Molecular testing for the clinical diagnosis of fibrolamellar carcinoma.

Fibrolamellar carcinoma has a distinctive morphology and immunophenotype, including cytokeratin 7 and CD68 co-expression. Despite the distinct findings, accurate diagnosis of fibrolamellar carcinoma continues to be a challenge. Recently, fibrolamellar carcinomas were found to harbor a characteristic somatic gene fusion, DNAJB1-PRKACA. A break-apart fluorescence in situ hybridization (FISH) assay was designed to detect this fusion event and to examine its diagnostic performance in a large, multicenter, multinational study. Cases initially classified as fibrolamellar carcinoma based on histological features were reviewed from 124 patients. Upon central review, 104 of the 124 cases were classified histologically as typical of fibrolamellar carcinoma, 12 cases as 'possible fibrolamellar carcinoma' and 8 cases as 'unlikely to be fibrolamellar carcinoma'. PRKACA FISH was positive for rearrangement in 102 of 103 (99%) typical fibrolamellar carcinomas, 9 of 12 'possible fibrolamellar carcinomas' and 0 of 8 cases 'unlikely to be fibrolamellar carcinomas'. Within the morphologically typical group of fibrolamellar carcinomas, two tumors with unusual FISH patterns were also identified. Both cases had the fusion gene DNAJB1-PRKACA, but one also had amplification of the fusion gene and one had heterozygous deletion of the normal PRKACA locus. In addition, 88 conventional hepatocellular carcinomas were evaluated with PRKACA FISH and all were negative. These findings demonstrate that FISH for the PRKACA rearrangement is a clinically useful tool to confirm the diagnosis of fibrolamellar carcinoma, with high sensitivity and specificity. A diagnosis of fibrolamellar carcinoma is more accurate when based on morphology plus confirmatory testing than when based on morphology alone

Current Neuroethical Perspectives on Deep Brain Stimulation and Neuromodulation for Neuropsychiatric Disorders: A Scoping Review of the Past 10 Years

Background: The use of neuromodulation for the treatment of psychiatric disorders has become increasingly common, but this emerging treatment modality comes with ethical concerns. This scoping review aims to synthesize the neuroethical discourse from the past 10 years on the use of neurotechnologies for psychiatric conditions. Methods: A total of 4496 references were imported from PubMed, Embase, and Scopus. The inclusion criteria required a discussion of the neuroethics of neuromodulation and studies published between 2014 and 2024. Results: Of the 77 references, a majority discussed ethical concerns of patient autonomy and informed consent for neuromodulation, with neurotechnologies being increasingly seen as autonomy enablers. Concepts of changes in patient identity and personality, especially after deep brain stimulation, were also discussed extensively. The risks and benefits of neurotechnologies were also compared, with deep brain stimulation being seen as the riskiest but also possessing the highest efficacy. Concerns about equitable access and justice were raised regarding the rise of private transcranial magnetic stimulation clinics and the current experimental status of deep brain stimulation. Conclusions: Neuroethics discourse, particularly for deep brain stimulation, has continued to focus on how post-intervention changes in personality and behavior influence patient identity. Multiple conceptual frameworks have been proposed, though each faces critiques for addressing only parts of this complex phenomenon, prompting calls for pluralistic models. Emerging technologies, especially those involving artificial intelligence through brain computer interfaces, add new dimensions to this debate by raising concerns about neuroprivacy and legal responsibility for actions, further blurring the lines for defining personal identity

LAIR-1 agonism as a therapy for acute myeloid leukemia

Effective eradication of leukemic stem cells (LSCs) remains the greatest challenge in treating acute myeloid leukemia (AML). The immune receptor LAIR-1 has been shown to regulate LSC survival; however, the therapeutic potential of this pathway remains unexplored. We developed a therapeutic LAIR-1 agonist antibody, NC525, that induced cell death of LSCs, but not healthy hematopoietic stem cells in vitro, and killed LSCs and AML blasts in both cell- and patient-derived xenograft models. We showed that LAIR-1 agonism drives a unique apoptotic signaling program in leukemic cells that was enhanced in the presence of collagen. NC525 also significantly improved the activity of azacitidine and venetoclax to establish LAIR-1 targeting as a therapeutic strategy for AML that may synergize with standard-of-care therapies