Citations

Abstract Background Fibroblast growth factor receptors inhibitors (FGFRi) are approved treatments for various malignancies. FGFRi-associated retinopathy is a class effect of FGFRi, including erdafitinib, pemigatinib, infigratinib, and rogaratinib. Patients and Methods We summarized FGFRi-associated retinopathy with erdafitinib across 5 clinical studies in patients with metastatic urothelial cancer (mUC pooled studies) and one study in patients with advanced solid tumors (RAGNAR). We also present changes in visual acuity, retinal pigment epithelial elevation, and subretinal fluid in RAGNAR. Results One hundred and three (21.5%) of 479 patients in the mUC pooled studies and 43/314 (13.7%) patients in RAGNAR experienced FGFRi-associated retinopathy. Most FGFRi-associated retinopathy were Grade 1/2 events. Grade 3 FGFRi-associated retinopathy were infrequent (mUC pooled studies, 11/479 [2.3%]; RAGNAR, 3/314 [1.0%]). No Grade 4 events occurred. Most FGFRi-associated retinopathy events (mUC pooled studies, 81/103 [78.6%]; RAGNAR, 30/43 [70.0%]) occurred within 90 days of treatment initiation and were managed with erdafitinib dose interruption (mUC pooled studies, 41/479 [8.6%]; RAGNAR, 23/314 [7.3%]) or reduction (mUC pooled studies, 58/479 [12.1%]; RAGNAR, 21/314 [6.7%]); few required treatment discontinuation (mUC pooled studies, 14/479 [2.9%]; RAGNAR, 3/314 [1.0%]). By the data cutoff, 63.1% (65/103) patients in the mUC pooled studies and 65.1% (28/43) patients in RAGNAR had their FGFRi-associated retinopathy events resolve. Most unresolved FGFRi-associated retinopathy events were persistent Grade 1 events. In RAGNAR, 92.0% of patients had their visual acuity return to baseline and 78.5% of patients had their retinal pigment epithelial elevation resolve. Conclusions FGFRi-associated retinopathy with erdafitinib can be managed with dose reductions, interruptions, or discontinuations. Proactive collaboration between oncologists and ophthalmologists is required to ensure that erdafitinib delivers clinical benefit to patients while managing their potential adverse symptoms of FGFRi-associated retinopathy.

ABSTRACT Objectives While maxillary sinus fungal balls (MSFB) can be associated with odontogenic conditions (MSFBO), MSFBO clinical and dental features have not been compared to odontogenic sinusitis (ODS). This multicenter study aimed to compare characteristics of MSFB, MSFBO, and ODS. Methods A multicenter international retrospective cohort study was conducted on adults with MSFBs and ODS who underwent sinus surgery. First in MSFBs, it was determined whether different dental conditions were more likely in FB versus non‐FB sides. Second, clinical features and dental pathologies were compared between MSFBO and ODS. For analyses, dental conditions were considered individually and as two groups: infectious pathologies and dental/oral procedures with indwelling metallic materials. Results After exclusions, there were 203 MSFBs and 163 ODS. Among MSFBs, 141 were MSFBOs. FB sides were associated with sinus protrusion of root canal treatment (RCT) materials ( p = 0.040) and dental implants ( p = 0.040). Compared to MSFBO, ODS patients were younger, more likely to have MS purulence (OR = 40.9, p < 0.010), more likely associated with apical periodontitis (OR = 2.59, p = 0.010) and oroantral fistulas (OR = 6.94, p = 0.020), and less likely associated with extruded RCT materials (OR = 0.01, p = 0.010) and protruded midface screws (OR < 0.01, p = 0.010). Comparing purulent MSFBO and ODS, ODS was more associated with infectious dental pathologies ( p < 0.009). Conclusion Compared to MSFBs, MSFBOs were associated with RCT extrusion and implant protrusion. Compared to MSFBOs, ODS was more likely purulent and associated with infectious dental pathologies. While ODS is often distinct from MSFBO, the two conditions can coexist, and surgeons must determine whether patients have infectious dental pathology requiring treatment with both conditions. Level of Evidence 4.

Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve and prevent vision loss leading to blindness. Rifampicin, a small-molecule antibiotic, has previously been reported to exhibit anti-angiogenic properties and a topical safety profile that is well-tolerated. Based on this evidence, we investigated the feasibility of formulating rifamycin as an ophthalmic drop capable of delivering therapeutic concentrations to the posterior segment of the eye. Methods: Inhibition of neovascularization by administration of rifampicin was analyzed in the rat oxygen-induced retinopathy (OIR) and mouse laser-induced choroidal neovascularization (CNV) models. Pharmacokinetic (PK) studies were conducted in mice, rats, and rabbits by dosing various formulations containing rifampicin, and the compound was quantified by LC/MS analysis. Results: Results from dose escalation studies in the mouse laser-induced CNV model suggested the minimum effective dose of rifampicin required for inhibiting neovascularization in subretinal tissues to be 0.7 mg/kg, which is substantially lower than the 20 mg/kg dosage approved for infectious disease treatments. The previous studies did not report the minimum effective dose in the anti-angiogenesis effects. The effective area under the concentration-time curve (AUC) in the sub-retina was evaluated as 0.27 h·ng/mg. In rabbits, rifampicin was delivered to the sub-retina by a single topical application of various formulations in a dose-dependent manner. The topical application of the formulations containing 1% rifampicin, which was well-tolerated in clinical trials previously reported for ocular trachoma, achieved subretinal delivery approximately 2–32 times greater than the effective AUC. Plasma exposure of the compound by the topical application was evaluated to range approximately 0.5–10 ng/mL. Conclusions: Rifampicin was delivered to the sub-retina in rabbits with an efficiency greater than the effective dose required for inhibiting neovascularization. Limited amounts of plasma exposure by the topical application were detected. These results suggested the therapeutic potential of the rifampicin formulations for the topical treatment of exudative macular degeneration.

INTRODUCTION: To assess strategies for optimizing participation of underserved minorities in a blood-based early colorectal cancer detection test study (PREEMPT CRC; NCT04369053) at a hospital serving primarily Black individuals. METHODS: Culturally sensitive, racially congruent research staff approached individuals undergoing average-risk screening colonoscopy. Consent/study procedures were synchronized with clinical appointments. Enrolled and not-enrolled patient characteristics were compared. Recruitment was compared with other study sites. RESULTS: In total, 247 of 509 eligible individuals were enrolled; most were identified as Black (88.7%). No baseline characteristics were associated with participation. Recruitment was high compared with other sites (11th centile). DISCUSSION: Recruitment barriers for Black individuals can be overcome when easy, culturally sensitive access is facilitated.

Purpose of review To review role of artificial intelligence in medicine. Recent findings Artificial intelligence is continuing to revolutionize access, diagnosis, personalization of medicine, and treatment in healthcare. As a matter of fact, artificial intelligence contributed to the research that resulted in 2024 Nobel Prizes in physics, chemistry, and economics. We are only at the tip of the iceberg in utilizing the abilities of artificial intelligence in medicine to improve accuracy of diagnoses and to enhance patient outcomes. Artificial intelligence has allowed better image analysis, prediction of progression of disease, personalized treatment plans, incorporations of genomics, and improved efficiency in care and follow-up utilizing home monitoring. In ocular health diagnosis and treatment of diabetic retinopathy, macular degeneration, glaucoma, corneal infections, and ectasia are only a few examples of how the power of artificial intelligence has been harnessed. Even though there are still challenges that need more work in the areas of patient privacy, Health Insurance Portability and Accountability Act (HIPAA) compliance, reliability, and development of regulatory frameworks, artificial intelligence has revolutionized and will continue to revolutionize medicine. Summary Artificial intelligence is enhancing medical diagnosis and treatment, as well as access and prevention. Ocular imaging, visual outcome, optics, intraocular pressure, and data points will continue to see growth it the field of artificial intelligence.

A substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. We showed that this unfavorable group displays increased expression of IRF4, dysregulated immune signaling and an immunosuppressive microenvironment. At the molecular level, IRF4 controls expression of antigen presentation and immune molecules (e.g. HLA-DR, CD40, PDL1). Furthermore, silencing of IRF4 triggers anti-lymphoma immunity ( Mondello P et al, Blood 2022;140 Suppl 1:168-169). However, little is known on the molecular mechanisms whereby IRF4 controls the crosstalk between B and T cells. To address this question, first we performed RNA-seq, ATAC-seq and CUT&TAG of active (H3K27Ac, H3K4me3) and repressive (H3K27me3, H3K4me1) histone marks in TMD8 and HBL1 (lymphoma cells with high IRF4 expression) transfected with two pairs of siIRF4 or siCtr for 72 hours. Gene expression revealed a broad change in transcription, with 432 upregulated genes and 136 downregulated genes in siIRF4 compared to siCtr. Notably, the genes with increased expression following IRF4 silencing coded for antigen presentation, immune molecules and cytokines (e.g. HLA-DR, CD86, IL6, IL10). Accordingly, we observed significant enrichment of antigen presentation, interferon and immune response signatures ( Fig 1A). Integrating RNA-seq with chromatin accessibility showed a significant shift towards transcriptional upregulation at genes nearest to upregulated ATAC peaks, with significant enrichment at enhancers (n=771). Conversely, transcriptional suppression was enriched at enhancers (n=2,458) of downregulated peaks. k-means analyses of all union peaks, generated by merging ATAC with CUT&TAG peaks, revealed a significant gain of H3K4me3, with concordant loss of H3K4me1 at enhancers with upregulated gene expression. In contrast, H3K4me3 was severely decreased at suppressed peaks. TF motif analysis revealed an enrichment for PU.1 and E2A at IRF4-bound regions, suggesting their cooperation in regulating immune signaling. Since antigen presentation and other immune molecules are critical components of the immune synapse, we explored the role of IRF4 on the interaction between germinal center (GC) B and T cells by crossing irf4 fl/fl mice with conditional deletion of irf4 ( Klein et al, Nat Immunol 2006) and Cγ 1cre mice ( Cγ 1cre; irf4 fl/fl) to induce recombination in GC B cells. After 10 days of immunization (GC reaction peak), Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cells showed significant increase of HLA-DR and CD40 expression compared to WT. As expected, Cγ 1cre; irf4 fl/fl mice displayed a significantly skewed light-zone:dark-zone ratio in favor of increased dark-zone, which are the cells that most reflect the action of BCL6, with concordant suppression of plasma cells. Additionally, we observed a significant increase of CD4 + T cells after partial or complete deletion of irf4, with upregulation of T FH cells and decrease of T reg cells ( Fig 1B). Notably, mice with loss of irf4 showed a significant decrease in exhausted T FH cells. To test if this effect was dependent on MHC:TCR interaction, we cocultured CD4 + T cells with TMD8 cells transfected with two siIRF4 or siCtr in presence of blocking antibodies for MHC class I, MHC class II or both. Blocking one or the other MHC class I or II partially rescued the IRF4 effect on T reg and T FH cells respectively as well as reduced anti-lymphoma cytotoxicity. Further experiments blocking IRF4-dependent IL6 and IL10 identified these two cytokines as responsible for the additional effects on T cells. To confirm this as an antigen-dependent immune response we coculture sorted GC B cells from NP-OVA-immunized Cγ 1cre; irf4 fl/fl, Cγ 1cre; irf4 fl/+ and WT mice with CSFE-labeled OVA-specific OT-II CD4 + T cells at a ratio of 2:1 in an organoid system for 5 days. We observed induced antigen specific proliferation of CD4 + T cells in the presence of Cγ 1cre; irf4 fl/fl and Cγ 1cre; irf4 fl/+ GC B cellscompared to WT,as indicated by decrease in CSFE expression . We confirmed an increase of T FH cells and a decrease of T reg cells, supporting the conclusion that IRF4 directly controls the antigen-dependent immune response . In summary, IRF4 expression in GC and lymphoma B cells regulates immune signaling with PU.1 and E2A, thereby modulating antigen-dependent immune responses with potential implications for lymphomagenesis. Future studies investigating targeting of IRF4 in lymphoma are warranted.

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.

Abstract Recurrent chromosomal rearrangements are a hallmark of hematologic malignancies and play critical roles in pathogenesis. The TP53 analog TP63 is rearranged in 5-10% of diverse subtypes of both aggressive T- and B-cell lymphomas. Patients with TP63-rearranged lymphomas have dismal outcomes, with 5-year overall survival rates between 0-17%, depending on cohorts. The function and mechanisms of TP63 rearrangements and TP63 fusion proteins in tumorigenesis are poorly understood. As a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to understand how TP63 fusions contribute to tumorigenesis and to translate the findings into novel therapeutic options for these patients. Here, we demonstrated that TP63 fusions are essential for the propagation of T-cell lymphomas (TCLs). Knockdown of TP63 fusions with specific shRNAs in TCL cell lines harboring TP63 fusions suppressed both cell growth in vitro and tumor growth in vivo. Retroviral expression of TBL1XR1-TP63, the most common TP63 fusion, conferred cytokine independence in Ba/F3 cells, consistent with its role as an oncogene. To investigate the role of TP63 fusions in T- and B-cell lymphomagenesis, we engineered a CAG-Loxp-Stop-Loxp-TBL1XR1-TP63 conditional knock-in mouse model and crossed with hCD2-Cre mice. This results in expression beginning during early lymphoid development. As observed in patients, transgenic mice developed multiple subtypes of both T- and B-cell lymphoma. To define the effects and mechanisms of TP63 fusions within T cells, we performed CRISPR scanning, transcriptomic, epigenomic, and proteomic analyses. Our data showed that domains within both the N-terminal TBL1XR1 and C-terminal TP63 portions contribute to the function of this fusion. We found that the N-terminal component of TP63 fusions interacts with components of the NCOR/SMRT complex. At the same time, the C-terminal portion of TP63 (which recapitulates the deltaN-p63 isoform expressed in some carcinomas) interacts with the enhancer modifier KMT2D and its complex members. TBL1XR1-TP63 binds to a novel distal enhancer to drive MYC expression, and thus upregulates the expression of the histone H3K27 methylase EZH2. Finally, we assessed whether EZH2 is a vulnerability of TP63-rearranged lymphomas. We found that knockdown of EZH2 in TP63-rearranged lines significantly impaired cell growth, as did treatment with the EZH2 and 1 dual inhibitor valemetostat. Valemetostat, which is now being tested in patients with lymphoma, counteracted the oncogenic effects of TP63 fusions in multiple preclinical models in vivo. Together, our results identify the TP63 fusion as a highly unique oncogenic driver in lymphomagenesis capable of recruiting multiple epigenetic modifier complexes and inducing a targetable dependence on EZH2. Citation Format: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla Heavican-Foral, Huiyun Liu, Geoffrey Nelson, Lu Yang, Renee Chen, Katherine Donovan, Marcus Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit Nirmal, Salvia Jain, Catharine Leahy, Kristen Jones, Kristen Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing Chan Chan, Shannan Ho Sui Ho Sui, Samuel Ng, Andrew Feldman, Steven M. Horwitz, Mathew Meyerson, Karen Adelman, Eric Fischer, Chun-Wei Chen, David Weinstock, Myles Brown. TP63 fusions drive enhancer rewiring, lymphomagenesis, and dependence on EZH2. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5755.

Abstract More than 6 million adults in the United States are affected by Alzheimer’s Disease and related dementias (ADRD), the majority of whom rely on assistance from an unpaid caregiver (family, friends). The goal of the 2021 Conference on Engaging Family and Other Unpaid Caregivers of Persons with Dementia in Healthcare Delivery, funded by the National Institute on Aging, was to establish a policy- and practice-aligned research agenda for enhancing ADRD caregiver engagement and support in healthcare settings. The Conference convened multidisciplinary thought leaders from across the United States to establish a set of actionable recommendations to advance the field. Recommendations centered on five key topics: 1) Identification and assessment of ADRD caregivers, 2) Reimbursement and financing for provider time spent on ADRD caregiver, identification, assessment, and support, 3) ADRD caregiver training and support, 4) Healthcare provider education, and 5) Technology. To support future work in each of the five priority areas, conference participants highlighted the importance of leveraging lessons from implementation science and models of equity and inclusion. Recommendations are intended to inform federal agencies and foundations about high-priority areas and motivate multidisciplinary collaborations to design care delivery systems that effectively engage and support ADRD caregivers.