Clinical Features, Prognostic Factors, and Pattern of Failure in H3 G34-Mutant Diffuse Hemispheric Glioma: A Multi-Institutional Experience and Meta-Analysis

doi:10.21203/rs.3.rs-5375436/v1

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Clinical Features, Prognostic Factors, and Pattern of Failure in H3 G34-Mutant Diffuse Hemispheric Glioma: A Multi-Institutional Experience and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-5375436/v1

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Background:

H3 G34-mutant diffuse hemispheric glioma (DHG) is an aggressive tumor with a poor prognosis. We investigated the relationship between patient outcomes and molecular characteristics, extent of resection, and temozolomide (TMZ) use. Additionally, we reviewed the patterns of treatment failure.

Methods:

Retrospective multi-institutional review of clinical, imaging, and molecular characteristics of 38 patients with newly diagnosed H3 G34-mutant DHG, supplemented by a meta-analysis.

Results:

The median age was 14 years (8–28 years). The median progression-free survival (PFS) was 0.6 years (95% CI 0.4–1.2 years), and the median overall survival (OS) was 1.8 years (95% CI 1.1-3.0 years). Gross total resection (GTR) was associated with improved PFS (p = 0.0078) compared to non-GTR. Twenty-two patients (57.9%) received frontline TMZ and had improved PFS compared to those without (p = 0.0034). Of the evaluable patients with progressive disease, 78% progressed within the high-dose RT field. MGMT promoter methylation was not significantly associated with PFS/OS or TMZ efficacy (33 evaluable cases, n = 19 with MGMT silencing, n = 14 without). PDGFRA amplification (n = 10) was associated with inferior OS (p = 0.0443), and CDKN2A homozygous deletion (n = 16) was associated with inferior PFS (p = 0.0204). In the meta-analysis cohort (n = 252), GTR/near-total resection had significantly better PFS (p < 0.0001) and OS (p < 0.0001), and MGMT promoter methylation was not associated with PFS/OS.

Conclusions:

In our cohort, MGMT promoter methylation was not a prognostic factor and was not associated with TMZ utility. The resection extent and TMZ use were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields are not warranted.

H3 G34-mutant diffuse hemispheric glioma

MGMT promoter methylation

Temozolomide

Prognostic factors

Pattern of failure

Surgery, TMZ, and molecular status correlated with outcomes in H3 G34-mutant DHG.

TMZ use demonstrated benefits regardless of MGMT promoter methylation status.

Most treatment failures occurred within the high-dose radiation field.

We assembled a multi-institutional cohort of 38 patients with H3 G34-mutant diffuse hemispheric glioma, providing the most extensive centralized review of molecular, clinical, and imaging features and their associations with survival outcomes in this poorly characterized disease. Variability in imaging characteristics and patterns of treatment failure are described. We identify prognostic factors related to survival outcomes, including surgical extent, therapeutic regimen, and concomitant molecular alterations. Findings from our multi-institutional experience are strengthened by a meta-analysis of 252 patients with H3 G34-mutant diffuse hemispheric glioma following a systematic review of the literature. Our integrated analysis offers recommendations for frontline diagnostic and therapeutic strategies.

Pediatric-type diffuse high-grade gliomas (pHGGs) encompass a molecularly diverse and clinically devastating spectrum of central nervous system malignancies and represent the leading cause of cancer-related morbidity and mortality in children [25, 31]. In nearly 30% of pHGGs occurring in the cerebral hemispheres of older adolescents and young adults, recurrent alteration in H3-3A at amino acid 34 (glycine to arginine/valine) is a defining molecular feature of H3 G34-mutant diffuse hemispheric glioma (DHG) [22, 30, 36]. In addition to harboring concomitant loss of function mutations in TP53 and ATRX, H3 G34-mutant DHG frequently exhibits amplification and activating mutations in PDGFRA [6]. Homozygous deletion of CDKN2A/B is also an increasingly recognized feature of this rare brain tumor [35].

While efforts to decipher the unique developmental origins and epigenetic mechanisms contributing to tumor formation and tumor maintenance in H3 G34-mutant DHG have yielded new insight, there remains a paucity of cohorts that have been granularly clinically annotated [4, 6, 15, 28]. Apart from surgery and focal radiation therapy (RT), a standard of care treatment regimen for patients diagnosed with H3 G34-mutant DHG is lacking. This has inevitably contributed to increased variability in the choice of frontline medical therapy for these patients. The incorporation of an adjuvant and concomitant temozolomide (TMZ) regimen with RT is a well-established treatment approach conferring survival benefits in adults with newly diagnosed high-grade glioma (glioblastoma) harboring epigenetic silencing of the O⁶-methylguanine-DNA methyltransferase (MGMT) promoter [17, 32]. Despite these findings, the addition of TMZ to standard-of-care surgery and RT is inconsistent for adolescents and young adults diagnosed with H3 G34-mutant DHG. While some pediatric data suggests that the use of TMZ concurrently with RT followed by adjuvant TMZ combined with lomustine (CCNU) confers a survival benefit to patients with pHGG, [11, 18] the outcomes remain dire, and the survival benefit small, leading to variability in practice. It is also unclear if MGMT promoter methylation represents a prognostic and/or predictive biomarker in the setting of concurrent and adjuvant TMZ for patients with pHGG, including H3 G34-mutant DHG. Moreover, insufficient literature surrounding H3 G34-mutant DHG has further limited the identification of robust molecular prognosticators and a clear understanding of the pattern of treatment failure.

To address these critical questions, we report a comprehensive evaluation of clinical, molecular, and imaging features and therapeutic modalities and their association with treatment response and survival outcomes in a multi-institutional cohort with newly diagnosed H3 G34-mutant DHG. We complement our findings with a meta-analysis of patients with H3 G34-mutant DHG following a systematic literature review. To our knowledge, our multi-institutional study represents the largest cohort with detailed clinical annotation and extended follow-up for patients diagnosed with H3 G34-mutant DHG. Importantly, it is the first report to offer data-driven recommendations for frontline medical therapy.

Multi-Institutional Clinical Review

A retrospective chart review was performed on 38 patients with newly diagnosed H3 G34-mutant DHG between 2006 and 2024. Twenty-four patients were treated at St. Jude Children’s Research Hospital, and 14 patients were treated at collaborating institutions (The University of Oklahoma Health Sciences Center, Akron Children’s Hospital, The University of North Carolina School of Medicine, The University of Texas Health San Antonio, Children’s Mercy Kansas City, American University of Beirut Medical Center, Kaiser Permanente Los Angeles Medical Center, and Lucile Packard Children’s Hospital Stanford). Collected data included patient demographics, tumor location, molecular alterations, surgical resection status, treatment details, and survival outcomes. Frontline TMZ use was defined as the receipt of at least ten doses of TMZ during RT and/or at least one completed maintenance cycle of TMZ (any dose). Institutional review board approval was obtained at St. Jude (IRB# 19–0338, 22-1199, 24-1699) and external institutions based on local guidelines.

Systematic Review of Literature

An electronic search of PubMed was performed using the terms “H3 G34-mutant OR G34 OR H3 G34 OR G34R OR H3 G34R OR H3.3 G34R” AND “Brain Tumor OR Glioma OR PNET OR Brain OR Diffuse Hemispheric Glioma” to yield articles discussing H3 G34-mutant DHG. One hundred fifty-four articles were identified and independently reviewed by two investigators (J.T.R. and D.T.). Thirty-four articles reporting patient-level survival data and associated molecular findings were included in our meta-analysis cohort. Patient data duplicated across articles was identified and subsequently removed prior to analysis. Based on the initial identification of histone H3 mutations in pHGG in 2012, only articles published between January 1, 2012, and March 15, 2024, were considered. Non-peer-reviewed preprint articles and abstracts were excluded from the review. The systematic review and meta-analysis were conducted in accordance with PRISMA reporting guidelines.

Whole genome sequencing

Genomic DNA was extracted from snap-frozen tumor tissue using an automated Maxwell RSC Instrument (Promega), as previously described [7, 14, 16]. DNA quality was assessed on a 4200 TapeStation (Agilent). Paired-end sequencing was conducted on the Illumina HiSeq platform with a 100- or 125-bp read length or NovaSeq with a 150-bp read length. Sequencing results were analyzed using an institutionally established pipeline for alignment and calling of single nucleotide variants (SNVs). Insertions or deletions (indels) were annotated and ranked by putative pathogenicity using a workflow named “medal ceremony” and subsequently manually reviewed [37].

Whole exome sequencing

Genomic DNA was extracted from formalin-fixed paraffin-embedded (FFPE) tissue using a QIAamp DNA FFPE Tissue Kit (Qiagen), as previously described [7, 9, 14, 16]. The genomic libraries were generated using the SureSelectXT kit (Agilent Technologies), followed by exome enrichment using the SureSelectXT Human All Exon V8 bait set (Agilent Technologies). The resulting exon-enriched libraries were then subjected to the paired-end, 100-cycle sequencing performed on a NovaSeq X Plus (Illumina). Sequencing results were analyzed as mentioned above.

Methylation array analysis

Genomic DNA was extracted as stated above and subjected to genome-wide methylation profiling on an Illumina Infinium MethylationEPIC platform, as previously described [7–10, 16, 20]. Copy number variation analysis was performed using conumee, as previously described [13]. MGMT promotor methylation was assessed using MGMT-STP27, as previously described [2, 3].

Histopathology review and immunohistochemistry

Hematoxylin and eosin-stained 5 µm sections of FFPE tissue specimens of all tumor samples were centrally reviewed by a board-certified neuropathologist specialized in pediatric CNS tumors (JC) to confirm the diagnosis. The following antibodies were used on 5 µm FFPE tissue sections: p53 (Zeta Corp, Z2029M, clone DO-7, 1:200) and ATRX (Sigma, HPA001906, 1:600).

Imaging

For each patient, the baseline MRI (before any therapy) and all the following scans were reviewed by a neuroradiologist (AKB) until evidence of recurrence. Each scan consisted of pre- and post-contrast T1-weighted sequence, T2-weighted sequence, FLAIR, and diffusion-weighted sequences. Blood-sensitive sequences, gradient recalled echo (GRE), or susceptibility weighted sequence (SWI) were used to evaluate intra-tumoral hemorrhage when available. Non-contrast CT scans at the time of presentation were also reviewed for evaluation of hemorrhage. At presentation, scans were categorically evaluated for a) location of the tumor, midline vs. lobar vs. multi-lobar; b) patterns of tumor margins, well defined vs. infiltrative; c) focality of the tumor, focal vs. multifocal; d) presence of hemorrhage; e) presence of enhancement; f) patterns of diffusion restriction; and g) presence of metastasis throughout the neuraxis. A focal lesion was defined as a single lesion with well-defined margins on postcontrast T1-weighted sequence with or without proportionate T2 abnormality suggestive of peritumoral edema surrounding the T1-enhancing lesion. An infiltrative lesion is defined as a lesion with either poorly defined T1 enhancing margins, abnormal disproportionate T2 signal around the T1 enhancing lesion, or ill-defined margin in tumors with no enhancing component. Infiltrative lesions were further evaluated for contiguous multiple lobar involvement. Recurrence was defined as the development of a new lesion or worsening of a previously treated lesion and was evaluated for either local or distant recurrence, as defined below. The focality of the recurrence was also assessed, as was the extent of recurrence with respect to crossing midline and the presence of subventricular spread. A gross total resection (GTR) was defined as a clean, well-defined surgical margin with no evidence of residual tumor on any sequence. A near-total resection (NTR) was defined when imaging appearance across all sequences resembled a focal residual tumor (~ 5% of the initial mass), predominantly along well-defined and clean surgical margins. A subtotal resection (STR) was defined as substantial residual tumor.

Radiation Dosimetry and Pattern of Failure Analysis

For radiotherapy dosimetric assessment, complete CT data sets of RT treatment plans were transferred to MIM software (MIM Software Inc, Cleveland, OH), and composite radiation dose data were assembled. MRI scans at progression were co-registered to CT data sets with standard vendor-supplied software, and the anatomic tumor extent at progression was manually delineated based on T2-weighted fluid-attenuated inversion recovery and T1 postcontrast abnormalities on MRI. Dose-volume histograms were calculated for the progression volumes, and progression with respect to radiation dose distribution was categorized as previously done for adult and pediatric patients with HGG [5, 33].

Statistical Analysis

Progression-free survival (PFS) was defined as the time interval from the date of first surgery to the date of disease progression or death from any cause or to the date of last contact for patients without events. Overall survival (OS) was defined as the time interval from the date of first surgery to the date of death from any cause or to the date of last contact for survivors. The Kaplan-Meier (KM) method was used to estimate survival outcomes. The difference between survival curves was compared by log-rank test. Fisher’s exact tests were used to investigate associations between categorical variables. A p-value < 0.05 was considered significant.

Demographic, Imaging, and Molecular Characteristics

Our multi-institutional cohort included 38 patients with a new diagnosis of H3 G34-mutant DHG. The demographic, clinical, and molecular characteristics of the multi-institutional study cohort are summarized in Fig. 1. The median age was 14 years (8–28 years). Twenty-three (60.5%) were male, and 15 (39.5%) were female. Tumor location was determined at central review (n = 32) and from the clinic notes (n = 5). The temporal lobe was involved in 20 (52.6%) patients. The maximum dimension of the tumor ranged from 2.8 cm to 10.9 cm. Out of the 32 patients who had pre-operative imaging available for central review, imaging appearances were variable (Fig. 2A-H). Fourteen tumors (43.8%) involved more than one lobe at presentation, 23 tumors (71.8%) were unifocal, and 10 (31.2%) tumors were multifocal. Nineteen (50%) had a methylated MGMT promoter, 14 (36.7%) had an unmethylated MGMT promoter, and five (13.2%) had an unknown MGMT promoter status due to the unavailability of tissue. Sixteen (42.1%) had CDKN2A homozygous deletion, 18 (47.4%) did not have the homozygous deletion, and four (10.5%) had unknown CDKN2A status due to the unavailability of tissue. PDGFRA amplification was detected in 10 (26.3%), negative in 24 (63.2%), and unknown in four (10.5%) due to the unavailability of tissue. ATRX alteration was present in 25 (65.8%), absent in two (5.3%), and unknown in 11 (28.9%) due to the unavailability of tissue. TP53 alteration was detected in 28 (73.7%), absent in three (7.9%), and unknown in seven (18.4%) due to the unavailability of tissue.

Treatment and Survival Outcomes

Twelve (31.6%) had a GTR, two (5.3%) had an NTR, 14 (36.8%) had a STR, and 10 (26.3%) had a biopsy. Thirty-seven (97.4%) received upfront RT, and one (2.6%) did not receive RT due to rapid disease progression. Of the patients who received RT, 31 (83.8%) received focal treatment, three (8.1%) received whole brain RT (WBRT), and three (8.1%) received craniospinal irradiation (CSI). Two patients were noted to have symptomatic and radiographic progression during focal RT and were transitioned to WBRT. Twenty-two (57.9%) received frontline TMZ, either concurrent with RT, adjuvant, or both. Seven patients (18.4%) received adjuvant CCNU and TMZ. Median follow-up was 2.1 years (0.4–5.1 years). Thirty-three (86.8%) had disease progression during the follow-up period, including one who progressed before receiving RT. Of the patients who progressed following RT with evaluable radiographic progression (N = 23), nine (39.1%) had an isolated local recurrence, five (12.7%) had distant recurrence only, and nine (39.1%) had combined local and distant recurrence (Fig. 3A-F). Of those with local progression, 14/18 (77.7%) patients experienced a central local failure (i.e., 95% of the recurrent tumor volume was within the high-dose RT field). Cumulative RT dose ranged from 39 Gy (in 3 Gy fractions) to 64.8 Gy (in 1.8 Gy fractions); 7 (18.9%) received proton therapy.

The 1-year, 2-year, and 5-year PFS were 39.1% (24.0%, 54.2%), 16.3% (6.6%, 30.1%), and 10.9% (2.8%, 25.8%), respectively. The median PFS was 0.6 years (95% CI 0.4 to 1.2 years) (Fig. 4A). The 1-year, 2-year, and 5-year OS were 74.7% (56.8%, 86.0%), 44.2% (26.8%, 60.0%), and 20.9% (7.6%, 38.9%), respectively. The median OS was 1.8 years (95% CI 1.1 to 3.0 years) (Fig. 4B). Patients who had a GTR had significantly better PFS (p = 0.0078) (Fig. 4C) but no significant change in OS compared to patients with non-GTR (Fig. 4D). Patients who received frontline TMZ had significantly better PFS (p = 0.0034) (Fig. 4E) but demonstrated no significant change in OS compared to patients who did not receive frontline TMZ (Fig. 4F). MGMT promoter methylation status was not associated with survival outcomes (Fig. 5A and 5B), and response to TMZ was not associated with MGMT promoter methylation status. CDKN2A homozygous deletion was associated with significantly worse PFS (p = 0.0204) (Fig. 5C) but had no significant association with OS (Fig. 5D). PDGFRA amplification was not associated with worse PFS (Fig. 5E) but was associated with significantly worse OS (p = 0.0443) (Fig. 5F).

Meta-Analysis of Patients with Diffuse Hemispheric Glioma, H3 G34-Mutant

Demographic and Molecular Characteristics of the Meta-Analysis Cohort

Following a systematic literature review, we identified 252 patients diagnosed with H3 G34-mutant DHG. The demographic, clinical, and molecular characteristics of the meta-analysis study cohort are summarized in Supplementary Table 1. The median age was 17 years (7–66 years). One hundred thirty-one (52.0%) were male, 110 (43,7%) were female, and 11(4.4%) lacked reporting information. One hundred eighty-three (72.6%) had a G34R alteration, 14 (5.6%) had a G34V alteration, and 55 (21.8%) had a G34 alteration, not otherwise specified. One hundred twenty (47.6%) had a methylated MGMT promoter, 37 (14.7%) had an unmethylated MGMT promoter, and 95 (37.7%) had an unknown MGMT promoter methylation status. Median follow-up was 1.3 years (0.01-7.0 years).

Treatment and Survival Outcomes of Meta-Analysis Cohort

Fifty-seven (22.6%) had a GTR or NTR, 42 (16.7%) had an STR, 27 (10.7%) had a biopsy, and 126 (54.8%) lacked reporting information. One hundred nine (43.3%) received radiation therapy, five (2.0%) did not receive radiation therapy, and 138 (54.8%) lacked reporting information. Seventy-four (29.4%) received TMZ, eight (3.2%) did not receive TMZ, and 170 (67.5%) lacked reporting information.

The 1-year, 2-year, and 5-year PFS of the meta-analysis cohort were 51.9% (44.2%, 59.4%), 21.7% (15.2%, 28.7%), 3.7% (0.5%, 5.9%), respectively. The median PFS was 1.1 years (95% CI 0.95 to 1.25 years) (Fig. 6A). The 1-year, 2-year, and 5-year OS of this cohort were 75.9% (69.4%, 81.3%), 45.8% (37.2%, 53.0%), 16.1% (8.3%, 25.1%), respectively. The median OS was 1.8 years (95% CI 1.4 to 2.08 years) (Fig. 6B). Patients with a GTR or NTR had significantly better PFS (p < 0.0001) (Fig. 6C) and OS (p < 0.0001) (Fig. 6D). Similar to our multi-institutional cohort, MGMT promoter methylation status was not associated with survival outcomes (Fig. 6E and 6F). Due to the limited number of patients with survival data not having received TMZ chemotherapy, survival outcomes could not be evaluated by TMZ treatment status. No difference in survival status was identified based on G34 alteration status. Patients with tumors harboring an EGFR mutation (N = 10 of 73 evaluable cases) had worse PFS (p = 0.0045) and OS (p = 0.023), while mutations in CCND (N = 10 of 43 evaluable cases) conferred a worse OS (p = 0.0092). Based on Cox regression models, age was not associated with PFS (p = 0.842) nor OS (p = 0.611).

H3 G34-mutant DHG is a devastating tumor type for which there is no curative therapy. Due to the paucity of clinical data, there is no established standard of care outside of surgery and RT. This has led to considerable variability in the choice of a frontline adjuvant treatment regimen. While TMZ is often incorporated in the treatment of these tumors, either as a monotherapy or in combination with other agents, the addition of TMZ by providers remains inconsistent. Historically, the utilization of TMZ has been extrapolated from adult data and pediatric clinical trials that recruited patients with pHGG [11, 18, 32]. Our study suggests that frontline TMZ confers PFS benefits to patients with H3 G34-mutant DHG but does not significantly impact OS. We could not draw conclusions about the utility of the addition of CCNU in this patient population due to the limited number of patients having received both CCNU and TMZ in our cohort.

In adult high-grade glioma, MGMT promoter methylation testing is a well-established prognosticator, whereby a methylated MGMT promoter confers a survival advantage and contributes to increased TMZ efficacy [17]. Our cohort demonstrated no significant association between MGMT promoter methylation status and survival outcomes in patients with H3 G34-mutant DHG. Our study also revealed no association between MGMT promoter methylation status and TMZ response, in distinction from adult data [17]. Our complementary meta-analysis further supports the lack of prognostication. While these findings do not align with the results of ACNS0126 [11], they are concordant with several subsequent pediatric studies, namely ACNS0423 [18], ACNS0822 [21], and the HERBY trial [23]. These findings can assist providers in navigating the uncertainty that arises when treating H3 G34-mutant DHG. Many debate the necessity of performing MGMT promoter methylation testing at diagnosis, as it adds costs and extends turnaround time. Our findings suggest that prognostication and treatment decisions should not be contingent on MGMT promoter status in this patient population.

In our cohort, we did not find any characteristic imaging appearances for H3 G34-mutant DHG, as imaging appearances were variable between patients. This is in alignment with previous studies [19]. As to the extent of surgical resection, our data demonstrates improved survival outcomes in patients with a GTR/NTR in our multi-institutional cohort (PFS) and the meta-analysis cohort (PFS and OS), highlighting the importance of adequate surgery upfront. However, it is crucial to recognize that despite the improved outcomes with an extensive resection, quality of life remains critical in a largely incurable tumor type. Thus, we advise careful surgical planning and making every effort to preserve eloquent brain areas and neurological function while seeking a maximal safe resection.

While most patients treated with RT received only focal radiation, a surprising proportion were treated with either WBRT (8.7%) or CSI (8.7%) given extensive disease burden, and two patients required transition to WBRT after initiation of focal RT due to symptomatic and radiographic disease progression. Evaluation of the patterns of disease progression demonstrated that 39.1% of patients developed a local-only recurrence, 39.1% developed a combined local and distant recurrence, while only 12.7% had an isolated distant recurrence. Thus, as most treatment failures occurred within the high-dose RT field, extended radiation fields do not appear to be justified.

In addition to our findings surrounding the medical and surgical management of H3 G34-mutant DHG, we identified molecular prognostic markers in our cohort. These include CDKN2A homozygous deletion and PDGFRA amplification, both associated with inferior survival outcomes. Our meta-analysis review also found EGFR and CCND amplification, while rare in H3 G34-mutant DHG, associated with worse survival outcomes. Our findings suggest that testing for these alterations, most commonly by fluorescence in situ hybridization or methylation array, aids in prognostication for this patient population.

While our multi-institutional report offers the most extensive comprehensive evaluation of clinical findings and outcomes for patients with H3 G34-mutant DHG, variability in clinical practice and reporting across providers is a concern. To address this, we performed a centralized review of all clinical data at our institution. Given the rarity of H3 G34-mutant DHG, an increasing emphasis will need to be placed on international collaboration to design and implement effective prospective clinical studies for improved outcomes. In the setting of childhood cancer, employing a global perspective is particularly important as more than 90% of children diagnosed with cancer reside in low- and middle-income countries (LMICs) [34]. For children and adolescents with central nervous system tumors in LMICs, access to quality multimodal care, including neurosurgical care, radiotherapy, and essential medications for cancer treatment, remains suboptimal [12, 24, 26, 27, 29]. Based on the findings from our study, we suggest further we suggest further consideration of including TMZ in the World Health Organization (WHO)’s list of essential anti-neoplastic medicines [1]. Ultimately, we believe that multi-institutional collaborations and prospective efforts are necessary to help enhance our knowledge about this tumor type and to help improve outcomes in a patient population in dire need of hope.

Based on our study results, we support the use of TMZ as part of the frontline chemotherapy regimen for patients with H3 G34-mutant DHG. Future research should explore novel therapeutic agents or combination therapies built upon a TMZ backbone to further improve outcomes for this patient population. Given the lack of association between MGMT promoter methylation status and the efficacy of TMZ, we do not recommend delaying the initiation of TMZ treatment until MGMT promoter status is determined, nor withholding TMZ in cases of an unmethylated promoter. Additionally, GTR or NTR appears to provide a survival benefit, and CDKN2A and PDGFRA status serve as important molecular prognostic markers for H3 G34-mutant DHG.

Funding:

National Cancer Institute (P30CA021765 to JC, P01CA096832 to JC, and F30CA271570 to JTR)

American Lebanese Syrian Associated Charities (to JC)

The V Foundation (to JC)

RSNA R&E Foundation (to AKB)

Treovir Inc. (to AKB)

Conflict of Interest: None declared.

Authorship:

Conceptualization: DT, JTR, JC, CLT, AKB

Data collection, analysis, and interpretation: DT, JTR, JC, CLT, AKB, QZ, XL, TL, AM, DCM, RYMK, SZR, BHL, SS, AA, KFG, RMG, SP, AOT

Drafting of the manuscript: DT, JTR, JC, CLT, AKB, TL, AOT

Manuscript editing and critical revision: DT, JTR, JC, CLT, AKB, QZ, XL, TL, AM, DCM, RYMK, SZR, BHL, SS, AA, KFG, RMG, SP, AOT

Supervision: JC, DT, CLT, AKB

Data availability: The data generated and analyzed by the study will be made available upon reasonable request.

Acknowledgments: This publication was supported by the Hartwell Center. Preliminary findings from this study were presented at the 2024 ISPNO Conference.

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Clinical Features, Prognostic Factors, and Pattern of Failure in H3 G34-Mutant Diffuse Hemispheric Glioma: A Multi-Institutional Experience and Meta-Analysis

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Abstract

Background:

Methods:

Results:

Conclusions:

Figures

Key Points

Importance of the study

Introduction

Materials and Methods

Multi-Institutional Clinical Review

Systematic Review of Literature

Whole genome sequencing

Whole exome sequencing

Methylation array analysis

Histopathology review and immunohistochemistry

Imaging

Radiation Dosimetry and Pattern of Failure Analysis

Statistical Analysis

Results

Demographic, Imaging, and Molecular Characteristics

Treatment and Survival Outcomes

Meta-Analysis of Patients with Diffuse Hemispheric Glioma, H3 G34-Mutant

Demographic and Molecular Characteristics of the Meta-Analysis Cohort

Treatment and Survival Outcomes of Meta-Analysis Cohort

Discussion

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1