Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type glioblastoma

Bart R. J. van Dijken; Alfred O. Ankrah; Gilles N. Stormezand; Rudi A. J. O. Dierckx; Peter Jan van Laar; Anouk van der Hoorn

doi:10.1371/journal.pone.0264387

Peer Review History

Original SubmissionSeptember 7, 2021
1 Dec 2021 Decision Letter - Kevin Camphausen, Editor PONE-D-21-28633Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type gliomasPLOS ONE Dear Dr. Van Dijken, 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. Please submit your revised manuscript by Jan 15 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This paper on the prognostic value of 11C-methionine volume-based PET parameters in IDH wild type gliomas is timely and deals with an important imaging niche (11C-methionine PET) and specifically the need for acquired parameters to become increasingly clinically meaningful (SUV vs. volume based ). It is to be commended on not simply going after the SUV and in its emphasis on focusing on wild type IDH mutant gliomas. However it deals with only 15 patients (which the authors acknowledge as a limitation) and a larger cohort as well as validation with larger scale data perhaps from another institution and/or in conjunction with large scale data bases (TCGA/BRATS) would add weight to the findings and advance the field. Reviewer #2: Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type gliomas. This article aims to demonstrate the prognostic value of 11C-methionine (11C-met) PET in the survival of IDH wild type glioma. While previous trials of 11C-met trials have proven inconclusive, the authors of this paper employ volume-based parameters such as metabolic tumor volume (MTV) and total lesion methionine metabolism (TLMM) in an attempt to improve prognostic accuracy. This is an important question, as better non-invasive methods of diagnosing glioma are desperately needed. Unfortunately, this paper has several structural issues that cannot be fixed and prevent its publication: 1) The sample size of this study is too small and heterogenous to make any conclusions. While it is true that IDH wild type gliomas do generally carry worse prognosis that IDH mutants, grade IV, grade III and grade II gliomas represent different pathologies with different behaviors and responses to treatment. 2) The definition of MTV and TLMM are unclear. In the legend of Figure 1, you state that SUVmean and MTV are combined and multiplied to obtain TLMM however the diagram accompanied does not clearly demonstrate how this is applied in practice. 3) The Kaplan Meier curves from figure 2 is unclear. Are the values based on volume or metabolic activity? 4) While table 1 provides individual data on extent of resection, age and radiation dose, graphical data may better delineate how these factors impact survival ****** 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 [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0264387.r001
Revision 1
26 Jan 2022 Author Response Response to the reviewers Reviewer #1: Comment: This paper on the prognostic value of 11C-methionine volume-based PET parameters in IDH wild type gliomas is timely and deals with an important imaging niche (11C-methionine PET) and specifically the need for acquired parameters to become increasingly clinically meaningful (SUV vs. volume based ). It is to be commended on not simply going after the SUV and in its emphasis on focusing on wild type IDH mutant gliomas. However, it deals with only 15 patients (which the authors acknowledge as a limitation) and a larger cohort as well as validation with larger scale data perhaps from another institution and/or in conjunction with large scale data bases (TCGA/BRATS) would add weight to the findings and advance the field. Answer: We would like to thank the reviewer for critically reading our manuscript and commending us on the scope of this study. The small sample size indeed is one of the most important limitations of our study, which we also acknowledge in the discussion section. A larger study cohort would definitely strengthen the study. However, due to the retrospective nature of our study and the study niche (11C-methionine PET in IDH wild type gliomas) this was not possible. We thank the reviewer for the suggestion of using large scale databases to increase the number of subjects. Unfortunately, the TCGA and BRATS databases do not include preoperative 11C-methionine PET data. Therefore, producing a larger cohort for our study at this stage was not deemed feasible. Despite small sample size, the found correlation of the volume-based parameters MTV and TLMM with survival was statistically significant and TLMM was even suggested to be an independent factor in paired analysis with other clinical parameters. We feel that our results should thus be seen as an encouragement for larger prospective studies focusing on the prognostic role of volume-based 11C-MET PET parameters to confirm our results. At a present, a prospective study on 11C-MET PET treatment evaluation in glioma patients is undertaken at our tertiary hospital (Netherlands Trial Register number NL6536; https://www.trialregister.nl/trial/6536), which includes preoperative imaging as well. The value of volume-based parameters for prognostication (and treatment response assessment) will also be a scope of this study. A sentence to highlight this was added to the final paragraph of the discussion. Reviewer #2: Comment: Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type gliomas. This article aims to demonstrate the prognostic value of 11C-methionine (11C-met) PET in the survival of IDH wild type glioma. While previous trials of 11C-met trials have proven inconclusive, the authors of this paper employ volume-based parameters such as metabolic tumor volume (MTV) and total lesion methionine metabolism (TLMM) in an attempt to improve prognostic accuracy. This is an important question, as better non-invasive methods of diagnosing glioma are desperately needed. Unfortunately, this paper has several structural issues that cannot be fixed and prevent its publication. Answer: We thank the reviewer for the thorough assessment of our manuscript. We agree with the reviewer that establishing more accurate non-invasive methods for the diagnosis and prognostication of IDH wild type gliomas is crucial. This study investigated the value of volume-based 11C-MET PET parameters in addition to SUV, as it is known that SUV does not reliably detect the heterogeneity of IDH wild type gliomas. Comment: The sample size of this study is too small and heterogenous to make any conclusions. While it is true that IDH wild type gliomas do generally carry worse prognosis that IDH mutants, grade IV, grade III and grade II gliomas represent different pathologies with different behaviors and responses to treatment. Answer: We understand the concern of the reviewer about the small sample size of this study. We also acknowledge this limitation in the last paragraph of the discussion section. Nevertheless, our results were statistically significant and showed that volume-based parameters were correlated with overall survival while conventional parameters were not. Volume-based parameters could play a future role in tailoring treatment decisions in patients with IDH wild type glioblastomas, but we agree that future studies are necessary to confirm our results. We also refer to our answer to reviewer #1. Historically, the pathological grade was one of the most important predictors of survival in glioma patients. However, with recent guideline updates, molecular markers now play a prominent role. Due to the poor prognosis, IDH wild type tumors are seen as a different entity than IDH mutated gliomas. In addition, certain molecular markers (TERT promoter mutation, EGFR gene amplification, +7/-10 chromosome changes) now define glioblastoma IDH wild type WHO grade 4, even if histologically the tumor is of lower grade. We agree with the reviewer that the heterogeneity was a point of concern. The reviewer’s comment prompted us to critically re-review our dataset according to the most recent guidelines (2021 WHO Classification of Tumors of the Central Nervous System, Louis et al, Neuro-Oncology, 2021). EGFR gene amplification was seen in a subset of patients in absence of glioblastoma grade 4 defining features such as microvascular proliferation or necrosis. We updated the grades of these patients in table 1. Two patients did not demonstrate any glioblastoma-defining molecular markers, and were therefore deleted from the analysis. In agreement with the newest guidelines, we have also changed the terminology throughout the manuscript to IDH wild type glioblastoma, WHO grade 4. Comment: The definition of MTV and TLMM are unclear. In the legend of Figure 1, you state that SUVmean and MTV are combined and multiplied to obtain TLMM however the diagram accompanied does not clearly demonstrate how this is applied in practice. Answer: We agree that the legend of figure 1 was somewhat brief. TLMM is the product of SUVmean and MTV within the lesion border. This parameter can be of course be calculated by hand, but most software allow for automatic calculation and extraction of this TLMM; equal to Total Lesion Glycolysis (TLG) in FDG PET imaging. To clarify the definitions of MTV and TLMM to the reader, we have made the following changes to the text and the legend of figure 1: Method section, final sentence of paragraph 3: TLMM was automatically calculated in Syngo.via by multiplying SUVmean and MTV within the lesion border, in an equal manner as the Total Lesion Glycolysis (TLG) in FDG imaging. Legend of figure 1: (…) (E) MTV is the volume of increased uptake within the lesion borders. (F) For TLMM the SUVmean and MTV within lesion borders are combined and multiplied to provide both metabolic and volume-based information. TLMM is automatically calculated and extracted within the Syngo.via software. Comment: The Kaplan Meier curves from figure 2 is unclear. Are the values based on volume or metabolic activity? Answer: We agree with the reviewer that the Kaplan Meier curves from figure 2 are unclear. Therefore, to increase clarity, we included the thresholds (median values) of both MTV (�14) and TLMM (�51) for which the data were dichotomized. The group with higher values is displayed with the dotted line while the group with lower values is displayed with the bold line as can be read in the legend. The values for MTV are based on volume and TLMM is a dimensionless parameter which combines the volumetric and metabolic information and is thus not expressed in a particular unit. Comment: 4) While table 1 provides individual data on extent of resection, age and radiation dose, graphical data may better delineate how these factors impact survival. Answer: In accordance with the reviewer’s suggestion we have included the paired analyses between MTV/TLMM and clinical parameters, as well as graphical data (Kaplan Meier curves) for the impact of clinical parameters on survival in supplementary data 1 and 2, respectively. https://doi.org/10.1371/journal.pone.0264387.r002
10 Feb 2022 Decision Letter - Kevin Camphausen, Editor Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type glioblastoma PONE-D-21-28633R1 Dear Dr. Van Dijken, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Kevin Camphausen Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0264387.r003
Formally Accepted
14 Feb 2022 Acceptance Letter - Kevin Camphausen, Editor PONE-D-21-28633R1 Prognostic value of 11C-methionine volume-based PET parameters in IDH wild type glioblastoma Dear Dr. Van Dijken: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Kevin Camphausen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0264387.r004

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