Brain tumors are one of the leading causes of cancer related death in both the adult and pediatric patient population. Gliomas represent a cohort of brain tumors derived from glial cell lineages which include astrocytomas, oligodendrogliomas and glioblastomas (GBMs). These tumors are known to grow aggressively and have a high lethality with GBM being the most aggressive tumor in this group. Currently, few treatment options exist for GBM outside of surgical resection, radiation therapy and chemotherapy. While these measures have been shown to marginally improve patient survival, patients, especially those diagnosed with GBM, often experience a recurrence of their disease. Following disease recurrence, treatment options become more limited as additional surgical resections can pose life threatening risk to the patient, patients may be ineligible for additional radiation, and the recurrent tumor may be resistant to chemotherapy. Immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer immunotherapy as many patients with cancers residing outside the central nervous system (CNS) have experienced a survival benefit from this treatment modality. It has often been observed that this survival benefit is increased following neoadjuvant administration of immune checkpoint inhibitors as tumor antigen is still present in the patient which enables a more robust anti-tumor immune response. Interestingly, results for ICI-based studies for patients with GBM have been largely disappointing which is a stark contrast from the success this treatment modality has had in non-central nervous system cancers. In this review, we will discuss the various benefits of neoadjuvant immune checkpoint inhibition such as how this approach reduces tumor burden and allows for a greater induction of an anti-tumor immune response. Additionally, we will discuss several non-CNS cancers where neoadjuvant immune checkpoint inhibition has been successful and discuss why we believe this approach may provide a survival benefit for GBM patients. We hope this manuscript will foster future studies aimed at exploring whether this approach may be beneficial for patients diagnosed with GBM.

Chordomas are a locally invasive, low-grade, CNS malignancy that are primarily found in the skull base, spine, and sacrum. They are thought to be derived from notochordal remnants and remain a significant clinical challenge due to their local invasiveness, resistance to chemoradiation, and difficulty in achieving a complete resection. Adjuvant therapy such as proton beam therapy is critical in preventing recurrence in patients who are at high risk, however this treatment is associated with increased risk of complication. Currently, intraoperative observation and imaging findings are used to determine recurrence and success of gross total resection. These methods can be unreliable due to limited operative view, bony and soft tissue involvement, and complex post-operative changes on MRI. Earlier detection of incomplete resection or recurrence will allow for earlier ability to intervene and potentially improve patient outcomes. Circulating-tumor DNA (ctDNA) is cell-free DNA that is released by tumor cells as they undergo cellular turn-over. Monitoring ctDNA has been shown to be more sensitive at predicting residual tumor than imaging in numerous solid malignancies. Furthermore, ctDNA could be detected earlier in peripheral blood as opposed to imaging changes, allowing for earlier intervention. In this review, we intend to give a brief overview of the current state of molecular diagnosis for skull base chordomas. We will then discuss current advances in the utilization of ctDNA for the management of CNS pathologies such as glioblastoma (GBM) and brain metastases. We will also discuss the role ctDNA has in the management of non-CNS pathologies such as osteosarcoma and Ewing sarcoma (EWS). Finally, we will discuss potential implications of ctDNA monitoring for chordoma management.