Publications by Year: 2026

Chronic Graft versus Host Disease (cGVHD) remains a major hurdle to the success of hematopoietic stem cell transplantation (HSCT), directly impacting patient morbidity and mortality. Impaired Treg recovery in patients with cGVHD has led to clinical studies aiming to increase peripheral Treg numbers. We performed Phase I dose escalation clinical trials, testing the feasibility and safety of using freshly isolated donor-derived Treg infusions in steroid-refractory/dependent cGVHD. The Phase I was extended to a preliminary Phase II trial, resulting in a total of 33 treated patients. We report that Treg purification from donor leukapheresis using CliniMACS were feasible and that Treg infusions were safe. Importantly, Treg infusions resulted in improved symptoms, particularly at higher Treg doses. Global responses were observed in 71% of patients, and 52% of patients had at least a 2-point improvement in the cGVHD severity scale. Furthermore, improvement in cGVHD symptoms resulted in reductions in corticosteroids, ruxolitinib and mycophenolate (MMF) in 58%, 83% and 33% of patients, respectively, while calcineurin inhibitors were discontinued in 75% of patients. Exploratory analyses revealed the detection of infused Treg clonotypes up to 12 months post-infusion and suggest increased Treg numbers in circulation. We observed increases in serum levels of IL-7, IFN-g, and decreases in sCD13 and ST2 over time, which were not statistically significant following adjustment for multiple comparisons. Although these studies were not powered to assess efficacy, they suggest potential therapeutic benefits of donor-derived Treg in cGVHD treatment and highlight the need for larger Phase II clinical trials. NCT02385019 NCT03683498 (clinicaltrials.gov).

PURPOSE: To characterize gastric cancer epidemiology in Latin America and the Caribbean, identify country-level predictors of the mortality-to-incidence ratio (MIR), and describe the clinical research landscape with emphasis on precision oncology (PO).

METHODS: We conducted a retrospective, country-level study integrating GLOBOCAN 2022 incidence and mortality data, ClinicalTrials.gov records (2004-2025), and socioeconomic indicators (United Nations Development Program Human Development Index [HDI] 2023 and current health expenditure). MIR was calculated per country. Precision-oncology studies were flagged by a curated drug dictionary applied to the Interventions field; country involvement was measured as country-study participations. Analyses included geospatial mapping, Spearman correlation, ordinary least squares regression, K-Means clustering (k = 3), and a Random Forest classifier for feature ranking and discrimination.

RESULTS: Across 24 countries, incidence ranged from 3.97 to 14.31 per 100,000 and mortality from 2.98 to 11.06 per 100,000. MIR was highest in Honduras (0.93), Belize (0.89), and Guatemala (0.88) and lowest in Cuba (0.65), Uruguay (0.66), and Costa Rica (0.68). The HDI correlated inversely with MIR (ρ = -0.71, P < .001); the association with number of trials was weak (ρ = -0.09). Three regional archetypes were identified. The Random Forest model achieved an AUC of 0.94 and ranked HDI as the top predictor. Of the 105 studies, 81 were interventional; phase III accounted for 40.7% and phase II for 30.9%. Country-study participations were concentrated in Brazil (23.4%), Chile (19.1%), and Argentina (15.2%). In PO, participation was dominated by Brazil, Chile, Argentina, and Mexico (72.2% of 140 participations), mostly involving trastuzumab, pembrolizumab, ramucirumab, and nivolumab.

CONCLUSION: Socioeconomic context was more associated with outcomes than research volume. Regional research remains concentrated and drug-limited, supporting policies to strengthen diagnostics, access, and equitable clinical investigation.

PURPOSE: We conducted the PediQUEST Response to the Pediatric Oncology Symptom Experience (PQ Response) randomized controlled trial (RCT) to assess whether combining feedback from an electronic patient-reported outcome (ePRO) system with specialized pediatric palliative care (SPPC) consultation improved health-related quality of life (HRQOL) in children with advanced cancer.

METHODS: This multicenter open-label RCT enrolled children 2 years and older with advanced cancer. The study was conducted between April 2018 and December 2021 at five US tertiary-level pediatric cancer centers. All parents and children 5 years and older answered weekly child HRQOL and symptom surveys over 18 weeks (2-week run-in). Child-parent dyads were assigned (1:1) to PQ Response (n = 74) or usual care (n = 80) for 16 weeks. Primary outcomes were the difference between average 16-week and baseline Pediatric Quality of Life Inventory (PedsQL-4.0) total scores reported by parents and children (range, 0-100; higher = better HRQOL; minimal clinically important difference [MCID], 4.5). Secondary outcomes were PedsQL subscales and symptom scores. Analyses followed an intention-to-treat approach.

RESULTS: Of 154 participants randomly assigned, 50% were girls, 78% were White, 17% were Hispanic, and 45% had brain tumors. The mean age was 11 years (standard deviation, 6.1). Parents assigned to PQ Response reported greater improvements in child HRQOL (PedsQL total mean difference 3.45 points [{95% CI, 0.48 to 6.43}; P = .023]; PedsQL physical 4.61 [{95% CI, 0.40 to 8.82}; P = .032]). Children reported similar improvements. Effects did not exceed MCIDs. No improvements were observed in PedsQL-psychosocial or symptom scores. Sensitivity analyses showed consistent effects, with most physical HRQOL scores and several child-reported symptom scores exceeding MCIDs. We observed site-specific variability. At the site with the largest adherence, all effects exceeded MCIDs. No adverse events reported.

CONCLUSION: Findings suggest benefits of integrating electronic patient-reported outcome feedback and SPPC into pediatric advanced cancer care. Enhanced implementation strategies are needed to optimize clinical impact.

BACKGROUND AND OBJECTIVES: Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD.

METHODS: A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse.

RESULTS: A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents.

DISCUSSION: Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

BACKGROUND: Pulmonary vein (PV) isolation is a well-established treatment for atrial fibrillation (AF), however, strategies for patients with recurrent AF and isolated PVs remain elusive.

OBJECTIVE: This study aimed to evaluate the effectiveness of a personalized artificial intelligence (AI)-guided spatiotemporal dispersion mapping and ablation in patients undergoing a repeat ablation and whose PVs remain isolated from previous ablation procedures.

METHODS: The Re-Ablation Using a Tailored Approach Targeting EGM-Dispersion (RESTART) trial (NCT05477147) was an interventional, prospective, single-arm, multicenter clinical trial. Patients with previous catheter or surgical ablation for paroxysmal, persistent, or long-standing persistent AF and with documented symptomatic AF recurrences were enrolled. Patients with documented reconnected PVs during the procedure were prospectively withdrawn from the trial. Follow-up included 3-, 6-, and 12-month visits with 12-lead electrocardiogram and 24-hour Holter. The primary endpoint of the study was freedom from documented AF at 12 months after a single AI-guided repeat ablation procedure.

RESULTS: Of the 213 patients enrolled, the main causes for premature study exit were PV reconnection (n = 80) or noninducibility of AF (n = 14). The primary endpoint was achieved in 83% of patients (77 of 93), and freedom from any atrial arrhythmia after a single procedure was 70% (65 of 93). Notably, AF termination during ablation was achieved in 54% of patients, and right atrial dispersion was identified in 59%. The procedure was associated with improvements in quality-of-life metrics (AF Effect on Quality-of-Life questionnaire and 36-Item Short Form Survey scores).

CONCLUSION: In patients with documented isolated PVs, AI-guided dispersion ablation is safe and effective and represents an alternative to other ablative strategies.

Expanding the number of clinically approved choices for osteoanabolic therapy represents the next hurdle on the osteoporosis treatment horizon. The WNT pathway is involved in stimulating new bone formation, and the most recent FDA-approved anabolic therapy-sclerostin neutralizing antibody-works by stimulating the WNT pathway in bone. The challenge with all current osteoanabolic therapies is the short treatment window in which they are efficacious. One strategy to dealing with this limited anabolic window is to further maximize bone formation during the window, using combination therapy. For example, simultaneous pharmacological or genetic inhibition of the WNT antagonists sclerostin and DKK1 potentiate the already strong effects of sclerostin inhibition alone, particularly in cancellous bone. Considerable interest has emerged regarding other candidates that might be co-inhibited along with sclerostin to potentiate its effects in bone, with specific action on cortical bone. In this communication, partnering sclerostin inhibition with the inhibition of another secreted WNT antagonist, NOTUM, is explored. NOTUM is a secreted WNT deacylase that inactivates WNT ligands and has preferential effects on cortical bone. To evaluate combination therapy involving sclerostin/NOTUM inhibition, double knockout mice for Sost and Notum (Sost-/-;Notum-/-) were generated and compared to single knockouts and WT controls. Further experiments were conducted using pharmacologic inhibitors, rather than genomic mutations, for sclerostin (sclerostin neutralizing antibody) and a small molecule inhibitor of NOTUM (LP-922056). Each experiment included evaluation by DXA-derived radiography, μCT, biomechanical testing and bone dynamic histomorphometry. Deletion of Notum alone had mild cortical effects but co-deletion of Sost and Notum improved cortical and some cancellous parameters significantly beyond Sost-/- mice. Co-inhibition of the protein products with antibody/small molecule were less synergistic, with only a small cortical effect, particularly in younger mice. Taken together, the results suggest the potential to improve efficacy of sclerostin inhibition using NOTUM inhibition is promising, but development of additional NOTUM inhibiting tools and optimization of current tools might be necessary to strengthen the partnership.

OBJECTIVES: Chronic ankle instability (CAI) is not only associated with those peripheral neuromuscular impairments but also with the functional changes in the supraspinal regions. Nevertheless, the characteristics of the cortical elements in CAI remain poorly understood. This study aimed to examine the dynamics of resting-state BOLD and ankle-related functional performance in recreational athletes with CAI, as well as explore the associations between neural fluctuations and ankle functional performance.

METHODS: This cross-sectional design study recruited 82 participants, comprising 41 active recreational athletes with CAI (CAI group) and 41 active recreational athletes without CAI (Control group). Data on joint position sense, one-leg standing balance, and resting-state fMRI were collected from both groups. A two-sample t-test was used to determine the difference in amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo) between the two groups. Linear regression analysis evaluated the associations between functional performance and dynamics of resting-state BOLD in the two groups.

RESULTS: Compared with control group, athletes with CAI had lower ALFF values in the bilateral supplementary motor area and reduced ReHo values in the right precentral gyrus and postcentral gyrus, while higher ALFF and ReHo values in the right cerebellum. Moreover, athletes with CAI had lower fALFF values in the left superior frontal gyrus and the right superior frontal gyrus than controls. The sway velocities of center of pressure in the one-leg standing with eyes closed condition were negatively associated with ALFF and ReHo values in the right cerebellum cluster.

CONCLUSIONS: Athletes with severely right-sided CAI had different neural fluctuations compared with controls. Elevated ALFF and ReHo values in the right cerebellum cluster were associated with balance control, suggesting that high ipsilateral cerebellar activity and homogeneity may compensate for balance control in athletes with CAI.

OBJECTIVE: The Wound, Ischaemia, and foot Infection (WIfI) staging system for chronic limb threatening ischaemia (CLTI) predicts outcomes after revascularisation, but individual components of WIfI have not been evaluated. This study was designed to evaluate changes in WIfI ischaemia grade as a predictor of major amputation after open and endovascular revascularisation in the Best Endovascular versus Best Surgical Therapy in Patients with CLTI (BEST-CLI) trial.

METHODS: A secondary analysis was conducted of patients with CLTI randomised to surgical bypass or endovascular therapy as part of the BEST-CLI trial with available WIfI ischaemia scores at baseline and one month post-procedure. Risk adjusted Cox regression models were used to assess the effect of change in WIfI ischaemia grade on the rate of major amputation, while controlling for potential confounders.

RESULTS: Among 785 patients with CLTI who underwent revascularisation and were alive at one year, 629 (80.1%) achieved improvement in their WIfI ischaemia grade within 30 days after undergoing surgical and or endovascular interventions. Patients with improved ischaemia grade were younger and were more likely to smoke, have lower baseline ankle brachial indices, and have a worse overall WIfI stage at the time of revascularisation compared with patients with worsening or no improvement in limb perfusion (p < .050 for all comparisons). The major amputation incidence at one year was 14% and was increased among those with higher baseline WIfI stage (3/4 vs. 1/2) and with unchanged or worse WIfI ischaemia grade after revascularisation. Patients with improved WIfI ischaemia grade early after revascularisation had a statistically significantly lower likelihood of major amputation at one year (hazard ratio 0.27, 95% confidence interval 0.18 - 0.41; p < .001) after risk adjustment.

CONCLUSION: Achieving early improvement in limb perfusion based on WIfI ischaemia grade predicts major amputation following revascularisation independent of other risk factors. Changes in ischaemia grade after interventions should be closely monitored to determine the adequacy of revascularisation, risk of CLTI progression, and need for major amputation.

AIMS: Risk factor-weighted clinical likelihood (RF-CL) estimates the probability of obstructive coronary artery disease (CAD) in patients without known CAD. We examined whether adding lipoprotein(a) [Lp(a)] measurements to the RF-CL model improves predictions of obstructive CAD.

METHODS AND RESULTS: In a derivation cohort (N = 4262; 54% male; mean age 58 years), the prevalence of obstructive CAD at invasive angiography with fractional flow reserve was assessed by Lp(a)-strata. On the basis of initial results, an Lp(a)-adjusted model (RF-CLLp(a)) was developed: RF-CL was multiplied by 1.5 in patients with elevated Lp(a) (≥125 nmol/L) and otherwise unchanged. Discrimination, calibration, and reclassification were compared. Findings were validated in an external validation cohort (N = 1595; 49% male; mean age 60 years) using a comparative endpoint; significant stenosis at invasive angiography or coronary computed tomography.In the derivation cohort, 473 patients (11.1%) had obstructive CAD; in the validation cohort, 206 patients (12.9%) had significant stenosis. The relative risk in patients with elevated Lp(a) was 1.51 [95% confidence interval (CI) 1.23-1.86] and 1.19 (95% CI 0.88-1.60) in the derivation and validation cohort, respectively. In the derivation cohort, the RF-CLLp(a) model showed a higher area under the receiver operating curve than the RF-CL model [0.743 (standard error 0.011) vs. 0.740 (0.013)] and better calibration in patients with elevated Lp(a). Reclassification from RF-CL to RF-CLLp(a) improved likelihood stratification in the derivation cohort but not in the validation cohort.

CONCLUSION: Adding elevated Lp(a) as a risk factor to the RF-CL model improves accuracy of obstructive CAD in patients with high Lp(a).