Citations

Abstract Genomic alterations and molecular subgroups between extracranial disease sites and brain metastases often differ, yet the prevalence and clinical significance of divergent evolution in brain metastases is not fully understood. This study examined genomic alterations and molecular subgroup divergence rates between matched brain metastases and extracranial disease sites. A retrospective, two-center study was conducted on patients who underwent resection of brain metastases between 2014-2022 with clinical and matched genomic data and/or molecular markers available. The overall cohort comprised 256 patients with matched tumors from multiple cancer types, most commonly from breast (n=108, 42.2%), melanoma (n=83, 32.4%), and NSCLC (n=43, 16.8%). Targeted next-generation sequencing of over 500 oncogenes was performed on resected tumors as part of clinical care (n=41 patients with matched specimens). Molecular subgroups for breast, melanoma, and non-small cell lung cancer were also assessed by immunohistochemistry to evaluate rates of molecular subgroup discordance between sites. Subgroup discordance by immunohistochemistry was observed most frequently across breast cancer (22.2%, n=24/108) with loss of the estrogen receptor (ER) and progesterone receptor (PR) and gain of HER2 most frequently observed within brain metastases. Molecular subgroup discordance was rare within melanoma (7.3%, n=6/82) and NSCLC (14.0%, n=6/43) patients. When evaluating oncogenomic alterations from targeted DNA sequencing in 41 patients with matched specimens, 80.5% (33/41) of brain metastases demonstrated a unique oncogene alteration profile compared to an extracranial disease site. Fourteen patients (34.1%) had a gain of at least 1 targetable alteration within a brain metastasis that was not observed in an extracranial disease site. Brain metastases demonstrated high rates of genomic divergence compared to primary and extracranial metastatic disease sites. This data supports obtaining brain metastasis tissue and conducting molecular profiling of this tissue to help select optimal CNS penetrant systemic therapies for each patient.

Abstract BACKGROUND Glioma radiotherapy planning requires accurate tumor delineation. While T1- contrast-enhanced-MRI (T1-CE-MRI) is the standard, due to blood-brain-barrier breakdown dependencies, T1-CE-MRI fails to reflect the extent of glioma. Studies using amino acid PET tracers report glioma uptake up to 3cm-4cm beyond T1-CE. In this study, amino acid tracer 18F-fluoro-dihydroxyphenylalanine (18F-DOPA) uptake was correlated with histopathological features to determine tumor thresholds. METHODS Using registered 18F-DOPA-PET and T1-CE-MRI images in the Stealth Neuronavigation system targeting concordant and discordant regions, 181 stereotactic biopsy samples (newly-diagnosed=74; recurrent=107) were obtained from 59 enrolled astrocytoma patients across two prospective phase II clinical trials between 2010-2019. An experienced neuropathologist reviewed each sample with hematoxylin and eosin stain and assigned an alphanumeric score: mitotic activity (0=no tumor; 1=no mitosis; 2=few/scattered mitosis; 3=frequent mitosis) and cellular density (A=<25%; B=25%-50%; C=50%-75%; D=>75%). Samples assigned 1C-1D, 2B-2D, or 3A-3D were categorized as histopathological high-score (aggressive disease), remaining samples as low-score. Relative mean (rFDOPA_mean) tumor-to-background uptake ratios were computed for 5mm uniformly expanded volumes from each Stealth biopsy coordinate using the crescent and wedge normalization methods. Relative uptake was compared overall and separately within newly-diagnosed/recurrent disease subgroups. An optimal rFDOPA_mean threshold to delineate high- from low-score was determined using the maximal Youden index of ROC curves. RESULTS Overall, high-score samples (n=116) had higher median (IQR) rFDOPA_mean uptake than low-score samples (n=65): high-score rFDOPA:mean=1.70(1.16-2.26), low-score rFDOPA:mean=1.16(0.83-1.49), Kruskal-Wallis p<0.001. The uptake difference between high- vs. low-score samples was observed within newly-diagnosed and recurrent subgroups, but was only significant for newly-diagnosed (p<0.001). For newly-diagnosed, an rFDOPA:mean=1.49 cutoff between high- and low-score groups shows 69% accuracy, 63% sensitivity, 80% specificity (AUC=0.782). Using the wedge normalization method, rFDOPA_mean values were 0.2 higher than crescent method values. CONCLUSIONS This work presents histologically verified 18F-DOPA-PET thresholds for aggressive disease in newly-diagnosed astrocytoma patients. Separate thresholds will need to be determined for recurrent glioma patients.

Abstract Protease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache. MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury. MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures. These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.

Abstract Background The extravascular implantable cardioverter defibrillator (EV ICD) has recently emerged as an option for guideline indicated ICD patients. Results from the EV ICD Pilot and Pivotal studies demonstrated that the device can provide safe and effective therapy through chronic follow up. Lead placement outside the vasculature has the potential to reduce systemic infections. Infection occurrence and management details from the Pivotal are reported. Purpose To report on details of infection occurrence and management from the EV ICD Pivotal study. Methods The EV ICD Pivotal study was an international, prospective, single-arm, premarket clinical study. Patients with a class I or IIa indication for a single-chamber ICD per ESC or ACC/AHA/HRS guidelines were enrolled. Results In the EV ICD Pivotal study, 316 patients had an implant attempt, (74.7% male, age 53.8±13.1 years, 82% primary prevention, LVEF of 38.9%±15.4%, and NYHA Class I [23.7%] or II/III [65.5%]), of which 15 had a system or procedure-related infection (4.7%, 9 - 737 days post-implant) through an average 16.2 months follow-up. Of these infections, 8 were classified as major complications, 3 as minor, and 4 as observations. Most (n=9) infections were addressed through medication with or without wound care (2.8% of patients) while 6 (1.9% of patients) resulted in system removal. There was a single lead-related infection addressed through system explant. However, there were no reports of mediastinitis, sepsis, or endocarditis. No system removal resulted in sequelae. Conclusions Infection rates observed in the EV ICD Pivotal study were similar to those reported in the subcutaneous implantable cardioverter defibrillator. The results from this study support that EV ICD related infections are treatable with antibiotic therapy or system removal. No system or procedure-related systemic infections such as mediastinitis, sepsis, or endocarditis have been reported in the Pivotal study.

AbstractBackgroundCochlear implants (CIs) are used to rehabilitate moderate to profound sensorineural hearing loss and stimulate the auditory system via a multichannel electrode array positioned in the scala tympani. Imaging evaluation of CIs is substantially degraded by metallic artifacts. Photon‐counting detector (PCD)‐CT has the potential to minimize such artifacts, though this has not been convincingly established in prior studies. This study compared the visualization of CI electrodes on PCD‐CT to conventional energy integrating detector (EID)‐CT.Materials and MethodsFive patients with CIs were prospectively recruited to undergo temporal bone imaging on both EID‐CT and PCD‐CT scanners yielding 2D and 3D Volume Rendering Technique (VRT) images. Three nonblinded neuroradiologists reviewed 2D and 3D VRT images for the ability to resolve CI electrode leads using a Likert scale. The average Likert scores of PCD‐CT versus EID‐CT were calculated for each reader for both 2D and 3D VRT images. (Likert scores 1–5 based on inferior to superior rating of PCD‐CT compared to EID‐CT). Inter‐rater agreement was assessed using Krippendorff's alpha with ordinal weights. ResultsFive patients underwent temporal bone CT for CI array evaluation. As evidenced by 5‐point Likert scales that were independently used by the three reviewers, this study demonstrated superior resolution of CI electrode array using PCD‐CT as compared to EID‐CT with an average score of 4.2 ± 0.8 for 2D images and 4.9 ± 0.4 for 3D VRT images.ConclusionsPCD‐CT is superior to EID‐CT in the visualization of CI electrodes, particularly in 3D VRT imaging.

Abstract Purpose: Cardiovascular health disparities are present in African Americans, but it remains unknown whether this phenomenon affect Somali Americans. Study of Somali Americans is warranted due to distinct genetic and cultural differences from African Americans of western African ancestry. Orthostatic hemodynamic responses have implications for cardiovascular risk, especially among African American females. We sought to examine race and sex differences in systolic (SAP) and diastolic (DAP) arterial pressure and heart rate (HR) responsiveness to standing. We hypothesized that SAP, DAP, and HR change from supine to standing position would be higher in Somali Americans. Methods: We studied blood pressure and HR responsiveness in 139 (70 Somali; age: 29±10 years, 69 White; age: 31±9 years) participants. Supine SAP, DAP, and HR were measured after at least five minutes of supine rest, and again after one minute of standing. SAP, DAP, and HR change was compared between groups. Results: ΔSAP and ΔDAP were similar between groups (race × sex: p>0.05). However, HR responsiveness to orthostasis varied between race and sex comparisons (race×sex: p=0.011). Somali females exhibited an augmented HR response to orthostasis compared to White females (Δ19±13 vs. 11±9 beats/min, p=0.005) and Somali males (Δ19±13 vs. 12±9 beats/min, p=0.020). Conclusion: ΔHR to standing is augmented in young female Somali Americans. These findings highlight an early potential impairment in hemodynamic regulation that may heighten future cardiovascular risk. Further work is warranted to identify the potential autonomic nervous system underpinnings that may contribute to potentiated orthostatic responses and cardiovascular risk in Somali American females. Clinical Trial Registration: www.clinicaltrials.gov; unique identifier, NCT04124848; NCT05411029; NCT03308578.

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has utilized its Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. In a phase 1b study in patients with ndGBM, IGV-001 was well tolerated without unexpected adverse events. Multiple efficacy signals were also observed, including significant improvements in progression-free survival, overall survival, radiographic evidence of tumor response, and changes in immune response biomarkers. A phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (ClinicalTrials.gov identifier: NCT04485949) is ongoing. Here, we present the first safety data from the study. MATERIAL AND METHODS After surgical resection, patients are treated with IGV-001 or placebo followed by SOC. The study will enroll approximately 93 patients at 20 sites in the United States, with a 2:1 randomization favoring IGV-001. The primary outcome is progression-free survival, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety. RESULTS As of February 2, 2024, a total of 72 patients have been randomized and 69 have been implanted with IGV-001 or placebo plus SOC. The median age was 60.0 years (range, 24-70 years). Most randomized patients (76.4%) were 51-70 years of age, and the male:female ratio was 2.27. A total of 39/45 (86.7%) patients with enough follow-up time, initiated treatment with concurrent radiation and temozolomide. A total of 9/72 (12.5%) randomized patients discontinued treatment, including 7 patients who discontinued during the SOC treatment period. No patients discontinued treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized patients discontinued the study after randomization. CONCLUSION To date, the review of blinded safety data did not show any emerging risk and supports that there is no change to the benefit-risk profile of treatment with IGV-001 versus placebo. The data will be updated before presentation.

Abstract BACKGROUND Mouse double minute 2 (MDM2) inhibits the tumor suppressor protein 53 (p53). Brigimadlin, a potent oral MDM2-p53 antagonist, restores wild-type (wt) p53 function and has shown early efficacy in patients with solid tumors. Glioblastoma (GBM) is an area of unmet need with 5-year survival at <10%. In p53 wt GBM patient-derived xenograft models, brigimadlin promotes tumor cell apoptosis and extends survival in combination with radiotherapy (RT). METHODS NCT05376800 is a Phase 0/Ia non-randomized, open-label, single-arm trial that aims to measure brigimadlin concentration in brain tumor tissue in patients with histologically or radiologically newly diagnosed GBM eligible for resection (Phase 0), and determine the maximum tolerated dose of brigimadlin plus RT in patients with TP53 wt, IDH wt, MGMT promoter unmethylated GBM (Phase Ia). In Phase 0, patients received one brigimadlin dose (30 mg or 45 mg) ~12-24 hours before resection. Phase 0 primary endpoints are the measured total concentration and the calculated unbound concentration of brigimadlin in brain tissue homogenate from non-contrast enhancing (NCE) and contrast enhancing (CE) regions. The predefined threshold for trial continuation is 0.5 nmol/L (corresponding to IC50 in GBM cell lines) unbound brigimadlin in CE samples in ≥50% of patients. Brigimadlin concentration was measured using liquid chromatography-mass spectrometry and corrected for amount of brigimadlin in residual blood. Unbound concentration was calculated using an in vitro estimate of unbound fraction (fu): 0.654% (rat brain slice). fu in human plasma was 0.22%. Ratio of unbound concentration in brain versus plasma (Kp,uu) was calculated. Biomarker testing was performed. RESULTS Data are available for 11 patients (brigimadlin 30 mg: n=6; 45 mg: n=5). In the 30 mg group, median total brigimadlin concentration in NCE samples was 267 nmol/L (4 samples, range 86-316 nmol/L) and 332 nmol/L (6 samples, range 272-952 nmol/L) in CE samples. In the 45 mg group, median total brigimadlin concentration in NCE samples was 197 nmol/L (5 samples, range 140-347 nmol/L) and 603 nmol/L (5 samples, range 441-905 nmol/L) in CE samples. Unbound concentration exceeded the 0.5 nmol/L threshold in most cases. Post-brigimadlin, an increase in selected p53 target gene expression was observed in CE versus NCE tissue. CONCLUSION Unbound brigimadlin concentrations in CE regions in all patients receiving the low dose of 30 mg brigimadlin exceeded the 0.5 nmol/L threshold. Kp,uu in most patients was close to 1 in CE regions. Biomarker data support target engagement in brain tissue. Our findings support continued investigation of brigimadlin in GBM. Recruitment is ongoing. Updated data will be presented.The trial is funded by Boehringer Ingelheim.