Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges

Abstract

Diffuse midline gliomas harboring the H3 K27M mutation-including the previously named diffuse intrinsic pontine glioma (DIPG)-are lethal high-grade pediatric brain tumors that are inoperable and without cure. Despite numerous clinical trials, the prognosis remains poor, with a median survival of ~1 year from diagnosis. Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation.

Keywords: H3K27M mutation; alternative delivery method; blood brain barrier (BBB); convection-enhanced delivery (CED); diffuse intrinsic pontine glioma (DIPG).

Figure 1

MRI imaging of an 8 year-old girl with a DIPG tumor (white arrows). T2-weighted sagittal (A) and axial (B) images demonstrate the enlargement of the brainstem and highlight the diffuse infiltrative characteristic of DIPG tumors. (C,D) Gadolinium-enhanced T1-weighted MRI images of the same patient demonstrating scant patchy enhancement.

Figure 2

Cannula-guided convection enhanced delivery in the rat pons (Daniels Laboratory—Mayo Clinic). (A) Infusion pump is attached to the cannula installed on rat brain where the infusate was delivered at a constant rate over time. (B) Photograph of ink solution injected at 8 mm of depth with a Hamilton syringe through the cannula validating V_d. (C) Coronal section of athymic nude rat brainstem with DIPG patient derived xenograft showing representative images of low magnification scan of H&E and high magnification scan of H3K27M and H3K27me3 immunohistochemical (IHC) staining.

Figure 3

Schematic diagram of cannula-guided convection-enhanced delivery in rat. Cannula and tumor cell implantation coordinates in relation with lambdoid (1 mm lateral) and sagittal (1 mm posterior) sutures. The guide cannula is implanted into the animal post tumor cell implantation at 6 mm below the pedestal. A dummy cannula is inserted into the guide to protect the brain when there is no infusion (resting). During drug delivery, the dummy cannula is replaced with an internal cannula that projects 8 mm into the brain and the input end is connected with a microinjection syringe infusion pump that deliver infusate at a fixed rate.