Navigating Rarity: Pathological Challenges and Diagnostic Ambiguity in Rare Gliomas—A Case Series with a Focus on Personalized Treatment and Quality of Life

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear editor and authors,

The manuscript entitled "Navigating Rarity: Pathological Challenges and Diagnostic Ambiguity in Rare Gliomas, with a Focus on Personalized Treatment and Quality of Life" provides a case series of patients with rare gliomas treated highlighting the challenges of diagnosis and treatment despite advancements in molecular classification per WHO 2021 guidelines. The manuscript is scientifically relevant to the fields of medicine and pharmacy, among others. The English language is satisfactory (I suggest a final revision)! However, some details/information need to be changed in the 'Abstract', 'Introduction, results, discussion and conclusions' sections, as well as in other sections.

* Abstract: Adequate, but I suggest:

- Please, to include information about the "methodological design"! Inclusion criteria for patients, materials analyzed, search period, database, etc.

* Introduction section: It is well written, but:

- I suggest adding an opening paragraph with general information to introduce the article to the reader. Then, begin the review itself.

- I also suggest highlighting that QoL encompasses physical, psychological, social, and disease- and treatment-related symptoms. Please add more references.

- After the introduction, create a "Methodology" section indicating the "methodological design" for writing this manuscript. Include "inclusion criteria" for patients/materials analyzed/search period, etc. What about ethical aspects? What is the protocol for approving the study?

* Results and discussion sections: It is well written, but:

- All 3 cases are well described with images and technical aspects. I suggest including data on clinical and biochemical examinations. I suggest expanding the discussion and using more recent references.

- On “Long-Term Survival and Life Quality”: I suggest inserting tables/figures (and discussing them) for better visualization and reading.

- I suggest adding a paragraph at the end of the subsection “discussion”, highlighting the main ideas and perspectives discussed.

* Conclusions section:

- At the end of the section, I suggest emphasizing the importance of manuscript for medicine and other fields.

* References: Please check that the references comply with the journal's rules.

Author Response

Comment 1: Abstract: Adequate, but I suggest: Please, to include information about the "methodological design"! Inclusion criteria for patients, materials analyzed, search period, database, etc.

We have revised the Abstract to include key elements of the methodological design. Specifically, we have now added information on the retrospective nature of the study, the inclusion criteria for patient selection, the treatment period (2002–2024), and the use of clinical records and molecular diagnostics in accordance with WHO 2021 guidelines. Additionally, we have noted the assessment tools used for evaluating quality of life (EQ-5D-5L, EQ VAS, MoCA, and the Distress Thermometer).

Comment 2: 

Inroduction section: It is well written, but:

-I suggest adding an opening paragraph with general information to introduce the article to the reader. Then, begin the review itself.

We have revised the Introduction to include a new opening paragraph that provides general background information on rare gliomas.

- I also suggest highlighting that QoL encompasses physical, psychological, social, and disease- and treatment-related symptoms. Please add more references.

In response to your suggestion, we expanded the discussion of quality of life in the Introduction.  Additional references have been added to support this expanded definition and emphasize the importance of QoL as a key outcome in neuro-oncology.

- After the introduction, create a "Methodology" section indicating the "methodological design" for writing this manuscript. Include "inclusion criteria" for patients/materials analyzed/search period, etc. What about ethical aspects? What is the protocol for approving the study?

We have created a separate “Methodology” section following the Introduction, and therefore deleted the methods and materials section due to overlapping content. This section now clearly outlines the retrospective design of the study, the inclusion criteria for case selection, the time frame (2002–2024), the types of data analyzed (clinical, radiological, molecular, and patient-reported outcomes), and the instruments used for QoL assessment (EQ-5D-5L, EQ VAS, MoCA, Distress Thermometer). We have also clarified the ethical considerations: the study was approved by the Ulm University Ethics Committee (Approval Code: 381/15), and written informed consent was obtained from all participants.

Comment 3:

Results and discussion sections: It is well written, but:

- All 3 cases are well described with images and technical aspects. I suggest including data on clinical and biochemical examinations. I suggest expanding the discussion and using more recent references.

Thank you for this helpful suggestion. In response, we confirm that clinical neurological findings have been described for all four cases:

Case 1: Neurological examination is detailed in lines 160-163. The patient currently shows no neurological deficits.

Case 2: Clinical neurological status is described in lines 217-219, with an additional clarification added in line 230. The patient is currently neurologically intact.

Case 3: The patient's current neurological condition is addressed in lines 280–281, with no deficits reported.

Case 4: Neurological symptoms and ongoing pain are described in lines 310–312.

While biochemical parameters were not the focus of this retrospective case series, all available clinical data relevant to the neurological and functional status of the patients have been included and clarified where necessary.

- On “Long-Term Survival and Life Quality”: I suggest inserting tables/figures (and discussing them) for better visualization and reading.

Thank you for this suggestion. In response, we have included a new summary table (Table 2) that presents key clinical, diagnostic, treatment, and quality-of-life data for all four patients. This table allows for improved visualization and comparison across cases and is discussed accordingly in the manuscript.

- I suggest adding a paragraph at the end of the subsection “discussion”, highlighting the main ideas and perspectives discussed.

A summarizing subsection was added.

Comment 4: 

Conclusions section:

- At the end of the section, I suggest emphasizing the importance of manuscript for medicine and other fields.

We have revised the final paragraph of the Conclusions section to emphasize the broader relevance of the manuscript beyond neuro-oncology, highlighting its applicability to other medical fields involved in the management of rare and complex diagnoses.

References: Please check that the references comply with the journal's rules.

We did check the references according to the Journal’s rules.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents a well-written and clinically relevant case series focusing on rare and diagnostically challenging gliomas, emphasizing the impact of molecular diagnostics and the WHO 2021 classification on clinical decision-making. I have only minor observations

• Consider aligning the structure of each case presentation (e.g., Initial Diagnosis, Molecular Profile, Treatment Timeline, Outcome, Quality of Life) to improve readability and allow easier comparison across cases.
• A short paragraph highlighting how the updated classification criteria altered diagnostic labeling and management decisions in your series—especially in Case 3 and Case 4—would strengthen the manuscript’s relevance.
• Some minor grammar and syntax improvements are needed (e.g., replacing “created this treatment” with “discontinued this treatment”).
• To better frame the manuscript within the current landscape of personalized glioma care, I recommend including PMID: 36011350, which provides a comprehensive overview of molecular diagnostics and individualized treatment approaches in gliomas.
• Improve figure legends with more descriptive details, scale bars, and labeling of timepoints. A summary table comparing key features across all four cases would also be helpful.

Author Response

1.Consider aligning the structure of each case presentation (e.g., Initial Diagnosis, Molecular Profile, Treatment Timeline, Outcome, Quality of Life) to improve readability and allow easier comparison across cases.

Thank you for this helpful suggestion. We have revised the case presentations to follow a uniform structure, including the subheadings Initial Diagnosis, Molecular Profile and Treatment Timeline, and Long-Term Outcome and Life Quality, to improve readability and facilitate comparison across cases. For a better overview we added Table 2.

2.A short paragraph highlighting how the updated classification criteria altered diagnostic labeling and management decisions in your series—especially in Case 3 and Case 4—would strengthen the manuscript’s relevance.

We agree that the updated WHO classification of 2021 in many cases allows more exact diagnosing and is helpful with labeling. In our case 2, the detection of MN1-alteration has strengthened the diagnosis of MN1-altered astroblastoma according to the WHO classification. A definite change in disease management did not result from this more accurate labeling of diagnosis. In case 3, however, the current diagnosis has remained unsatisfactory. It is not plausible that the patient suffers from a glioblastoma, because of the IDH-mutant status with excludes GBM according to the revised WHO classification of 2021. The long-term survival of >20 years supports this assessment. Most likely and according to the novelation of WHO classification, because of the oligondroglial dominant component, the IDH-mutation and the 1p19q-codeletion, the patient suffers from oligodendroglioma, IDH-mutant, 1p19q codel, grade 3. Therefore, we commented in the discussion section, that case 3 “highlights the need for reconsideration of the tumor’s actual biological behavior”. We would opt for diagnostic reassessment (e.g. re-resection or tumor biopsy) in case of a future tumor progression. Because of these inconsistencies, we suggest remaining with the case descriptions as in the manuscript. We included a new Table 2, where the reader can find a quick overview on how diagnoses has changed and their molecular findings.Changes in the discussion section were made (line 394-401)

3.Some minor grammar and syntax improvements are needed (e.g., replacing “created this treatment” with “discontinued this treatment”).

Thank you for pointing this out. We have revised the manuscript for grammar and syntax, including the suggested correction—“created this treatment” has been replaced with “discontinued this treatment.”

4.To better frame the manuscript within the current landscape of personalized glioma care, I recommend including PMID: 36011350, which provides a comprehensive overview of molecular diagnostics and individualized treatment approaches in gliomas.

The paper was included as a reference.

5.Improve figure legends with more descriptive details, scale bars, and labeling of timepoints. A summary table comparing key features across all four cases would also be helpful.

Figure legends were adjusted. A summary table with key features was included as Table 2.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors improved the manuscript based on my suggestions.