The Role of PET in Supratentorial and Infratentorial Pediatric Brain Tumors
, Domenico Albano 3, Pierpaolo Alongi 4,*, Riccardo Laudicella 5, Daniele Antonio Pizzuto 6, Giuseppe Formica 5, Cinzia Romagnolo 7, Federica Stracuzzi 5, Viviana Frantellizzi 8, Arnoldo Piccardo 1,2 and Natale Quartuccio 2,9
Michail Plotkin
Round 1
Reviewer 1 Report
This review summarizes the recent data on use of PET technique in the diagnostic evaluation of pediatric brain tumors. Overall, the presented work is thoroughly performed and well written.
However, some issues should be addressed:
- I would suggest to use the more general specification “PET” instead of “PET/CT” in the topic of the manuscript taking in consideration the increasing use of PET/MRI in pediatric studies (some of the citied works had been performed using PET/MRI).
- The authors discuss the role of PET using amino acid tracers and mention that the “available literature involving pediatric patients is limited”. Indeed, the restricted availability of amino acid tracers hampers their clinical use; and the 18F-FDG-PET/CT still be a more common diagnostic tool in some countries. However, in some topics, the available data on use of amino acid tracers exceed those on use of FDG. So, in the sub-section 3.1 the authors cite two studies with 18F-FDG (in one of which 11C-MET was also used) and ten studies with different amino acid tracers.Therefore, the work must be supplemented by an additional table, summarizing results of the published studies on amino acid PET in pediatric neurooncology.
- The authors should mention the main pharmacokinetic differences between the PET tracers and their particularities in regard to the imaging of brain tumors (ex. BBB-independent uptake of amino acid tracers in glioma and their accumulation in the vast majority of brain tumours, low uptake of 18F-Cholin in low grade gliomas).
- In the “conclusion” the authors correctly point out the advantages of non-FDG tracers. It is however unclear why they explicitly mention the 18F-DOPA. There are no comparative data suggesting that 18F-DOPA would be more useful as other amino acid tracers (18F-FET, 11C-MET) in evaluation of pediatric brain tumors.
- The legends under the Figures 1 and 3 seem to be mixed up. There is no MIP image in the Figure 2.
Author Response
Reviewer 1: This review summarizes the recent data on use of PET technique in the diagnostic evaluation of pediatric brain tumors. Overall, the presented work is thoroughly performed and well written.
However, some issues should be addressed:
- I would suggest to use the more general specification “PET” instead of “PET/CT” in the topic of the manuscript taking in consideration the increasing use of PET/MRI in pediatric studies (some of the citied works had been performed using PET/MRI).
REPLY: thank you for the suggestion. We changed the title using general specification : “PET”
- The authors discuss the role of PET using amino acid tracers and mention that the “available literature involving pediatric patients is limited”. Indeed, the restricted availability of amino acid tracers hampers their clinical use; and the 18F-FDG-PET/CT still be a more common diagnostic tool in some countries. However, in some topics, the available data on use of amino acid tracers exceed those on use of FDG. So, in the sub-section 3.1 the authors cite two studies with 18F-FDG (in one of which 11C-MET was also used) and ten studies with different amino acid tracers.Therefore, the work must be supplemented by an additional table, summarizing results of the published studies on amino acid PET in pediatric neurooncology.
REPLY: many thanks for your comment and suggestion. We added a table (table3) summarizing results on non-FDG PET discussed in this subsection as requested.
- The authors should mention the main pharmacokinetic differences between the PET tracers and their particularities in regard to the imaging of brain tumors (ex. BBB-independent uptake of amino acid tracers in glioma and their accumulation in the vast majority of brain tumours, low uptake of 18F-Cholin in low grade gliomas).
REPLY: we added a final sentences of the discussion section as follow: “Pharmacokinetics and biodistribution of PET radiopharmaceuticals greatly influence their ability for imaging brain tumors, therefore an overall knowledge of their main features is of paramount importance for the choice of the most appropriate radiotracer based on the brain tumor to investigate [42]. 18F-FDG readily crosses the BBB and its accumulation in tumor cells is mainly regulated by expression of the glucose transporter protein (GLUT) and the action of hexokinase. Nevertheless the high uptake 18F-FDG in normal grey matter has limited its use in the vast majority of low-grade tumors Uptake of amino-acid tracers is independent of BBB breakdown and show low retention in normal grey matter [43]. Their uptake in tumor cells reflect the level of aminoacid transport. Still, some low-grade tumors may show increased amino acid uptake due to augmented vascularity and/or upregulation of amino acid transporters at the BBB [44].”
- In the “conclusion” the authors correctly point out the advantages of non-FDG tracers. It is however unclear why they explicitly mention the 18F-DOPA. There are no comparative data suggesting that 18F-DOPA would be more useful as other amino acid tracers (18F-FET, 11C-MET) in evaluation of pediatric brain tumors.
Reply: dear reviewer, We completely agree with you. We changed the sentence as follow: Non-FDG tracers may provide a higher performance in each clinical scenario.
The legends under the Figures 1 and 3 seem to be mixed up. There is no MIP image in the Figure 2.
REPLY: sorry. We corrected the legends. We did not have the possibility to retrieve the MIP of this figure for technical problems in the institution where the images were acquired.
Author Response File: 
Author Response.doc
Reviewer 2 Report
Very nice, comprehensive, well-organized, and up-to-date review of a topic which most radiologists and nuclear medicine physicians know little about and will be greatly interested in learning more about.
In addition to addressing my specific comments below, I would like to see the authors include one or two more image examples (Figures) in the manuscript, if at all possible. Thank you.
p.1
Line 25, settings
Line 28, amino acid analogues,
Line 29, adds not “add”
Line 30, or not “o”
Line 38- “pilocytic” not pylocitic
Line 44- “medulloblastoma (Fig.1)”- Figure 1 legend mentions L frontal ganglioglioma while the image is of a cerebellar tumor, presumably medulloblastoma? This should be corrected.
Line 45- “(DIPG; Fig.2)”- Fig 2 legend mentions medulloblastoma but the image is of a pontine tumor. Please correct.
p.3
Fig 3- again, image (L frontal tumor) does not match figure legend, which talks about pontine glioma)
Line 73-74- limited ability in these settings (not “issues”)
Line 74- institutions
Line 78- more common in “the” pediatric population
Line 81- children are more sensitive (not “sensible”)
Line 83- change to “appears to be of paramount importance because it may provide…”
Line 85- delete “consumption”
p.6
Line 145- change to “another area in which… my be clinically useful is in the targeting of stereotactic biopsy in children with supratentorial tumors”
Line 153, 155- *provide to a higher grading*- it is unclear what you mean to say here
p.7
Line 199- change to “and found false positive results in only two pretreated patients…”
Line 210- change to “has been found to also detect”
Line 214- remove “the”
Line 225- please comment on why you or the study authors think 18F-DOPA uptake would be higher in high grade tumors as opposed to low grade tumors- this is not intuitive (e.g. in carcinoid, DOTATATE uptake is higher in low grade tumors).
p.8
First paragraph is hard to read; please split up into several paragraphs
Line 268- “histogram”- change to other word, maybe “textural”, to be more intelligible to reader
Line 275- evidence not “evidences”
p.9
Line 310- acid not “oacid”
p.10
Line 345 - “targeting L-amino acid transport system”
Line 378- explain “neuronavigation”
Line 398- need period at end of sentence
Line 400- change to “The literature…last 10 years focusing on PET imaging…”.
Line 402- clinical settings not “setting”
Line 406- “Non-FDG tracers, especially 18F-DOPA, appear”
Line 410- or, not “o”
Author Response
Very nice, comprehensive, well-organized, and up-to-date review of a topic which most radiologists and nuclear medicine physicians know little about and will be greatly interested in learning more about.
In addition to addressing my specific comments below, I would like to see the authors include one or two more image examples (Figures) in the manuscript, if at all possible. Thank you.
p.1
Line 25, settings
REPLY: done
Line 28, amino acid analogues,
REPLY: done
Line 29, adds not “add”
REPLY: done
Line 30, or not “o”
REPLY: done
Line 38- “pilocytic” not pylocitic
REPLY: done
Line 44- “medulloblastoma (Fig.1)”- Figure 1 legend mentions L frontal ganglioglioma while the image is of a cerebellar tumor, presumably medulloblastoma? This should be corrected.
REPLY: corrected
Line 45- “(DIPG; Fig.2)”- Fig 2 legend mentions medulloblastoma but the image is of a pontine tumor. Please correct.
REPLY: corrected
p.3
Fig 3- again, image (L frontal tumor) does not match figure legend, which talks about pontine glioma)
REPLY: corrected
Line 73-74- limited ability in these settings (not “issues”)
REPLY: corrected
Line 74- institutions
REPLY: corrected
Line 78- more common in “the” pediatric population
REPLY: corrected
Line 81- children are more sensitive (not “sensible”)
REPLY: corrected
Line 83- change to “appears to be of paramount importance because it may provide…”
REPLY: corrected
Line 85- delete “consumption”
REPLY: deleted
p.6
Line 145- change to “another area in which… my be clinically useful is in the targeting of stereotactic biopsy in children with supratentorial tumors”
REPLY: we modified this part accordingly
Line 153, 155- *provide to a higher grading*- it is unclear what you mean to say here
REPLY: corrected
p.7
Line 199- change to “and found false positive results in only two pretreated patients…”
REPLY: corrected
Line 210- change to “has been found to also detect”
REPLY: corrected
Line 214- remove “the”
REPLY: corrected
Line 225- please comment on why you or the study authors think 18F-DOPA uptake would be higher in high grade tumors as opposed to low grade tumors- this is not intuitive (e.g. in carcinoid, DOTATATE uptake is higher in low grade tumors).
REPLY: Thank you for the suggestion. We modified this part as requested: “Although with the limit of the small number of patients, the higher uptake of 18F-DOPA in high grade tumors than in low-grade lesions may reflect additional factors other than the expression of aminoacid transporters, namely tumor and aggressiveness (e.g. ki-67 proliferation and tumor grade) and correlation with outcome. Fur-thermore, since treatment of low-grade gliomas was heterogenous, it is not possible to exclude that treatment influenced 18F-DOPA uptake.
p.8
First paragraph is hard to read; please split up into several paragraphs
REPLY: Thank you for the suggestion. We do not agree in splitting the introduction in several paragraphs; however, we improved the text format and the English Language accordingly.
Line 268- “histogram”- change to other word, maybe “textural”, to be more intelligible to reader
REPLY: Thanks. Modified as suggested
Line 275- evidence not “evidences”
REPLY: corrected
p.9
Line 310- acid not “oacid”
REPLY: corrected
p.10
Line 345 - “targeting L-amino acid transport system”
REPLY: corrected
Line 378- explain “neuronavigation”
REPLY: we added the following text: as computer-assisted technologies integrating imaging modality on neurosurgery assessment
Line 398- need period at end of sentence
REPLY: We added the period at the end of the sentence.
Line 400- change to “The literature…last 10 years focusing on PET imaging…”.
REPLY: corrected
Line 402- clinical settings not “setting”
REPLY: corrected
Line 406- “Non-FDG tracers, especially 18F-DOPA, appear”
REPLY: corrected
Line 410- or, not “o”
REPLY: corrected
Author Response File: Author Response.doc
