Citations

Objective To assess integration of a single-use robotic-assisted cochlear implant (RA-CI) electrode array insertion system into surgical workflows, identify potential challenges, and inform best practices. Study Design Survey. Setting Survey data from 16 surgeons across 10 US hospitals. Patients CI candidates 12 years and older with radiographically normal cochleae. Intervention CI surgery with single-use RA-CI insertion system during electrode array insertion. Main Outcome Measures Number of RA-CI to achieve proficiency, estimated additional time for RA-CI, and best practices to successfully incorporate the RA insertion system into CI surgery. Results A total of 121 RA-CI cases were performed. All surgeons completed the survey. Most surgeons (62.5%) reported they would feel comfortable using the device within five cases. Eight (50%) reported use of the RA system added 5 to 10 minutes to the case, and seven (44%) reported an added 10–15 minutes. Providing adequate incision size to secure the unit base superior to the temporal line and maximizing exposure of the facial recess were the most recommended best practices. Additional recommendations included pulling the receiver/stimulator forward within the pocket to facilitate a full electrode array insertion and considering drive head placement and mastoidectomy size to maximize overall visibility during electrode array insertion. Conclusions Proficiency with an RA electrode array insertion system during CI surgery can be achieved with minor adjustments to the surgical approach, within relatively few use cases (generally <5) and with minimal time addition (between 5 and 15 min). Training to specific best practices is important before initial clinical use.

Osteoarthritis (OA) is a major global health problem with no disease-modifying therapies. Interleukin-1 (IL-1) is a critical cytokine associated with the pathophysiology of OA and can be inhibited by IL-1 receptor antagonist (IL-1Ra). Here, we tested the delivery of a gene therapeutic encoding the human IL-1Ra to the knee in a phase 1, open-label clinical trial that enrolled nine patients with radiographic knee OA. The IL-1Ra gene was delivered by a self-complementary (sc)–recombinant adeno-associated virus (rAAV) serotype 2.5 (sc-rAAV2.5IL-1Ra) by intra-articular injection into an index knee at one of three doses: low [1 × 10 11 viral genomes (vg)], mid (1 × 10 12 vg), or high (1 × 10 13 vg). The primary outcome was safety. There were no serious adverse events (AEs) related to sc-rAAV2.5IL-1Ra. Two AEs occurred that were possibly related to the vector. Both were effusions with increased pain and resolved with conservative treatment. sc-rAAV2.5IL-1Ra did not cause changes in vital signs, physical findings, or clinical laboratory measures. Less than 1% of the injected dose of sc-rAAV2.5IL-1Ra vg was detected in circulation after 1 day and was cleared within a week. Titers of neutralizing antibodies to AAV2.5 rose in serum and synovial fluid. In all cases, IL-1Ra concentration increased in the synovial fluid, and IL-1Ra concentrations remained elevated after 1 year. Baseline pain and function scores improved during the study. Therefore, we found that intra-articular gene therapy with sc-rAAV2.5IL-1Ra was safe. The sustained increase in local IL-1Ra in human knee joints supports the further clinical examination of this therapy to provide therapeutic benefit in OA.

Aims An angular proximal femoral deformity, in association with osteoarthritis (OA) of the hip, considerably increases the technical complexity of primary total hip arthroplasty (THA). The aims of this study were to determine the long-term implant survival, the risk factors for failure, complications, and clinical outcomes of contemporary primary THA in this difficult group of patients. Methods Our institutional total joint registry was used to identify 119 primary THAs performed in 108 patients with an angular proximal femoral deformity, between January 1997 and September 2017. The deformity was related to a previous femoral osteotomy in 102 THAs (86%), and developmental or metabolic disorders in 17 THAs (14%). A total of 62 hips (53%) had a predominantly varus deformity. The mean age of the patients was 44 years (SD 13), their mean BMI was 29 kg/m 2 (SD 6), and 70 (59%) were female. An uncemented femoral component with metaphyseal fixation was used in 35 THAs (30%), an uncemented femoral component with diaphyseal fixation in 34 (29%), an uncemented modular femoral component with a metaphyseal fixation sleeve in 29 (24%), and a cemented femoral component in 21 (18%). Simultaneous corrective femoral osteotomy was performed in 22 THAs (18%). Kaplan-Meier survival and Harris Hip Scores (HHSs) were reported. The mean follow-up was eight years (2 to 22). Results The ten-year survival free of femoral loosening, any femoral revision, any revision and any reoperation was 95%, 93%, 90%, and 88%, respectively. A total of 13 revisions were undertaken, for aseptic femoral loosening in three, fracture of the femoral component in two, dislocation in two, aseptic acetabular loosening in two, polyethylene liner exchange in two, and infection in two. A preoperative varus deformity was associated with a higher risk of any revision (hazard ratio (HR) 12.5, p = 0.020), and those with a simultaneous osteotomy had a higher risk of any reoperation (HR 3.6, p = 0.023). The mean HHSs improved significantly from 52 preoperatively to 82 at ten years (p < 0.001). Conclusion In the largest series to date of primary THAs in patients with hip OA and an angular proximal femoral deformity, we found a good ten-year survival free from any revision. Varus deformities, particularly those treated with a simultaneous osteotomy due to the magnitude or location of the deformity, had a higher rate of further surgery. Cite this article: Bone Joint J 2025;107-B(6 Supple B):101–108.

ABSTRACTPrimary lymphedema (i.e., a chronic condition characterized by the accumulation of protein‐rich fluid in the interstitial spaces due to impaired lymphatic drainage) and lipomatosis of nerve (LN) (i.e., a congenital lesion characterized by the presence of fat interspersed within nerve) can involve a significant overgrowth of the affected limb, but their pathophysiology and treatment are totally different. This report addresses the misdiagnosis of both entities. The purpose is to highlight how both entities can be differentiated through two case reports. The first patient, a 69‐year‐old man, presented in our lymphedema clinic with multiple debulking operations; he was diagnosed with right upper extremity lymphedema during childhood. The thumb, index, and middle fingers had previously been amputated due to sequelae from the bony overgrowth. MRI of the right upper extremity showed pathognomonic features of LN affecting the median nerve associated with soft tissue fatty overgrowth. He had a 3 months follow‐up for this condition in our institution during which his symptoms remained stable. The second patient, an 81‐year‐old man, presented in our lymphedema clinic. He carried a long time diagnosis of primary left lower extremity lymphedema and had been followed at our institution for more than 25 years. Physical examination revealed overgrowth (increased volume) affecting the entire leg and foot. MRI showed pathognomonic features of LN of the left sciatic nerve. No surgical interventions were performed. At the last follow‐up, his extremity showed slightly worsened diameter measurements. Based on our 2 cases presented and 2 additional cases identified in the literature, we believe that primary lymphedema and LN are two different entities that could be confused. Plastic surgeons treating patients with lymphedema should be aware of LN and rule out this condition clinically and with imaging (US or MRI).

Palliative care (PC) has been shown to improve quality of life (QoL), reduce symptom burden, and align care with patient goals in those with serious illnesses. However, its integration into the emergency department (ED), where many patients with advanced illness present, remains underexplored and inconsistently applied. This narrative review evaluates several recent studies on ED-based palliative care, aiming to clarify whether the early benefits in symptom management and QoL are associated with reduced healthcare utilization and cost. A comprehensive literature search identified five new key studies with significant methodological differences, including variations in patient populations, outcome measures, and study designs. Some studies demonstrated short-term symptom relief, yet only one showed significant improvements in QoL at long-term follow-up. For healthcare utilization, still only one of these new studies reported substantial cost savings, underscoring the need for further research to validate financial benefits. We suggest how future work should be designed to explore both clinical and economic outcomes in tandem to establish a clear value proposition for ED-based palliative care. By addressing this lack of cohesion, we can determine the merit of ED-palliative care integrations with the goal of improving patient care and optimizing resource utilization.

AbstractBackgroundStimulation‐induced dyskinesias (SID) from deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) are uncommon; however, they are increasingly recognized. Once considered transient and indicative of effective neuromodulation, SID are now seen as potential therapy‐limiting side effects, akin to internal capsule activation. The mechanism and anatomical basis for SID remain poorly understood.MethodsWe conducted a retrospective study of individuals with Parkinson's disease with STN or GPi DBS who experienced SID in the dopaminergic medication OFF state during the monopolar review 1‐month post‐implantation.ResultsWe analyzed 137 monopolar stimulation observations (105 GPi, 32 STN). In the GPi cohort, discriminative fiber tract analysis showed a strong association between SID and the modulation of subthalamo‐pallidal fibers. This correlation was confirmed using leave‐one‐out and five‐fold cross‐validation. We further validated this model by predicting SID in independent STN and GPi cohorts, with the GPi‐based model accounting for significant variance in SID occurrence in both cohorts.ConclusionsSID from STN or GPi DBS likely shares a common pathway via subthalamo‐pallidal connectivity. DBS modulation of these fibers correlates with SID, as confirmed by multiple cross‐validation methods. These findings suggest that the fibers are part of a more extensive and yet‐to‐be‐fully‐characterized dyskinesia network. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

11507 Background: Advanced uterine leiomyosarcoma (uLMS) is an aggressive malignancy with poor prognosis. Standard-of-care treatments, including trabectedin (Tb) or pazopanib (P), provide median progression-free survival (PFS) of 3-4 months (mo) and objective response rates (ORR) of ~11%. Homologous recombination deficiency (HRD) in a subset of uLMS supports the use of PARP inhibitors combined with DNA-damaging agents. Preclinical studies demonstrated synergistic activity of olaparib and temozolomide (T+O), and a prior single-arm Phase II study of T+O showed promising efficacy independent of an established biomarker, warranting further investigation in a randomized setting. Methods: Alliance A092104 is a Phase II/III trial evaluating olaparib (200 mg BID) plus temozolomide (75 mg/m² daily, days 1-7, every 21 days) versus investigator’s choice of Tb or P in patients (pts) with advanced uLMS who progressed on ≥2 prior systemic therapies. Stratification factors included ECOG (0-1 vs. 2) and prior lines (2 vs. ≥3). The Phase II (Phase III) primary endpoint was PFS (OS), with a planned suspension of accrual at the end of Phase II. A total of 70 evaluable pts (58 PFS events) were needed to detect an improvement in PFS from 4 vs. 8 mo with power of 90% and 1-sided type I error of 10%, with futility assessed after 29 PFS events. Upon meeting the Phase II futility threshold for PFS, the trial was permanently closed. Data were released from the data and safety monitoring board. Pts continue to be followed for outcomes. Results: 74 pts enrolled (Arm 1: T+O, n = 37; Arm 2: investigator’s choice, n = 37 (Tb, 18; P, 13; 6 pts did not start treatment). The arms were balanced for baseline demographics except race, with the T+O arm having a higher proportion of black/African American (29.7% vs. 16.2%). 21 pts remain on treatment. Hematologic adverse events (AEs) were more frequent in the T+O arm, with Grade 4 neutropenia (19.5%) and thrombocytopenia (8.3%) both managed by dose reductions. Non-hematologic Grade 3 AEs were higher in the investigator’s choice arm (45.2% vs. 13.9%). No Grade 5 AEs were reported. In the first 70 pts, with a median follow-up of 5.9 mo, and 39 total PFS events, the median PFS was 3.2 mo (95% CI: 2.0-NE) for T+O versus 5.6 mo (95% CI: 2.8-NE) for investigator’s choice (HR = 1.00; 95% CI: 0.60-2.17; 1-sided stratified log rank p = 0.50). Within Arm 2, the median PFS for Tb and P were respectively 5.6 (95% CI: 3.1-NE) and 3.8 (95% CI: 1.5-NE) mo. 3 pts in the T+0 arm and 1 patient in the investigator’s choice arm (Tb) had a confirmed partial response. Conclusions: The trial did not meet its primary endpoint of PFS in Phase II. This suggests that a biomarker may be needed before there is further exploration of PARP inhibitor-based regimens in uLMS. Overall survival and analysis of tissue-based biomarkers will be presented. Clinical trial information: NCT05432791 .

e14545 Background: Next generation sequencing (NGS) identifies genomic alterations in DNA obtained from tissue biopsies and/or blood [circulating tumor (ct)DNA]. We anticipate a lower rate of copy number loss (CNL) in ctDNA compared to tissue, as lower ctDNA tumor fraction may limit the ability to detect a deletion. However, we observed several instances of a CNL in ctDNA that was not identified in a tissue specimen, prompting this systematic evaluation of an institutional dataset. We focused on BRCA1/2 pathogenic variants (PVs) given their therapeutic implications and coverage across testing platforms. Methods: Using an IRB-approved protocol, we evaluated an institutional repository of NGS results performed across the Mayo Clinic Enterprise. We focused on patients (pts) who had both tissue and blood NGS testing performed. We further narrowed this cohort to those with a BRCA1/2 PVs, somatic and/or germline, as determined by testing performed at Guardant Health, Tempus, or Foundation Medicine. We abstracted information about each variant, including type of alteration classification and functional impact. Demographic information, cancer characteristics, and germline testing information was collected. Fisher’s exact test was used to compare alteration frequencies in ctDNA vs tissue using GraphPad Prism v 10.1. Results: From Dec 2015-Sept 2024, we identified 158 unique pts with BRCA1/2 PV who had NGS results for both tissue and ctDNA. The median age at first reporting BRCA1/2 variant was 67 years (range: 29-98 years). 48% of pts were female, and the most common cancer type sites were lung (23%), colorectal (20%), and pancreaticobiliary (20%). We identified 198 unique pathogenic genomic alterations; 71 in BRCA1 & 127 in BRCA2 . Most common alteration was an SNV or indel (127/198), followed by CNL (n = 63), splice site variants (n = 5), fusions (n = 2), and rearrangements (n = 1). Of the 126 SNV or indels, 50 (39.7%) were identified in both ctDNA and tissue, 40 (31.7%) were detected in blood only, 36 (28.6%) identified only in tissue (p < 0.0001). Amongst the 63 CNL, only 3 (4.8%) were identified in both ctDNA and tissue; 41(65.1%) were only identified in ctDNA, and 19 (30.2%) in tissue only (p < 0.0001). In the 19 tissue-only CNL tests, 12/19 noted one or more additional pathogenic SNV/Indel in BRCA1/2. In the 41 ctDNA-only CNL tests, 1/41 noted one or more additional pathogenic SNV/Indel in BRCA 1/2 . Germline testing was available in 41/63 pts with copy number loss. 3/41 deletions were identified in germline (2 in ctDNA, 1 in tissue). Conclusions: We observed a low degree of concordance in CNL between tissue and ctDNA for BRCA1/2 . CNL detection in ctDNA that could not be confirmed in germline or with a second alteration warrants further attention. In particular, clinicians should be cautioned when interpreting ctDNA reports noting BRCA1/2 CNL without clarity if this represents biallelic loss or a synchronous loss of function.