Citations

Since its US Food and Drug Administration approval in 2016, magnetic resonance–guided focused ultrasound (MRgFUS) thalamotomy has grown into one of the procedures of choice among patients with essential tremor (ET). Approved applications for the procedure have expanded over time from unilateral thalamotomy to treat ET and Parkinson disease tremor to bilateral staged thalamotomy for ET. As the procedure expands to healthcare environments beyond large academic centers, guidance is required to ensure that the responsible clinicians are appropriately trained to undertake this operative procedure. Although multidisciplinary movement disorder teams are important for the optimal management of patients, MRgFUS lesions are inherently surgical interventions. Neurosurgeons are trained to evaluate these patients, consider surgical alternatives and conduct these operations, particularly after completing a fellowship in the subspecialty of stereotactic and functional neurosurgery. At present, all high-level evidence regarding the safety and efficacy of MRgFUS lesions to treat movement disorders derives from procedures performed by neurosurgeons, so those results may not be generalizable to other physicians. Based on these considerations and potential liability issues, the American Society for Stereotactic and Functional Neurosurgery, which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, puts forth this position statement that only neurosurgeons appropriately trained to conduct functional neurosurgery procedures should conduct MRgFUS surgical lesions.

Abstract Recent single-cell transcriptomic studies of follicular lymphoma (FL) have revealed heterogeneity among malignant B (MB) cells and selected components of the tumor microenvironment (TME), but have been constrained by relatively small sample sizes and a lack of spatial context. We performed comprehensive cellular profiling and spatial dissection of over five million cells by integrating single-nucleus RNA sequencing (snRNA-seq) from 182 samples (FL, n = 167; control, n = 15) with single-cell spatial transcriptomics (ST) from 386 samples (FL, n = 365; control, n = 21). After stringent quality control, 1,289,073 and 3,968,427 cells from snRNA-seq and ST data, respectively, were analyzed. Unsupervised clustering of snRNA-seq data identified 58 TME cell subtypes. To extend this classification to the ST dataset, we integrated snRNA-seq and ST data by co-embedding them into a shared principal component space, enabling robust batch correction and cell-type label transfer across modalities. Using this supervised annotation framework, ST data recapitulated 54 TME cell subtypes. MB, proliferating MB (MBprolif), and healthy B (HB) cells were classified using sample-level unsupervised clustering in ST. Macrophages exhibited previously uncharacterized heterogeneity in transcriptomic profiles and spatial distribution. We identified CXCL13-expressing macrophage subtypes with high intra- and peri-follicular abundance, termed follicular macrophages (FMs). Non-negative matrix factorization of intrafollicular cell fractions identified five TME archetypes: FM, follicular stroma, two follicular T, and HB archetypes. The FM archetype was enriched for intrafollicular macrophages, including FMs, and showed a significantly higher proportion of grade 3A/3B cases (53.4%) compared to other archetypes (≤16.5%). It was also associated with a higher frequency of high tumor burden requiring treatment initiation rather than a watch-and-wait (WW) approach. Among patients managed by WW, those with the FM archetype showed significantly shorter event-free survival (EFS) compared to those with non-FM archetypes, whereas this association was not observed among treated patients. The percentage of intrafollicular macrophages (IFMP) showed excellent predictive performance for the FM archetype (area under the curve: 0.90). IFMP calculated in a published multiplex spatial protein imaging dataset from an independent cohort of 242 FL patients validated the associations between high IFMP and both pathology grade 3A/3B and shorter EFS in WW patients. Consistently, spatial neighborhood and cell–cell communication analyses revealed co-localization of FMs and MBprolif cells, forming a distinct niche with activated signaling mediated by FM-derived CXCL13, APRIL, and BAFF. Our integrative multi-modal analysis defines previously unrecognized cellular heterogeneity and spatial architecture in FL and highlights macrophage-enriched follicular ecosystems associated with aggressive clinicopathological features, providing a framework for improved biological understanding and patient management. Citation Format: Yoshiaki Abe, Bijal Thakkar, Atish Kizhakeyil, Ashley Wilson, Andrew L. Feldman, Jared Henderson, Amy Ayers, Sara Borgschatz, R. Andrew Harkins, Priya Lakra, Daisuke Kaji, Jonathon B. Cohen, David Russler-Germain, Eric Mou, Francisco Vega, Jennifer Chapman, Giorgio Inghirami, Carla Casulo, Izidore S. Lossos, Jean L. Koff, Chijioke Nze, Peter Martin, Sergei Syrbu, Kiran Vij, David L. Jaye, James R. Cerhan, Christopher R. Flowers, Anne J. Novak, Richard Burack, Dai Chihara, Mamiko Sakata-Yanagimoto, Joshua Tobin, Xubin Li, Michael R. Green. Spatially resolved microenvironment profiling reveals distinct follicular lymphoma archetypes [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A049.

Abstract Embryonal tumors with multilayered rosettes (ETMR) are rare, highly aggressive tumors of infancy with extremely poor outcomes and no established standard of care therapy. ETMRs were recognized as a distinct molecular entity in 2016, however, the absence of prospective, biology-driven clinical trials has limited translation of these insights into standardized, risk-adapted treatment approaches for this vulnerable population. To address this gap, the Collaborative Network for Neuro-oncology Clinical Trials (CONNECT) developed CURE(Clinical trial advancing Understanding of Rare Embryonal Brain Tumors), an international, multi-institutional, molecularly guided umbrella trial. All patients enroll through the centralized CURE-Screening protocol, which provides rapid comprehensive molecular profiling with real-time central pathology, molecular, and radiographic review to confirm diagnosis, define molecular subtype, and determine eligibility and assignment to disease-specific treatment arms. CURE-ETMR represents the first disease-specific arm to open within this platform. Following centralized screening, children with newly diagnosed ETMR are assigned to clinically defined risk strata using integrated molecular, radiographic, and clinical criteria. Patients will be treated using a risk-adapted multimodal approach in which we prioritize maximal safe surgical resection with consideration of second-look surgery based on centralized imaging review; administer induction chemotherapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic cell rescue or dose-intensified chemotherapy, selectively incorporate radiation sparing approach or early focal radiotherapy for patients with unresectable residual disease or brainstem involvement; deliver intrathecal chemotherapy for leptomeningeal prophylaxis; and include biologically informed maintenance therapy. In parallel, protocol-required longitudinal collection of tumor tissue, cerebrospinal fluid, blood, and advanced neuroimaging supports integrated molecular, liquid biopsy, and imaging biomarker analyses to identify predictors of treatment response, resistance, and relapse. Primary objectives include evaluation of feasibility, safety, progression-free survival, and overall survival compared with molecularly annotated historical cohorts. This centralized screening to assignment framework establishes a scalable model for prospective, biology-driven trials in rare embryonal brain tumors.

Abstract Pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine glioma (DIPG), are among the most aggressive childhood brain tumors, with five-year survival rates below 10%. Current treatment options are limited to radiation, highlighting the urgent need for novel therapies. Telomere maintenance via telomerase activation is a hallmark of cancer, enabling replicative immortality. Our prior studies demonstrate telomerase activity in 73% of HGGs and 47% of DIPG, implicating telomere biology as a critical therapeutic target. 6-thio-dG (THIO) is a first-in-class telomere-targeting agent that incorporates into telomeres of telomerase-positive cells, inducing telomere uncapping, genomic instability, and apoptosis. THIO crosses the blood–brain barrier and exhibits synergy with radiation in preclinical DIPG models. Telomere dysfunction is confirmed by telomere dysfunction-induced foci (TIFs), marked by colocalization of DNA damage response proteins (ATM S1981-P, γH2AX, 53BP1) at telomeres. Historical pediatric leukemia trials established THIO’s safety profile, and recent adult studies in non-small cell lung cancer demonstrated efficacy at lower doses. As part of the biologically-guided umbrella trial CONNECT TarGeT [NCT05839379], we are developing TarGeT-H, a phase 1/2 and surgical study to evaluate THIO combined with focal radiation in pediatric, adolescent, and young adult patients with newly diagnosed HGG or DIPG harboring telomerase activation, confirmed by hTERT mRNA expression—assessed via tumor submission, profiling, and rapid central screening through TarGeT-SCR. Specific aims include: (1) determining pharmacokinetics and safety to establish the recommended Phase 2 dose (RP2D); (2) estimating efficacy by progression-free survival (HGG) and overall survival (DIPG) compared to historical controls; and (3) assessing telomere dysfunction in resected HGG tumors via TIF analysis. Up to 90 patients will receive THIO intravenously during radiation and maintenance cycles for up to two years. By leveraging a selective telomere-targeting mechanism distinct from current therapies and demonstrating synergy with radiation, THIO represents a promising strategy to improve outcomes in devastating pediatric cancers.

Importance TMEM106B is a frontotemporal lobar degeneration (FTLD) genetic susceptibility factor, and TMEM106B protein aggregates are a feature of aging and neurodegeneration. Whether TMEM106B protein levels are associated with clinical features is unknown. Objective To investigate the clinical associations of cerebrospinal fluid (CSF) TMEM106B in FTLD. Design, Setting, and Participants This cross-sectional study was conducted in 2 independent frontotemporal dementia (FTD) cohorts (recruitment from April 2009 through July 2023, with analyses from January 2025 through April 2026), with a 2-year follow up. This multicenter clinical study integrated clinical, genetic, biomarker, and neuroimaging data. Individuals were recruited through the University of California, San Francisco (n = 3733), or ALLFTD (n = 2343). Participants with available CSF were included. A discovery cohort (n = 271) included participants with sporadic neuropathology-confirmed FTLD; presymptomatic or symptomatic carriers of pathogenic variants in C9orf72 , GRN , or MAPT ; or controls. An independent validation cohort (n = 383) included participants with clinically diagnosed sporadic FTD, Alzheimer disease (AD), and controls. Exposures CSF samples for TMEM106B quantification with aptamer proteomics (SomaScan version 3.0 [discovery cohort] and SomaScan version 4.1 [validation cohort]). Main Outcomes and Measures Parametric tests compared the primary outcome, CSF TMEM106B, by disease severity, TMEM106B rs1990622 genotype, sex, clinical syndrome, pathological diagnosis, and pathogenic variant and determined associations with brain volume. Results In the discovery (n = 271; 136 women [51%]; median [IQR] age, 59 [38-80] years) and validation (n = 383; 183 women [48%]; median [IQR] age, 64 [50-78] years) cohorts, lower CSF TMEM106B was associated with more severe disease (β, −0.15; 95% CI, −0.24 to −0.04; P = .003), lower frontotemporal brain volumes (β, 0.42; 95% CI, 0.24-0.61; P < .001), and faster clinical progression (β, −2.21; 95% CI, −3.70 to −0.72; P = .001). Associations of TMEM106B with clinical disease severity were independent of those with neurofilament light chain. TMEM106B levels were influenced by TMEM106B rs1990622 genotype, where individuals with the protective G/G genotype had lower levels than the risk A/A genotype. CSF TMEM106B levels did not differentiate between FTLD subtypes or between FTLD and AD. Conclusions and Relevance Per the results of this cross-sectional study, TMEM106B is detectable in CSF and levels reflect disease severity in sporadic and genetic FTLD and AD, but levels are also influenced by the TMEM106B rs1990622 genotype. CSF TMEM106B could support further studies to understand the mechanisms of disease and develop clinical tools in FTLD and other neurodegenerative diseases.

Abstract Background Adipose tissue influences blood pressure regulation through depot-specific endocrine, inflammatory, and exosome-dependent mechanisms. While obesity is a well-established risk factor for hypertension, emerging evidence suggests that distinct fat depots may contribute to vascular dysfunction independent of total adiposity. Methods: This review synthesizes post-2020 literature on 6 anatomically defined depots: visceral, perivascular, epicardial, bone marrow, brown, and beige adipose tissue, with an emphasis on their mechanistic roles, imaging biomarkers, and translational relevance. Results Alterations in adipose depot function can impair nitric oxide signaling, promote oxidative stress, and modulate sympathetic tone, even in the absence of obesity. Exosomal microRNAs from dysfunctional adipose tissue further disrupt vascular homeostasis. Although clinical tools for assessing depot dysfunction are limited, advances in imaging and molecular profiling may enable targeted therapeutic strategies. Conclusions Reframing adipose tissue as a modular regulator of blood pressure, rather than a passive consequence of obesity, may unlock new venues for precision management of hypertension.

Abstract Objective To evaluate otolaryngology (ENT) residency match trends before and after the USMLE Step 1 transition to pass/fail. Study Design Observational longitudinal analysis of annual, publicly available specialty‐level data (2010‐2025). Setting National Resident Matching Program (NRMP). Methods Data from 2010 to 2025 were used to calculate applicants per PGY‐1 position, fill rate, and nonmatch‐in‐specialty rate. ENT was compared with plastic surgery, orthopedic surgery, neurological surgery, and general surgery. We used ordinary least squares (OLS), segmented regression with a 2023 breakpoint, and difference‐in‐differences (DID) models. Results From 2010 to 2025, ENT programs increased from 105 to 139 and positions from 280 to 394. Applicants per position ranged from 1.06 to 1.60 (mean 1.38). OLS showed no significant long‐term trend in applicants per position (+0.002/year, P = .86), fill rate (+0.03 percentage points/year, P = .68), or nonmatch‐in‐specialty rate (+0.04 percentage points/year, P = .94). Segmented regression showed no significant post‐2023 changes in applicants per position (slope change +0.03/year, P = .78), and no significant changes in applicant counts ( P = .7). ENT had the largest 2022 to 2023 decline in this cohort, in both applicants (−14.1%) and applicants per position (−16.9%). However, in two‐way fixed‐effects DID models, there was no ENT‐specific post‐transition change in applicants per position ( P > .05 in primary and sensitivity analyses). Conclusion ENT remained highly competitive but trend‐stable from 2010 to 2025. Although 2023 showed a notable drop in applicants, we found no consistent evidence of a sustained ENT‐specific competitiveness shift after the Step 1 pass/fail transition. Level of Evidence 4.

Background Long-term corticosteroid (LTC) use is a known risk factor for adverse outcomes after various surgical procedures. However, the impact of LTC use on surgical complications after TSA remains underexplored. This study aims to assess the influence of LTC use on 90-day and 5-year complications following TSA. Methods A retrospective cohort study utilizing the PearlDiver database was conducted. Patients undergoing primary TSA with a minimum 5-year follow-up were included. LTC users were propensity-matched 1:10 with controls based on demographic variables and comorbidities. Postoperative complications within 90 days of surgery and long-term complications within 5 years were compared between groups. Multivariable logistic regressions were used to compare complications controlling for demographic variables and comorbidities. Results In a matched cohort of 556 LTC users to 4942 controls, corticosteroid users exhibited a 2.91-fold higher risk of pneumonia (95% CI: 1.69–4.80, p < 0.001) and a 2.19-fold higher risk of venous thromboembolism (VTE) (95% CI: 1.30–3.51, p = 0.001) within 90 days following TSA. No significant differences in 5-year surgical outcomes were observed. Discussion LTC users are at a heightened risk for 90-day medical complications, including pneumonia and VTE following TSA. However, their 5-year risk of surgical complications was comparable to patients without LTC use.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

Objective: Percutaneous needle tenotomy (PNT) and ultrasonic debridement (UD) are minimally invasive interventions for the management of chronic tendinopathy. Despite their increasing use, no standardized, evidence-based rehabilitation guidelines currently exist to direct clinicians in post-procedural management. This systematic review aimed to characterize and synthesize reported rehabilitation protocols following PNT and UD for patellar, proximal hamstring, and gluteal tendinopathies. Design: Systematic Review Results: Twenty-seven studies met inclusion criteria, with patellar tendon procedures (n=13) being the most common, followed by gluteal (n=6), proximal hamstring (n=3), and multi-tendon protocols (n=5). Of the included studies, 21 (78%) utilized percutaneous needle tenotomy (PNT) and six (22%) used ultrasound debridement or Tenex. Exercise restrictions were mandated in 19 studies (70%), while 12 (44%) provided a detailed, structured rehabilitation program, frequently emphasizing eccentric loading for patellar and hamstring tendons. Weight-bearing limitations were uncommon, appearing in only three studies (11%). Fifteen studies (56%) combined the procedure with platelet-rich plasma (PRP). Pharmacological protocols also showed high variance, with NSAID restrictions ranging from 1 to 28 days and corticosteroid avoidance lasting between 10 days and one year. Overall, substantial variability remains regarding recommended activity progression, exercise initiation, and mechanical loading strategies across current research. Conclusion: PNT and UD appear effective for managing refractory tendinopathy, yet post-procedure rehabilitation guidelines remain inconsistent and supported by limited high-quality evidence. Future research should aim to identify key variables that guide individualized rehabilitation progressions, optimizing recovery timelines, and facilitating safe and efficient return to activity following PNT and UD procedures.