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Summary: Epilepsy neuromodulation treatment failure is a significant challenge, with multiple possible causes. The responsive neurostimulation (RNS) system delivers stimulation from a single current source, and the relative flow of the electrical current through each stimulating contact is inversely proportional to the relative impedance of each contact. Current shunting through low-impedance contacts (i.e., intraventricular contacts) can divert therapy away from the intended targets and may be a cause of treatment failure. We present a case of a patient with bitemporal epilepsy and bitemporal encephaloceles, with poor response to bilateral mesial temporal RNS, who completed stereotactic EEG (sEEG) monitoring to investigate the possible causes of treatment failure. The sEEG was safely completed without damaging the RNS device. The sEEG recorded independent bitemporal interictal epileptiform discharges and seizures, which did not arise from sampled encephalocele regions. The sEEG-recorded RNS stimulation artifact was reduced in the left mesial temporal region relative to the right, which suggested potential current shunting through the right-sided contacts. Impedance measurements confirmed several low-impedance contacts from the right lead, with associated intraventricular position on imaging. At last follow up, 161 days after replacement of the right lead, the patient experienced an additional 58% reduction in seizure burden. Effective therapy delivery by single-current-source neurostimulation systems, such as RNS, critically depends on relative electrode impedances. Current shunting through low-impedance contacts is an underappreciated potential cause of treatment failure. Routine impedance assessments and individualized stimulation programs are recommended to avoid unintended current diversion. Concurrent sEEG monitoring and active RNS are feasible and can characterize stimulation effects.

ObjectivesAchalasia is an esophageal motility disorder that impairs quality of life and is often missed (20–50%) on endoscopy. A newly developed computer‐aided detection (CAD) software has shown high accuracy for achalasia diagnosis in preclinical settings. However, its benefit in a clinical setting remains unclear.MethodsBetween February and August 2023, 83 endoscopists from 27 centers assessed 50 randomized endoscopic videos (25 achalasia, 25 nonachalasia) without and with CAD. Endoscopists assessed videos without CAD, then with CAD after 2 months. The primary end‐point was improvement in sensitivity for nonexperienced endoscopists (no endoscopic experience of achalasia). Sensitivity, specificity, and accuracy with and without CAD were compared using the McNemar test.ResultsSensitivity for diagnosing achalasia increased significantly with CAD, rising from 74.2% (95% confidence interval [CI] 72.2–76.0%) to 91.2% (95% CI 89.9–92.4%) for all readers, showing a difference of 17.1% (95% CI 15.1–19.0%). Specifically, sensitivity improved from 66.9% (95% CI 63.6–70.0%) to 91.9% (95% CI 89.9–93.6%) among nonexperienced endoscopists, resulting in a difference of 25.0% (95% CI 21.7–28.4%), and from 79.5% (95% CI 77.1–81.8%) to 90.8% (95% CI 89.0–92.3%) among experienced endoscopists (endoscopic experience of at least one achalasia case), with a difference of 11.3% (95% CI 8.9–13.6%). Accuracy and specificity improved significantly with CAD assistance, regardless of reader's experience.ConclusionCAD improves achalasia detection by 17%, confirming preclinical results. The benefit was higher for nonexperienced endoscopists. CAD assistance may lead to prompt and effective treatment, minimizing the risk of false‐negative diagnosis in clinical practice.Trial registrationThis study was registered in the University Hospital Medical Information Network Clinical Trial Registry (https://www.umin.ac.jp/ctr/) number: UMIN000053047.

The NCCN Guidelines for Survivorship include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from adult-onset cancer and its treatment and provide a framework for coordination of survivorship care. They also include recommendations to help cancer survivors enhance their wellness and maintain a healthy lifestyle. These NCCN Guidelines Insights summarize the panel’s current recommendations and recent updates regarding physical activity, nutrition, and weight management for cancer survivors.

Myoepithelial tumors are typically characterized by distinct molecular profiles that have been shown to correlate with their anatomical locations. EWSR1 or FUS rearrangements are common in cutaneous, soft tissue and bone tumors, whereas salivary gland myoepithelial tumors are frequently associated with PLAG1 and HMGA2 alterations. This apparent molecular divergence led some previous studies to doubt a common pathogenetic relationship between myoepithelial tumors of soft tissue and bone with their salivary gland counterparts. Herein, we present primary intraosseous myoepithelioma harboring HMGA2::WIF1 fusion. This fusion has been previously identified in a range of salivary gland myoepithelial tumors including myoepitheliomas, myoepithelial carcinomas arising from pleomorphic adenomas, and pleomorphic adenomas themselves. Primary myoepithelial tumors of the bone are exceedingly rare, and to our knowledge, HMGA2 rearrangements have not been previously reported in soft tissue or bone myoepithelial neoplasms. Through this report, we aim to enhance the existing literature on myoepithelial neoplasms, while highlighting the importance of recognizing primary bone myoepitheliomas and contributing to a broader understanding of the pathogenetic landscape of myoepithelial tumors across diverse tissue types.

OBJECTIVE Calcium phosphate cement (CPC) use has been previously described as a strategy to reduce the rates of pseudomeningocele and CSF leakage following skull base surgery. The authors aimed to present their institutional experience with CPC in retrosigmoid craniotomy and perform a systematic review of the literature to determine the effectiveness of CPC in reducing postoperative complications, including pseudomeningocele and craniotomy-site CSF leakage. METHODS A retrospective single-institution cohort study of patients who underwent retrosigmoid craniotomy with and without CPC cranioplasty from January 2017 to April 2024 was performed. A systematic literature review and meta-analysis of CPC use in retrosigmoid craniotomy was also performed. RESULTS Of 336 patients who underwent retrosigmoid craniotomy, 193 (57%) were female and the median age at surgery was 55 years (range 18–81 years). The median follow-up duration was 23 months (range 3–80 months). CPC was used to seal the edge of the craniotomy in 66 patients (20%). Among all patients, 50 (15%) experienced a postoperative complication, and 28 (8%) were wound-specific complications. Patients in the non-CPC group experienced significantly more postoperative wound-specific complications than those in the CPC group (10% vs 0%, p = 0.002). Specifically, pseudomeningocele occurred in 0 patients (0%) in the CPC group compared with 24 patients (9%) in the non-CPC group (p = 0.006), which progressed to CSF leaks at the craniotomy site in 6 patients (p = 0.60). Additionally, no patients (0%) in the CPC group experienced wound infection, dehiscence, or breakdown compared with 10 patients (4%) in the non-CPC group (p = 0.22). Five patients (8%) in the CPC group reported prolonged mild incisional pain at the craniotomy site, and there were no instances of major complications related to the CPC. In the meta-analysis, 10 studies met the inclusion criteria, yielding a total of 2166 patients (including the current study), 1101 of whom received CPC. In the pooled analysis, CPC was significantly associated with lower risk of CSF leakage at the craniotomy site (OR 0.23, 95% CI 0.13–0.42; p < 0.01) and lower risk of infection (OR 0.17, 95% CI 0.08–0.38; p < 0.01). CONCLUSIONS CPC use in retrosigmoid craniotomies could be a safe and effective strategy to reduce the incidence of pseudomeningocele and craniotomy-site CSF leakage, leading to lower rates of wound-related complications and infection.

OBJECTIVE Chronic spinal degenerative diseases have been associated with reduced quality of life and dependency on others for personal needs and care. The change between preoperative and postoperative care dependency has yet to be explored in patients with cervical spondylotic myelopathy (CSM). In this retrospective study of a prospectively collected database, the authors evaluated the return to independence in performing self-care following surgical intervention for CSM. METHODS The CSM dataset of the Quality Outcomes Database (QOD) Spine CORe study group was queried. Care dependency was assessed using the personal care component of the Neck Disability Index (NDI) questionnaire, having an ordinal scale from 0 to 5, with 5 representing the inability to independently perform activities of daily living. Numeric rating scale (NRS) scores for arm pain and neck pain were recorded at a 24-months postoperative follow-up. Multivariable logistic regression analyses were performed to identify baseline risk factors for an inability to care for oneself and the symptoms leading to care dependency at 24 months postoperatively. Satisfaction with surgery was measured using the 4-point North American Spine Society (NASS) index. RESULTS Of the 1137 patients with CSM and baseline personal care scores, 167 (14.7%) were care dependent at baseline (NDI personal care score ≥ 3). Patients with care dependency at baseline were predominantly Medicare beneficiaries and had a high school or lower level of education. Long-term follow-up rates for this study were 82.5% for NDI, 84.8% for patient satisfaction with surgery, 82.4% for NRS arm pain, and 81.8% for NRS neck pain. Of the care-dependent patients, more than 80% became independently able to care for themselves by the 24-month follow-up. Patients with resolved care dependency at 24 months had demonstrated lower baseline NDI and NRS neck pain scores (p < 0.01 for both). Neck pain was significantly associated with care dependency at 24 months’ follow-up (p < 0.01). Patients who reported improvement in their ability to care for themselves noted higher postoperative satisfaction (NASS score 1–2) at the 3-month (89.4% vs 80.2%, p < 0.01) and 24-month (88.2% vs 67.4%, p < 0.01) follow-ups. CONCLUSIONS Fifteen percent of patients with CSM depended on others for care preoperatively. After surgery to treat CSM, 81.8% of those who had depended on others for care became independent. Patients with improvements in care dependency noted higher postoperative satisfaction at the 3-month and 24-month follow-ups. Patients with resolved care dependency on long-term follow-up had lower NDI and NRS neck pain scores at baseline. Surgery had a significant impact on patients’ attainment of independence.

Type 2 diabetes (T2D) and obesity are chronic metabolic diseases with global morbidity and mortality. Decades of evidence from surgical and endoscopic procedures bypassing the duodenum underscore the duodenum’s critical role in regulating glycemia and body weight. Although metabolic surgeries and endoscopic procedures are effective, their invasiveness, cost, and scalability limit patient access. We developed an orally administered mucin complexing polymeric (MCP) drug, designed to replicate duodenal exclusion physiology. MCPs, intended to have electrostatic and covalent cross-linkages with mucin glycoproteins, form extended network structures with resulting alteration of mucus barrier properties. Selective targeting of the duodenum is achieved via pH-based activation chemistry. Following screening for physiochemical properties, pharmacokinetics, and efficacy, GLY-200 emerged as the lead drug candidate replicating duodenal exclusion physiology with improved glycemia, reduced body weight, and modulation of gut hormones in rodent models. This targeted oral therapy holds promise for treatment of T2D and obesity by mimicking duodenal exclusion without the invasiveness of surgery or endoscopic procedures.

Background: When missing data are present in clinical outcomes studies, complete-case analysis (CCA) is often performed, whereby patients with missing data are excluded. While simple, CCA analysis may impart selection bias and reduce statistical power, leading to erroneous statistical results in some cases. However, there exist more rigorous statistical approaches, such as single and multiple imputation, which approximate the associations that would have been present in a full dataset and preserve the study’s power. The purpose of this study is to evaluate how statistical results differ when performed after CCA analysis versus imputation methods. Methods: This simulation study analyzed a sample dataset consisting of 2204 shoulders, with complete datapoints from a larger multicenter total shoulder arthroplasty database. From the sampled dataset of demographics, surgical characteristics, and clinical outcomes, we created five test datasets, ranging from 100 to 2000 shoulders, and simulated 10–50% missingness in the postoperative American Shoulder and Elbow Surgeons (ASES) score and range of motion in four planes in missing completely at random (MCAR), missing at random (MAR), and not missing at random (NMAR) patterns. Missingness in outcomes was remedied using CCA, three single imputation techniques, and two multiple imputation techniques. The imputation performance was evaluated relative to the native complete dataset using the root mean squared error (RMSE) and the mean absolute percentage error (MAPE). We also compared the mean and standard deviation (SD) of the postoperative ASES score and the results of multivariable linear and logistic regression to understand the effects of imputation on the study results. Results: The average overall RMSE and MAPE were similar for MCAR (22.6 and 27.2%) and MAR (19.2 and 17.7%) missingness patterns, but were substantially poorer for NMAR (37.5 and 79.2%); the sample size and the percentage of data missingness minimally affected RMSE and MAPE. Aggregated mean postoperative ASES scores were within 5% of the true value when missing data were remedied with CCA, and all candidate imputation methods for nearly all ranges of sample size and data missingness when data were MCAR or MAR, but not when data were NMAR. When data were MAR, CCA resulted in overestimates of the SD. When data were MCAR or MAR, the accuracy of the regression estimate (β or OR) and its corresponding 95% CI varied substantially based on the sample size and proportion of missing data for multivariable linear regression, but not logistic regression. When data were MAR, the width of the 95% CI was up to 300% larger when CCA was used, whereas most imputation methods maintained the width of the 95% CI within 50% of the true value. Single imputation with k-nearest neighbor (kNN) method and multiple imputation with predictive mean matching (MICE-PMM) best-reproduced point estimates and intervariable relationships resembling the native dataset. Availability of correlated outcome scores improved the RMSE, MAPE, accuracy of the mean postoperative ASES score, and multivariable linear regression model estimates. Conclusions: Complete-case analysis can introduce selection bias when data are MAR, and it results in loss of statistical power, resulting in loss of precision (i.e., expansion of the 95% CI) and predisposition to false-negative findings. Our data demonstrate that imputation can reliably reproduce missing clinical data and generate accurate population estimates that closely resemble results derived from native primary shoulder arthroplasty datasets (i.e., prior to simulated data missingness). Further study of the use of imputation in clinical database research is critical, as the use of CCA may lead to different conclusions in comparison to more rigorous imputation approaches.

1107 Background: Chronic stress-mediated β2-adrenergic receptor (β2-AR) signaling promotes tumor growth via immunosuppression in the tumor microenvironment (TME) in preclinical models. Blockade of β2-AR has shown higher survival benefit in patients with TNBC in observational studies compared to other breast cancer (BC) subtypes. However, the molecular and immunological features associated with ADRB2 (gene for β2-AR) gene expression in TNBC are unknown, prompting this investigation. Methods: 3,038 TNBC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ). Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. TNBC ADRB2 -high(H) and ADRB2 -low(L) RNA expression were classified as above or below the 50 th percentile, respectively. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact using Kaplan-Meier estimates. Statistical significance was assessed using chi-square and Mann-Whitney U tests with multiple comparison adjustments (q < 0.05). Results: ADRB2 gene expression was lowest in TNBC (median (TPM: 1.6) compared to N = 453 HR-HER2+ (1.9), N = 629 HR+HER2+ (2.0) and N = 4,918 HR+HER2- (2.2) BC (all q < 0.05). African American or Black patients (N = 670) had lower expression of ADRB2 compared to European American or White (N = 1,412) TNBC patients (1.3 vs 1.7, q < 0.05). ADRB2 -H TNBC had higher mutation frequency of PIK3CA (21% vs 15.4%), CDH1 (7% vs 3.5%), NF1 (8% vs 4%), AKT1 (3.5% vs 2.1%), but lower frequency of TP53 (81.6% vs 87.5%), NOTCH1 (2.5% vs 4.5%) and NOTCH3 (4.4% vs 11.7%) compared to ADRB2 -L, all q < 0.05. ADRB2 -H had greater PD-L1 (22C3) positivity (39.1% vs 30.2%, q < 0.05), higher % of B cells (4.5 vs 3.4), M1 Mφ (3.4 vs 2.8), M2 Mφ (3.9 vs 2.2), Tregs (2.2 vs 1.3), NK cells (3.1 vs 2.6), DC (3.1 vs 2.9), CD8 + T cells (0.9 vs 0.2), all q < 0.05. ADRB2 -H TNBC had higher T-cell inflamed score (95 vs -80), IFN γ score (-0.23 vs -0.37), MAPK activation score (-0.46 vs -1.7), all q < 0.05; and higher expression of immune checkpoint genes ( CD274, PDCD1, PDCD1LG2, CTLA4, LAG3, HAVCR2, FOXP3, IDO1, TNFSF14, TIGIT, BTLA, CEACAM1, CD47, CD274 ; fold change: 1.6-3.7, all q < 0.05). ADRB2 -H tumors had higher expression of genes related to inflammatory response, IFNγ response, IL6-JAK-STAT3 signaling (normalized enrichment score (NES): 1.9 – 2.1), while ADRB2 -L had enrichment of MYC targets V1, MYC targets V2, E2F targets and G2M checkpoint (NES: 2.5 – 4.2), all FDR < 0.01. ADRB2 -H TNBC had better OS (mOS: 23.6 vs 18.6 months; HR 0.81, 95% CI 0.73-0.89, p < 0.0001) compared to ADRB2 -L. Conclusions: High ADRB2 expression in TNBC is associated with better survival and an immune enriched TME, elevated immune checkpoints and other targetable vulnerabilities. Future studies are needed to investigate ADRB2 as a potential stress biomarker and therapeutic target.

1106 Background: TNBC, although an aggressive breast cancer (BC) subtype, is highly immunogenic and the only BC subtype where the ICI pembrolizumab is approved. However, predictive biomarkers for pembrolizumab benefit are limited. The chemokines CXCL9 and CXCL10 attract CD8 + T cells into the tumor microenvironment (TME) and are associated with chemotherapy benefit, but little is known about their role in prediciting pembrolizumab benefit in TNBC. We investigated the association of CXCL9 , CXCL10 and their cognate receptor CXCR3 with TME and ICI efficacy. Methods: 3,038 TNBC samples were analyzed via NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high > 10 mt/MB). Immune cell fractions were estimated using WTS deconvolution (Quantiseq). CXCL9 / CXCL10 / CXCR3 -high (H) and -low (L) tumors were classified by RNA expression above or below the 50th percentile. Real-world overall survival (OS) was derived from insurance claims and calculated from start of pembrolizumab to last contact using Kaplan-Meier. Statistical significance was assessed using chi-square and Mann-Whitney U with multiple comparison adjustments (q < .05). Results: TNBC expressed higher levels of CXCL9 and CXCL10 (median (TPM): 5.3 and 14.7) compared to N = 1,082 HER2+ (4.8 and 10.3, p < 0.05) and N = 4,918 HR+HER2- (2.7 and 7, q < .05) BC. CXCR3 expression was higher in TNBC compared to HR+HER2- (1.9 vs 1.7, q < .05), but no difference when compared to HER2+ (1.9 vs 2, q = 0.97) BC. CXCL9 / CXCL10 / CXCR3 -H TNBC had higher median OS post pembrolizumab [ CXCL9 -H vs -L: 26.5 vs 15.7 months (mo), HR: 0.65 (95% CI 0.5-0.84); CXCL10 -H vs -L: 26.0 vs 20.6 mo, HR 0.74 (0.57-0.95); CXCR3 -H vs -L: 32.6 vs 18.3 mo, HR 0.68 (0.52-0.88), all p < 0.05 ]. CXCL9 -H, CXCL10 -H and CXCR3 -H had higher PD-L1 positivity (22C3), TMB high, higher T cell inflamed score, TP53 mutations, elevated B and CD8 + T cells infiltration, but not neutrophils, and higher expression of immune checkpoint genes (Table). Conclusions: High CXCL9 / CXCL10 / CXCR3 expression is associated with longer survival in patients with TNBC post pembrolizumab, and characterized by an immune-enriched TME. Further investigation is needed to evaluate this chemokine axis in TNBC and its potential as a therapeutic target to enhance ICI efficacy. TME characteristics by CXCL9, CXCL10 and CXCR3 expression. CXCL9 CXCL10 CXCR3 High Low q-value High Low q-value High Low q-value PD-L1 % 54 14 <.05 54 14.7 <.05 49 19 <.05 TMB high % 14.3 8 <.05 12.6 9.7 <.05 12.4 9.8 <.05 B cell (median %) 4.4 3.5 <.05 4.3 3.6 <.05 5 3.4 <.05 CD8+T cell (median %) 1.2 0 <.05 1 0 <.05 1.3 0 <.05 Neutrophil (median %) 4.2 4.5 <.05 4.2 4.4 <.05 4.2 4.3 0.2 T cell inflamed score 100 -84 <.05 98 -84 <.05 108 -100 <.05 CTLA4 (median TPM) 3.2 0.7 <.05 3 0.8 <.05 3.4 0.7 <.05 LAG3 (median TPM) 6.6 2.1 <.05 6.9 2 <.05 6.8 2 <.05 TP53 mutation % 88 81 <.05 90.5 78.6 <.05 86 83 0.08