Pediatric Diffuse Midline Gliomas: An Unfinished Puzzle

Abstract

Diffuse midline glioma (DMG) is a heterogeneous group of aggressive pediatric brain tumors with a fatal prognosis. The biological hallmark in the major part of the cases is H3K27 alteration. Prognosis remains poor, with median survival ranging from 9 to 12 months from diagnosis. Clinical and radiological prognostic factors only partially change the progression-free survival but they do not improve the overall survival. Despite efforts, there is currently no curative therapy for DMG. Radiotherapy remains the standard treatment with only transitory benefits. No chemotherapeutic regimens were found to significantly improve the prognosis. In the new era of a deeper integration between histological and molecular findings, potential new approaches are currently under investigation. The entire international scientific community is trying to target DMG on different aspects. The therapeutic strategies involve targeting epigenetic alterations, such as methylation and acetylation status, as well as identifying new molecular pathways that regulate oncogenic proliferation; immunotherapy approaches too are an interesting point of research in the oncology field, and the possibility of driving the immune system against tumor cells has currently been evaluated in several clinical trials, with promising preliminary results. Moreover, thanks to nanotechnology amelioration, the development of innovative delivery approaches to overcross a hostile tumor microenvironment and an almost intact blood–brain barrier could potentially change tumor responses to different treatments. In this review, we provide a comprehensive overview of available and potential new treatments that are worldwide under investigation, with the intent that patient- and tumor-specific treatment could change the biological inauspicious history of this disease.

Pediatric diffuse midline glioma H3K27- altered: A complex clinical and biological landscape behind a neatly defined tumor type

“…The description of the rationale and results of such new therapeutic approaches is beyond the scope of this review. That said, so far, none of the recent clinical trials with published results has demonstrated a relevant impact on improving survival ( 8 ), although many of them are still ongoing and many others are not active yet. Much hope and scientific effort are being invested in those modern approaches.…”

“…We have been learning that all tumors labeled as H3K27altered DMG globally share the same dismal prognosis: they are aggressive gliomas, not amenable to radical surgery, that respond only to radiotherapy and just for a limited period of time, and then progress lethally in more than 90% of patients within one year (8). Various medical approaches using neoadjuvant or postirradiation chemotherapy have been tested over the decades, but none has demonstrated that it is able to substantially improve OS or PFS, sometimes resulting in increased toxicities and the need for hospitalization (70)(71)(72).…”

“…They represent around 20% of all pediatric CNS tumors, with around 200-300 cases per year in the United States ( 7 ). DMGs, and DIPGs in particular, are leading causes of solid tumor death in children; overall, their prognosis has remained extremely poor, and for many years, no significant improvement has been achieved in their treatment ( 8 ). The majority of DMGs occur in children aged 5 to 10 years, without any gender predilection ( 9 ).…”

“…Current treatment strategies for DMG encompass focal intensity-modulated radiation therapy (IMRT) to the primitive tumor (usually 54–60 Gy in 1.8–2 Gy fractions, given over 6 weeks) and variable lines of chemotherapy. Nonetheless, despite the various attempts at new treatment approaches described so far, the prognosis remains poor ( 8 ). Re-irradiation, which represents the only effective treatment for recurrent disease, can lead to symptom relief or neurological improvement in the majority of patients and slightly prolong survival after relapse but remains a palliative and not a curative option ( 17 – 21 ).…”

Adult-type and Pediatric-type Diffuse Gliomas

“…Of note, even a preoperative confirmation of malignancy in several diffuse hemispheric gliomas with H3G34 mutation but without imaging features of a high-grade tumor could be achieved by means of 18 F-FET-PET [84]. Especially for those diffuse gliomas without or with questionable features of a higher tumor grade, there is considerable motivation and discussion concerning the general need for a biopsy assessment [78,96]. Several important differential diagnoses for diffuse high-grade gliomas must be addressed, especially from the group of circumscribed astrocytic gliomas.…”