Operative planning for a functional precision medicine assay of recurrent high-grade glioma: illustrative case

Andrew P Mathews Departments of Neurosurgery

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William J Shelton Departments of Neurosurgery

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Erika Santos Horta Oncology

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Prashanth Reddy Damalcheruvu Radiology, and

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J. Stephen Nix Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

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Murat Gokden Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas

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Analiz Rodriguez Departments of Neurosurgery

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BACKGROUND

Functional precision medicine (FPM) represents a personalized and efficacious modality for treating malignant neoplasms. However, acquiring sufficient live tissue to perform FPM analyses is complicated by both difficult identification on imaging and radiation necrosis, particularly in cases of recurrence. The authors describe a case of planning biopsy trajectories for an FPM assay in a patient with recurrent high-grade glioma.

OBSERVATIONS

A 25-year-old male with a history of recurrent high-grade glioma was scheduled for laser ablation and biopsy with ChemoID assaying after regions of potential recurrence were identified on follow-up imaging. Preoperative magnetic resonance (MR) spectroscopy of the regions showed areas of high choline/creatine ratios within lesions of radiation necrosis, which helped in planning the biopsy trajectories to selectively target malignancies for FPM analysis. ChemoID results showed high tumor susceptibility to lomustine, which was implemented as adjuvant therapy.

LESSONS

FPM therapy in the setting of recurrence is complicated by radiation necrosis, which can present as malignancy on imaging and interfere with tissue acquisition during biopsy or resection. Thus, operative approaches should be carefully planned with the assistance of imaging modalities such as MR spectroscopy to better ensure effective tissue acquisition for accurate FPM analysis and to promote more definitive treatment of recurrence.

ABBREVIATIONS

Cho/Cr = choline/creatine; CNS = central nervous system; FPM = functional precision medicine; HGG = high-grade glioma; MR = magnetic resonance; MRI = magnetic resonance imaging; RN = radiation necrosis; RT = radiotherapy; TMZ = temozolomide; WHO = World Health Organization

BACKGROUND

Functional precision medicine (FPM) represents a personalized and efficacious modality for treating malignant neoplasms. However, acquiring sufficient live tissue to perform FPM analyses is complicated by both difficult identification on imaging and radiation necrosis, particularly in cases of recurrence. The authors describe a case of planning biopsy trajectories for an FPM assay in a patient with recurrent high-grade glioma.

OBSERVATIONS

A 25-year-old male with a history of recurrent high-grade glioma was scheduled for laser ablation and biopsy with ChemoID assaying after regions of potential recurrence were identified on follow-up imaging. Preoperative magnetic resonance (MR) spectroscopy of the regions showed areas of high choline/creatine ratios within lesions of radiation necrosis, which helped in planning the biopsy trajectories to selectively target malignancies for FPM analysis. ChemoID results showed high tumor susceptibility to lomustine, which was implemented as adjuvant therapy.

LESSONS

FPM therapy in the setting of recurrence is complicated by radiation necrosis, which can present as malignancy on imaging and interfere with tissue acquisition during biopsy or resection. Thus, operative approaches should be carefully planned with the assistance of imaging modalities such as MR spectroscopy to better ensure effective tissue acquisition for accurate FPM analysis and to promote more definitive treatment of recurrence.

ABBREVIATIONS

Cho/Cr = choline/creatine; CNS = central nervous system; FPM = functional precision medicine; HGG = high-grade glioma; MR = magnetic resonance; MRI = magnetic resonance imaging; RN = radiation necrosis; RT = radiotherapy; TMZ = temozolomide; WHO = World Health Organization

Functional precision medicine (FPM) is a promising alternative to traditional cancer therapies for its specific and personalized treatment approach. FPM requires live tissue to extract cancer cells and perform drug screens ex vivo. This is particularly useful given the often unpredictable and heterogeneous presentations of neoplasms among individuals, even in cases of histological similarity.1 In the context of recurrent central nervous system (CNS) neoplasms, functional assays such as ChemoID represent a promising modality to identify personalized therapy plans. ChemoID involves the testing of multiple clinically indicated chemotherapeutics against cancer stem cells from patient tumor samples to better determine susceptibility and target resistance on an individual basis.2 However, the process of conducting such assays requires sufficient collection of the malignant cells in question, via either biopsy or resection, to allow for ex vivo culturing and subsequent vulnerability assessment.2,3 In this article, we address the tissue acquisition process for conducting FPM assays in the setting of recurrence with a focus on the considerations made by the surgical team in planning for biopsy under such conditions.

Illustrative Case

History and Examination

A 25-year-old male with a history of recurrent IDH-1 mutant, MGMT methylation indeterminate (low), TP53 mutant high-grade glioma (HGG; astrocytoma grade 4) presented to the neurosurgical clinic in mid-2023 after follow-up imaging revealed areas concerning for radiation necrosis (RN) with surrounding cerebral edema. This finding was also associated with a region of possible tumor recurrence in the right parietotemporal lobe. At that time, the patient was on a temozolomide (TMZ) regimen. He had previously undergone two craniotomies for excisions of right intraaxial brain masses, the first in late 2018 and the second in 2022 (Fig. 1), with appropriate adherence to postoperative TMZ/radiotherapy (RT) regimens. Upon a review of imaging conducted almost 10 months after the second resection (Fig. 2), the recurrent regions were identified, and plans for a third procedure were discussed. The patient was ultimately determined to be a candidate for biopsy of the new regions, alongside laser thermal ablation. Plans were also made to perform a ChemoID assay with the acquired tissue for more targeted and definitive management of his recurrence.

FIG. 1
FIG. 1

Preoperative axial postcontrast T1-weighted and axial T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. A and B: Initial diagnosis was a 5 × 4.5 × 6 cm right posterior temporoparietal lobe wedge-shaped nonenhancing mass with cortical expansion and extension to the lateral ventricle atrium with leftward midline shift of 5 mm. C and D: The 19-month follow-up scan indicated multiple punctate foci of postcontrast enhancement along the inferior margin of the right temporal surgical cavity with a significant increase in the FLAIR signal abnormality.

FIG. 2
FIG. 2

Preoperative MR spectroscopy. A: Contrast T1-weighted sequence with increased heterogeneous enhancement surrounding the resection site extending to the right splenium of the corpus callosum. B and C: Spectroscopy showing a prominent increased Cho/Cr ratio and decreased N-acetylaspartate peak, particularly along the medial aspect of the previous resection cavity in the right parieto-occipital lobe.

Preoperative Planning

Prior to the biopsy and ablation procedure, mass spectroscopy images were obtained and analyzed to better differentiate areas concerning for recurrence from areas of RN, given the extensive history of postoperative RT delivered to this region. Because regions with particularly high choline/creatine (Cho/Cr) ratios are indicative of heightened metabolic activity associated with neoplastic proliferation,4 expression of this signal on the spectroscopy images proved invaluable in isolating specific biopsy targets, which helped to ensure optimal tissue collection for subsequent FPM assay. For this patient in particular, high Cho/Cr ratios were identified in medial portions of the lesion (Fig. 2B and C) with the surrounding regions containing elevated choline signals, which likely also represented viable tumor sites. Once the regions were identified, the neurosurgical team planned biopsy trajectories accordingly, and the patient was scheduled for surgery in 2023.

Surgical Procedure and Postoperative Follow-Up

During the procedure, the preplanned biopsy and ablation trajectories were registered with stereotactic imaging and used to acquire a total of 8 tissue cores for both pathological and ChemoID analysis using the biopsy needle. Pathological analysis (Fig. 3) revealed predominantly reactive changes, with a few atypical cells, lacking mitotic figures and showing no tumor necrosis or vascular proliferation. Immunohistochemically, GFAP was diffusely positive, highlighting reactive astrocytosis. P53 was positive in a small cell population, which was again consistent with a TP53 mutation since this glioma was previously known to be TP53-mutant. The scattered atypical cells were positive for IDH-1 (R132H) mutant protein. Because this glioma was already known to carry this mutation, this finding indicated the presence of individual neoplastic cells amid treatment-related changes, consistent with the previously diagnosed astrocytoma, IDH-mutant. Although the tumor comprised only 2% to 3% of the specimen, stem cells could still be successfully isolated for the ChemoID assay.

FIG. 3
FIG. 3

Microscopic findings of tumor tissue from resections in 2022 (A) and 2023 (B–D). A: Brain tissue showing features of a CNS WHO grade 3 astrocytoma, composed of cells with irregular hyperchromatic nuclei, scattered mitotic figures, and apoptotic debris. Arrows indicate areas with vascular proliferation. B: Brain tissue showing few atypical cells representative of residual CNS WHO grade 4 astrocytoma with evidence of prominent reactive changes consistent with a treatment effect. Asterisk marks the area of RN in the specimen. C and D: Immunohistochemistry for IDH-1 R132H showing scattered atypical cells positive for IDH-1 (R132H) mutant protein stain. Asterisk indicates RN; boxes, IDH-mutant residual astrocytoma cells. Hematoxylin and eosin (A and B), original magnification ×100 (B and C), ×200 (A), and ×400 (D).

Once the samples were collected, magnetic resonance imaging (MRI)-assisted laser thermal ablation of the enhancing lesion was performed. Postablation MRI showed near 80% ablation of the enhancing regions. Postoperatively, the patient was doing well and was discharged the following day. He was started on an adjuvant procarbazine and lomustine chemotherapy regimen just over 1 week after the procedure, with plans to reevaluate after FPM results. One month later, the ChemoID assay results were received, indicating both susceptibility and resistance profiles of the biopsied neoplasm to an array of chemotherapy regimens (Fig. 4). Importantly, the functional assay not only demonstrated susceptibility to the combination of both lomustine and procarbazine for both the bulk of the tumor and cancer stem cells, but also indicated resistance to TMZ. This finding clinically correlated with the observed tumor progression during the patient’s TMZ regimen, thereby validating the effectiveness of the established chemotherapeutic protocol. The decision on maintaining procarbazine was made based on the TP53 mutation status of the tumor, which has been shown to correlate with increased sensitization of tumors to this drug.5 Upon our review of the results, the patient continued his existing regimen and tolerated the subsequent cycles well. Follow-up MRI 2 months postoperatively indicated central necrosis of the ablated region without an elevation in relative cerebral blood volume, suggestive of treatment efficacy.

Fig. 4
Fig. 4

ChemoID results depicting the percentage of responsiveness of several chemotherapeutic drugs used on cancer cells in an in vitro assay. BCNU = carmustine; CCNU = lomustine.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

HGGs (World Health Organization [WHO] grades 3 and 4) have a poor prognosis with median overall survivals of approximately 24 to 72 and 14 to 16 months, respectively,6 and a 5-year survival rate of less than 10%.7,8 Although the standard treatment relies on maximal resection, RT, and chemotherapy, the aggressive nature of HGG makes it highly invasive and resistant to treatment.6,9 Recurrence rates for these tumors are high despite aggressive treatment.7,10

Observations

One of the complications associated with standard treatments for aggressive brain tumors is cerebral RN associated with whole-brain radiation, which can occur anywhere from 2 to 32 months after initiation of the therapy.11 Such risks are compounded by the inclusion of adjuvant chemotherapy regimens, raising the risk by a factor of five.12 This complication is of particular concern to clinicians since the clinical and radiological presentation of a patient with RN is nonspecific and can resemble that of a patient with tumor recurrence.11 What is even more challenging is the fact that both pathologies could present simultaneously, further complicating disease management. Timely management is imperative because an early operative approach for tumor recurrence may improve a patient’s overall survival.13,14 Although the gold standard for definitively diagnosing these two pathologies is brain biopsy or resection, either is an invasive procedure and is not necessary for treating RN.12,15 Imaging modalities play a significant role in differentiating between both pathologies and could guide treatment for patients suspected of having a recurrence versus RN or both. For example, in a recent systematic review and diagnostic meta-analysis by Smith et al.,11 who compared various imaging modalities to differentiate tumor recurrence and RN, single photon emission computed tomography and MR spectroscopy performed the best for differentiating both pathologies, with a pooled sensitivity and specificity of 88.7%, 88.3%, 90.7%, and 84.1%, respectively.

On the other hand, the use of FPM in aggressive tumors has shown promising results, as it offers the possibility of individually addressing the particular tumor factors that promote therapy resistance and cancer progression such as cancer stem cells.16,17 Analyzing the different chemotherapeutic agents that are effective against a particular tumor can improve the median overall survival.2 A randomized trial by Ranjan et al.,2 in which 78 patients with a diagnosis of recurrent glioblastoma multiforme or WHO grade 3 glioma were randomly assigned to standard of care chemotherapy versus treatment directed by a ChemoID assay. In that study, a statistically significant difference was observed in the risk of death between groups, in which the median overall survival was 3.5 months longer in the ChemoID assay group than in the control chemotherapy group.2

In our case, we highlighted the use of an assay-guided intervention and operative planning for a young patient with concerns of both RN and recurrence of a previously known HGG. Our primary aim was to perform a less invasive brain biopsy and laser ablation with the intention of sending a functional assay sample to guide the patient’s chemotherapy regimen. With the use of MR spectroscopy, we were able to target the most likely areas of tumor recurrence within RN and were able to obtain tissue samples via robotized stereotaxy-assisted brain biopsy. Despite the tissue having treatment changes present and only a small percentage of viable tumor, stem cell isolation was possible to give FPM results. Additionally, sending multiple core areas of the tumor, guided by anatomical regions with high Cho/Cr ratio on MR spectroscopy, ensured the recollection of the most viable tumor samples necessary for generating primary tumor cell cultures ex vivo. For this case, we sent a total of three biopsy cores for the assay. This sample and the resulting analysis proved invaluable for tailoring the patient’s chemotherapy approach for this tumor, specifically using lomustine (Fig. 4). To our knowledge, operative planning for an assay-guided intervention is not a common practice in neurosurgery, but it has shown promising results and could be of use in cases of recurrence and RN.

Importantly, one of the main limitations of functional assays involves the need for viable tumor cells to establish primary cell cultures; obtaining viable cells is essential for conducting a successful ex vivo drug response assay. Additionally, tumor heterogeneity, driven by different factors such as genetic and epigenetic modifications, makes it unlikely for all the cells within a tumor to respond evenly to a given treatment.18 This poses a challenge to functional assays, as their foundation relies on identifying successful drugs for cancer treatment. This challenge is particularly pronounced in highly aggressive and heterogeneous tumors, especially when treatment changes are present from previous chemoradiation. Advances in the use of genomic and functional assays could provide a better approach to overcoming these barriers.

Lessons

We presented a case involving a 25-year-old male with recurrent HGG in which operative planning utilizing MR spectroscopy was used for a robotized stereotaxy-assisted brain biopsy with the goal of sending a live tumor sample for a functional assay. This approach aided in guiding the patient’s chemotherapy treatment. FPM for recurrent tumors can be a valuable tool in determining the most effective therapy. The role of the neurosurgeon is vital to access viable regions of tumor for these assays. The utilization of advanced radiological studies can aid in successful preoperative planning for FPM, which can ultimately lead to personalized regimens to improve prognosis.

Author Contributions

Conception and design: Rodriguez. Acquisition of data: Rodriguez, Shelton, Horta, Nix, Gokden. Analysis and interpretation of data: Mathews, Shelton, Horta, Nix. Drafting the article: Mathews, Shelton, Nix, Gokden. Critically revising the article: Rodriguez, Mathews, Shelton, Horta, Reddy Damalcheruvu, Nix. Reviewed submitted version of manuscript: Rodriguez, Mathews, Nix, Gokden. Approved the final version of the manuscript on behalf of all authors: Rodriguez. Administrative/technical/material support: Rodriguez. Study supervision: Rodriguez. Pathology: Gokden.

References

  • 1

    Mathis SE, Alberico A, Nande R, et al. Chemo-predictive assay for targeting cancer stem-like cells in patients affected by brain tumors. PLoS One. 2014;9(8):e105710.

  • 2

    Ranjan T, Sengupta S, Glantz MJ, et al. Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial. Cell Rep Med. 2023;4(5):101025.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Howard CM, Zgheib NB, Bush S 2nd, et al. Clinical relevance of cancer stem cell chemotherapeutic assay for recurrent ovarian cancer. Transl Oncol. 2020;13(12):100860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Gao W, Wang X, Li F, Shi W, Li H, Zeng Q Cho/Cr ratio at MR spectroscopy as a biomarker for cellular proliferation activity and prognosis in glioma: correlation with the expression of minichromosome maintenance protein 2. Acta Radiol. 2019;60(1):106112.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Russell SJ, Ye YW, Waber PG, Shuford M, Schold SC Jr, Nisen PD p53 mutations, O6-alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors. Cancer. 1995;75(6):13391342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Frosina G Recapitulating the key advances in the diagnosis and prognosis of high-grade gliomas: second half of 2021 update. Int J Mol Sci. 2023;24(7):6375.

  • 7

    Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol. 2022;24(5 suppl 5):v1v95.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mladenovsk M, Valkov I, Ovcharov M, Vasilev N, Duhlenski I High grade glioma surgery: clinical aspects and prognosis. Folia Med (Plovdiv). 2021;63(1):3541.

  • 9

    Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee ShU Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18(1):39.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Xu Y, Guan H, Yu K, Ji N, Zhao Z Efficacy and safety of pharmacotherapy for recurrent high-grade glioma: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1191480.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Smith EJ, Naik A, Shaffer A, et al. Differentiating radiation necrosis from tumor recurrence: a systematic review and diagnostic meta-analysis comparing imaging modalities. J Neurooncol. 2023;162(1):1523.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(2):499508.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Birk HS, Han SJ, Butowski NA Treatment options for recurrent high-grade gliomas. CNS Oncol. 2017;6(1):6170.

  • 14

    Hervey-Jumper SL, Berger MS Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014;75(5):491499, discussion 498–499.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Vellayappan B, Tan CL, Yong C, et al. Diagnosis and management of radiation necrosis in patients with brain metastases. Front Oncol. 2018;8:395.

  • 16

    Batlle E, Clevers H Cancer stem cells revisited. Nat Med. 2017;23(10):11241134.

  • 17

    Lin EH, Jiang Y, Deng Y, Lapsiwala R, Lin T, Blau CA Cancer stem cells, endothelial progenitors, and mesenchymal stem cells: “seed and soil” theory revisited. Gastrointest Cancer Res. 2008;2(4):169174.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    McGranahan N, Swanton C Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27(1):1526.

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  • FIG. 1

    Preoperative axial postcontrast T1-weighted and axial T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. A and B: Initial diagnosis was a 5 × 4.5 × 6 cm right posterior temporoparietal lobe wedge-shaped nonenhancing mass with cortical expansion and extension to the lateral ventricle atrium with leftward midline shift of 5 mm. C and D: The 19-month follow-up scan indicated multiple punctate foci of postcontrast enhancement along the inferior margin of the right temporal surgical cavity with a significant increase in the FLAIR signal abnormality.

  • FIG. 2

    Preoperative MR spectroscopy. A: Contrast T1-weighted sequence with increased heterogeneous enhancement surrounding the resection site extending to the right splenium of the corpus callosum. B and C: Spectroscopy showing a prominent increased Cho/Cr ratio and decreased N-acetylaspartate peak, particularly along the medial aspect of the previous resection cavity in the right parieto-occipital lobe.

  • FIG. 3

    Microscopic findings of tumor tissue from resections in 2022 (A) and 2023 (B–D). A: Brain tissue showing features of a CNS WHO grade 3 astrocytoma, composed of cells with irregular hyperchromatic nuclei, scattered mitotic figures, and apoptotic debris. Arrows indicate areas with vascular proliferation. B: Brain tissue showing few atypical cells representative of residual CNS WHO grade 4 astrocytoma with evidence of prominent reactive changes consistent with a treatment effect. Asterisk marks the area of RN in the specimen. C and D: Immunohistochemistry for IDH-1 R132H showing scattered atypical cells positive for IDH-1 (R132H) mutant protein stain. Asterisk indicates RN; boxes, IDH-mutant residual astrocytoma cells. Hematoxylin and eosin (A and B), original magnification ×100 (B and C), ×200 (A), and ×400 (D).

  • Fig. 4

    ChemoID results depicting the percentage of responsiveness of several chemotherapeutic drugs used on cancer cells in an in vitro assay. BCNU = carmustine; CCNU = lomustine.

  • 1

    Mathis SE, Alberico A, Nande R, et al. Chemo-predictive assay for targeting cancer stem-like cells in patients affected by brain tumors. PLoS One. 2014;9(8):e105710.

  • 2

    Ranjan T, Sengupta S, Glantz MJ, et al. Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial. Cell Rep Med. 2023;4(5):101025.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Howard CM, Zgheib NB, Bush S 2nd, et al. Clinical relevance of cancer stem cell chemotherapeutic assay for recurrent ovarian cancer. Transl Oncol. 2020;13(12):100860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Gao W, Wang X, Li F, Shi W, Li H, Zeng Q Cho/Cr ratio at MR spectroscopy as a biomarker for cellular proliferation activity and prognosis in glioma: correlation with the expression of minichromosome maintenance protein 2. Acta Radiol. 2019;60(1):106112.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Russell SJ, Ye YW, Waber PG, Shuford M, Schold SC Jr, Nisen PD p53 mutations, O6-alkylguanine DNA alkyltransferase activity, and sensitivity to procarbazine in human brain tumors. Cancer. 1995;75(6):13391342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Frosina G Recapitulating the key advances in the diagnosis and prognosis of high-grade gliomas: second half of 2021 update. Int J Mol Sci. 2023;24(7):6375.

  • 7

    Ostrom QT, Price M, Neff C, et al. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol. 2022;24(5 suppl 5):v1v95.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Mladenovsk M, Valkov I, Ovcharov M, Vasilev N, Duhlenski I High grade glioma surgery: clinical aspects and prognosis. Folia Med (Plovdiv). 2021;63(1):3541.

  • 9

    Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee ShU Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18(1):39.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Xu Y, Guan H, Yu K, Ji N, Zhao Z Efficacy and safety of pharmacotherapy for recurrent high-grade glioma: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1191480.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Smith EJ, Naik A, Shaffer A, et al. Differentiating radiation necrosis from tumor recurrence: a systematic review and diagnostic meta-analysis comparing imaging modalities. J Neurooncol. 2023;162(1):1523.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys. 2006;65(2):499508.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Birk HS, Han SJ, Butowski NA Treatment options for recurrent high-grade gliomas. CNS Oncol. 2017;6(1):6170.

  • 14

    Hervey-Jumper SL, Berger MS Reoperation for recurrent high-grade glioma: a current perspective of the literature. Neurosurgery. 2014;75(5):491499, discussion 498–499.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Vellayappan B, Tan CL, Yong C, et al. Diagnosis and management of radiation necrosis in patients with brain metastases. Front Oncol. 2018;8:395.

  • 16

    Batlle E, Clevers H Cancer stem cells revisited. Nat Med. 2017;23(10):11241134.

  • 17

    Lin EH, Jiang Y, Deng Y, Lapsiwala R, Lin T, Blau CA Cancer stem cells, endothelial progenitors, and mesenchymal stem cells: “seed and soil” theory revisited. Gastrointest Cancer Res. 2008;2(4):169174.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    McGranahan N, Swanton C Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27(1):1526.

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