LAUSR

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG) are metastatic diseases, as demonstrated by early convection-enhanced delivery (CED) clinical trials in which prolonged local tumor control can sometimes be achieved, but fatal disseminated disease then develops. We hypothesize that improvements in treatment of both focal disease and the entire neuraxis are necessary for long-term survival, and patient-derived xenograft (PDX) models can help advance these efforts. METHODS We used a BT245 murine orthotopic DIPG PDX model for this work. We developed a protocol and specialized platform to deliver craniospinal irradiation (CSI) with a pontine boost. We separately compared intratumoral drug concentration by CED and intraperitoneal delivery. In our CED model, mice receive gemcitabine 60 ug x1 in 15 ul at 0.5 ul/minute through a stepped catheter design with silica tubing extending 2mm beyond a 27G needle. RESULTS Mice receiving CSI (4 Gy x2d) plus boost (4 Gy x2d) showed minimal spinal and brain leptomeningeal metastatic disease by bioluminescence, MRI, and pathology compared to mice receiving radiation to the pons only (4 Gy x4d) or no radiation. CED achieved an intratumoral gemcitabine concentration 50-fold greater than intraperitoneal dosing when controlled for dose. CONCLUSIONS In a DIPG PDX model, CSI+boost minimizes tumor dissemination compared to focal radiation, and CED achieves clinically significant improvements in intratumoral chemotherapy concentration compared to systemic delivery. Adding these modalities to current treatment could improve both focal and metastatic tumor control, leading to meaningful improvements in survival.