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Introduction MYD88 L265P mutations (MUT) are found in 90% of patients with Waldenstrom macroglobulinemia (WM) and lead to the activation of pro-survival signaling. Limited literature has demonstrated that patients with MYD88 wild-type (WT) WM have poorer responses to conventional therapies and a higher likelihood of histological transformation. Increasingly the role of non-coding genomics in lymphomagenesis has demonstrated importance and currently, the epigenetic landscape of MYD88 WT WM remains underexplored. This study utilized a multi-omics approach to assess DNA methylation in MYD88 WT WM compared to MYD88 MUT patients and controls. Methods Bone marrow samples were prospectively collected from 20 subjects [3 MYD88 WT/CXCR4 WT WM, 12 MYD88 MUT WM and 5 normal controls] and positive selection for CD19+ and/or CD138+ B cells was performed. The analysis focused on the comparison between MYD88 WT WM to normal controls and MYD88-WT to MUT WM. Genome-wide DNA methylation analysis was performed, and CpG methylation ratios were segmented into 200-bp regions. Differentially methylated regions (DMRs) were determined using a Q-value <0.05 and absolute methylation difference ≥10%. Next, RNA-seq data was interrogated and differentially expressed genes (log2fold change>0.5 or <-0.5, false discovery rate<0.05) with corresponding promoter hypo- or hypermethylation were assessed. Ingenuity Pathway Analysis was used to determine potentially epigenetically regulated pathways using a corrected p<0.05. Results Comparing MYD88 WT WM samples to controls, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (29129 vs 6300), 3'untranslated region (UTR) (2068 vs 1551), 5'UTR (10169 vs 735), intron (30344 vs 24511), exon (2224 vs 6855), CpG island (30372 vs 1240) and CpG shore (14477 vs 5872) (all p<0.001). Next, mRNA analysis demonstrated that 214 genes were differentially up-/downregulated with concordant promoter hypo-/hypermethylation. On the assessment of promoter-methylation-based pathways, multiple pathways involved in cell signaling, proliferation, gene regulation, cytokine and immune signaling and metabolism were found to be deregulated. Most pathways were found to be negatively enriched in MYD88 WT patients compared to controls including several members of interleukin (IL) signaling (IL-2, IL-3, IL,7) and regulators of cell proliferation and signaling including mTOR, PI3K/AKT, and p53. Positive enrichment of the PTEN, FGFR3 and ERK/MAPK pathways were observed. Underlying multiple pathways was promoter hypermethylation with corresponding mRNA downregulation of AKT3 and PIK3CA. Furthermore, promoter hypomethylation with transcript upregulation of PTEN was observed. Next, in comparison of MYD88 WT to MUT samples, a statistically greater number of hypermethylated DMRs were observed across genomic regions (hyper- vs hypomethylated): promoter (24829 vs 2544), 3'UTR (3534 vs 378), 5'UTR (6111 vs 605), intron (52292 vs 5360), exon (21066 vs 2187), CpG island (18334 vs 1551) and CpG shore (16351 vs 1957) (all p<0.001). Assessing mRNA expression, 354 genes were up-/downregulated with concordant promoter hypo-/hypermethylation. Pathway analysis revealed positive enrichment of the mitotic G1 phase to G1/S transition pathway with upregulation of the CDK4, LYN, and PSMA6 transcripts in MYD88 WT compared to MUT samples. Further, negative enrichment of cell signaling regulators including the RHO GTPase family, IL pathways (IL-4, IL-8, IL-13, IL-17) and integrin signaling were found in MYD88 WT compared to MUT samples. Underlying multiple pathways were downregulation with promoter hypermethylation of BCL2, an important regulator of apoptosis. Conclusion Genome-wide methylation analysis of MYD88 WT WM revealed a unique DNA methylation profile, with potential epigenetic alteration of key oncogenic transcripts and pathways. The negative enrichment of cell signaling and cytokine/inflammatory pathways in MYD88 WT samples compared to controls and MYD88 MUT WM suggests an epigenetic mechanism for immune evasion and potentially underlies the reduced response to conventional WM-directed therapies. Overall, this study reveals that MYD88 WT WM is epigenetically distinct from MYD88 MUT WM and regulators such as methylation may underlie the unique clinical and phenotypic properties observed.

OBJECTIVE Preclinical studies suggest that robotic carotid artery stenting (CAS) could be superior to manual CAS. However, very limited comparative data exist for patients who have undergone robotic versus manual CAS. In addition, no data exist comparing the costs of manual and robotic CAS. METHODS All robotic CAS cases at two academic neurosurgery centers were retrospectively reviewed and 1:1 propensity matched with manual CAS cases. Personnel costs, supply costs, and total procedure costs were collected in collaboration with hospital administration by using time-driven activity-based cost analysis. RESULTS A total of 24 robotic CAS operations were performed between 2019 and 2023. Comorbidities and baseline procedural characteristics were well matched between robotic and manual cases. Unplanned manual conversion was observed in only 1 robotic case (4.2%). Robotic CAS complications and outcomes were comparable to manual. Robotic CAS was associated with a significantly increased fluoroscopy time (29.0 vs 19.2 minutes; p < 0.001). Robotic procedure time (88.9 ± 18.2 minutes) was significantly (p = 0.003) longer than manual time (68.72 ± 22.4 minutes). Health personnel costs ($1589.71 ± $176.92 vs $1375.99 ± $233.39, p = 0.005); supply costs ($3918.25 ± $421.20 vs $2152.74 ± $1030.26, p < 0.001); and total procedure costs ($5306.11 ± $608.95 vs $3437.56 ± $1165.67, p < 0.001) were greater for robotic CAS. CONCLUSIONS In the first multicenter study and largest sample to date, the authors show that robotic CAS, with a low rate of procedural failure and postoperative complications, is safe and feasible. In addition, robotic CAS achieves comparable clinical outcomes to manual CAS. Robotic CAS was associated with increased fluoroscopy time, but fluoroscopy time decreased as operators gained familiarity with the CorPath GRX system. Robotic CAS was associated with a greater procedural cost, which was driven by greater personnel and supply costs. Robotic CAS failed to show superiority to manual CAS. These findings set a foundation for randomized controlled trials of robotic CAS, and also highlight the need for further studies to optimize robotic CAS and reduce its associated costs.

Abstract Many medical facilities across the United States use ionizing-radiation-producing machines and radioactive materials for diagnostic and therapeutic purposes on a regular basis. While institutions are required to ensure full-term fetal doses are below the regulatory limit, clear guidance on how pre-declaration fetal doses should be estimated is not available. This paper provides a process that can be used to estimate the pre-declaration fetal dose and provides a predictive screening tool for licensees to use to recommend workload adjustments prior to actual fetal dosimetry results that could exceed the institutions derived investigation levels. The evaluation process presented herein serves as a guide for medical licensees when performing fetal dose evaluations for declared pregnant workers.

Introduction: Psychological resilience is the ability to adapt to significant adversity. Higher resilience has been associated with better quality of life in HF, but its association with outcomes is not known. Herein, we characterize resilience and its association with outcomes in HF. Research Questions/Hypothesis: Greater resilience is associated with better health status and outcomes in high-risk HF. Methods: In a prospective study, adult residents of 11 counties in Southeastern Minnesota with HF who had been hospitalized with decompensated HF or ventricular arrhythmia (“high-risk HF”) in the preceding 1 year were mailed a survey that included questionnaires to assess resilience (Connor Davidson resilience scale, CD-RISC2), health status (KCCQ-12), and other psychosocial constructs in March 2022. Patients were divided into tertiles by resilience scores, and association with outcomes (survival and hospitalization) were examined using Cox proportional hazard regression and Andersen-Gill models, respectively. Results: Among 649 respondents (mean age 76 ± 11.5 years, 40% women, 64.3% HFpEF), patients with greater resilience were older ( p=0.015 ), had lower BMI ( p=0.003 ) and were more often retired or employed (vs disabled or unemployed, p<0.001 ). Greater resilience was moderately correlated with better health status (r=0.33), social support (r=0.27), and health literacy (r=-0.30); and lower treatment burden (r=-0.42), symptom burden (r=-0.41), and fewer depressive symptoms (r=-0.41) ( p<0.001 for all ). At 1-year follow up, patients with the lowest resilience (lowest tertile) were at a significantly increased risk for HF hospitalizations (adjusted HR 2.09, 95% CI 1.06-4.11) and CV mortality (adjusted HR 1.90, 95% CI 1.01-2.57) compared to those with highest resilience. There was no statistically significant association of resilience with risks of all-cause mortality or all-cause hospitalizations after adjustment ( Figures 1A-D ). Conclusion: Higher resilience is associated with better health status and psychosocial profile. Patients with low resilience are at increased risk for HF hospitalizations and CV mortality. Impact of resilience on long term outcomes and response to interventions must be tested in future studies.

Background: Papillary fibroelastomas (PFE) arising between the left upper pulmonary vein and left atrial appendage, commonly referred to as the coumadin ridge or Q-tip, are extremely rare and best detected by transesophageal echocardiography (TEE). Although PFEs are benign, they have been associated with a range of serious embolic events. Objective: To analyze the characteristics, clinical findings, and diagnostic techniques of PFEs originating from the coumadin ridge. Methods: We describe 13 cases of pathology proven papillary fibroelastomas uniquely attached to the Q-tip. Patient data, including demographics, mass characteristics and diagnostic imaging were collected and analyzed. Results: Thirteen patients with pathology-proven PFEs attached to the coumadin ridge were included in the study. The median age of the cohort is 73 (IQR 67-77), and 54% of the patients were male. Tumor sizes ranged from 2mm to 20mm with a median of 5mm (IQR 3.5-8.5). Twelve (92%) of the PFEs were initially visualized on TEE, and one case was diagnosed postoperatively by pathologists after the excision of the left atrial appendage. The majority of cases were incidental diagnoses, with 46% of cases incidentally discovered intraoperatively by routine TEE, and 30% visualized on TEE done for diverse reasons including valvular assessment, exclusion of infective endocarditis, and coronary artery disease (CAD) assessment. One case was incidentally detected on CMR performed as part of a metastatic tumor workup. Four (30%) patients presented with symptoms of stroke/TIA, of which 2 had a previous history of stroke. One patient had symptoms of both TIA and angina pectoris. Cardiovascular disease risk factors were prevalent: 69% had hyperlipidemia, 46% had atrial fibrillation (Afib), 31% had CAD, 54% had hypertension, and 46% were former smokers. Conclusions: Masses on the Q-tip are rare but significant intracardiac sources of embolism. Accurate identification and categorization of these masses are challenging, yet critical, to guide appropriate surgical intervention and improve patient outcomes. Further studies are needed to establish standardized diagnostic and treatment protocols for this unique presentation of PFEs.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (&gt;28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P &lt; .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (&gt;46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Abstract Purpose: Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCP) represent 8-20% of cases. We assessed surgical outcomes of these very rare tumors among patients treated in the last decade. Methods: Retrospective data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were used to evaluate patients with PCP treated between 2011 and 2023 at 14 US-based academic skull base centers. Demographic, imaging, surgical, and outcome variables were analyzed. Results: Ninety-nine patients with PCP were included. Mean age was 51.8±14.7 and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were trans-infundibular (50.0%), and were treated endoscopically (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 68.8% and was associated with pituitary stalk sacrifice (p=0.02). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Return to the operating room was associated with discharge to a skilled nursing or rehabilitation facility (p=0.0001). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p=0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only 1 patient was treated with a BRAF inhibitor. Conclusion: To our knowledge, the RAPID consortium enabled the largest real-world clinical information dataset for PCP. Our data can be used as a benchmark for short-term surgical outcomes. Longer-term follow-up studies are needed to understand how to optimize outcomes from each treatment modality.

Abstract BACKGROUND As an adjunct to direct electrical stimulation (DES), intraoperative electrocorticography (ECoG) can aid detection of language-eloquent cortex. However, it is unclear how surgical impact upon mapping findings relates to cognitive-linguistic outcomes. METHODS Ten patients underwent awake craniotomy for tumor resection with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to an electrode array capable of both recording ECoG activity and delivering DES. Time-frequency gamma band activations were visualized (Early, Long, Late, Double Peak) for 3 naming paradigms (Object, Action, Auditory). DES was also conducted for each task. Mapping results were overlayed on postoperative MRI to examine proximity to parenchymal trauma (cavity, sulcal displacement). Patients completed cognitive-linguistic testing [WAB-R (N=3) or Neuropsychological Assessment (N=7)] prior to surgery and &lt;2 months postoperatively. Patients with persisting aphasia at 6-month follow-up were also identified. RESULTS Postoperative language decline was found in 50% of patients, with 30% showing worsening (&gt;1SD) in Naming and Phonemic Fluency, and 60% in Semantic Fluency. Surgery impacted ECoG features in 60% of patients and DES arrest sites in 30%. A trend was observed where Early and Late Object naming ECoG features were associated with Semantic Fluency decline [rpb(5)=-.69, p=.067]. Arrest during Auditory naming DES &lt;1 cm of surgical effect was associated with decline in Abstraction [rpb(5)=-.83, p=.042; FET, p=.029] and Semantic Fluency [rpb(5)=-.87, p=.012; FET, p=.024]. Excluding the 3 transsulcal surgeries, arrest during Auditory naming DES &lt;1 cm of resection was associated with general language decline [FET, p=.047]. All 3 patients with persisting aphasia had Auditory naming arrest &lt;1 cm of resection and 2/3 patients had Object naming ECoG features resected. CONCLUSIONS While preliminary, results suggest that surgical proximity to ECoG and DES mapping results may inform risk of surgically-acquired cognitive-linguistic decline. Findings support the potential of multimethod-multitask intraoperative language mapping.

Abstract BACKGROUND Few studies have examined concordance between intraoperative electrocorticography (ECoG) and direct electrical stimulation (DES) language mapping, especially across varied naming tasks. METHODS Twelve patients (Mdn age=59; 75% HGG) underwent awake craniotomy with ECoG and DES language mapping. Mapping utilized iPad stimulus presentation coupled to a 4x8 electrode array for both ECoG and DES. Time-frequency ECoG gamma band activity (Early and Late) was visualized for 3 naming paradigms (Object, Action, Auditory). Bipolar DES was also conducted for each task at each electrode pair. ECoG activations and DES hits were overlayed on preoperative MRI. DES hits represented ground truth for eloquence. ECoG accuracy was examined for each task with 3 different criteria: exact (identical electrodes for ECoG activation and DES hits), adjacent (ECoG &lt;1cm of DES hits), and adjacent within a predefined peritumoral region of interest (&lt;2 cm from boundaries). RESULTS 32 DES hits (40% Auditory, 32% Action, 28% Obj) were observed across patients. Exact ECoG-DES accuracy ranged from 78%-90% [Object: Sens=11%, Spec=91%, PPV=6%, NPV=95%; Action: Sens=40%, Spec=93%, PPV=24%, NPV=97%; Auditory: Sens=69%, Spec=78%, PPV=19%, NPV=78%]. Adjacent ECoG-DES accuracy ranged from 82%-91% [Object: Sens=33%, Spec=92%, PPV=18%, NPV=97%; Action: Sens=44%, Spec=93%, PPV=25%, NPV=97%; Auditory: Sens=91%, Spec=81%, PPV=37%, NPV=99%]. When restricted to the peritumoral region, adjacent ECoG-DES accuracy ranged from 94%-97% [Object: Sens=14%, Spec=99%, PPV=25%, NPV=97%; Action: Sens=25%, Spec=99%, PPV=25%, NPV=99%; Auditory: Sens=100%, Spec=94%, PPV=54%, NPV=100%]. For patients with DES hits (N=10), all had at least 1 task activation &lt;1 cm of DES hits, with 7/10 having convergence of activations across at least 2 tasks. CONCLUSIONS Negative ECoG mapping is strongly predictive of non-eloquence confirmed by DES for all naming tasks. Additionally, gamma band activation elicited by auditory naming within the peritumoral region is strongly predictive of eloquence. Findings support task-based ECoG language mapping for prediction of eloquence and identification of targets for DES confirmation.

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.