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AbstractBackgroundPediatric esthesioneuroblastoma (EN) can infiltrate skull base anatomy, presenting challenges due to high radiation doses and pediatric tissue sensitivity. This study reports outcomes of pediatric EN treated with proton radiotherapy (PT).ProcedureUsing an IRB‐approved prospective outcomes registry, we evaluated patient, tumor, and treatment‐related variables impacting disease control and toxicity in pediatric nonmetastatic EN treated with modern multimodality therapy, including PT.ResultsFifteen consecutive patients (median age 16) comprising Kadish stage B (n = 2), C (n = 9), and D (n = 4) tumors were assessed, including six with intracranial involvement, four with cranial nerve deficits, and four with cervical lymphadenopathy. Before radiation, two had subtotal and 13 had gross total resections (endoscopic or craniofacial). Two underwent neck dissection. Eleven received chemotherapy before radiation (n = 5), concurrent with radiation (n = 4), or both (n = 2). Median total radiation dose (primary site) was 66 Gy/CGE for gross disease and 54 Gy/CGE (cobalt Gray equivalent) for microscopic disease. Median follow‐up was 4.8 years. No patients were lost to follow‐up. Five‐year disease‐free and overall survival rates were 86% (no local or regional recurrences). Two patients developed vertebral metastases and died. Two required a temporary feeding tube for oral mucositis/dysphagia. Late toxicities included symptomatic retinopathy, major reconstructive surgery, cataracts, chronic otitis media, chronic keratoconjunctivitis, hypothyroidism, and in‐field basal cell skin cancer.ConclusionsA multimodality approach for pediatric EN results in excellent local control. Despite the moderate‐dose PT, serious radiation toxicity was observed; further dose and target volume reductions may benefit select patients. Longer follow‐up and comparative data from modern photon series are necessary to fully characterize any relative PT advantage.

AbstractObjectiveTo investigate the association between standard pure tone and speech audiometry with neuroimaging characteristics reflective of aging and dementia in older adults.Study DesignProspective population‐based study.SettingSingle tertiary care referral center.MethodsParticipants from the Mayo Clinic Study of aging 60 years old or older with normal cognition or mild cognitive impairment, baseline neuroimaging, and a behavioral audiogram associated with neuroimaging were eligible for study. Imaging modalities included structural MRI (sMRI) and fluid‐attenuated inversion recovery MRI (FLAIR‐MRI; N = 605), diffusion tensor imaging MRI (DTI‐MRI; N = 444), and fluorodeoxyglucose‐positron emission tomography (FDG‐PET; N = 413). Multivariable logistic and linear regression models were used to evaluate associations with neuroimaging outcomes.ResultsMean (SD) pure tone average (PTA) was 33 (15) dB HL and mean (SD) word recognition score (WRS) was 91% (14). There were no significant associations between audiometric performance and cortical thinning assessed by sMRI. Each 10‐dB increase in PTA was associated with increased likelihood of abnormal white‐matter hyperintensity (WMH) from FLAIR‐MRI (odds ratio 1.26, P = .02). From DTI‐MRI, participants with <100% WRSs had significantly lower fractional anisotropy in the genu of the corpus callosum (parameter estimate [PE] −0.012, P = .008) compared to those with perfect WRSs. From FDG‐PET, each 10% decrease in WRSs was associated with decreased uptake in the anterior cingulate cortex (PE −0.013, P = .001).ConclusionPoorer audiometric performance was not significantly associated with cortical thinning but was associated with white matter damage relevant to cerebrovascular disease (increased abnormal WMH, decreased corpus callosum diffusion). These neuroimaging results suggest a pathophysiologic link between hearing loss and cerebrovascular disease.

AbstractPatient‐derived cancer organoids (PDOs) hold considerable promise for personalizing therapy selection and improving patient outcomes. However, it is challenging to generate PDOs in sufficient numbers to test therapies in standard culture platforms. This challenge is particularly acute for pancreatic ductal adenocarcinoma (PDAC) where most patients are diagnosed at an advanced stage with non‐resectable tumors and where patient tissue is in the form of needle biopsies. Here the development and characterization of microfluidic devices for testing therapies using a limited amount of tissue or PDOs available from PDAC biopsies is described. It is demonstrated that microfluidic PDOs are phenotypically and genotypically similar to the gold‐standard Matrigel organoids with the advantages of 1) spheroid uniformity, 2) minimal cell number requirement, and 3) not relying on Matrigel. The utility of microfluidic PDOs is proven by testing PDO responses to several chemotherapies, including an inhibitor of glycogen synthase kinase (GSKI). In addition, microfluidic organoid cultures are used to test effectiveness of immunotherapy comprised of NK cells in combination with a novel biologic. In summary, our microfluidic device offers considerable benefits for personalizing oncology based on cancer biopsies and may, in the future, be developed into a companion diagnostic for chemotherapy or immunotherapy treatments.

AbstractBackground and ObjectiveShape‐sensing robotic‐assisted bronchoscopy (ssRAB) has expanded as an important diagnostic tool for peripheral pulmonary nodules (PPNs), with diagnostic yields ranging from 60% to 88%. However, sampling and diagnosing PPN less than 2 cm in size has historically been challenging. Mobile cone‐beam computed tomography (mCBCT) has been recently integrated into ssRAB to improve diagnostic accuracy, but its added value remains uncertain. We aim to describe the role of mCBCT and determine if it provides any diagnostic advantage.MethodsA multicentre, retrospective study on the use of ssRAB and mCBCT in two tertiary care institutions: Mayo Clinic Florida and Massachusetts General Hospital. The primary outcome was diagnostic yield and sensitivity for malignancy of ssRAB complemented with mCBCT, compared to ssRAB with the standard 2D fluoroscopy.ResultsA total of 192 nodules were biopsied from 173 patients. mCBCT was used in 117 (60.9%) nodules. The overall diagnostic yield was 85.4%. Diagnostic yield between subgroups with and without mCBCT was 83.8% and 88% (p = 0.417), respectively. The mCBCT group had fewer solid nodules (65.8% vs. 81.3%, p = 0.020) and a higher number of ground‐glass nodules (10.3% vs. 1.3%, p = 0.016).ConclusionOverall, diagnostic yield between subgroups with and without mCBCT was similar. The complementary use of mCBCT to ssRAB allows proceduralists to target more complex and subsolid PPNs with a diagnostic yield comparable to simple solid PPNs while maintaining an excellent safety profile.

Background Post-traumatic headache is very common after a mild traumatic brain injury. Post-traumatic headache may persist for months to years after an injury in a substantial proportion of people. The pathophysiology underlying post-traumatic headache remains unknown but is likely distinct from other headache disorders. Identification of brain areas activated in acute and persistent phases of post-traumatic headache can provide insights into the underlying circuits mediating headache pain. We used an animal model of mild traumatic brain injury-induced post-traumatic headache and c-fos immunohistochemistry to identify brain regions with peak activity levels across the acute and persistent phases of post-traumatic headache. Methods Male and female C57BL/6 J mice were briefly anesthetized and subjected to a sham procedure or a weight drop closed-head mild traumatic brain injury . Cutaneous allodynia was assessed in the periorbital and hindpaw regions using von Frey filaments. Immunohistochemical c-fos based neural activity mapping was then performed on sections from whole brain across the development of post-traumatic headache (i.e. peak of the acute phase at 2 days post- mild traumatic brain injury), start of the persistent phase (i.e. >14 days post-mild traumatic brain injury) or after provocation with stress (bright light). Brain areas with consistent and peak levels of c-fos expression across mild traumatic brain injury induced post-traumatic headache were identified and included for further analysis. Results Following mild traumatic brain injury, periorbital and hindpaw allodynia was observed in both male and female mice. This allodynia was transient and subsided within the first 14 days post-mild traumatic brain injury and is representative of acute post-traumatic headache. After this acute post-traumatic headache phase, exposure of mild traumatic brain injury mice to a bright light stress reinstated periorbital and hindpaw allodynia for several hours – indicative of the development of persistent post-traumatic headache. Acute post-traumatic headache was coincident with an increase in neuronal c-fos labeling in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and the nucleus accumbens. Neuronal activation returned to baseline levels by the persistent post-traumatic headache phase in the spinal nucleus of the trigeminal caudalis and primary somatosensory cortex but remained elevated in the nucleus accumbens. In the persistent post-traumatic headache phase, coincident with allodynia observed following bright light stress, we observed bright light stress-induced c-fos neural activation in the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens. Conclusion Examination of mild traumatic brain injury-induced changes in peak c-fos expression revealed brain regions with significantly increased neural activity across the acute and persistent phases of post-traumatic headache. Our findings suggest mild traumatic brain injury-induced post-traumatic headache produces neural activation along pain relevant pathways at time-points matching post-traumatic headache-like pain behaviors. These observations suggest that the spinal nucleus of the trigeminal caudalis, primary somatosensory cortex, and nucleus accumbens may contribute to both the induction and maintenance of post-traumatic headache.

Abstract Background Aortic pseudoaneurysms are complications that arise following cardiac surgery, thoracic trauma, infections, or inflammatory conditions. The mainstay treatment for aortic pseudoaneurysm is surgical management. Given significant morbidity and mortality related to thoracotomy, high-risk patients are not considered for cardiac surgery. Novel percutaneous repair using a variety of devices are being explored, especially in those with prohibitive risk for cardiac surgery. Case summary This case describes the use of an Amplatzer atrial septal defect (ASD) occluder device to manage an aortic pseudoaneurysm in a 69-year-old male who had previously undergone coronary artery bypass graft surgery and pericardial drainage for purulent pericarditis. Following successful implant, there were no complications seen after 2 years of follow-up. Discussion Percutaneous closure of a mycotic pseudoaneurysm with an Amplatzer ASD occluder device can be a safe and efficacious treatment option, especially in patients with prohibitive surgical risk.

Abstract Purpose This study investigated whether Ki-67 labeling index (LI) correlated with clinical outcomes after SRS for atypical meningiomas. Methods This retrospective study examined 39 patients with atypical meningiomas who underwent SRS over a 10-year study period. Ki-67 LI was categorized into 3 groups: low (< 5%), intermediate (5–10%), and high (> 10%). Local tumor control rates (LCRs), progression-free rates (PFRs), disease-specific survival (DSS) rates, and adverse radiation-induced events (AREs) were evaluated. Results The median follow-up periods were 26 months. SRS was performed at a median prescription dose of 18 Gy for tumors with a median Ki-67 LI of 9.6%. The 3-year LCRs were 100%, 74%, and 25% in the low, intermediate, and high LI groups, respectively (p = 0.011). The 3-year PFRs were 100%, 40%, and 0% in the low, intermediate, and high LI groups (p = 0.003). The 5-year DSS rates were 100%, 89%, and 50% in the low, intermediate, and high LI groups (p = 0.019). Multivariable Cox proportional hazard analysis showed a significant correlation of high LI with lower LCR (hazard ratio [HR], 3.92; 95% confidence interval [CI], 1.18–13.04, p = 0.026), lower PFR (HR, 3.80; 95% CI, 1.46–9.88, p = 0.006), and shorter DSS (HR, 6.55; 95% CI 1.19–35.95, p = 0.031) compared with intermediate LI. The ARE rates were minimal (8%) in the entire group. Conclusion Patients with high Ki-67 LI showed significantly more tumor progression and tumor-related death. Ki-67 LI might offer valuable predictive insights for the post-SRS management of atypical meningiomas.

While acknowledging that newer therapies have improved survival rates in chronic lymphocytic leukemia (CLL), patients with high-risk disease features are at an increased risk of treatment failure. Allogeneic hematopoietic cell transplantation (allo-HCT) was traditionally offered as front-line consolidation in high-risk CLL; however, with the emergence of targeted therapies like Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors, the role of allo-HCT has been relegated to later stages of the disease. Patients with relapsed/refractory (R/R) CLL who have failed both BTK and BCL-2 inhibitors represent a therapeutic challenge owing to a poor prognosis. Chimeric antigen receptor T-cell (CAR T) therapies targeting CD19 have improved response rates and overall survival in various types of R/R B-cell non-Hodgkin lymphomas. For CLL, no approved CAR T-cell therapies are yet available. Emerging data appear to show a therapeutic benefit of CAR T-cell therapy in patients with R/R CLL, even after failing an allo-HCT.

Arterial stiffness predicts cardiovascular disease, the leading cause of death worldwide. Ultrasound elastography methods that measure wave velocity have promise for evaluating the stiffness of blood vessels in vivo. However, vessel geometry modulates wave velocity by inducing geometric dispersion. Here, we compare Young's modulus E estimates obtained using in vivo wave velocity measurements and techniques that either do or do not consider geometry to ex vivo reference E values from mechanical testing . An acoustic radiation force was applied to generate propagating waves in the right common carotid artery (N = 9) and external jugular vein (N = 10) of anesthetized pigs. Vessels were imaged with ultrafast ultrasound to measure wave motion. Group velocity cg was estimated from wave motion using a Radon transform. E was estimated from cg using a bulk media assumption which neglects geometry, as well as the Moens–Korteweg equation and a semi-analytical finite element model, which consider geometry. Pigs were euthanized and vessels were excised. Ring-shaped samples were extracted and tested in a uniaxial tension setup to obtain reference E values for comparison with E values obtained from wave-based techniques. Techniques considering geometry exhibited higher correlation with reference E values, underscoring the need to incorporate geometry for accurate vascular elastography assessments.