PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.

MR monitoring of NaCl-enhanced radiofrequency ablations: observations on low- and high-field-strength MR images with pathologic correlation.

PURPOSE: To test the hypothesis that magnetic resonance (MR) imaging can be used to monitor both intraparenchymal injection of NaCl solution and subsequent radiofrequency ablation (RFA) within tissues pretreated with NaCl, report the low- and high-field-strength MR appearance of NaCl-enhanced RFAs, and compare MR findings with pathologic findings. MATERIALS AND METHODS: Ten ex vivo calf liver specimens were injected with saturated NaCl (seven were mixed with methylene blue during MR fluoroscopic monitoring) and reexamined with fast imaging with steady-state progression (FISP), true FISP, reversed FISP (PSIF), and fast spin-echo T2-weighted MR sequences. The NaCl-to-liver contrast-to-noise ratio (CNR) was calculated for various sequences, and CNRs were compared with the Student t test. Distribution on MR images was compared with the results of pathologic analysis. Forty additional in vivo monopolar RFAs were performed in paraspinal muscles of seven minipigs after animal care committee approval (10 standard control ablations, 30 were preceded by direct injection of saturated NaCl at various volumes [3-9 mL] and rates [1 or 6mL/min]). Postablation low-field-strength (n = 20) and high-field-strength (n = 20) MR examinations consisted of T2-weighted imaging, short inversion time inversion-recovery (STIR) imaging, and contrast material-enhanced T1-weighted imaging. Ablation shape, conspicuity, volume, and signal intensity were compared between the two groups and with the results of pathologic analysis. The difference in volumes with and without NaCl injection was evaluated by using two-way analysis of variance. RESULTS: Mean CNR was highest on fast spin-echo T2-weighted images and was significantly higher for PSIF than for FISP (P < .0001) or true FISP (P = .003). NaCl distribution on MR images corresponded with the results of pathologic analysis in ex vivo livers. Interactive in vivo monitoring of NaCl injection and electrode placement was feasible. NaCl-enhanced ablations had irregular shapes, a higher CNR, and significantly larger volumes (F = 22.0; df = 1, 90; P < .00001). All ablations had intermediate or low signal intensity with high-signal-intensity rims on all images. Fluid signals overlaid NaCl-enhanced ablations on fast spin-echo T2-weighted and STIR images, particularly on high-field-strength MR images. CONCLUSION: MR imaging can be used to reliably monitor the distribution of injected NaCl solution in tissues. Interventional MR imaging techniques can be used to guide and monitor RFAs within NaCl pretreated tissues, with good correlation with pathologic results.

Dynamics of MRI-Guided thermal ablation of VX2 tumor in paraspinal muscle of rabbits.

This study combines fast magnetic resonance imaging (MRI) and model simulation of tissue thermal ablation for monitoring and predicting the dynamics of lesion size for tumor destruction. In vivo experiments were conducted using radiofrequency (RF) thermal ablation in paraspinal muscle of rabbit with a VX2 tumor. Before ablation, turbo-spin echo (TSE) images visualized the 3-D tumor (necrotic core and tumor periphery) and surrounding normal tissue. MR gradient-recalled echo (GRE) phase and magnitude images were acquired repeatedly in 3.3 s at 30-s intervals during and after thermal ablation to follow tissue temperature distribution dynamics and lesion development in tumor and surrounding normal tissue. Final lesion sizes estimated from GRE magnitude, post-ablation TSE, and stained histologic images were compared. Model simulations of temperature distribution and lesion development dynamics closely corresponded to the experimental data from MR images in tumor and normal tissue. The combined use of MR image monitoring and model simulation has the potential for improving pretreatment planning and real-time prediction of lesion-size dynamics for guidance of thermal ablation of tumors.