Citations

AbstractBackground and PurposePrevious studies have proposed multiple parallel channels for waste clearance from the brain, though many gaps remain in our understanding of these systems. In this study, we examined periarterial fluid drainage around intracranial and extracranial segments of the internal carotid arteries (ICAs) from the brain into the cervical lymph nodes using a noninvasive and clinical‐based method.MethodsEighty‐one subjects (45 females, aged 15‐80 years old) with nonlesioned epilepsy underwent high‐resolution 3‐dimensional T2‐weighted fluid‐attenuated inversion recovery (FLAIR) MRI. We utilized a noninvasive and clinical‐based method with a manual semiautomated approach to characterize the periarterial lymphatic system's maximum thickness and signal intensities along the ICAs using high‐resolution 3‐dimensional FLAIR imaging. We conducted group comparisons and correlation analyses to investigate sex‐ and age‐based trends. Results were corrected with Bonferroni's test for multiple comparisons, and we performed power analysis for sample size calculations.ResultsUsing high‐resolution FLAIR images, we show evidence that fluid drainage emerges around the ICA petrous segment and joins lymphatic flow from cranial nerves in the upper neck, with this flow ultimately draining into the cervical lymph nodes bilaterally. Lymphatic signal at the petrous segment level was significantly thinner in females compared to males bilaterally (w = 413, p = .0001 on the right, w = 356, p < .0001 on the left). Lymphatic drainage around the petrous segments of the ICAs bilaterally was thicker with age in males but not in females.ConclusionsWe describe the in vivo high‐resolution imaging characteristics of periarterial fluid drainage along the vessel walls of ICAs. This represents a potentially major channel for brain waste clearance. We also report interesting sex‐ and age‐based trends in these structures within our cohort.

Abstract PURPOSE: A subset of pediatric, adolescent and young adult (AYA) gliomas are located in the brainstem, eloquent locations, or present with diffuse/leptomeningeal disease, and are associated with high risk and low yield of biopsy. At the same time, accurate molecular diagnosis is necessary to direct optimal therapy. In such cases, analysis of cell free DNA (cfDNA) form cerebral spinal fluid (CSF) may represent a diagnostic alternative to biopsy. METHODS: We investigated the utility of CSF cfDNA sequencing through a stepwise approach, using clinically validated, targeted molecular assays. Testing was performed using a broad hybrid capture next generation sequencing assay (MSK-IMPACT) and subsequent targeted digital droplet PCR in a subset of cases. RESULTS: We analyzed 17 CSF samples from 17 pediatric (n=6) and AYA (n=11) glioma patients with primary or recurrent disease. Thirteen had tumors located within the brainstem, and four had leptomeningeal involvement. Somatic alterations were detected in 12/17 samples (71%). In 3/4 patients with leptomeningeal involvement, cfDNA testing revealed a BRAF fusion consistent with the diagnosis of diffuse leptomeningeal glioneuronal tumor (DLGNT). Among the 13 patients with brainstem involvement, four had somatic H3 K27M mutations, three had IDH mutations, and one had TP53 and ATRX mutations; five patients had no detectable mutations. CONCLUSION: In our analysis, we found that established glioma hotspot mutations were able to be detected within the CSF. We propose that in patients for whom tissue biopsy is high risk, not feasible, or tissue was nondiagnostic, CSF cfDNA sequencing has a substantial diagnostic yield and should be considered as a valuable novel diagnostic tool. Ongoing research is aiming to further increase the sensitivity of cfDNA testing, especially in patients with very low levels of CSF cfDNA.

Abstract Purpose177Lu-PSMA is a promising therapy for patients with metastatic castration resistant prostate cancer patients (mCRPC). To our knowledge, no study has compared the pharmacokinetic profiles of 177Lu-PSMA therapy delivered intra-arterially. We aimed to compare the feasibility and safety of selective intra-arterial (IA) administration vs conventional intravenous (IV) administration of 177Lu-PSMA in mCRPC. MethodsIn this within-patient pilot study, four patients (median age, 62.5; range, 53-72) with mCRPC who were referred to our clinic between January 2018 and September 2019 for treatment with 177Lu-PSMA. Patients were treated in two visits; in each visit receiving half of the total empiric therapeutic dose of 200 mCi, IV at the first visit and IA at the second visit. They were followed upto 8 weeks using routine parameters such as hematological status, renal function, and serum PSA levels. For each patient, organ biodistribution in lesions, kidneys, liver, bone marrow, prostate, and whole body was calculated for both administration routes according to the Medical Internal Radiation Dose (MIRD) schema. Mean absorbed doses (MAD) across all patients were compared between both administration routes. ResultsThe MAD of all metastatic lesions was significantly higher by IA vs IV administration (1.59 vs 1.20 MGy/MBq; p=0.024). The prostate gland had a lower MAD between IA and IV administrations, but the difference was not significant (0.27 vs 0.36 MGy/MBq; p=0.22). Patients tolerated IA administration very well without unexpected side effects. ConclusionThese preliminary results of an ongoing study showed that IA 177Lu-PSMA therapy is feasible and safe to treat metastatic lesions, potentially having a higher delivery efficacy compared to IV administration.This study is approved by Cerrahpasa Medical Faculty ethics committee on March 5, 2019 and retrospectively registered with file no: 83045809-604.01.02.

Key PointsIKZF1 associations with high-risk B-ALL may differ by age and sex. A novel variant on chromosome 14, rs189434316, is associated with over a 3.5-fold risk of normal cytogenetic B-ALL.