Citations

Chimeric antigen receptor T-cell (CAR-T) and CD20xCD3 bispecific antibody (BsAb) therapies are both effective for relapsed/refractory (R/R) follicular lymphoma (FL), but comparative real-world survival outcomes and time toxicity have not been characterized. We performed a multicenter retrospective study of 228 patients with R/R FL treated with standard-of-care CAR-T (n = 141) or BsAb (n = 87) across 17 U.S. academic centers in the third-line or later setting. Progression-free survival (PFS) and overall survival (OS) were stratified by 2 or ≥3 prior lines of therapy (LOT2 or LOT3+), including propensity matching. Time toxicity was measured by physical health care contact days. Median PFS was not reached (NR) with CAR-T and 581 days with BsAb in the LOT2 cohort (p < .0001), and was NR with CAR-T and 584 days with BsAb in the LOT3+ cohort (p = .0064). CAR-T recipients were younger (p < .0001) and had better performance status (p = .007) but were more refractory to prior LOT (p = .017). PFS advantages of CAR-T were independent of these differences. OS did not differ between treatment groups. CAR-T had significantly greater time toxicity over the first year, with higher mean contact days than BsAb in both the LOT2 (58 vs 44) and LOT3+ (69 vs 49) cohorts. In this large multicenter cohort of patients with R/R FL, CAR-T was associated with superior PFS but greater time toxicity compared with BsAb therapy. These findings provide real-world outcomes data and time toxicity benchmarks to support treatment sequencing decision-making in R/R FL.

Objective During open chondral defect preparation, audible debridement sound changes mark the transition from deep cartilage to the calcified cartilage layer. We developed a novel curette microphone to characterize these audio feature differences during arthroscopic defect preparation. Design A piezoelectric curette microphone was used to transmit and record debridement sound from 12 defect preparations (6 deep cartilage, 6 CCL) using human osteochondral allograft remnants. Live audio from the device was used to stop each debridement at the intended level, which was verified histologically. Spectrograms and power-spectral density plots were used to describe the audible transition from deep cartilage to CCL. We compared 22 audio features describing loudness, frequency, and complexity between the two tissue levels. Results Curette strokes against the deep cartilage were louder, higher frequency, and more acoustically complex than strokes against the CCL (p < 0.001). Cartilage debridement generated acoustically complex frequency bands above 2.5 kHz that diminished upon reaching the CCL. Debridement of the CCL produced a simpler audio profile that was predominant below 350 Hz. Conclusion The novel curette microphone presented here transmits high-fidelity debridement audio that can be used to accurately distinguish tissue depth based on the distinct audio profiles of the deep cartilage and CCL.

Abstract Background The T6 neurological level of spinal cord injury (SCI) is classically taught as differentiating who is and is not at risk for autonomic dysreflexia (AD); yet the reliability of this metric has rarely been tested. Objectives To determine how often individuals with SCI above and below the T6 neurological level of injury (NLI) experience symptomatic AD, quantify AD in the autonomic physiology laboratory, and describe underlying mechanisms that clinically manifest. Design Cross‐sectional. Setting Academic medical center. Participants 138 individuals with/without SCI. Interventions Not applicable. Main Outcome Measures Symptoms of AD were quantified using the validated Autonomic Dysfunction Following SCI‐AD survey. Deep autonomic physiology characterization was further completed ( n = 34 uninjured controls, n = 28 individuals with SCI) to identify underlying AD mechanisms. Continuous blood pressure, heart rate, regional vascular resistance in the arm/leg, and pre/posttest catecholamines were recorded. Vascular responsiveness and baroreflex sensitivity were assessed with intravenous phenylephrine boluses. Foot cold pressor and bladder pressor tests served as below level mild noxious stimuli to elicit controlled AD. Results AD symptoms were, as expected, significantly higher after SCI compared to uninjured controls ( p < .001). Symptomatic AD was identified in 77% of individuals with SCI at/above T6, compared to 38% with injuries below T6. McNemar's statistic indicated the T6 neurological level poorly differentiated who developed symptomatic AD ( p = .039). During laboratory testing, 57% of those with SCI at/above T6 experienced AD, as did 57% of those with injuries below T6 ( p = .33). Physiologically, AD in individuals with SCI below T6 can be due to heightened vascular responsiveness and poor baroreflex sensitivity, leading to minimal compensatory bradycardia. Conclusions Symptomatic and objective AD occurs in those with SCI above and below the T6 NLI threshold. As such, targeted autonomic testing must translate to the bedside to accurately quantify AD risk. In the interim, though the T6 threshold has become cannon in many patient and resident education materials regarding AD risk, evidence suggests clinical care should avoid using this strict cutoff.

Abstract Positron emission tomography (PET)-based molecular imaging is a clinically important tool for the evaluation of dementia and other neurodegenerative disorders, using radiotracers that target specific molecular and pathophysiological processes. Fluorodeoxyglucose brain PET has historically supported neurodegenerative disorder evaluation through detection of characteristic patterns of regional glucose hypometabolism. In recent years, the molecular imaging of protein aggregates has taken on an increasingly important role. This is evident with the widespread clinical adoption of amyloid PET and early use of tau PET to provide diagnostic and prognostic information for patients with suspected Alzheimer’s disease. Additional classes of radiotracers relevant to neurodegenerative diseases are under active investigation, including those targeting neuroinflammation, synaptic density, and α-synuclein aggregates. We review the major classes of PET radiotracers for neurodegenerative diseases, describing their molecular mechanisms, diagnostic performance, and their current and emerging clinical roles in dementia evaluation. Case examples for clinically used tracers illustrate imaging features relevant to diagnosis and characterization of prognosis and treatment effect. Finally, we discuss early developments and current challenges in the development of theranostic approaches and novel radiotracers for neurodegenerative diseases.

Background: Iliopsoas impingement (IPI) is a known cause of persistent anterior hip pain following total hip arthroplasty (THA). Management of IPI has often relied on an 8-mm anterior acetabular overhang threshold to guide operative treatment, favoring acetabular revision for greater overhang and iliopsoas tenotomy for lesser overhang. These thresholds were initially established on the basis of the outcomes of open tenotomy, and now, with an improved understanding of IPI and the advent of arthroscopic iliopsoas fractional lengthening (IPFL), a review of the 8-mm threshold is warranted. Methods: A retrospective review was performed to identify patients who underwent arthroscopic IPFL following primary THA between 2017 and 2024, with a minimum follow-up of 1 year. Acetabular overhang was measured for all patients using cross-table lateral radiographs, and patients were stratified into <8-mm and ≥8-mm cohorts. Patient-reported outcome measures, reoperations, revisions, and complications were collected and analyzed on the basis of both the classic 8-mm threshold and continuous statistical methods. Results: We evaluated 86 hips undergoing IPFL. There were 83 patients (30 men and 53 women), with a mean age of 63.0 ± 11.2 years; with regard to race, 80 patients were White, 1 patient was Black or African American, and 2 patients listed other race or chose not to disclose. The acetabular overhang was <8 mm for 67 hips and ≥8 mm for 19 hips. The mean follow-up was 2.5 ± 1.6 years (range, 1 to 7.5 years). When comparing patients with <8-mm and ≥8-mm acetabular overhang, we observed no significant differences (p > 0.06) in the preoperative and postoperative visual analog scale (VAS) pain scores, modified Harris hip score, Single Assessment Numeric Evaluation (SANE) score, Tegner activity level, subjective groin pain improvement, subjective hip flexion strength improvement, and overall satisfaction. Reoperation (2.9% compared with 10.5%; p = 0.210) and acetabular revision rates (1.5% compared with 5%; p = 0.387) were not significantly different between the <8-mm and ≥8-mm overhang groups. Conclusions: Arthroscopic IPFL provided satisfactory outcomes for patients with IPI, independent of the magnitude of acetabular overhang. IPFL should be considered for first-line surgical management of IPI refractory to nonoperative management, even in the setting of substantial acetabular overhang, given positive outcomes and low rates of subsequent acetabular revision. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Regorafenib and anti-EGFR monoclonal antibodies are standard therapies for RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) in the refractory setting, but the optimal sequencing remains unknown. Herein, we report results from REVERCE II, a randomized phase II trial evaluating the efficacy and safety of sequencing these therapies. Methods Patients with RAS WT mCRC previously treated with fluoropyrimidine, oxaliplatin, and irinotecan were randomized to receive (R-E) regorafenib followed by anti-EGFR therapy ± irinotecan or (E-R) anti-EGFR therapy ± irinotecan, followed by regorafenib sequentially. The primary endpoint was overall survival (OS). Key secondary endpoints included progression-free survival (PFS) with initial (PFS1) and second treatment (PFS2), sequential treatment PFS (stPFS), objective response rate (ORR), and safety. Exploratory endpoints included serial biomarker analyses. Unfortunately, the trial was closed prematurely due to slow enrollment and lack of funding. Results Twenty-two patients were enrolled (R-E: n = 12; E-R: n = 10) with sequential treatment initiated in 33% (4/12) and 80% (8/10) of patients in R-E and E-R, respectively. Median OS for R-E and E-R was 21.9 and 13.3 months, respectively (one-sided P = .114). PFS1 was 2.5 (R-E) vs 5.6 months (E-R) (one-sided P = .998), while PFS2 was 3.7 vs 2.0 months (one-sided P = .086). stPFS was similar (9.3 vs 9.6 months; one-sided P = .358). ORR for initial treatment was 0% in R-E and 20% (2/8) in E-R. Sequential treatment ORR was 25% (n = 1/4) in R-E and 0% in E-R. No significant differences were observed adverse effects between arms. Conclusion While the study was closed prematurely prior to completion, the sequence of regorafenib before to anti-EGFR therapy suggested a possible survival benefit. Further studies may help better determine the optimal treatment sequencing strategy in refractory mCRC.

Objective To evaluate the efficacy of cytokine‐directed therapies in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. Methods All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin‐1 (IL‐1) or IL‐6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3‐, 6‐, and 12‐month follow‐up time points. Treatment response was labeled as complete response (CR; normalization of C‐reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Results Overall, 52 patients received an IL‐1i, IL‐6i, or JAKi therapy. At six‐month follow‐up, 3 of 19 IL‐6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL‐1i or TNFαi experienced CR, and only 1 of 5 IL‐1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL‐6i and 0 of 7 receiving JAKi experienced CR. Conclusion IL‐6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL‐1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.

Antisense oligonucleotides (ASOs) represent a promising therapeutic modality for RNA-based disease mechanisms, but identifying high-efficacy candidates from large sequence spaces remains a major bottleneck in drug development. Here, we present ASOFormer, a novel Transformer-based neural network that predicts the inhibition efficiency of RNase H-mediated ASOs from sequence, predicted secondary structure, and chemical modification features. ASOFormer was trained on a knockdown efficacy dataset spanning over 170,000 ASO-target pairs compiled largely from published patents. Ablation analysis confirmed that the addition of chemical modification features to the primary sequence drove the largest performance gains, with predicted secondary structure providing complementary benefit when combined with modification information. Further analysis highlighted the importance of the wings of gapmer ASOs and other features. As independent validation, ASOFormer was applied to ASOs targeting seven genes that were not in the training dataset gene list. For four out of the seven genes, the ground truth ASO inhibition efficiency was obtained from a public dataset, whereas the others were measured in-house via qPCR. Compared to two published state-of-the-art methods, ASOFormer achieved the best overall accuracy and prioritized the strongest inhibitors. Crucially, only ASOFormer consistently exceeded random expectation for top-candidate recovery across all seven test genes.

Abstract Background: Sexual and gender minority (SGM) representation is growing in the United States. This study estimated the future SGM cancer burden amidst shifting cancer patterns. Methods: Age-specific incidence data for breast, prostate, colorectal, lung, and melanoma were obtained from the Surveillance, Epidemiology, and End Results Program’s 12-registry database. Nordpred age-period-cohort models projected incidence through 2040 to 2044. Rates were applied to US Census population estimates and generation- and sex-specific SGM identification proportions from Gallup’s 2023 to 2024 surveys. Prophet was used for sensitivity analysis. Results: At ages 55 to 59, breast cancer cases among Millennial SGMs were 3,672% higher than among Silent Generation SGMs (34,850 vs. 924 cases), melanoma cases were 1,061% higher (5,526 vs. 476 cases), and colorectal cancer cases were 2,206% higher (23,594 vs. 1,023 cases). Compared with Generation X, Millennial prostate cancer cases were 142% higher (8,100 vs. 3,344 cases), and lung cancer cases were 169% higher (5,451 vs. 2,029 cases). By 2040 to 2044, Millennials were projected to account for 68.4% of breast cancer cases and 59.7% of colorectal cancer cases among SGMs. Conclusions: At ages 55 to 59, the 5-year cancer burden was projected to be 15 times higher among Millennials than Silent Generation SGMs (77,521 vs. 5,134 cases), driven primarily by the larger SGM population in younger generations. Oncology systems will need to prepare for the increase in cancer care demand. Impact: These findings identify a substantial generational shift in the SGM cancer burden and may inform oncology workforce capacity, culturally responsive cancer care, and healthcare system preparation for this growing population.