Faculty Bibliography

BACKGROUND:Soft tissue sarcoma (STS) is a rare and heterogeneous malignancy with more than 100 histologic subtypes that can arise in virtually any part of the body. Although surgical resection is the standard of care, complete surgical resection is often limited by involvement of critical anatomy, and most subtypes are resistant to systemic therapies. Histotripsy uses microsecond length, high-pressure ultrasound (US) pulses delivered externally to generate cavitation inside the target tumor to mechanically liquefy tissue to acellular homogenate. This study tested the effect of histotripsy in a variety of soft tissue tumors (STTs) including benign tumors and sarcomas. METHODS:Histotripsy was delivered to 45 surgically excised ex vivo human samples with a custom 1 MHz 8-element US transducer guided by US imaging. RESULTS:Histotripsy was successful in creating an identifiable treatment effect across all subtypes including adipocytic tumors, benign myxoid and nerve sheath tumors, aggressive fibrous sarcomas, and high-grade sarcomas. Immediately after histotripsy, B-mode and shear-wave elastography US imaging was shown to effectively evaluate the treatment. Tissue structure heterogeneity among the tumor subtypes dictated the variation in histologic treatment effects. CONCLUSIONS:The data demonstrate effective US-guided histotripsy ablation on a robust cohort of ex vivo STTs. The variable treatment effects observed across tumor subtypes highlight the need for histotripsy parameter optimization, with support for its potential as a promising non-invasive treatment modality for sarcoma patients who currently have limited therapeutic options.

BACKGROUND:Visual evoked potential (VEP) P100 latency is routinely used to assess optic nerve demyelination. However, there is no established methodology for disentangling whether shifts in VEP P100 latency may reflect upstream changes in the visual pathway, such as the level of the retina, or whether these delays could be reflective of downstream disturbances in broader brain structure and functioning. OBJECTIVE:To determine the relationship between VEP-based P100 and MRI-based outcomes in people with MS (PwMS) after accounting for structural retinal changes assessed by spectral domain optical coherence tomography (OCT). METHODS:64 study participants underwent OCT, VEP, and MRI. Standardized VEP assessment derived monocular P100 latency for both eyes. Similarly, OCT performed on Heidelberg Spectralis hardware provided peripapillary retinal nerve fiber layer (pRNFL) thickness. Mediation analyses were performed to assess the relationship between P100 and MRI-based outcomes, adjusting for mediating effects of pRNFL and age. RESULTS:VEP-based P100 was significantly associated with lower whole brain volume (WBV) (p=0.0037), with 87.8% of the total effect being both direct and independent from RNFL and the significant age-WBV covariate effect. Similarly, greater VEP-based P100 latency was directly and independently predictive of lower gray matter volume (GMV) (p=0.015) and greater T2-FLAIR LV (p=0.0036) after adjusting for RNFL and age mediating effects. CONCLUSION/CONCLUSIONS:VEP-based P100 latency shows both age- and RNFL-independent associations with MRI-based MS outcomes. In addition to their established diagnostic utility, VEP measures may provide a neurophysiological, objective metric to assess neurodegeneration.

The phase III CEPHEUS trial (ClinicalTrials.gov identifier: NCT03652064) of patients with transplant-ineligible (TIE) or transplant-deferred newly diagnosed multiple myeloma (NDMM; N = 395) demonstrated improved overall minimal residual disease (MRD) negativity rates among patients achieving ≥complete response and progression-free survival (PFS) with daratumumab plus bortezomib, lenalidomide, and dexamethasone (DVRd) versus VRd. We present efficacy and safety outcomes in the CEPHEUS TIE subgroup (N = 289; DVRd, n = 144; VRd, n = 145). Patients were either age 18-70 years with ≥1 comorbidity likely to negatively affect tolerability of high-dose chemotherapy with autologous stem cell transplantation or age ≥70 years. At a median follow-up of 58.7 months, the MRD negativity rate (10^-5) was 60.4% (DVRd) versus 39.3% (VRd; P = .0004). Rates of sustained MRD negativity (10^-5) for ≥12 months (47.2% v 28.3%; P = .0010) and ≥24 months (40.3% v 22.8%; P = .0015) were significantly higher with DVRd. Risk of disease progression or death was 49% lower for DVRd versus VRd (hazard ratio [HR], 0.51 [95% CI, 0.35 to 0.74]; P = .0003). Although immature, overall survival favored DVRd (HR, 0.66 [95% CI, 0.42 to 1.03]). Adverse events were consistent with known safety profiles. This analysis demonstrates that the deep responses achieved with DVRd translate into improved PFS in patients with TIE NDMM, reinforcing DVRd as a standard of care.

OBJECTIVE:The objective of this scoping review was to synthesize evidence on the proportion of individuals living with Sjögren's disease who experience central nervous system (CNS) manifestations. METHODS:We searched MEDLINE (via PubMed) and Embase from 1980 through January 29, 2026, and the ECRI Guidelines Trust from 2020 through January 29, 2026. Title and abstract screening, followed by full-text review, were performed in duplicate using prespecified inclusion and exclusion criteria. One reviewer extracted data, with an independent audit completed by one of the project co-leads. Meta-analyses of proportions were conducted. Sensitivity analyses were planned a priori to evaluate the influence of statistical outliers. RESULTS:We identified 22,857 citations, of which 108 met the inclusion criteria. Pooled proportion estimates were generated for 23 CNS manifestations. Several manifestations occurred at frequencies exceeding those reported in the general population, including depression, migraine, insomnia, cognitive dysfunction, psychosis, movement disorders, aseptic meningoencephalitis, neuromyelitis optica spectrum disorder, optic neuritis, multiple sclerosis, cerebral vasculitis, cerebellar syndrome, spinal cord involvement, and non-localizing somatosensory complaints. The degree of increased frequency differed substantially across manifestations, and several estimates were highly influenced by individual studies, as indicated by sensitivity analyses. CONCLUSION/CONCLUSIONS:The spectrum of CNS involvement in Sjögren's disease is broad and heterogeneous. Attributing CNS manifestations to direct SjD involvement or coexisting conditions remains unclear and cannot be assumed to be causally linked. Our findings underscore the complexity of CNS manifestations in Sjögren's disease and highlight the need for evidence-informed guidance to support accurate diagnosis, attribution, and management of neurologic manifestations.

PURPOSE/OBJECTIVE:To evaluate whether the duration between staged bilateral hip arthroscopy affects patient-reported outcomes, the rate of arthroscopic revision, or conversion to total hip arthroplasty. METHODS:A retrospective comparative case series was conducted of a single-surgeon prospective database of patients who underwent hip arthroscopy for femoroacetabular impingement syndrome with a minimum of 2-year follow-up. Modified Harris Hip Score and Nonarthritic Hip Score were recorded preoperatively and 2 years postoperatively for each hip. For analysis, patients were allocated into 2 groups: staged procedures <1 year apart and ≥1 year apart. RESULTS:A total of 76 patients (152 hips) underwent staged bilateral primary hip arthroscopies. Overall, the mean age at the first surgery was 36.1 ± 13.1 years and the cohort was 59.2% women. Of these, 43 patients (56.6%) underwent staged procedures <1 year apart, whereas 33 patients (43.4%) were staged 1 year apart. Age (P = .092), sex (P = .828), and body mass index (P = .867) did not significantly differ between groups. At 2-year follow-up, modified Harris Hip Score (first hip: 85.2 ± 17.9 vs 82.5 ± 13.3, P = .588; second hip: 84.7 ± 19.3 vs 79.3 ± 16.0, P = .514) and Nonarthritic Hip Score (first hip: 85.3 ± 19.1 vs 83.2 ± 12.4, P = .660; second hip: 86.5 ± 22.8 vs 84.9 ± 12.2, P = .823) were similar between groups staged <1 year and ≥1 year. There were no significant differences in rates of revision arthroscopy (7.0% vs 12.1%, P = .460) or conversion to total hip arthroplasty (4.7% vs 3.0%, P > .999) between groups staged <1 year and ≥1 year. Based on logistic regression, the duration between hip arthroscopy stages was not associated with the risk of arthroscopic failure (odds ratio: 1.29, P = .227). CONCLUSIONS:There were no significant differences in patient-reported outcomes, rates of revision arthroscopy, and conversion to total hip arthroplasty between patients who underwent staged bilateral hip arthroscopy less than or greater than 1 year apart. Duration of time between staged procedures was not found to affect rates of arthroscopic failure. LEVEL OF EVIDENCE/METHODS:Level III, retrospective comparative case series.

BACKGROUND:There are limited studies comparing the impact of transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) by annular size. OBJECTIVES:The aim of this post hoc analysis from the PARTNER (Placement of Aortic Transcatheter Valves) 3 trial was to assess the relationship between annular size and outcomes among patients with severe aortic stenosis (AS) who underwent TAVR or SAVR. METHODS:). The primary endpoint was the composite of death, stroke, or rehospitalization. Interactions among annular size, treatment strategy, and adjudicated 5-year clinical outcomes were assessed. RESULTS:Of the 925 patients with available computed tomographic angiography-derived annular size, 293 had small and 632 had large aortic annuli, respectively. Median follow-up duration was 5.2 years (Q1-Q3: 5.0-6.0 years). Five-year rates of the primary endpoint were similar for TAVR and SAVR in the overall cohort, results that were consistent for patients with small (21.2% vs 31.0%; OR: 0.60; 95% CI: 0.35-1.02) and large (23.5% vs 25.5%; OR: 0.90; 95% CI: 0.62-1.29) annuli, without effect modification by annular size (P for interaction = 0.22). Rates of bioprosthetic valve failure were similar and low at 5 years, without effect modification by annular size. Five-year health status was also similar between treatment modalities across annulus strata (P for interaction = 0.12). CONCLUSIONS:TAVR with the SAPIEN 3 valve led to similar 5-year clinical and health status outcomes compared with SAVR, irrespective of annular size. (PARTNER 3 Trial: Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis [P3]; NCT02675114).

BACKGROUND:Transcatheter aortic valve replacement (TAVR) is an established alternative to surgical aortic valve replacement for symptomatic severe aortic stenosis, but long-term, comparative clinical outcomes and echocardiography data are lacking. OBJECTIVES/OBJECTIVE:Our goal was to compare 10-year clinical and echocardiographic outcomes after balloon-expandable TAVR or surgery in intermediate-risk surgical patients in the PARTNER 2A randomized trial. METHODS:Between 2011 and 2013, patients with severe, symptomatic aortic stenosis at intermediate surgical risk were randomized at 57 centers to TAVR with the balloon-expandable SAPIEN XT system (Edwards Lifesciences) or to surgery. Randomization was stratified by anatomical suitability for transfemoral (TF) or transthoracic (transapical/transaortic [TA/TAo]) access. Ten-year outcomes were evaluated in the valve implant population and included all-cause mortality, aortic valve reintervention, and core laboratory-adjudicated echocardiographic outcomes. To obtain 10-year data, patient reconsent at 5 years was required, and vital status sweeps were implemented to improve data completeness for all-cause mortality. RESULTS:Among 1,910 randomized patients who received a valve, 974 underwent TAVR (TF: 749/974 [76.9%]) and 936 had surgery. Mean patient age was 81.6 years, 45.4% were women, and the mean Society of Thoracic Surgeons score was 5.8%. At 10 years, vital status was available for 881 of 974 patients (90.5%) and 838 of 936 patients (89.5%). All-cause 10-year mortality with vital status sweeps was 86.1% after TAVR and 82.8% after surgery (HR: 1.13; 95% CI: 1.02-1.25; P = 0.02). When stratified by access route, rates of all-cause mortality for TAVR and surgery in the TF group were similar (83.9% vs 82.1%, respectively; P = 0.27), whereas mortality was higher for TAVR in the TA/TAo group (93.2% vs 85.1%; P < 0.01; P for interaction = 0.03). Cumulative incidence rates of aortic valve reintervention at 10 years were 6.3% for TAVR and 1.6% for surgery (P < 0.001). Of the 24 TAVR and 35 surgical patients with available echocardiographic data at 10 years, mean gradients were 12.6 mm Hg and 12.7 mm Hg, respectively. CONCLUSIONS:At the 10-year follow-up, TAVR in intermediate-risk patients with the SAPIEN XT prosthesis compared with surgery was associated with lower survival rates, with differences predominantly observed in the TA/TAo access cohort. TAVR with the XT valve was also associated with significantly higher rates of aortic valve reintervention. (PARTNER II Trial: Placement of AoRTic TraNscathetER Valves II - XT Intermediate and High Risk [PII A]; NCT01314313).

Dysembryoplastic neuroepithelial tumors (DNTs) are low-grade glioneuronal tumors with FGFR1 alterations. They show significant histologic and molecular overlap with other glioneuronal tumors, complicating diagnosis. We analyzed 44 tumors that were either classified as DNT by DNA methylation (n = 37), or were diagnosed histologically as DNT but did not classify as DNT by DNA methylation (n = 7). 13/37 (35%) DNT-classifying tumors were histologically diagnosed as DNTs. High-confidence DNTs (score >0.9, 23 cases, 62%) demonstrated variable histology, most frequently DNT (39%), oligodendroglioma, and ganglioglioma and most frequently harbored FGFR1 alterations. Lower-confidence DNTs (score < 0.9, 14 cases, 38%) showed greater heterogeneity; their histologic diagnoses included papillary glioneuronal tumor, extraventricular neurocytoma, and pilocytic astrocytoma. Tumors with low confidence score exhibited diverse molecular alterations including BRAF V600E mutations, PDGFRA amplification, or multiple gene fusions. Among 7 histologically diagnosed DNTs that did not classify as DNT by methylation, most grouped with the myxoid glioneuronal PDGFRA-mutant class despite lacking canonical PDGFRA mutations. Thus, DNTs with high confidence scores are relatively homogenous but DNTs with low methylation confidence scores are heterogenous, highlighting the importance of integrated molecular profiling. Our findings also suggest that the myxoid glioneuronal tumor methylation class may require further classification of underlying drivers.

OBJECTIVE/UNASSIGNED:The objective of this study is to determine the optimal first trimester reticulocyte hemoglobin cutoff to predict iron deficiency anemia at 24 to 28 weeks' gestation and to compare its performance to first trimester ferritin. STUDY DESIGN/UNASSIGNED:weeks. Patients with first trimester anemia or blood transfusion 3 months prior to pregnancy were excluded. Iron deficiency anemia was defined as hemoglobin < 10.5 g/dL and ferritin < 30 µg/L. Optimal cutoffs were calculated using the receiver operating characteristic curve and the sensitivity/specificity pairs with the largest Youden index. RESULTS/UNASSIGNED:Of 600 nonanemic, pregnant participants enrolled, 499 participants were eligible for analysis at 24 to 28 weeks' gestation; 40 (8%) had iron deficiency anemia. The area under the curve of reticulocyte hemoglobin was 0.69 (95% confidence interval [CI]: 0.61-0.78) compared with 0.73 (95% CI: 0.65-0.81) for ferritin. The optimal first trimester cutoff was 32.6 pg for reticulocyte hemoglobin (sensitivity 42.5%, specificity 86.9%) and 29 µg/L for ferritin (sensitivity 47.5, specificity 87.6%). CONCLUSION/UNASSIGNED:First trimester reticulocyte hemoglobin did not outperform ferritin in predicting iron deficiency anemia at 24 to 28 weeks' gestation. Both reticulocyte hemoglobin and ferritin were weak predictors of iron deficiency anemia at 24 to 28 weeks and were more effective in identifying patients at low risk of iron deficiency anemia at 24 to 28 weeks.