Background: The blood-brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A$$subscript$$2A$atsubscriptat$ receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A$$subscript$$2A$atsubscriptat$ receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma. Methods: Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m$$superscript$$2$atsuperscriptat$). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations. Results: Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h μg/ml for temozolomide alone and 16.6 ± 2.87 h μg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h μg/ml with temozolomide alone and 3.0 ± 1.7 h μg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and T$$subscript$$max$atsubscriptat$ in brain were not significantly different. Conclusions: Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.

Background: Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to thechallenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. Case presentation: We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. Conclusions: A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques.