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Abstract Background Patients with myeloproliferative neoplasms (MPNs) are at risk of splanchnic vein thrombosis (SVT). Prior studies failed to demonstrate a benefit of hydroxyurea in preventing SVT extension/recurrence, but these were limited by small sample sizes and inability to account for starting, stopping, or switching of cytoreductive therapies. We therefore investigated the role of cytoreduction as a time-dependent covariate on thrombosis recurrence in a large, international cohort of MPN-SVT patients. Methods We performed a retrospective cohort study of MPN-SVT patients included in the international GASTRO-MPN consortium. Patients diagnosed with MPN at any time before, concurrently with, or up to 60 days after initial SVT were included. Primary outcome was time from initial SVT to first thrombosis recurrence, defined as the composite of SVT extension/recurrence, transjugular intrahepatic portosystemic shunt (TIPS) thrombosis, or venous/arterial thrombosis outside the splanchnic veins. Secondary outcomes included SVT extension/recurrence, TIPS thrombosis or extra-SVT thrombosis individually, clinically relevant bleeding (composite of major and clinically relevant non-major bleeding), MPN progression to myelofibrosis or blast phase, and death. Cytoreductive therapy was treated as a time-dependent covariate to account for discontinuation and therapy changes. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results A total of 757 patients were included for this analysis. Median age was 51 years (IQR 38-62), 59% were female. SVT involved the portomesenteric veins in 558 (77%) patients, hepatic veins in 95 (13%), and both in 54 (7.4%). MPN was known prior to initial SVT in 316 patients (42%) and diagnosed concurrently or up to 60 days after SVT in 441 (58%). Polycythemia vera (PV) was the most common MPN subtype (43%), followed by essential thrombocythemia (ET) in 24%, and primary myelofibrosis in 14%. JAK2V617F mutation was present in 86% and CALR in 2.9%. 13% had prior non-SVT thrombosis. 607 patients (83%) were treated with cytoreduction. At time of SVT, 131 patients (17%) were already on cytoreduction; in those who started after SVT, median time to initiation was 54 days after SVT, and median duration of cytoreduction per patient was 63 months. Cytoreductive therapies used at any point in treatment included hydroxyurea in 504 (69%), ruxolitinib in 182 (25%), and interferon-based in 85 (12%) patients. Anticoagulation (AC) was started within 30 days after SVT in 504 (68%) patients. Median duration of any AC per patient was 24.6 months. During a median follow up of 7.4 years, 245 patients (33%) had thrombosis recurrence; 143 (20%) had SVT extension/recurrence/TIPS thrombosis, 129 (18%) extra-SVT thrombosis (of which 74% venous), 237 patients (32%) experienced clinically relevant bleeding, and 163 (22%) died. After adjusting for age, sex, timing of MPN diagnosis relative to SVT diagnosis, AC within 30 days of SVT, PV/ET vs other MPN, JAK2 mutation, previous thrombosis, non-MPN cancer, and cirrhosis, cytoreductive therapy was associated with a significantly decreased risk of recurrent thrombosis (HR 0.67 95%CI 0.50-0.89, p=0.01). Age was associated with an increased risk of recurrent thrombosis (p=0.01). When considering types of recurrent thrombosis, cytoreduction was associated with a decreased risk of SVT extension/recurrence/TIPS thrombosis (HR 0.62 95%CI 0.42-0.90, p=0.01), but not thrombosis outside the splanchnic veins (HR 0.97 95%CI 0.72-1.30, p=0.82). There was no association between cytoreduction and bleeding (HR 1.10 95%CI 0.82-1.47, p=0.52). Similarly, there was no association between cytoreduction and time to MPN progression (p=0.24) or overall survival (p=0.30). In a subgroup of patients without erythrocytosis/thrombocytosis at initial SVT (n=271), cytoreductive therapy was associated with a HR 0.65 (95%CI 0.40-1.10, p=0.09) for recurrent thrombosis. Limited sample size and low event-rate precluded evaluation of the impact of individual cytoreductive therapies. Conclusions In the largest cohort of MPN-SVT patients to date, we show for the first time that cytoreductive therapy is associated with a decreased risk of thrombosis recurrence, driven largely by decreased SVT extension/recurrence/TIPS thrombosis. Collectively, these findings support use of cytoreductive therapy in individuals with MPN-SVT to prevent recurrent thrombosis.

Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients <30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (<18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (<0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed <18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p<.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses <18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.

Aims Arthrofibrosis affects a notable percentage of patients after total knee arthroplasty (TKA). Elevated serum mast cell tryptase (SMCT) levels have been linked to fibrosis, suggesting that SMCT could serve as a biomarker for arthrofibrosis. As such, the aims of this study were to assess SMCT levels in TKA patients, and their possible association with arthrofibrosis and clinical outcomes in a prospective clinical trial. Methods We conducted a prospective study involving 219 patients undergoing primary TKA at a single academic medical centre between January 2018 and December 2022. SMCT levels were measured preoperatively, immediately postoperatively, and at six weeks, three months, and one year postoperatively. Secondary outcomes included revision rates, complications, and Knee Society Scores (KSSs). Allergic and inflammatory conditions were assessed for their influence on SMCT levels. Results At one year postoperatively, eight patients had developed arthrofibrosis (4%), and three (1.5%) had undergone manipulation under anaesthesia. The mean preoperative SMCT level was 5.6 µg/L (SD 3.4), which decreased significantly to 4.1 µg/L (SD 2.7) immediately postoperatively (p < 0.001). At six weeks the mean SMCT level was 6.4 µg/l (SD 4.1), and was 6.1 µg/l at both three months (SD 4.1) and one year (SD 4.0). Elevated preoperative SMCT levels were not significantly associated with the risk of arthrofibrosis development (OR 3; p = 0.370), nor were immediate postoperative levels (OR 2; p = 0.754) or those at six weeks (OR 1; p = 0.989). Of note, elevated SMCT levels at three months (OR 5; 95% CI 0.4 to 64; p = 0.191) and one year (OR 13; 95% CI 1 to 232; p = 0.077) trended toward an increased risk of arthrofibrosis development, without reaching significance. Conclusion In patients undergoing TKA, with the numbers included in this study, there was no significant difference in SMCT levels between patients who did and did not develop arthrofibrosis at any timepoint. However, there was a trend towards elevated SMCT levels at three months and one year in those who developed arthrofibrosis, which merits further study. Cite this article: Bone Joint Res 2025;14(11):1045–1052.

Arthrofibrosis is a common complication following total knee arthroplasty and is the result of a dysregulated immuno-inflammatory cascade, which culminates in excessive scar deposition by myofibroblasts within the knee joint. Pharmacotherapies for arthrofibrosis are limited, with treatment reliant on manipulation under anesthesia or lysis of adhesions with or without component revision. Bupivacaine (a local anesthetic) and meloxicam (a nonsteroidal anti-inflammatory drug) combination therapy may exert antifibrotic properties by limiting inflammatory cell recruitment and the subsequent release of profibrotic cytokines. The purpose of this study was to evaluate the effects of this combination therapy in a rabbit model of arthrofibrosis by evaluating live and postsacrifice knee biomechanics and gene expression of posterior knee capsule tissue. Forty New Zealand white rabbits were equally divided into two experimental groups and prospectively studied to assess knee passive extension angles (PEA), terminal posterior capsular stiffness, and the inflammatory milieu of the posterior knee joint capsule. Experimental limbs with and without combination therapy showed similar live PEAs and terminal posterior capsular stiffness, with no significant differences between the groups. Gene expression analysis, however, revealed significant reduction in inflammatory genes but not profibrotic genes. In summary, bupivacaine and meloxicam combination therapy did not exert antifibrotic effects in a rabbit model of arthrofibrosis but significantly reduced the expression of inflammatory markers in the local environment of the posterior capsule.

Background Myxomatous mitral valve disease (MMVD) is a degenerative disorder marked by excess tissue fibrosis and matrix remodeling, leading to leaflet prolapse. While recent studies linked transforming growth factor beta (TGF-β) activation to MMVD development and progression, upstream regulators of this and other modulatory/causal pathways remain largely unexplored. Objectives In this study, we utilized high-throughput sequencing to conduct unbiased analyses of mRNA and microRNA (miRNA) levels in myxomatous and healthy mitral valve tissues, aiming to uncover novel molecular mechanisms involved in MMVD. Methods We defined differentially expressed mRNAs and miRNAs transcripts displaying a fold-change > 1.5 and P < .05. Pathway analysis was performed using Ingenuity Pathway Analysis and DAVID, with key findings validated via qRT-PCR. A total of 2378 transcripts were differentially expressed between myxomatous and normal valves. Established pathways, including TGF-β signaling, were confirmed as major contributors to MMVD. Additionally, Random Forests with Boruta Feature Selection identified transcripts with a 95% likelihood of importance, and subsequent pathway analysis on this subset of genes revealed unique signaling pathways. Results Most notably, circadian rhythm disruption emerged as a novel, highly ranked pathway in MMVD. Key miRNAs, such as miR-1, miR-133a, and miR-217 were highlighted as highly relevant, with miRNA–mRNA interactions displaying distinct molecular signatures predictive of MMVD. Conclusions Collectively, this study represents the first comprehensive analysis of both miRNA and mRNA expression in MMVD, revealing both established and novel disease-associated pathways. The discovery of circadian rhythm disturbances and new regulatory miRNAs suggests promising directions for further research and potential therapeutic targets for nonsurgical treatment strategies in patients with MMVD.

ABSTRACTSurgical biopsy of brainstem tumors carries a risk of neurological injury. We performed magnetic resonance spectroscopy (MRS) of 2‐hydroxyglutarate (2HG) and glycine in patients with brainstem tumors to assess the feasibility of detecting and quantifying 2HG in the brainstem to obviate the need for a diagnostic biopsy and to establish the clinical significance of glycine MRS in brainstem tumors in vivo. Twenty adult patients with radiographically identified presumed brainstem gliomas were prospectively enrolled in the study. Proton MRS was obtained at 3T with a protocol tailored for detection of 2HG and glycine (TE 97‐ms PRESS). Spectra were fit using LCModel software and in‐house basis signals of metabolites and lipids. The metabolite concentrations were quantified with reference to water and examined with respect to clinical outcomes, including postgadolinium MRI and overall survival time. MRS data from 19 patients were included in subsequent analysis, excluding suboptimal data from one patient. Tumors with elevated 2HG (> 1.9 mM, N = 8) and undetectable 2HG (< 0.3 mM, N = 11) were clearly distinguishable. Tumors with elevated glycine (> 1.5 mM, N = 4) showed rapid progression. Kaplan–Meier survival analyses with metabolite measures demonstrated that tumors with 2HG higher than 1.0 mM were significantly associated with a favorable prognosis (p = 0.01). In contrast, tumors with glycine higher than 2.5 mM showed a strong association with poor survival (p = 0.0005). The data confirm detection of 2HG in brainstem tumors at a concentration that is consistent with an IDH mutation and expected good prognosis, whereas elevated glycine in brainstem tumors portends rapid tumor progression and a worse prognosis.

Background: An extended trochanteric osteotomy (ETO) is commonly used to improve exposure and facilitate femoral component removal in revision total hip arthroplasty (THA). An additional medial corticotomy may be used in conjunction with an ETO to correct a femoral deformity, particularly varus remodeling in association with a failed femoral component. This study evaluated the outcomes of combining an ETO with a medial corticotomy in revision THA, with emphasis on implant fixation, femoral alignment, bone union, and clinical outcomes. Methods: Of the 612 ETOs performed between 2003 and 2013, 13 patients (9 men and 4 women) underwent ETO combined with a medial corticotomy to correct varus remodeling, representing 2% of all ETOs during that period. The average follow-up was 8 ± 3.5 years. The mean age at surgery was 67 ± 13.5 years. The mean body mass index was 32 ± 7.7 kg/m 2 . Radiographs were reviewed to measure preoperative and postoperative femoral deformity, time to consolidation, and femoral fixation. Clinical outcomes were evaluated using the Harris Hip Score (HHS). Results: All patients had preoperative varus femoral deformity (mean 16.3° ± 5.7°). The mean postoperative alignment was 4.3 ± 1.6° varus achieving an average correction of 12° (95% CI −15.7 to −8.3, p < 0.0001). Both the ETO and the medial corticotomy consolidated in 10 of 11 patients (91%) with available 1-year radiographs at a mean of 11 ± 7.7 months. The mean HHS improved significantly from 42 preoperatively to 82 at 5-year follow-up (p = 0.0002). Complications related to the ETO and corticotomy occurred in 4 patients (30%), including 1 intraoperative fracture, 1 postoperative greater trochanteric fracture, 1 nonunion of the medial corticotomy, and 1 postoperative wound-hematoma. All femoral components remained well fixed at final follow-up. Conclusion: The combination of ETO and medial corticotomy in revision THA effectively corrected femoral alignment in patients with a preoperative varus deformity and was associated with significant functional improvement at the final follow-up. Level of Evidence: Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Black or African Americans (AA) with Parkinson’s disease (PD) are underrepresented in both care and research and experience significant health disparities. The existing literature provides limited guidance on how to enhance the engagement of AA individuals in PD care and research, particularly from the perspectives of AA patients, care partners, and healthcare providers. This project aimed to (1) describe the use of Community Engagement (CE) Studios as a community-engaged research approach to inform culturally appropriate and inclusive research and (2) examine factors influencing AA engagement in PD-related activities. Methods: We conducted three CE Studios: one with AA with PD and care partners (N = 6), one with healthcare providers of AA with PD (N = 8), and one with AA with PD, care partners, and healthcare providers (N = 4). Results: The CE Studios informed the design (e.g., cultural appropriateness) and conduct (e.g., accessibility) of the planned PD project, as well as identifying stakeholders to engage with, improving alignment between research and the AA community. We highlighted the importance of multifaceted factors, including environmental (e.g., segregation), biological (e.g., symptoms), sociocultural (e.g., not being invited), and behavioral (e.g., empowerment) domains, which influence AA engagement. Conclusions: The CE Studios method is a feasible and useful approach for understanding the perspectives of AA in PD. It is possible to conduct an in-depth exploration of community perspectives by synthesizing comprehensive analyses and leveraging additional frameworks. These efforts include identifying barriers to engagement, recognizing locally relevant individuals, and refining PD-related care to enhance cultural appropriateness.