Citations

Objectives: To summarize the current evidence for radiation therapy (RT) in the prevention and treatment of heterotopic ossification (HO), including patient selection, optimal RT technique, and associated risks. Methods: This multispecialty-led committee includes radiation oncologists, rheumatologists, orthopedic surgeons, and physical medicine/rehabilitation physicians. Using the population, intervention, comparator, outcome, timing and study design (PICOTS) framework, evidence regarding treatment outcomes was assessed using Cochrane and PRISMA methodology. Eligible studies included prospective and retrospective studies published between January 1, 1980, and November 1, 2025, from Embase, Medline, and PubMed databases. Of the 197 articles identified using the search strategy, 83 were selected for inclusion as evidence, including 27 well-designed studies (phase II randomized and phase III), 16 moderately well-designed studies that account for most common biases (matched cohort and phase II studies), 31 studies with design limitations (retrospective reviews), 2 supplemental studies (not useful as primary evidence), and 7 meta-analyses. Additional studies were included to provide context and were not used to guide recommendations. Well-established RAND-UCLA consensus methodology (modified Delphi) was used to rate the appropriateness of the treatment options. Results: The results of this analysis demonstrate that in appropriately selected patients, RT is an effective and safe therapy for prophylaxis of HO formation. Conclusions: This systematic review provides consensus guidelines for the use of RT as prophylaxis of HO based on current peer-reviewed evidence in the literature.

Abstract Background: Antigen receptor stimulation induces assembly of the CARMA1-BCL10-MALT1 (CBM) signaling complex, which leads to activation of downstream transcriptional regulators including NF-κB and subsequent lymphocyte activation. Gain-of-function mutations in B-cell receptor subunits, CARMA1, or BCL10 which lead to constitutive activation of MALT1 underly the pathogenesis of multiple lymphoid malignancies, including activated B-cell–type diffuse large B-cell lymphoma (ABC-DLBCL). During previous efforts to identify regulators of MALT1 activity in lymphocytes, we discovered that G-protein-coupled receptor kinase 2 (GRK2) binds to MALT1, inhibits MALT1 scaffolding and proteolytic activities, and functions as a tumor suppressor in MALT1-dependent lymphomas. Notably, GRK2 mRNA expression is markedly lower in a subset of DLBCL tumors in comparison to normal B cells and lower GRK2 is associated with decreased patient survival in ABC-DLBCL. In light of these findings, we investigated the molecular mechanisms regulating GRK2 expression and then characterized the roles of specific GRK2-targeting miRNAs in ABC-DLBCL. Methods and Results: After finding that global impairment of miRNA processing through DICER1 depletion leads to increased GRK2 protein, we conducted bioinformatic analyses of patient tumor samples and microRNA Data Integration Portal screening to identify candidate microRNAs that target GRK2 in ABC-DLBCL. Direct targeting of GRK2 by candidate miRNAs was then confirmed by GRK2 3’UTR reporter assay. We tested for expression of three candidate microRNAs in ABC-DLBCL cells and observed elevated expression in both OCI-LY3 and TMD8 cells, which exhibited reduced GRK2 mRNA expression compared with primary B cells. Inhibition of candidate miRNAs in ABC-DLBCL cells, using anti-miRNA Locked Nucleic Acids (LNA) inhibitors, led to enhanced GRK2 expression, reduced MALT1 activity and decreased cell proliferation. Conversely, stable overexpression of candidate microRNAs led to reduced GRK2 expression, enhanced MALT1 activity and increased cell proliferation. In vivo, treatment of mice with inhibitors of candidate microRNAs abrogates the growth of ABC-DLBCL xenograft tumors. Conclusion: We have identified three miRNAs that negatively regulate GRK2 expression in ABC-DLBCL. By targeting GRK2 for downregulation, these miRNAs promote MALT1 oncoprotein scaffold and protease activities. Furthermore, inhibitors of these miRNAs enhance GRK2 expression and thereby suppress MALT1 activity and MALT1-dependent tumor cell proliferation in vitro and inhibit MALT1-dependent tumor growth in vivo. MicroRNA inhibitors that enhance GRK2 expression could represent a new approach for restraining MALT1-dependent lymphoma. Citation Format: Jing Cheng, Mei Smyers, Matt Trotta, Neil M. Carleton, Lisa M. Maurer, Uma R. Chandran, Min Xia, Ari M. Melnick, Peter C. Lucas, Linda M. McAllister-Lucas. Inhibitors of GRK2-targeting-microRNAs: New therapeutic strategies for MALT1-dependent lymphomas [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A033.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease of motor neurons for which therapeutics are limited. Improved biomarkers are imperative to improve patient care and therapeutic development. Here, we employed 35-plex isobaric tandem mass tag labeling based on isobutyl-proline reporter group (TMTpro) to perform unbiased proteomic analysis of cerebrospinal fluid (CSF) and plasma from control (n= 28, n= 31) and sporadic ALS (sALS) (n= 39, n= 41), from the Target ALS Global Natural History Study (TALS GNHS). We identified 2,875 proteins in CSF and 1,118 proteins in plasma and identified known and novel differentially expressed proteins (DEPs) between controls and sALS, some of which were orthogonally validated using immunoassay. Comparison of TMTpro-MS and Olink proximity extension assay proteomics revealed common and non-overlapping differentially expressed proteins illustrating strengths unique to each platform. This initial cross-sectional proteomic study of biofluids from the TALS GNHS, with unrestricted availability of study results to the research community, highlights the potential of this resource as a potent platform for ALS biomarker discovery.

Importance Currently, there are no standardized outcome domains or measures in clinical trials for facial aging. Heterogeneity in outcome domains and measurement instruments across clinical trials creates difficulty in directly comparing interventions, determining superior therapies, and developing high-quality meta-analyses. Objective To develop a core outcome set (COS) of essential domains to be reported in clinical trials evaluating the efficacy of interventions for facial aging. Evidence Review PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, and CINAHL were searched from September 2005 to September 2015. An updated search of the same databases was performed from September 2015 to February 2026. Studies were included if (1) they were randomized clinical trial or controlled clinical trial in design, (2) they assessed the efficacy or safety of an intervention for facial aging, (3) they were published in English, and (4) they involved human participants. Complementary sources, including patient interviews, were used to capture further relevant outcomes. Two rounds of Delphi surveys, followed by consensus meetings, were used to identify outcome domains considered most important by both patient and physician stakeholders. Findings The final COS consists of 6 outcome domains: (1) overall convenience of treatment; (2) time to return to normal work and social activity; (3) overall assessment of focused area of treatment (at the point in time when treatment is expected to provide peak benefit); (4) duration of treatment effect; (5) severity of persistent local or systemic adverse events, including pigmentary change, skin texture change, delayed healing, scarring, and serious adverse events; and (6) patient satisfaction with treatment. Conclusions and Relevance The 6 outcome domains identified through a Delphi consensus are recommended for reporting in future facial aging trials to ensure that outcomes that matter most to patients and clinicians are measured and that results are comparable across interventions.

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

Abstract This literature‐based systematic review and associated guidelines provide evidence‐based paradigms for the management of locoregionally recurrent rectal cancer (LRRC). This multispecialty committee included gastrointestinal radiation and medical oncology, gastroenterology, radiology, and colorectal surgery. As is the standard, the previously described American Radium Society Appropriate Use Criteria methodology for this project was followed rigorously, with the Population, Intervention, Comparator, Outcome, Timing, and Study Design framework and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses methodology to assess the evidence. RAND/University of California Los Angeles consensus methodology (modified Delphi) was used to rate the appropriateness of treatment options. Published between January 1, 2013, and July 16, 2025, 116 peer‐reviewed trials provided the evidence: 10 were well‐designed randomized phase 2/3 trials, 29 were moderately well designed trials that accounted for most common biases (matched cohort and phase 2), 76 trials had design limitations (retrospective), and one was a meta‐analysis. Clinical cases were created as examples to illustrate current acceptable management of LRRC. Treatment and prognosis are influenced by prior therapy and the site(s) and extent of LRRC. The ability to achieve a margin‐negative surgical resection is the ultimate determinant of survival and local control. Preoperative systemic therapy, radiation therapy, or a combination of the two can facilitate tumor downsizing and improve the likelihood of a margin‐negative resection. An individualized multidisciplinary approach is required to ensure the best outcome. Although this review does not suggest a major alteration of current practice, it provides reassuring evidence of the importance of combined‐modality therapy.