Yttrium-90 Radioembolization to the Prostate Gland: Proof of Concept in a Canine Model and Clinical Translation.

PURPOSE: To investigate the feasibility, safety, and absorbed-dose distribution of prostatic artery radioembolization (RE) in a canine model. MATERIALS AND METHODS: Fourteen male castrated beagles received dihydroandrosterone/estradiol to induce prostatic hyperplasia for the duration of the study. Each dog underwent fluoroscopic prostatic artery catheterization. Yttrium-90 (90Y) microspheres (TheraSphere; Boston Scientific, Marlborough, Massachusetts) were delivered to 1 prostatic hemigland (dose escalation from 60 to 200 Gy), with the contralateral side serving as a control. Assessments for adverse events were performed throughout the follow-up (Common Terminology Criteria for Adverse Events v5.0). Positron emission tomography/magnetic resonance (MR) imaging provided a confirmation after the delivery of absorbed-dose distribution. MR imaging was performed before and 3, 20, and 40 days after RE. Tissue harvest of the prostate, rectum, bladder, urethra, penis, and neurovascular bundles was performed 60 days after RE. RESULTS: All the animals successfully underwent RE. Positron emission tomography/MR imaging demonstrated localization to and good coverage of only the treated hemigland. No adverse events occurred. The MR imaging showed a significant dose-dependent decrease in the treated hemigland size at 40 days (25%-60%, P < .001). No extraprostatic radiographic changes were observed. Necropsy demonstrated no gross rectal, urethral, penile, or bladder changes. Histology revealed RE-induced changes in the treated prostatic tissues of the highest dose group, with gland atrophy and focal necrosis. No extraprostatic RE-related histologic findings were observed. CONCLUSIONS: Prostate 90Y RE is safe and feasible in a canine model and leads to focal dose-dependent changes in the gland without inducing unwanted extraprostatic effects. These results suggest that an investigation of nonoperative prostate cancer is warranted.

5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder.

Autism spectrum disorders (ASDs) include a group of syndromes characterized by impaired language, social and communication skills, in addition to restrictive behaviors or stereotypes. However, with a prevalence of 1.5% in developed countries and high comorbidity rates, no clear underlying mechanism that unifies the heterogeneous phenotypes of ASD exists. 5-hydroxymethylcytosine (5hmC) is highly enriched in the brain and recognized as an essential epigenetic mark in developmental and brain disorders. To explore the role of 5hmC in ASD, we used the genomic DNA isolated from the postmortem cerebellum of both ASD patients and age-matched controls to profile genome-wide distribution of 5hmC. We identified 797 age-dependent differentially hydroxymethylated regions (DhMRs) in the young group (age ≤ 18), while no significant DhMR was identified in the groups over 18 years of age. Pathway and disease association analyses demonstrated that the intragenic DhMRs were in the genes involved in cell-cell communication and neurological disorders. Also, we saw significant 5hmC changes in the larger group of psychiatric genes. Interestingly, we found that the predicted cis functions of non-coding intergenic DhMRs strikingly associate with ASD and intellectual disorders. A significant fraction of intergenic DhMRs overlapped with topologically associating domains. These results together suggest that 5hmC alteration is associated with ASD, particularly in the early development stage, and could contribute to the pathogenesis of ASD.

Classification and Management Considerations for Intraosseous Dural Arteriovenous Fistulae.

BACKGROUND: Intraosseous dural arteriovenous fistulas (IODAVFs) are rare DAVFs that communicate with marrow. Given their infrequency, common nomenclature is nonexistent. Patients may present with benign symptoms, such as tinnitus, or venous hypertension symptoms including hemorrhage depending on the venous outflow pattern. OBJECTIVE: To describe all available cases of IODAVF in the literature, in addition to our cases, to better define presentation, and treatment outcomes. To advance a classification system to develop common language for these lesions for clinicians and researchers. METHODS: Neurointerventional procedure logs at 2 high-volume neurovascular centers were reviewed for all cases of IODAVFs, as was the English-based literature available in PubMed. The angioarchitecture, symptoms, management, and demographics were reviewed and summarized. RESULTS: Four institutional cases were identified, 2 of which had shunting within the marrow (clival or petrous), with venous drainage toward the heart. One case involved the dorsum sella with drainage into the superior petrosal sinus with reflux into the anterior and posterior spinal venous plexuses, and one involved the left petroclival junction, resulting in communication with the cavernous sinus with retrograde drainage into the superior ophthalmic veins. Two patients were managed by observation, one was treated with radiosurgery and one with microsurgical skeletonization. Twenty additional cases from the literature are summarized. CONCLUSION: IODAVFs of the cerebrocranial vasculature may present incidentally, with tinnitus, or with symptoms related to mass effect or venous hypertension. We propose a classification which accounts for drainage patterns. Further study is needed for these rare lesions.

Clinical Outcomes and Safety Comparison of Vertebroplasty, Balloon Kyphoplasty, and Vertebral Implant for Treatment of Vertebral Compression Fractures.

BACKGROUND AND PURPOSE: Vertebral compression fracture represents a major health burden for the aging populations globally. However, limited studies exist on the relative efficacy and safety of surgical interventions for vertebral compression fracture. Here, we aim to compare clinical and patient-reported outcomes following vertebral augmentation using balloon kyphoplasty, vertebroplasty, and SpineJack vertebral implant. MATERIALS AND METHODS: An institutional review board-approved, retrospective, multi-institutional review of patients undergoing vertebral augmentation with kyphoplasty, vertebroplasty, and/or a SpineJack vertebral implant was performed between 2018 and 2021. Primary outcomes included pre- and postprocedural pain ratings and vertebral body height restoration. The secondary outcome was a change in the local kyphotic angle. The Kruskal-Wallis test was used to compare outcomes across 3 treatment options. Complications were reviewed during and 30-90 days after the procedure. RESULTS: Vertebral augmentation of 344 vertebral compression fracture levels was performed during the study period. Sixty-seven patients had 79 kyphoplasty procedures (55% women; mean age, 64.2 [SD, 12.3] years). Seventy-four patients underwent a mean of 84 vertebroplasty procedures (51% women; mean age, 63.5 [SD, 12.8] years), and 61 patients had a mean of 67 SpineJack vertebral implant procedures (57.4% women; mean age, 68.3 [SD, 10.6] years). Following kyphoplasty, vertebroplasty, and SpineJack vertebral implant, pain scores improved significantly (P < .001). Resting pain improvement was similar across the 3 procedures, whereas improvement of "worst pain" was significantly better following a SpineJack vertebral implant compared with kyphoplasty and vertebroplasty (P < .001). Patients with a SpineJack vertebral implant had greater improvement in vertebral body height restoration and local kyphotic angle compared with those undergoing kyphoplasty and vertebroplasty. Adjacent level fractures (6.7% incidence) occurred similarly in the 3 procedure types. There were no other peri- or postoperative complications. CONCLUSIONS: The SpineJack vertebral implant showed equivalent pain improvement compared with vertebroplasty and kyphoplasty, but it had superior vertebral body height restoration and local kyphotic angle improvement. This study supports the SpineJack vertebral implant as a safe and effective alternative (adjunct) for vertebral augmentation, especially in patients with moderate-to-severe vertebral compression fractures for greater improvement in vertebral body height restoration.

Clinical outcomes and safety of the SpineJack vertebral augmentation system for the treatment of vertebral compression fractures in a United States patient population.

The SpineJack implant system was recently FDA approved for treatment of vertebral compression fractures (VCF), however United States-based outcomes data is lacking. We sought to examine the safety and clinical outcomes following vertebral augmentation using the SpineJack implant for treatment of VCF in a U.S. patient population. An IRB-approved, retrospective study of SpineJack implants used in vertebral augmentation was performed from 11/2018 to 2/2020. Outcome objectives included pain improvement, vertebral body height (VH) restoration, improvement in local kyphotic angle (LKA), and incidence of adjacent level fractures (ALF). Complications were reviewed to assess safety of the procedure. Thirty patients with VCF (60% female; mean [SD] age of 62.7 [±12.8] years) underwent a total of 53 vertebral augmentations with 106 SpineJack implants. Worst pain scores decreased significantly from 8.7 to 4.3 (95%CI of the change [Δ]: 4.3-4.4; p < 0.001). Middle and anterior VH significantly increased from 13.1 ± 0.2 to 15.9 ± 0.2 mm (95%CI Δ: 2.6-2.9 mm; p < 0.001) and 15.6 ± 0.2 to 16.8 ± 0.2 mm (95%CI Δ: 1.1-1.4 mm; p < 0.001), respectively. LKA was significantly decreased from 10.0 ± 2.1 to 7.4 ± 2.1 degrees (95%CI Δ: 2.4-2.8 degrees; p < 0.001). Four patients (13%) sustained ten ALF over a median (IQR) follow up period of 94 (17.5-203) days. There were no major adverse events during the follow up period. To summarize, vertebral augmentation with SpineJack implants of patients with VCF resulted in significantly decreased pain, restored VH, and improved LKA, without major adverse events. However, 13% of patients sustained ALF during a median follow up period of 3 months.

Yttrium-90 radioembolization as a possible new treatment for brain cancer: proof of concept and safety analysis in a canine model.

PURPOSE: To evaluate the safety, feasibility, and preliminary efficacy of yttrium-90 (90Y) radioembolization (RE) as a minimally invasive treatment in a canine model with presumed spontaneous brain cancers. MATERIALS: Three healthy research dogs (R1-R3) and five patient dogs with spontaneous intra-axial brain masses (P1-P5) underwent cerebral artery RE with 90Y glass microspheres (TheraSphere). 90Y-RE was performed on research dogs from the unilateral internal carotid artery (ICA), middle cerebral artery (MCA), and posterior cerebral artery (PCA) while animals with brain masses were treated from the ICA. Post-treatment 90Y PET/CT was performed along with serial neurological exams by a veterinary neurologist. One month after treatment, research dogs were euthanized and the brains were extracted and sent for microdosimetric and histopathologic analyses. Patient dogs received post-treatment MRI at 1-, 3-, and 6-month intervals with long-term veterinary follow-up. RESULTS: The average absorbed dose to treated tissue in R1-R3 was 14.0, 30.9, and 73.2 Gy, respectively, with maximum doses exceeding 1000 Gy. One month after treatment, research dog pathologic analysis revealed no evidence of cortical atrophy and rare foci consistent with chronic infarcts, e.g., < 2-mm diameter. Absorbed doses to masses in P1-P5 were 45.5, 57.6, 58.1, 45.4, and 64.1 Gy while the dose to uninvolved brain tissue was 15.4, 27.6, 19.2, 16.7, and 33.3 G, respectively. Among both research and patient animals, 6 developed acute neurologic deficits following treatment. However, in all surviving dogs, the deficits were transient resolving between 7 and 33 days post-therapy. At 1 month post-therapy, patient animals showed a 24-94% reduction in mass volume with partial response in P1, P3, and P4 at 6 months post-treatment. While P2 initially showed a response, by 5 months, the mass had advanced beyond pre-treatment size, and the dog was euthanized. CONCLUSION: This proof of concept demonstrates the technical feasibility and safety of 90Y-RE in dogs, while preliminary, initial data on the efficacy of 90Y-RE as a potential treatment for brain cancer is encouraging.

Correction to: Yttrium-90 radioembolization as a possible new treatment for brain cancer: proof of concept and safety analysis in a canine model.

An amendment to this paper has been published and can be accessed via the original article.

Induced Pluripotent Stem Cells: Generation Strategy and Epigenetic Mystery behind Reprogramming.

Possessing the ability of self-renewal with immortalization and potential for differentiation into different cell types, stem cells, particularly embryonic stem cells (ESC), have attracted significant attention since their discovery. As ESC research has played an essential role in developing our understanding of the mechanisms underlying reproduction, development, and cell (de)differentiation, significant efforts have been made in the biomedical study of ESC in recent decades. However, such studies of ESC have been hampered by the ethical issues and technological challenges surrounding them, therefore dramatically inhibiting the potential applications of ESC in basic biomedical studies and clinical medicine. Induced pluripotent stem cells (iPSCs), generated from the reprogrammed somatic cells, share similar characteristics including but not limited to the morphology and growth of ESC, self-renewal, and potential differentiation into various cell types. The discovery of the iPSC, unhindered by the aforementioned limitations of ESC, introduces a viable alternative to ESC. More importantly, the applications of iPSC in the development of disease models such as neurodegenerative disorders greatly enhance our understanding of the pathogenesis of such diseases and also facilitate the development of clinical therapeutic strategies using iPSC generated from patient somatic cells to avoid an immune rejection. In this review, we highlight the advances in iPSCs generation methods as well as the mechanisms behind their reprogramming. We also discuss future perspectives for the development of iPSC generation methods with higher efficiency and safety.