Fifty years of DIPG: looking at the future with hope

Diffuse Midline Gliomas: Challenges and New Strategies in a Changing Clinical Landscape

“…One of the first historical descriptions of diffuse midline gliomas is attributed to Harvey Cushing, the father of modern neurosurgery, who was challenged with the case of a 15-year-old girl presenting long tract signs and cranial neuropathies. Following an unsuccessful exploratory suboccipital craniectomy (lateral enough to approach the mastoid process), augmented by a cerebellar hemispherectomy, Cushing himself had to raise the white flag as the tumor, what was later defined as a diffuse intrinsic pontine glioma (DIPG), was not amenable to surgical resection given its inseparability from the high-stake cytoarchitecture of the pontine nuclei [ 1 , 2 , 3 ].…”

“…On the other hand, midbrain DMGs can present with Perinaud-like syndromes due to tectal and pineal-region involvement (e.g., upward gaze palsy, convergence-retraction nystagmus, and pupillary-light near dissociation), more commonly seen with more benign pineal lesions ( Figure 1 B) [ 17 , 18 ]. DIPGs, owing to their proximity to pontine nuclei and descending corticospinal tracts, can present with a triad of long-tract signs (e.g., myelopathy), cerebellar symptoms (e.g., ataxia or dysmetria), and cranial neuropathies (often starting as diplopia on lateral gaze) ( Figure 1 C) [ 1 ]. Spinal DMGs often present with symptoms associated with their location, with symptomatic myelopathy caudal to the level of the lesion (e.g., predominant leg symptoms for thoracic lesion) ( Figure 1 D) [ 19 ].…”

“…Given the wide variety of anatomical locations and presentations, it logically follows that DMGs have a complex appearance on MRI, the main modality of imaging (CT, owing to its lower tissue resolution, is not part of standard clinical practice except as a first-line screening tool). Prior to biopsy, a presumptive diagnosis is usually made, then confirmed with tissue sampling, given imaging features different from other pathologies often found in these locations [ 1 , 20 , 21 ]. It is important to note how DMGs are famous for their occasionally heterogenous radiographic and MRI appearances, with more than one expert practitioner challenged by unusual imaging characteristics.…”

“…Despite continuous failures, fueled by an otherwise unforgiving prognosis that led to the birth of numerous funding agencies whose goal was to change it, investigative efforts continued [ 1 ]. One of the main barriers to clinical success, some felt, was represented by the blood–tumor barrier, which led to a significant decrease in drug availability within tumor parenchyma compared to the rest of the body.…”

“…CED relies on cannula implantation into tumor parenchyma; drug delivery relies on convection which, when compared to regular diffusion, is able to achieve higher drug concentrations over a larger volume. Further, convection is mostly independent of infusate properties (i.e., it is able to achieve high drug concentration over large volumes for both small and large molecules or biologic agents), as demonstrated in pioneering experiments in the 1990s [ 1 , 51 , 52 , 53 ]. By virtue of its properties, CED bypasses the blood–tumor barrier and achieves high intratumoral drug concentrations, with overall low body exposure to the infusate, thus limiting systemic side effects that have caused the failure of multiple clinical trials.…”