that stereotactic frame-based biopsy through a trans-cerebellar approach is safe, reliable, and effective.

The methodology appears appropriate and the paper well written. Bibliography is up-to-date.

Regarding the issue: frameless technique would probably replace the frame-based one, but in such delicate field, surgical experience with one technique or the other would dictate the final choice; the authors reported this and other cues in the discussion.

1.      What is the main question addressed by the research?

The main question addressed by the research was assessing the safeness and the effectiveness of the stereotactic frame-based brainstem biopsy.

2.      Do you consider the topic original or relevant in the field, and if so, why?

The topic is not original: however, because of the relative rarity of the disease, a well described clinical series with more of twenty patients would be quite relevant. In fact, accurate description of the surgical technique as well as of the outcome would be a useful example for clinicians.

3.      What does it add to the subject area compared with other published material?

As I’ve already stated before, this paper does not bring novelties, but adds data in the field of brainstem biopsy that is a delicate chapter of neuro-oncology and neurosurgery.

4.      What specific improvements could the authors consider regarding the methodology?

Routine preoperative radio-metabolic exams (PET-SPECT) allowed a more targeted biopsy and reduced the amount of the harvested tissue necessary to yield a reliable diagnosis.  

5.      Are the conclusions consistent with the evidence and arguments presented and do they address the main question posed?

Yes, they do.

6.      Are the references appropriate?

Yes, they do

7.      Please include any additional comments on the tables and figures.

Figures and Table are clear and easy to look up.

Author Response

Thank you for your encouraging comments. We hope that with the modifications that we have made upon the advice of the reviewers, this article becomes more appealing and meaningful to readers.

Reviewer 2 Report

Yudai Hirano et al. evaluated the diagnostic accuracy and safety of stereotactic frame-based biopsy for brainstem tumors in 23 patients with brainstem tumors. The authors in the prone position under general anesthesia and integrate the nuclear medicine examination to target the tumor with greater accuracy. The authors found this approach to be generally safe and reliable for the diagnosis of brainstem lesions. The postoperative complications were all transient. SFB for brainstem tumors yields a high diagnostic rate with a low risk of morbidity.

 

This is an interesting study suggesting the safety and reliability of infratentorial stereotactic biopsy. It provides additional insights into current knowledge on the diagnosis of brainstem tumor. The study is well designed and the manuscript is well written.

 

Major issue

 

a.         Have you done genetic tests (i.e. IDH1/2 mutation, 1p/19q codel, TERT promoter mutation) from the biopsy material - especially the critical mutations for CNS5 WHO 2021? Diagnostic rate does not only consist in the assessment of the histopathological assessment itself, but also in the assessment of genetic markers. This is also a limitation of the study. Could you please supplement the histopathological results with genetic tests?

 

Minor issue is raised as follows: 

• Please elaborate in the discussion if there were differences (if any) in the SFB between adults and children.

• Were all the biopsies taken from the infratentorial approach or were there also the supratentorial biopsies? Please specify how many infratentorial and supratentorial biopsies were performed. Please elaborate more on that.

• In table 1, please do not use old nomenclature anaplastic and diffuse astrocytoma, instead please use Astrocytoma Grade 2, Astrocytoma Grade 3 according to the CNS5 WHO 2021.

• Why did you perform CT in pediatric patients? Please elaborate on that.

• Another limitation of this article is that the small study sample.

• Please explain why you have performed biopsies in a prone position under general anesthesia when such biopsies can be performed in a semi-sitting position under local anesthesia, what is more convenient and less invasive for the patient.

Author Response

We really appreciate your valuable comments regarding our manuscript. Please find below your itemized questions and concerns, followed by our replies.

Major issue
Q1: Have you done genetic tests (i.e., IDH1/2 mutation, 1p/19q codel, TERT promoter mutation) from the biopsy material - especially the critical mutations for CNS5 WHO 2021? Diagnostic rate does not only consist in the assessment of the histopathological assessment itself, but also in the assessment of genetic markers. This is also a limitation of the study. Could you please supplement the histopathological results with genetic tests?

A1: Thank you for your pointing this out. Ideally, this is true. Naturally, we regularly analyze IDH1/2 mutation, 1p/19q co-deletion, TERT promoter mutations, etc.1 However, the content, including genetic analysis, is being created in another paper, so we would like to avoid specifying it in this paper if possible, considering the risk of double submission. If you have any further ideas, please let us know.

1.    Nejo T, Tanaka S, Ikemura M, et al. Maffucci syndrome complicated by three different central nervous system tumors sharing an IDH1 R132C mutation: case report. Journal of neurosurgery. Dec 21 2018;131(6):1829-1834. doi:10.3171/2018.6.JNS18729

Minor issue
Q2: Please elaborate in the discussion if there were differences (if any) in the SFB between adults and children.

A2: Thank you for your pointing this out. Basically, SFBs were performed in the same fashion for both adults and children. Considering the variability in the thickness of the developing cranium, head fixation with Leksell Frame should be performed gently, especially in pediatric patients. We added the detailed description in the manuscript, as follows.

[Page 2, lines 91–94]
The head fixation was performed in the same fashion both for the adult and pediatric patients, but with caution, especially in the pediatric patient, due to the variability in the thickness of the developing skull.

Q3: Were all the biopsies taken from the infratentorial approach or were there also the supratentorial biopsies? Please specify how many infratentorial and supratentorial biopsies were performed. Please elaborate more on that.

A3: Thank you for your valuable comments. In this series, all the biopsies were performed via the infratentorial approach. Accordingly, we have added a more detailed description to the manuscript.

[Page 3, lines 104–105]
“During preoperative planning, we used the infratentorial transcerebellar approach with the patient in the prone position for all cases.”

Q4: In table 1, please do not use old nomenclature anaplastic and diffuse astrocytoma, instead please use Astrocytoma Grade 2, Astrocytoma Grade 3 according to the CNS5 WHO 2021.

A4: 
Thank you for providing critical comment. As you mentioned, we should describe in accordance with WHO2021. We have modified the Table 1 based on your concern, so please confirm.

[Table 1]

No.    Age, Sex    Tumor location    Target    Diagnosis    Stealth imaging    PET/SPECT    Follow-up    Latest mRS    Complications    Postoperative treatment
1    3 y, F    Pons    Middle CP    Astro, 
IDH-mt, Gr2    CT    Yes    33 months    5    Facial nerve palsy
(transient)    Chemo, RT
2    6 y, F    Midbrain
Pons
Medulla oblongata    Middle CP    GBM    CT    No    1 month    6    None    RT
3    11 y, F    Midbrain
Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr2    CT
MRI    Yes    9 months    6    None    Chemo, RT
4    13 y, M    Pons    Middle CP    Astro, 
IDH-mt, Gr3    MRI    Yes    12 months    6    None    Chemo, RT
5    21 y, M    Midbrain
Pons
Medulla oblongata
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr3    MRI    Yes    29 months    6    None    Chemo, RT
6    22 y, M    Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr2    MRI    No    61 months    6    None    Chemo, RT
7    28 y, M    Pons    Inferior CP    Astro, 
IDH-mt, Gr3    MRI    Yes    39 months    6    None    Chemo, RT
8    34 y, M    Midbrain
Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr3    MRI    Yes    17 months    5    None    Chemo, RT
9    34 y, M    Pons
Cerebellum    Middle CP    Metastatic
carcinoma    MRI    Yes    1 month    5    Abducens nerve palsy
(transient)    RT
10    34 y, M    Pons    Middle CP    DMG
H3 K27-altered    MRI    Yes    39 months    1    None    Chemo, RT
11    38 y, F    Pons
Cerebellum    Cerebellum    PCNSL    MRI    Yes    19 months    6    None    Chemo, RT
12    38 y, M    Pons    Inferior CP    Astro, 
IDH-mt, Gr2    MRI    Yes    86 months    2    Diplopia
(transient)    Chemo, RT
13    39 y, F    Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr3    MRI    Yes    8 months    N/A    None    Chemo, RT
14    47 y, F    Pons
Cerebellum    Middle CP    DMG
H3 K27-altered    MRI    Yes    7 months    6    None    Chemo, RT
15    47 y, M    Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr2    MRI    Yes    28 months    2    None    Chemo, RT
16    48 y, M    Midbrain
Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr3     MRI    Yes    16 months    4    None    Chemo, RT
17    54 y, F    Pons    Cerebellum    PCNSL    MRI    Yes    13 months    6    None    Chemo, RT
18    60y, M    Midbrain
Pons
Medulla oblongata
Cerebellum    Middle CP    DMG
H3 K27-altered    MRI    Yes    36 months    5    None    Chemo, RT
19-1    62 y, M    Pons
Cerebellum    Cerebellum    N/A    MRI    Yes    6 months     N/A    None    Chemo, RT
19-2    62 y, M    Pons
Cerebellum    Superior CP    GBM    MRI    Yes    6 months    6    Ataxia
(transient)    Chemo, RT
20    65 y, F    Pons
Medulla oblongata
Cerebellum    Cerebellum    PCNSL    MRI    Yes    88 months    1    None    Chemo, RT
21    70 y, F    Midbrain
Pons
Cerebellum    Middle CP    PCNSL    MRI    No    22 months    6    None    Chemo, RT
22    70 y, M    Pons
Cerebellum    Middle CP    Astro, 
IDH-mt, Gr2    MRI    Yes    9 months    1    None    Chemo, RT
Astro: astrocytoma, CP: cerebellar peduncle, CT: computed tomography, DMG: diffuse midline glioma, F: female, GBM: glioblastoma, Gr: grade, M: male, MRI: magnetic resonance imaging, mRS: modified Rankin Scale, mt: mutant, N/A: not available, PCNSL: primary central nervous system lymphoma, PET: positron emission tomography, RT: radiation therapy, SPECT; single-photon emission computed tomography

Q5: Why did you perform CT in pediatric patients? Please elaborate on that.

Thank you for your valuable comments. In order to obtain appropriate stereotactic imaging, it is essential to stay static for around 30 minutes or so in the MRI. For pediatric cases under 12 years old, we paid more attention to the risk of body movement during the imaging examination; therefore, it is better to shorten the examination time with the head fixation using the stereotactic frame. As our policy, the stereotactic CT is performed for pediatric cases under 12. Regarding this matter, we added the detailed description in the manuscript as follows.

[Page 3, lines 99–101]
“As our policy, the stereotactic CT is performed for pediatric cases under 12 years old instead of MRI to shorten the examination time with the fixation, considering the risk of body movement during the imaging examination.”

Q6: Another limitation of this article is that the small study sample.

A6: As you mentioned, the small sample size is one of the limitations. Please confirm the description below.

[Page 7, lines 221–222]
“The main limitations of this study were its retrospective nature and the small sample size.”

Q7: Please explain why you have performed biopsies in a prone position under general anesthesia when such biopsies can be performed in a semi-sitting position under local anesthesia, what is more convenient and less invasive for the patient.

A7: Thank you for noting your concern. The biopsy under the local anesthesia has a potential risk of patient movement, therefore general anesthesia was adopted in our institution. We routinely perform biopsies for brain stem tumors in a prone position under general anesthesia for recent 20 years as described in the manuscript. However, the surgical setting you recommended is less invasive and more valuable way. We would like to consider it in the future. We added the description in the manuscript, as follows.

[Page 7, lines 208–210]
“In addition, the stereotactic biopsy in the semi-sitting position under local anesthesia is also a candidate with further minimal invasiveness.”

 

Author Response File: Author Response.docx

Reviewer 3 Report

I have appreciate this work on sterotactic brainstem biopsy.

I would like to suggest only few observations.

- As bibliography 10 i think it would be important to highlight the existant pediatric experience using the paper of "Carai A, Mastronuzzi A, De Benedictis A, Messina R, Cacchione A, Miele E, Randi F, Esposito G, Trezza A, Colafati GS, Savioli A, Locatelli F, Marras CE. Robot-Assisted Stereotactic Biopsy of Diffuse Intrinsic Pontine Glioma: A Single-Center Experience. World Neurosurg. 2017 May;101:584-588. "

- At line 73 what does it mean " potrebbe general condition" to exclude the biopsy?  Neurological conditions in any way due to the tumor?

- At which type of PET are they referring? DOPA or FDG? 

- If possible, it would be interesting to understand in which wayband in how mani cases their biopsies have changed the therapeutic approach.    

Author Response

We really appreciate your valuable comments regarding our manuscript. Please find below your itemized questions and concerns, followed by our replies.

Q1. As bibliography 10 i think it would be important to highlight the existant pediatric experience using the paper of "Carai A, Mastronuzzi A, De Benedictis A, Messina R, Cacchione A, Miele E, Randi F, Esposito G, Trezza A, Colafati GS, Savioli A, Locatelli F, Marras CE. Robot-Assisted Stereotactic Biopsy of Diffuse Intrinsic Pontine Glioma: A Single-Center Experience. World Neurosurg. 2017 May;101:584-588. "

A1. Thank you for your thoughtful comment. As you pointed out, we have added the following description to the Discussion section in the revised manuscript.

[Page 7, lines 210–212]
Carai et al. also reported their experience in robot-assisted stereotactic pontine biopsy in a series of diffuse intrinsic pontine glioma pediatric patients as a safe procedure with a high diagnostic rate [22].

Q2. At line 73 what does it mean " potrebbe general condition" to exclude the biopsy?  Neurological conditions in any way due to the tumor?

A2. Thank you for your pointing this out. The stereotactic frame-based biopsy is a less invasive method but is not indicated for patients who could not tolerate general anesthesia, not because of neurological problems. Therefore, we have revised the description as below.

[Page 2, lines 73–74]
The patients who could not tolerate general anesthesia due to the exceedingly poor general condition were not eligible for the surgery.

Q3. At which type of PET are they referring? DOPA or FDG? 

A3. Thank you for your valuable comment. The type of PET is FDG-PET. We added it in the Material and Methods section.

[Page 2, lines 82–84]
Before surgery, contrast-enhanced computed tomography (CT) and MRI were routinely performed, and nuclear medicine examinations were performed via 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and single-photon emission computed tomography (SPECT), as needed to improve the accuracy of diagnosis (Figure 1a,b).

Q4. If possible, it would be interesting to understand in which way and in how mani cases their biopsies have changed the therapeutic approach.

A4. Thank you for providing critical comments. As you mentioned, the biopsy results in a definitive diagnosis, including neurodegenerative disease and post-stroke changes, other than the expected brain tumor. Fortunately, we did not experience an unexpected diagnosis in the brainstem biopsy. Therefore, we have added the description below in the Discussion section.

[Page 7, lines 193–195]
Although some cases may be diagnosed as non-neoplastic lesions as a result of SFB, in this series of SFB for brainstem lesions, all specimens were neoplastic lesions, leading to appropriate radiation and/or chemotherapy.

Author Response File: Author Response.docx