Magnetic Resonance Imaging during Proton Therapy Irradiation Allows for the Early Response Assessment of Pediatric Chordoma

Chordoma in pediatric patients is very rare. Proton therapy has become a gold standard in the treatment of these neoplasms, as high dose escalation can be achieved regarding the target while maximizing the sparing of the healthy tissues near the tumor. The aim of the work was to assess the evolution of morphological sequences during treatment using T1/T2-weighted magnetic resonance imaging (MRI) for the early response assessment of a classic chordoma of the skull base in a pediatric patient who had undergone surgical excision. Our results demonstrated a significant quantitative reduction in the residual nodule component adhered to the medullary bulb junction, with an almost complete recovery of normal anatomy at the end of the irradiation treatment. This was mainly shown in the T2-weighted MRI. On the other hand, the classic component of the lesion was predominantly present and located around the tooth of the axis. The occipital condyles were morphologically and dimensionally stable for the entire irradiation period. In conclusion, the application of this type of monitoring methodology, which is unusual during the administration of a proton treatment for chordoma, highlighted the unexpected early response of the disease. At the same time, it allowed the continuous assessment of the reliability of the treatment plan.

Plasma ctDNA Response Is an Early Marker of Treatment Effect in Advanced NSCLC

PURPOSE Plasma circulating tumor DNA (ctDNA) analysis is routine for genotyping of advanced non–small-cell lung cancer (NSCLC); however, early response assessment using plasma ctDNA has yet to be well characterized. MATERIALS AND METHODS Patients with advanced EGFR-mutant NSCLC across three phase I NCI osimertinib combination trials were analyzed in this study, and an institutional cohort of patients with KRAS-, EGFR-, and BRAF-mutant advanced NSCLC receiving systemic treatment was used for validation. Plasma was collected before treatment initiation and serially before each cycle of therapy, and key driver mutations in ctDNA were characterized by droplet digital polymerase chain reaction. Timing of plasma versus imaging response was compared in a separate cohort of patients with EGFR-mutant NSCLC treated with osimertinib. Across cohorts, we also studied ctDNA variability before treatment start. RESULTS In the NCI cohort, 14/16 (87.5%) patients exhibited ≥ 90% decrease in mutation abundance by the first on-treatment timepoint (20-28 days from treatment start) with minimal subsequent change. Similarly, 47/56 (83.9%) patients with any decrease in the institutional cohort demonstrated ≥ 90% decrease in mutation abundance by the first follow-up draw (7-30 days from treatment start). All 16 patients in the imaging cohort with radiographic partial response showed best plasma response within one cycle, preceding best radiographic response by a median of 24 weeks (range: 3-147 weeks). Variability in ctDNA levels before treatment start was observed. CONCLUSION Plasma ctDNA response is an early phenomenon, with the majority of change detectable within the first cycle of therapy. These kinetics may offer an opportunity for early insight into treatment effect before standard imaging timepoints.

Granzyme B nanoreporter for early monitoring of tumor response to immunotherapy

Despite recent advancements in cancer immunotherapy, accurate monitoring of its efficacy is challenging due to heterogeneous immune responses. Conventional imaging techniques lack the sensitivity and specificity for early response assessment. In this study, we designed a granzyme B (GrB) nanoreporter (GNR) that can deliver an immune checkpoint inhibitor to the tumor and track time-sensitive GrB activity as a direct way to monitor initiation of effective immune responses. Anti–programmed death-ligand 1 (PD-L1) antibody–conjugated GNRs inhibited PD-1/PD-L1 interactions efficiently and induced T cell–mediated GrB release that can be imaged using activatable imaging probe. GNRs enabled real-time immunotherapy response monitoring in a tumor-bearing mice model and distinguished between highly responsive and poorly responsive tumors. Furthermore, increasing doses resulted in a better response and enhanced sensitivity in poorly responsive tumors. These findings indicate that GNR has the potential to serve as a tool for sensitive and noninvasive evaluation of immunotherapy efficacy.