Longitudinal Monitoring of Circulating Tumor DNA to Assess the Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Genitourinary Malignancies.

PURPOSE: Circulating tumor DNA (ctDNA) detection in blood has emerged as a prognostic and predictive biomarker demonstrating improved assessment of treatment response in patients receiving immune checkpoint inhibitors (ICIs). Here, we performed a pilot study to support the role of ctDNA for longitudinal treatment response monitoring in patients with advanced genitourinary (GU) malignancies receiving ICIs. MATERIALS AND METHODS: Patients with histologically confirmed advanced GU malignancies were prospectively enrolled. All eligible patients received ICI treatment for at least 12 weeks, followed by serial collection of blood samples every 6-8 weeks and conventional scans approximately every 12 weeks until disease progression. ctDNA analysis was performed using Signatera, a tumor-informed multiplex-polymerase chain reaction next-generation sequencing assay. Overall, the objective response rate (ORR) was reported and its association with ctDNA status was evaluated. Concordance rate between ctDNA dynamics and conventional imaging was also assessed. RESULTS: ctDNA analysis was performed on 98 banked plasma samples from 20 patients (15 renal, four urothelial, and one prostate). The median follow-up from the time of initiation of ICI to progressive disease (PD) or data cutoff was 67.7 weeks (range, 19.6-169.6). The ORR was 70% (14/20). Eight patients ultimately developed PD. The overall concordance between ctDNA dynamics and radiographic response was observed in 83% (15/18) of patients. Among the three patients with discordant results, two developed CNS metastases and one progressed with extracranial systemic disease while ctDNA remained undetectable. CONCLUSION: In this pilot study, longitudinal ctDNA analysis for monitoring response to ICI in patients with advanced GU tumors was feasible. Larger prospective studies are warranted to validate the utility of ctDNA as an ICI response monitoring tool in patients with advanced GU malignancies.

Peripheral axon caliber and conduction velocity are decreased after burn injury in mice.

Peripheral neuropathies are reported to arise as a result of the systemic inflammatory response produced by a full-thickness cutaneous burn injury. This study was designed to characterize the magnitude and time course of functional and morphological changes in peripheral axons that arise after a full-thickness dermal burn injury in an animal model. A 20% body surface area (20% BSA) full-thickness dermal burn was applied to the back of C57BL6 female mice. Longitudinal H- and M-wave recordings were used to determine the conduction velocities (CV) of large myelinated motor and sensory axons in the tibial nerve of sham control and burn-injured mice. Motor CVs were significantly reduced from 6 h to 28 days after the burn, and sensory CVs were significantly reduced from 7 to 14 days after the burn. Morphological evaluation also showed that the mean caliber of large axons in tibial nerves and L5 ventral and dorsal roots in burned mice was significantly decreased. The results demonstrate that both functional and morphological deficits may be produced in peripheral nerve axons at sites well removed from a full-thickness dermal burn injury. The neural deficits may contribute to changes in neuromuscular transmission and the development of limb and respiratory muscle weakness that also accompany burn injury.