Citations

Précis: ASOCT features of greater bleb height, thicker bleb walls, and lower reflectivity are associated with trabeculectomy success, supporting the ASOCT’s utility in monitoring and predicting outcomes postsurgery through standardized imaging protocols. Purpose: To evaluate and quantify the relationship between bleb characteristics on ASOCT with surgical outcomes. Methods: A literature search was conducted across Medline, Embase, Cochrane, and Scopus for studies from the past 20 years, until 16 September 2024, on “glaucoma,” “trabeculectomy,” and “ASOCT.” Data collected included patient characteristics, each study’s definition of bleb success, clinical outcomes, as well as bleb characteristics. A literature review was conducted on studies that could not be used for meta-analysis. Results: Eleven studies, with a pooled total of 528 eyes in 517 patients, were included in the final meta-analysis. Successful blebs had significantly higher mean bleb height [mean difference (MD) 0.38 mm, 95% CI: 0.20-0.56 mm, P=0.002], greater maximum bleb wall thickness (MD: 0.21 mm, 95% CI: 0.07-0.35 mm, P=0.009), and decreased reflectivity (MD: −48.9%, 95% CI: −78.3 to −19.4%, P=0.010), compared with failed blebs. No significant differences were found in bleb fluid cavity height and bleb area. Narrative synthesis revealed that wider blebs, increased fluid-filled cavity height, increased number of microcysts, larger filtration opening widths, and multiform bleb walls were also associated with higher rates of bleb success. Early bleb parameters were statistically significant predictors of bleb success up to 12 months postoperatively. Conclusions: Greater bleb height, thicker bleb walls, and lower reflectivity on ASOCT are consistently associated with successful trabeculectomy outcomes. The ASOCT may be useful in predicting bleb success and in supplementing postoperative monitoring, hence guiding timely medical or procedural interventions, to ensure long-term bleb success.

Objective Present the rationale for the development of a new, patient-facing vital sign for adult hearing. Study Design Structured A3 process. Setting Fourteen virtual meetings and two in-person meetings held between May 2021 and June 2022. Main Outcome Measure(s) Identification and refinement of a countermeasure to develop and imbed a hearing health vital sign for adult hearing. Results Through a rigorous, structured A3 process, the Hearing Health Collaborative identified and refined the rationale for and the qualities associated with a public-facing vital sign for adult hearing loss. Specifically, such a vital sign must embody five qualities: simple, accessible, stable, inclusive, and meaningful. These qualities together would ensure that a hearing health vital sign would be useful not only as a screening tool but also as an instrument to guide next steps in workup and potentially treatment. Conclusions Successful identification and implementation of a hearing metric or “vital sign” for the presence of adult hearing loss, using precedent convention of other medical diseases, may help reframe public perceptions surrounding hearing loss, improve awareness and literacy regarding the presence of the disease, and prompt action to seek diagnostic assessment.

Ebola virus (EBOV) causes severe disease outbreaks in humans with high case fatality rates. EBOV requires adaptation to cause lethal disease in mice by acquiring single mutations in both the nucleoprotein (NP) and VP24 genes. As an attempt to model mouse-adapted EBOV (MA-EBOV), we engineered novel pentacistronic minigenomes (5xMG) containing a reporter gene, VP40, and glycoprotein genes as well as the NP and VP24 genes from either EBOV or MA-EBOV. The 5xMGs were constructed and optimized, and the produced transcription- and replication-competent virus-like particles (trVLPs) were demonstrated to infect several cell lines. Introduction of the mouse-adaptation mutations did not significantly impact the replication and transcription of the 5xMG or the relative infectivity of the trVLPs in vitro. This work demonstrates the development of the 5xMG system as a new versatile tool to study EBOV biology.

Abstract Single-cell sequencing technologies provide us with information at the level of individual cells. Combining single-cell RNA-seq and single-cell TCR-seq profiling enables the exploration of cell heterogeneity and T-cell receptor repertoires simultaneously. Integrating both types of data can play a crucial role in enhancing our understanding of T-cell-mediated immunity and, in turn, facilitate the advancement of immunotherapy. Here, we present immunopipe, a comprehensive and flexible pipeline to perform integrated analysis of scRNA-seq and scTCR-seq data. In addition to the command line tool, we provide a user-friendly web interface for pipeline configuration and execution monitoring, benefiting researchers without extensive programming experience. With its comprehensive functionality and ease of use, immunopipe empowers researchers to uncover valuable insights from scRNA-seq and scTCR-seq data, ultimately advancing the understanding of immune responses and immunotherapy development.

Abstract Purpose: Recent advances have seen the development of targeted therapeutics against the receptor tyrosine kinase (RTK)/RAS/MAPK pathway, which, when aberrantly activated, drives the malignant transformation of many cancer indications. However, the efficacy of inhibitors targeting single molecules is dampened by pathway feedback activation and acquired drug resistance. We seek to evaluate the application of JAB-3312 (sitneprotafib), a potent inhibitor of SHP2, in RTK/RAS/MAPK pathway–targeted combination therapies. Furthermore, SHP2 plays a vital role in PD-1–mediated immunosuppression. The rational combination of JAB-3312 with PD-1 blocking therapies is also explored. Experimental Design: Biochemical and cellular assays were applied to evaluate the potency of JAB-3312 in SHP2 inhibition. Tumor cell lines and cell line– and patient-derived xenografts were used to test different combinations of JAB-3312 with KRASG12C, MEK, EGFR, and PD-1 inhibitors. Results: JAB-3312 produced potent in vitro inhibition of SHP2 activity and downstream ERK phosphorylation, with IC50 values of 1.44 nmol/L and 0.68 to 4.84 nmol/L, respectively. When used in combination, JAB-3312 significantly increased the antitumor activity of the KRASG12C inhibitor glecirasib in naïve and resistant models. The combination of JAB-3312 with MEK inhibitors significantly delayed RTK signaling reactivation and enhanced tumor growth inhibition in KRAS-mutated cancer models. The JAB-3312–osimertinib combination exhibited great efficacy in osimertinib-resistant non–small cell lung cancer models. Additionally, JAB-3312 enhanced the efficacy of PD-1 blockade therapies by promoting an antitumor microenvironment. Representative cases of patients who responded to the combination therapies from two ongoing clinical trials (NCT05288205 and NCT04720976) were reported. Conclusions: JAB-3312 in combination with RTK/RAS/MAPK or PD-1 blockade therapies is a promising strategy that warrants further clinical investigation.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients. See related commentary by Anagnostou and Aggarwal, p. 1534