Citations

Background White matter hyperintensities (WMH) and their progression are associated with risk of dementia and stroke, so are an important target for clinical trials. The cost of broad magnetic resonance imaging (MRI) screening to identify eligible individuals, however, limits the feasibility of designing clinical trials targeting WMH. A low‐cost retinal or clinical screening measure before MRI could reduce recruitment costs versus an MRI‐only screening design in a hypothetical clinical trial. Methods and Results Data from the Atherosclerosis Risk in Communities study with valid retinal and WMH measurements ( N =1311) were used. To identify a population at greater likelihood of significant WMH on MRI and thus reduce the number of screening MRIs required, we evaluated 3 theoretical prescreening measures: (1) retinal, (2) clinical, (3) combined clinical‐retinal. Given a target sample for clinical trials ( N =646), we calculated screening sample sizes based on the proportion within the population having an elevated score for each prescreening measure (separately) multiplied by the proportion of significant WMH among those with that prescreening feature. Recruitment costs were calculated using estimated retinal and MRI cost estimates. Compared with the estimated cost of MRI‐only screening (>$4.24 million, requiring MRI on 6526 participants), prescreening for a high clinical score resulted in total cost of $2.47 million, with an initial screening group of 52 778 participants, with MRI in 3801. A high clinical‐retinal score cutoff resulted in costs of $2.9 million while requiring 13 572 participants, with 3801 completing MRI. Conclusions A 2‐stage design with low‐cost prescreening measures is a promising approach, resulting in reduced theoretical recruitment costs compared with an MRI‐only design.

Background: Acoramidis is a novel, potent, investigational, transthyretin (TTR) stabilizer under development for the treatment of TTR amyloidosis that results in near-complete (≥90%) TTR stabilization. In a phase 3 study, ATTRibute-CM, acoramidis demonstrated improved clinical outcomes in participants with transthyretin amyloid cardiomyopathy (ATTR-CM), including a 50% reduction in the risk of CVH compared to placebo over 30 months. The study also demonstrated that cardiovascular hospitalization (CVH) during the study predicted a higher subsequent mortality in participants with ATTR-CM. Hypothesis: CVH portends a higher risk of mortality in participants with ATTR-CM. Since acoramidis reduces CVH, it can improve the prognosis of participants with ATTR-CM. Aim: To evaluate the relationship between CVH and survival in the acoramidis group within ATTRibute-CM. Methods: In this post-hoc analysis, the relationship between those with or without CVH and survival was analyzed within the acoramidis treatment group using the Kaplan-Meier (KM) estimator method. Results: Demographics and baseline disease characteristics were mostly comparable between acoramidis-treated participants with and without CVH, although participants with CVH had a higher baseline NT-proBNP and lower eGFR. At Month 30, in acoramidis-treated participants, those without any CVH (n=300) had a higher survival [86.8% (95% CI = 82.2, 90.3)] versus 62.4% (95% CI = 52.6, 70.7) in those who had any CVH (n=109); p<0.0001 from log-rank test (Figure). Conclusion: In the ATTRibute-CM study, pts without any CVH receiving acoramidis have a higher survival rate. CVHs remain a powerful predictor of mortality. This reinforces the importance of an effective therapy that reduces CVH and in turn may improve survival in patients with ATTR-CM.

Background: As machine learning becomes increasingly utilized in orthopaedic clinical research, the application of machine learning methodology to cohort data from the Multicenter ACL Revision Study (MARS) presents a valuable opportunity to translate data into patient-specific insights. Purpose: To apply novel machine learning methodology to MARS cohort data to determine a predictive model of revision anterior cruciate ligament reconstruction (rACLR) graft failure and features most predictive of failure. Study Design: Cohort study; Level of evidence, 3. Methods: The authors prospectively recruited patients undergoing rACLR from the MARS cohort and obtained preoperative radiographs, surgeon-reported intraoperative findings, and 2- and 6-year follow-up data on patient-reported outcomes, additional surgeries, and graft failure. Machine learning models including logistic regression (LR), XGBoost, gradient boosting (GB), random forest (RF), and a validated ensemble algorithm (AutoPrognosis) were built to predict graft failure by 6 years postoperatively. Validated performance metrics and feature importance measures were used to evaluate model performance. Results: The cohort included 960 patients who completed 6-year follow-up, with 5.7% (n = 55) experiencing graft failure. AutoPrognosis demonstrated the highest discriminative power (model area under the receiver operating characteristic curve: AutoPrognosis, 0.703; RF, 0.618; GB, 0.660; XGBoost, 0.680; LR, 0.592), with well-calibrated scores (model Brier score: AutoPrognosis, 0.053; RF, 0.054; GB, 0.057; XGBoost, 0.058; LR, 0.111). The most important features for AutoPrognosis model performance were prior compromised femoral and tibial tunnels (placement and size) and allograft graft type used in current rACLR. Conclusion: The present study demonstrated the ability of the novel AutoPrognosis machine learning model to best predict the risk of graft failure in patients undergoing rACLR at 6 years postoperatively with moderate predictive ability. Femoral and tibial tunnel size and position in prior ACLR and allograft use in current rACLR were all risk factors for rACLR failure in the context of the AutoPrognosis model. This study describes a unique model that can be externally validated with larger data sets and contribute toward the creation of a robust rACLR bedside risk calculator in future studies. Registration: NCT00625885 (ClinicalTrials.gov identifier).

Background: Despite expert opinion recommending patient-tailored cardiac rehabilitation (CR) after acute aortic dissection, both patient participation in CR and the associated risk factor modification after CR following aortic dissection repair are poorly understood. Objectives: To describe the characteristics of patients referred to CR, as well as the enrollment rate and outcomes of those referred to CR following thoracic aortic dissection. Methods: We reviewed electronic health records of adults (≥18) discharged alive following thoracic aortic dissection surgery across the Mayo Clinic Enterprise (01/01/2020-11/15/2022) with follow-up to 05/15/2024 (IRB #24-001141). Data are presented using summary statistics. Results: During the study period, 85 patients were included (median [IQR] age: 65 [50-75] years; 40% female; Table 1 ). Across 84% (N=71) who were referred to CR at discharge, 55% (N=39) enrolled. In those patients referred versus not referred to CR, the prevalence of type A dissection (75% vs. 43%), end-organ involvement (27% vs. 0%), and underlying CAD (54% vs. 21%) were greater while current tobacco use (9% vs. 29%) was lower. Of those enrolled at Mayo Clinic (N=16), CR was started 35 (28-65) days following surgery. These patients completed 21 (13-30) CR sessions at an exercise intensity of 59% (50-65%) maximum predicted heart rate. CR was discontinued in 44% (N=7) due to non-cardiac reasons ( Table 2 ). Of the 9 patients who completed CR, general health status (Dartmouth index: 19 [17-21] vs. 26 [22-34]), depressive symptoms (PHQ-9: 1 [0-1] vs. 4 [1-4]), and exercise capacity (6MWT: 214 [196-244] vs. 384 [305-597] meters) improved ( Table 2 ). There were no reported complications or deaths, with stable aortic sizes reported at 18 months. Conclusions: CR improves functional capacity and well-being without complications in patients after thoracic aortic dissection surgery. Further investigation is needed to better assess CR efficacy and usage in this population.

Abstract Introduction: Blood-based tests represent a compelling option for early detection and management of cancers and other chronic diseases. While blood-based tests may offer potential to increase patient engagement, the assumption of greater adherence in clinical practice requires further evaluation. This systematic review aimed to evaluate the real-world adherence to established blood-based tests for commonly recommended screening indications, to better inform expectations for proposed application to average-risk colorectal cancer (CRC) screening. Methods: A systematic search of PubMed, Embase, and citations was performed to identify literature published from 2010 to 2023. Studies examined adherence to routine blood-based laboratory tests with a Grade A or B recommendation per the United States Preventive Services Task Force (USPSTF) for diabetes, dyslipidemia, human immunodeficiency virus (HIV), and hepatitis C virus (HCV) in an average-risk patient population were included. In addition, prostate-specific antigen (PSA) testing adherence for prostate cancer screening (Grade-C USPSTF recommendation), the only commonly accessible blood-based single-cancer screening test for average-risk adults, was also included. Studies without venipuncture-derived blood were excluded. Results: Of 53,067 articles screened, 69 were included in the analysis. Overall, adherence rates of blood-based tests were highly variable, with median values (interquartile range, IQR) of 66.3% (11.8%), 67.8% (18.0%), 34% (28.7%), and 36.8% (30%) for diabetes, dyslipidemia, HCV, and HIV, respectively. PSA testing adherence was 37.2% (18.4%). Beyond disease type, adherence varied by study design, data source, patient characteristics, clinical setting, and study country. Information and selection bias were the most common risks of bias. Conclusions: Based on data from this comprehensive systematic review, real-world adherence to currently recommended, blood-based screening strategies is suboptimal. Future research is needed to identify the extent to which these data are generalizable to blood-based CRC screening, and to determine if/how this candidate strategy would impact clinical, economic, and health equity outcomes. Citation Format: Quang A. Le, Takako Kiener, Heather A. Johnson, Rukaiyya S. Khan, Joyce Kong, Kevin H. Li, Gina Thompson, A. Burak Ozbay, Mallik Greene, Paul J. Limburg, A. Mark Fendrick, John B. Kisiel, Derek W. Ebner. Systematic review of real-world adherence to blood-based laboratory tests for average-risk disease screening: potential implications for emerging colorectal cancer screening modalities [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A027.

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

Abstract Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline &gt;9.7 points for adults, &gt;8.5 points for child self-report, and &gt;9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P&lt;.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.

Abstract BACKGROUND Glioblastoma (GBM), one of the deadliest primary tumors of the central nervous system, is characterized by a highly immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages and microglia (TAMs) are a dominant population of immune cells in the GBM TME and substantially contribute to immunosuppression, tumor progression, and treatment resistance. Elucidating the molecular mechanisms underlying TAM behavior is crucial to the development of effective immuno-therapeutic strategies for treating GBM. The adaptor protein, Caspase Recruitment Domain-containing protein 9 (CARD9) is primarily expressed in myeloid cells and its activation triggers assembly of the CARD9-BCL10-MALT1 (CBM) complex, which then promotes activation of NF-κB and/or MAPK pathways. The aim of this study was to investigate the role of the CBM complex in the GBM TME and assess its potential as a therapeutic target. METHODS/RESULTS In silico analyses revealed that GBM tumors demonstrate increased CARD9 and MALT1 expression in comparison to non-tumor brain tissue, with CARD9 expressed only within the myeloid compartment. Using co-culture, scratch wound, and transwell assays, we found that GBM tumor cells induce macrophage M2 polarization and migration via a mechanism that is dependent on CARD9/MALT1 signaling within macrophages. scRNA-Seq and flow-cytometric analysis of orthotopic syngeneic immunocompetent GBM tumor models revealed that the GBM TME is dominated by macrophages. Disruption of MALT1 protease activity within the TME leads to reduced tumor infiltration by immunosuppressive TAMs, remodeling of TAMs toward an immunoreactive anti-tumor phenotype, and improved survival of GBM-bearing mice. Additionally, we found that tumor growth was abrogated when GBM-bearing mice were treated with either a MALT1-protease inhibitor or a CARD9 inhibitor. CONCLUSIONS Our study suggests that blockade of the CARD9-MALT1 signaling axis impairs GBM-induced macrophage recruitment and M2 polarization and inhibits tumor progression. These findings nominate the CARD9-MALT1 signaling axis as a new target for TAM-directed immunotherapy for the treatment of GBM.

Context.— Cardiac and pulmonary allograft recipients represent a unique population, frequently interacting with support groups and exhibiting intense curiosity about their pathology. Like other solid organ transplant patients, they have enduring and frequent interaction with the laboratory for routine allograft surveillance. Objective.— To address patient requests to understand what happens to their explanted organ and to better understand their disease while simultaneously improving awareness of pathologists’ roles in their continuing care. Design.— At routine follow-up appointments, transplant nurse coordinators offer each allograft recipient the opportunity to interact with a pathologist in our “ On My Path ” program. Organ viewing occurs in a private setting, in a specialized room. Relevant pathology is discussed, and questions are answered, with documentation in the medical record. The patient is subsequently gifted a 3-dimensional model of their explanted organ. Transplant coordinators were surveyed for their feedback on the experience. Results.— One hundred fifty-eight interactions have been documented (2017–2022) at our institution, including patients who underwent cardiac transplant (96, 61%), single or bilateral lung transplant (54, 34%), or combination lung and heart transplant (8, 5%). Transplant coordinators reported an increase in patient understanding of their disease and emotional closure related to the disease through the On My Path program. Conclusions.— Pathologists providing direct patient care is a feasible model that addresses currently unmet desires of the transplant population to better understand their pathology. Providing a 3-dimensional model helps to empower patients and drives satisfaction. These interactions also improve awareness about pathology as a discipline and its importance in the continued care of transplant recipients.

PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration–approved for adults. METHODS ReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m 2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging. RESULTS Twenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was –41% (−90 to 13) in adults and –42% (−91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children. CONCLUSION In ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children.