Advanced Neuroimaging and Emerging Systemic Therapies in Glioblastoma: Current Evidence and Future Directions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear authors,

I have now completed the review of the manuscript titled Advanced Neuroimaging and Emerging Systemic Therapies in Glioblastoma.

The manuscript is interesting and, in general, fairly well-written. However, I still have some suggestions to further improve the quality of the manuscript.

I would like to suggest that the authors address these limitations in the article, either by discussing them in the limitations section or, where feasible, by making the appropriate revisions:

1. The inclusion and exclusion criteria are broadly defined but inconsistently applied. The authors include studies from 2019-2024 without explaining why earlier foundational research was excluded, particularly given that some key treatments like the Stupp protocol date to 2005.

2. Some recent findings could be stated in the introduction. For example, "Recent Deep Learning-Based Brain Tumor Segmentation Models Using Multi-Modality Magnetic Resonance Imaging: A Prospective Survey" directly relates to your extensive discussion of multiparametric MRI protocols. Since the research explains how different MRI sequences (DWI, PWI, FLAIR, spectroscopy) are combined for better tumor characterization - this article would show you the latest computational approaches to analyzing these complex datasets.

3. The neuroimaging section, while comprehensive, suffers from uneven depth. The authors provide extensive technical detail about basic imaging modalities but offer limited critical analysis of their clinical utility. The discussion of radiomics and artificial intelligence appears superficial, presenting these technologies as promising without adequately addressing their current limitations, including reproducibility challenges and lack of standardized protocols.

4. The discussion section could be enriched by incorporating a forward-looking perspective that highlights emerging research directions, thereby illuminating potential avenues for future investigation. This approach would demonstrate to readers how current findings connect to evolving research frontiers. Consider, for instance, integrating references to explainable artificial intelligence applications in clinical decision-making frameworks or developments in genomics-driven precision medicine approaches.
 
5. The treatment section demonstrates similar imbalances. The coverage of established therapies like temozolomide chemoradiotherapy is thorough, but emerging therapies receive uncritical treatment. The authors present CAR-T cell therapy as "promising" based on a single phase I trial with six patients, which represents insufficient evidence for such optimistic conclusions.

Thank you for your valuable contributions to our field of research. I look forward to receiving the revised manuscript.

Author Response

our response:

Dear authors,

I have now completed the review of the manuscript titled Advanced Neuroimaging and Emerging Systemic Therapies in Glioblastoma.

The manuscript is interesting and, in general, fairly well-written. However, I still have some suggestions to further improve the quality of the manuscript.

I would like to suggest that the authors address these limitations in the article, either by discussing them in the limitations section or, where feasible, by making the appropriate revisions:

1. The inclusion and exclusion criteria are broadly defined but inconsistently applied. The authors include studies from 2019-2024 without explaining why earlier foundational research was excluded, particularly given that some key treatments like the Stupp protocol date to 2005.

Thank you for your insightful comment. In the revised manuscript, we now state that we focused primarily on studies published between 2019 and 2024 to capture the most recent advances in neuroimaging and therapeutic approaches for glioblastoma. However, we also acknowledge including earlier landmark publications—such as the original Stupp protocol—because they remain essential for clinical or methodological context.

2. Some recent findings could be stated in the introduction. For example, "Recent Deep Learning-Based Brain Tumor Segmentation Models Using Multi-Modality Magnetic Resonance Imaging: A Prospective Survey" directly relates to your extensive discussion of multiparametric MRI protocols. Since the research explains how different MRI sequences (DWI, PWI, FLAIR, spectroscopy) are combined for better tumor characterization - this article would show you the latest computational approaches to analyzing these complex datasets.

Thank you for recommending this recent and important work. We dedicated a paragraph of the Introduction to this paper.

3. The neuroimaging section, while comprehensive, suffers from uneven depth. The authors provide extensive technical detail about basic imaging modalities but offer limited critical analysis of their clinical utility. The discussion of radiomics and artificial intelligence appears superficial, presenting these technologies as promising without adequately addressing their current limitations, including reproducibility challenges and lack of standardized protocols.

Thank you for this comment. In the revised manuscript we thoroughly expanded the sections on MRI, CT, and radiomics to provide a more critical view of their clinical utility. For MRI and CT, we now discuss not only their strengths but also key limitations in diagnosis, treatment planning, and follow-up. For radiomics/AI, we added detail on reproducibility, validation, standardization, regulatory challenges, and data privacy, thereby addressing the limitations highlighted by the Reviewer.

4. The discussion section could be enriched by incorporating a forward-looking perspective that highlights emerging research directions, thereby illuminating potential avenues for future investigation. This approach would demonstrate to readers how current findings connect to evolving research frontiers. Consider, for instance, integrating references to explainable artificial intelligence applications in clinical decision-making frameworks or developments in genomics-driven precision medicine approaches.

We agree with this valuable suggestion. In the revised manuscript we added a dedicated subchapter in the Discussion titled “Research gaps and future directions”. There, we emphasize the need for standardized imaging protocols and validation of AI/radiomics models, strategies to improve drug delivery across the blood–brain barrier, further development of targeted and immunotherapy approaches, and the prioritization of patient-centered outcomes such as cognition and quality of life. We also highlight the importance of multicenter collaboration and integration of molecular, imaging, and clinical data into precision-guided care. This forward-looking perspective directly addresses the Reviewer’s comment and links current findings to evolving research frontiers.

5. The treatment section demonstrates similar imbalances. The coverage of established therapies like temozolomide chemoradiotherapy is thorough, but emerging therapies receive uncritical treatment. The authors present CAR-T cell therapy as "promising" based on a single phase I trial with six patients, which represents insufficient evidence for such optimistic conclusions.

We absolutely agree that a more cautious interpretation of the available evidence on CAR-T cell therapy in glioblastoma is warranted. In the revised manuscript we have modified the relevant sentence to read: “The study demonstrated preliminary safety and bioactivity of CART EGFR IL13Rα2 cells in recurrent glioblastoma but evidence of efficacy remains inconclusive and requires confirmation in larger cohorts with longer follow up [38].”

Thank you for your valuable contributions to our field of research. I look forward to receiving the revised manuscript.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Find below some important comments and recommendations to improve your manuscript.

1. The structure should cover both the primary gliomas and brain metastases consistently, by clarifying adult only scope vs inclusion of pediatric data.
2. Consider reorganizing to this format flow:

Methods - Imaging (MRI, PET, AI/radiomics) - Therapeutic innovations - Clinical integration - Gaps/future directions - Conclusions.

3. Authors should provide effect sizes/dose response for hippocampal, white matter, and subcortical changes. You should clearly distinguish WBRT vs SRS dosing/exposures.
4. In the FreeSurfer software part, discuss performance in radiation altered brains, harmonization across scanners, QC, and compare briefly with alternative segmenters and state software version and or parameters.
5. Add practical recommendations or algorithms linking imaging findings to management decisions in the clinical translation part. Address generalizability or validation of AI/radiomics.
6. For BBB-opening/therapeutics, authors should do a balance claims with key clinical trial data such as safety, effect sizes, and indications. Do specify which drug classes may benefit and current limitations.

Author Response

 

Our response:

Reviewer 2.

Find below some important comments and recommendations to improve your manuscript.

1. The structure should cover both the primary gliomas and brain metastases consistently, by clarifying adult only scope vs inclusion of pediatric data.

Thank you for this comment. Our paper was intended to focus on glioblastoma, which is a primary tumor. To remain within this scope, we revised the manuscript by removing several references to metastases. Nevertheless, we retained discussion of differential diagnosis with brain metastases.

Regarding patient population, we confirm that pediatric-only data were excluded as stated in the Materials and Methods. Pediatric gliomas differ markedly in biology and treatment , so including them would confound interpretation of adult-focused evidence.

 

1. Consider reorganizing to this format flow:

Methods - Imaging (MRI, PET, AI/radiomics) - Therapeutic innovations - Clinical integration - Gaps/future directions - Conclusions.

In the revised manuscript, the ordering of the chapters and subchapters is:

• Materials and Methods,
• Results:
  1. Neuroimaging Methods in the Diagnosis and Monitoring (incl. MRI, PET, AI/radiomics),
  2. Treatment Strategies (where we write about therapeutic innovations),
• Discussion:
  1. Clinical integration,
  2. Research gaps and future directions,
•  

 

We believe this reorganization improves the clarity and logical flow of the review, and we appreciate your guidance in strengthening the manuscript.

 

1. Authors should provide effect sizes/dose response for hippocampal, white matter, and subcortical changes. You should clearly distinguish WBRT vs SRS dosing/exposures.

Thank you for this important comment. We have revised the manuscript accordingly. We now provide quantitative effect sizes and dose–response data for hippocampus (median –5 mm³ in the GC-ML-DG region), white matter (increased mean, axial and radial diffusivity; decreased fractional anisotropy detectable even at doses <10 Gy), and subcortical structures (0.16 to 1.37%/Gy). We have also clarified the distinction between WBRT and SRS, noting that the reported diffuse atrophic changes are associated with WBRT, whereas SRS generally spares distant hippocampal and subcortical regions.

 

1. In the FreeSurfer software part, discuss performance in radiation altered brains, harmonization across scanners, QC, and compare briefly with alternative segmenters and state software version and or parameters.

Thank you for this constructive comment. In the revised manuscript we have expanded the FreeSurfer part to explicitly address all the requested points. We now discuss its performance in radiation-altered brains, noting segmentation challenges caused by post-treatment structural distortions and the need for careful QC. We also highlight quality control strategies, including visual inspection/manual correction as well as automated approaches, and emphasize the importance of harmonization across scanners to reduce inter-scanner variability. Where possible, we have also specified the FreeSurfer version used in the cited studies (e.g., v7.1.1 in [15]). Finally, we had already included a brief comparison with alternative segmentation tools (FSL, SPM) in the original manuscript, and this content remains in the revised version.

 

1. Add practical recommendations or algorithms linking imaging findings to management decisions in the clinical translation part. Address generalizability or validation of AI/radiomics.

Practical recommendations linking imaging findings to management decisions are now included in the “Clinical integration” subchapter of the Discussion: “Multiparametric MRI techniques, such as perfusion, diffusion, and spectroscopy, are increasingly employed for precise tumor delineation, treatment monitoring, and differentiation of progression from therapy-related changes. When available, amino acid PET or hybrid PET/MRI is recommended for detection of recurrence and to guide biopsy targeting, especially in diagnostically ambiguous cases. Radiomics and AI tools further enhance diagnostic precision and may support prognostic modeling, but remain largely investigational.”

We agree on the importance of addressing the generalizability and validation of AI/radiomics. In the revised manuscript (3.1.8: Radiomics in Neuro-Oncology), we now explicitly discuss these aspects, noting that the lack of prospective multi-center cohorts limits generalizability, and that most studies rely on internal rather than independent external validation. We also emphasize calibration issues, potential biases, and regulatory challenges, which together provide a more critical and comprehensive view of current limitations.

 

 

1. For BBB-opening/therapeutics, authors should do a balance claims with key clinical trial data such as safety, effect sizes, and indications. Do specify which drug classes may benefit and current limitations.

Thank you for this insightful comment. The paragraph has been rewritten and divided by subheadings, regarding most important aspects of this novel method.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All comments addressed.

Reviewer 2 Report

Comments and Suggestions for Authors

All concerns from the previous round of review have been addressed. The manuscript has improved significantly from its previous form.