Multidimensional insights guide treatment for pediatric diffuse hemispheric glioma

The cerebral hemisphere of the brain is one of the largest brain regions and is responsible for functions such as movement, sensation and cognition. Tumors that arise in this region, called H3 G34–mutant diffuse hemispheric glioma (DHG), represent one of the most aggressive and understudied pediatric central nervous system (CNS) cancers.

H3 G34-DHG is a type of high-grade glioma characterized by a specific mutation in the histone H3 gene, in which arginine replaces a glycine at position 34. These tumors are treated by surgery, radiation and chemotherapy; however, the rarity of this disease, combined with its aggressive nature, has made it difficult to refine treatments to identify those that are most effective.

As a result, there is considerable variability in therapy for these patients, and outcomes remain poor. Clinicians often rely on preexisting institutional practices or extrapolation from adult glioma protocols to determine a treatment approach for children with H3 G34-DHG in the absence of standardized treatment guidelines and limited pediatric-specific evidence.

“Much of what we’ve done historically has been based on adult gliomas,” said corresponding author Jason Chiang, MD, PhD, Department of Pathology. “But children and adults have fundamentally different biology, and our treatments need to reflect that.”

To address these limitations, Chiang and his team conducted a comprehensive evaluation of the clinical, imaging and molecular features of a multi-institutional cohort of 36 pediatric patients newly diagnosed with H3 G34-DHG, along with their treatments and outcomes. The results were published in Acta Neuropathologica.

Adult glioma strategies fall short

Current treatments for H3 G34–DHG typically include surgical resection followed by focal radiation therapy. Treatment plans frequently incorporate temozolomide chemotherapy; however, data on its use in pediatrics are limited. To better understand the factors that influence patient outcomes, the researchers evaluated the relationship between treatment strategies and tumor-specific features. They found that frontline treatment with temozolomide improved progression-free survival, meaning it kept the tumor from growing or spreading for longer. However, this benefit did not translate into an improvement in overall survival.

These findings prompted a deeper investigation into the molecular determinants of treatment response, particularly the role of the protein MGMT. This DNA repair enzyme can counteract the effects of chemotherapies such as temozolomide. Notably, the investigators identified a previously unrecognized mechanism of MGMT regulation that challenges long-standing assumptions derived from adult glioma biology. In adult high-grade gliomas, MGMT promoter methylation is a well-established biomarker used to predict response to temozolomide. In contrast, this study found that MGMT promoter methylation did not correlate with outcomes or treatment responses in H3 G34–DHG.

Instead, MGMT mRNA expression emerged as a more informative biomarker. Lower MGMT expression was associated with improved progression-free and overall survival among patients receiving early temozolomide, suggesting a distinct regulatory mechanism in pediatric tumors.

“This helps explain why the test used in adults doesn’t really work in children,” said Chiang. “Our results suggest that looking at MGMT expression, instead of promoter methylation, would be a more useful way to predict outcomes and guide treatment in pediatric DHG.”

Beyond MGMT, the team also examined additional genetic alterations that may influence prognosis. The PDGFRA gene, which plays a critical role in cell growth and signaling in the brain, emerged as a strong predictor of overall survival. In tumors with amplified PDGFRA expression, the patients had reduced overall survival, suggesting that tumors with this alteration may be more severe, and that PDGFRA may be a useful biomarker for guiding clinical expectations.

Surgical strategies and setbacks 

While molecular markers can provide important insights into how a tumor might behave, clinical outcomes are also heavily influenced by what can be achieved surgically. The researchers found that maximal surgical removal of the tumor, or gross total resection, was one of the most important factors influencing outcomes in children with H3 G34–DHG.

The study found that patients who underwent gross total resection experienced longer periods without tumor progression, highlighting the critical role of surgery in slowing the disease. “Gross total resection can give these children the best chance at delaying progression, but in some cases, complete removal simply isn’t possible,” explained co-first author Dana Tlais, MD, Department of Oncology. “We have to consider patient safety when planning surgery, ensuring that quality of life remains a priority.”

At the same time, the investigators noted that tumors that spread diffusely across multiple brain regions (called a gliomatosis cerebri pattern) were associated with worse overall survival, even when resection was extensive.

Pediatric-guided clinical recommendations

Taken together, these findings offer meaningful clinical guidance for this challenging disease. The researchers concluded that MGMT mRNA expression should be assessed in pediatric cases whenever feasible, as it provides a more accurate indication of how tumors may respond to therapy. Temozolomide is recommended as a key component of frontline treatment for pediatric patients, particularly in cases with low MGMT expression.

“Based on what we’re seeing, temozolomide should be a central part of treatment for pediatric patients, rather than being replaced by other agents that may not offer the same benefit,” said Chiang. “It’s one of the few therapies that shows a meaningful impact on slowing disease progression.”

Molecular profiling adds a layer of guidance to these treatment decisions. By incorporating tumor-specific genetic and molecular features, clinicians can better stratify risk and tailor therapy.

“Instead of relying on MGMT promoter methylation, which doesn’t tell us much in these pediatric tumors, we should be looking at MGMT mRNA levels. Measuring expression directly gives a clearer picture of how the tumor will respond to therapy and can help guide treatment decisions more effectively for children with DHG,” Chiang added.

Together, these findings indicate a shift away from one-size-fits-all approaches adapted from adult gliomas and toward treatment strategies guided by the unique biology of each pediatric tumor.

“Improving outcomes for children with DHG will depend on our ability to understand the unique biology of these tumors better and translate that knowledge into more effective, targeted therapies,” said Tlais.