RESUMO
Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.
RESUMO
BACKGROUND: The mainstay of treatment for cerebellar pilocytic astrocytomas in the pediatric population is surgery. The use of intraoperative magnetic resonance imaging (iMRI) as a surgical adjunct may lower the likelihood of reoperation. Studies have examined iMRI in heterogenous tumor populations, but few have looked at single pathologies. OBJECTIVE: To compare iMRI vs non-iMRI for hemispheric cerebellar pilocystic astrocytomas, specifically looking at revision surgeries and residual disease in follow-up. METHODS: Retrospective review of medical records for 60 sequential patients with cerebellar hemispheric pilocytic astrocytoma at a single institution was conducted. Thirty-two patients with cerebellar pilocytic astrocytoma underwent surgery without iMRI, whereas 28 patients underwent surgical resection with iMRI. All patients had at least 3-year follow-up. RESULTS: There were no significant differences between the patient populations in age, tumor size, or need for cerebrospinal fluid diversion between groups. Operative time was shorter without iMRI (without iMRI 4.4 ± 1.3 hours, iMRI 6.1 ± 1.5, P = .0001). There was no significant difference in the patients who had repeat surgery within 30 days (9% without iMRI, 0% iMRI, P = .25), residual disease at 3 months (19% without iMRI, 14% iMRI, P = .78), or underwent a second resection beyond 30 days (9% without iMRI, 4% iMRI, P = .61). There were more total reoperations in the group without iMRI, although this did not reach significance (19% vs 4%, P = .11). CONCLUSION: For hemispheric cerebellar pilocytic astrocytomas, iMRI tended to leave less residual and fewer reoperations; however, neither of these outcomes achieved statistical significance leaving utilization to be determined by the surgeon.
