Citations

Introduction: Gray-white matter ratio (GWR) on non-contrast head computed tomography (HCT) is a helpful tool in neuro-prognostication in post-cardiac arrest patients. Its usage is unclear for those with angiography due to residual contrast. Hypothesis: GWR remains valid for neuro-prognostication in comatose patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) followed by coronary angiography (CAG) after out-hospital cardiac arrest (OHCA). Methods: We performed a retrospective study of comatose OHCA adults post ECPR and CAG at University of Minnesota from January to June 2022 with dual energy HCT within 12 hours. GWR was measured at basal ganglia, centrum semiovale, and high convexity levels. Gray matter areas of interest included caudate nucleus, putamen, thalamus, and medial cortex. The white matter areas of interest included the genu of the corpus callosum, posterior limb of the internal capsule, and medial white matter. Circular regions of interest (ROI, 10-15 mm 2 ) were placed bilaterally in corresponding areas to record the average attenuation in Hounsfield unit (HU). The basal ganglia, cerebrum, and overall GWRs were calculated as the ratio of average HU between the gray and white matter ROIs within the area. Primary outcome was inpatient death, further categorized by the primary cause being neurological or not. Logistic regression followed by receiver operating characteristic (ROC) curves was used to validate GWR in predicting death. All data analysis was performed by StataCorp Software (STATA 14). Result: 25 patients were included in the study. 18 (72%) were male with a median age of 60 (interquartile range (IQR): 45-67). The initial HCT was obtained at 2.08 hours (median, IQR: 1.37–2.43) post ECPR cannulation. 7 (28%) patients died from brain death or herniation and 15 (60%) died from non-neurological causes. None had intracranial bleeding. 1 patient had unilateral hypodensity on initial HCT, suggesting an acute embolic infarct. Patients who died had lower GWRs on initial HCT (Figure 1). ROC regression showed all GWRs demonstrated good prognostic performance on inpatient death with area under the curve (AUC) of 0.6970 (basal ganglia), 0.8485 (cerebrum), and 0.7576 (overall) (Figure 2). Conclusions: GWR in early HCT has prognostic value in predicting neurological outcomes despite residual contrast. It may be used as a risk stratification tool for comatose OHCA patients undergoing ECPR and angiography.

The growing adoption of advanced imaging modalities, such as transesophageal echocardiography (TEE), has led to more frequent detection of cardiac structural abnormalities. While intracardiac cardiac tumors and shunts are infrequent and typically asymptomatic, their existence can precipitate severe outcomes, including stroke, myocardial infarction and sudden death. Case Description: A 69-year-old female presented with left sided facial droop, slurred speech and left arm weakness. A computed tomography angiography revealed focal occlusion of the distal right middle cerebral artery. She was initiated on thrombolytic therapy and experienced resolution of symptoms. Transthoracic echocardiogram revealed right to left shunting consistent with a patent foramen ovale (PFO). Further workup with TEE confirmed the presence of a PFO but also detected a mobile echogenic mass on the aortic valve leaflet, indicative of papillary fibroelastoma (PFE). Cerebral infarction was attributed to an embolic event, with the PFO and PFE being likely culprits. Discussion: Current guidelines give a conditional recommendation, low certainty of evidence, for PFO closure in adults older than 60 years, although some observational studies have shown some risk reduction in older patients. The key trials showing clinical benefit of PFO closure were in adults younger than the age of 60. For left sided cardiac tumors, such as PFE, guidelines give a 2A recommendation for resection. Addressing the risk for recurrent stroke in this 69-year-old patient was an essential part of stroke care, as such, a multi-disciplinary team of experts including cardiology, neurology, and cardiothoracic surgery was conveyed. The decision was to proceed with surgical intervention in addition to antiplatelet therapy to achieve optimal risk reduction. The patient subsequently underwent successful surgical removal of the PFE with native valve preservation and PFO closure. Conclusion: Cardiac PFEs and PFOs can be associated with increased stroke risk. Employing appropriate imaging techniques and timely interventions are of utmost importance in stroke management.

Background: Nationally, many ASCVD patients fail to achieve an LDL-C <70 mg/dL, and uptake of both statin and non-statin therapies is low. The degree to which this varies across health systems is less clear. Methods: A cross sectional analysis was performed where lipid levels and lipid lowering therapies (LLT) were assessed using electronic health record data in patients with a previous diagnosis of ASCVD. The data was obtained across 14 US healthcare systems between 1/1/2021-12/31/2022. Proportions of patients with an active prescription of any statin, high intensity statin, ezetimibe, PCSK9i, and combination therapy (two or more agents) within 395 days of the most recent LDL-C value (index date) was evaluated overall and by participating site. Additionally, the proportion of patients with an LDL-C <70 mg/dL at the index date was also assessed. Results: Across 14 health systems, 1,118,623 patients with ASCVD were identified (median 61,840 per health system, range 8,161-182,315). Overall, 675,776 (60.4%) had an LDL-C level in the past year (range 39.1% - 70.8%). Of those with a lipid level, achievement of LDL-C <70 mg/dL ranged from 34.6-47.2%. In total, 42.6% were on any statin, 20.1% were on a high intensity statin, 4.3% on ezetimibe, and 1.2% on a PCSK9i. Only 2.9% were on combination therapy of a statin with ezetimibe or a PCSK9i. Variability was seen across health systems in utilization of each of these therapies, however even in the highest performing health systems, LLT uptake and achievement of LDL-C < 70mg/dL remained low ( Figure). Conclusion: Variability in utilization of LLT in ASCVD patients between health systems suggests that system-level factors may impact achieving guideline-based LDL-C goals. Despite the variability, the highest proportion of patients achieving an LDL-C <70mg/dL remained under 50% indicating the need for aggressive implementation efforts.

Background: As machine learning becomes increasingly utilized in orthopaedic clinical research, the application of machine learning methodology to cohort data from the Multicenter ACL Revision Study (MARS) presents a valuable opportunity to translate data into patient-specific insights. Purpose: To apply novel machine learning methodology to MARS cohort data to determine a predictive model of revision anterior cruciate ligament reconstruction (rACLR) graft failure and features most predictive of failure. Study Design: Cohort study; Level of evidence, 3. Methods: The authors prospectively recruited patients undergoing rACLR from the MARS cohort and obtained preoperative radiographs, surgeon-reported intraoperative findings, and 2- and 6-year follow-up data on patient-reported outcomes, additional surgeries, and graft failure. Machine learning models including logistic regression (LR), XGBoost, gradient boosting (GB), random forest (RF), and a validated ensemble algorithm (AutoPrognosis) were built to predict graft failure by 6 years postoperatively. Validated performance metrics and feature importance measures were used to evaluate model performance. Results: The cohort included 960 patients who completed 6-year follow-up, with 5.7% (n = 55) experiencing graft failure. AutoPrognosis demonstrated the highest discriminative power (model area under the receiver operating characteristic curve: AutoPrognosis, 0.703; RF, 0.618; GB, 0.660; XGBoost, 0.680; LR, 0.592), with well-calibrated scores (model Brier score: AutoPrognosis, 0.053; RF, 0.054; GB, 0.057; XGBoost, 0.058; LR, 0.111). The most important features for AutoPrognosis model performance were prior compromised femoral and tibial tunnels (placement and size) and allograft graft type used in current rACLR. Conclusion: The present study demonstrated the ability of the novel AutoPrognosis machine learning model to best predict the risk of graft failure in patients undergoing rACLR at 6 years postoperatively with moderate predictive ability. Femoral and tibial tunnel size and position in prior ACLR and allograft use in current rACLR were all risk factors for rACLR failure in the context of the AutoPrognosis model. This study describes a unique model that can be externally validated with larger data sets and contribute toward the creation of a robust rACLR bedside risk calculator in future studies. Registration: NCT00625885 (ClinicalTrials.gov identifier).

Background: Coronary heart disease (CHD) results from environmental and genetic factors. Lifestyle-psychosocial factors that capture environmental risk and polygenic risk scores (PRS) that capture genetic risk have been associated with CHD in prior studies. Aim: To assess whether higher CHD risk traditionally attributed to non-White race/ethnicty is mediated by PSS CHD or PRS CHD . Methods: In UK Biobank, we ascertained incident CHD (MI/coronary revascularization) and calculated an ancestry-specific PRS for CHD (PGS000018). Based on self-reported race/ethnicity, participants were classified as White and non-White. An age, sex, and ethnicity-adjusted polysocial score for CHD (PSS CHD ) was derived from 100 self-reported lifestyle-psychosocial factors across nine domains: Adulthood Relationship, Education, Entertainment, Housing, Income, Occupation, Physical Activity, Psychological Health, and Sleep. Those with CHD or statin use at recruitment or missing age, sex, race/ethnicity or genotype were excluded. Machine learning (elastic net model) was used to develop PSS CHD . Cox and mediation analyses were performed. Results: In 398,403 participants (56±8 y, 43% male, 96.3% White, 1.8% Asian, 1.6% Black, and 0.3% Chinese), 10,033 had an incident CHD event during a 10-year follow-up. The HRs (95% CIs) for a 1 SD increase in PSS CHD and PRS CHD for CHD risk were 1.5 (1.4–1.5, P <10 -16 ), and 1.6 (1.5 - 1.6, P <10 -16 ), respectively (Figure 1A-B). Asians and Blacks had the highest PSS CHD (mean±SD: 0.5±1, and 0.5±1, respectively), followed by Chinese (0.1±0.9), and Whites (0.0±1) (Figure 1C). After adjustment for age, sex, diabetes, hypertension, LDL-C, and smoking, non-Whites had higher CHD risk: HR (95% CI): 1.2 (1.0–1.4, P <10 -16 ), and the higher risk was mediated more substantially by PSS CHD than PRS CHD (63% (38%-100%) vs. 16% (8%-41%), both P <10 -16 ). Conclusions: The higher CHD risk observed in non-Whites in UK Biobank was mainly due to unfavorable lifestyle-psychosocial factors, rather than PRS, consistent with the paradigm that race/ethnicity is not a biological but rather a social construct. Our findings support substituting race/ethnicity with lifestyle-psychosocial factors and social determinants of health in CHD risk equations.

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

Abstract BACKGROUND BRAF pathway alterations are frequent in glial/neuroepithelial tumors. BRAF-targeted therapy with BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) has proven efficacy in clinical trials, though mainly enrolling pediatric patients. We sought to investigate real-world data for adult patients with BRAF-pathway mutant glial/neuroepithelial neoplasms treated with BRAFi/MEKi. METHODS Adults with BRAF-pathway mutated glial/neuroepithelial neoplasms treated with BRAFi/MEKi were retrospectively reviewed. RESULTS Five patients (n=4 female, median age at diagnosis 36) were identified (tumor types: glioblastoma n=1, high-grade astrocytoma with epithelioid features n=1, low-grade neuroepithelial tumor n=1, pilocytic astrocytoma n=1, pleomorphic xanthoastrocytoma n=1). Four had BRAF V600E and one had NF1 p.S2687Cfs*5 mutant tumors. Prior to targeted therapy initiation, patients underwent a median 2.4 treatments including surgery (n=4), radiation therapy (n=4), chemotherapy (temozolomide n=4; carboplatin/vincristine n=1). BRAF-targeted therapies included dabrafenib/trametinib (n=4), binimetinib/encorafenib (n=2), binimetinib (n=2). One NF1-mutant glioblastoma received binimetinib followed by binimetinib/bevacizumab. Median BRAFi/MEKi treatment was 15.2 months (range: 6-36 months). Toxicities included leukopenia (n=3), peripheral edema (n=1), reduced ejection fraction (n=1), skin rash (n=5), transaminitis (n=1) with all patients requiring dose reductions and 3 cases requiring discontinuation. Among patients where BRAFi/MEKi was discontinued due to toxicity, 2 received other treatments at progression, then switched to a different BRAFi/MEKi combination, which they tolerated (duration 6-10months). Best radiographic response was partial response, noted in 3 patients treated with dabrafenib/trametinib. Four patients remain alive and continue BRAFi/MEKi. CONCLUSIONS In this cohort of heavily-pretreated patients with glial/neuroepithelial neoplasms, BRAF-targeted therapy was associated with durable responses. Interestingly, two patients who were unable to tolerate one combination of BRAFi/MEKi were able to tolerate a different combination with sustained response. Our findings support ongoing use of BRAF targeted therapy for CNS tumors. Optimal timing and duration of treatment requires further prospective evaluation in adult patients.

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

Abstract BACKGROUND Pituitary adenomas are often effectively managed with medical therapy, surgery, and radiation therapy. However, up to 15% of pituitary neoplasms exhibit rapid growth, invasive behavior, or, rarely, metastasize despite optimal standard treatments. Temozolomide is associated with a survival benefit for patients with these aggressive pituitary tumors. METHODS We present a case series of 8 patients with an aggressive pituitary tumor (APT) or pituitary carcinoma (PC) treated with temozolomide. RESULTS Eight patients (3 female, median age at diagnosis 44) with APT (n=6) or PC (n=2) were treated. A variety of pituitary tumor types were represented (1 prolactinoma, 5 corticotroph adenomas, 1 gonadotroph adenoma, 1 thyrotropinoma). Prior to temozolomide initiation, patients underwent a median 5 treatments including medical management (n=4), surgery (n=7), radiation therapy (n=7). Temozolomide was started at median 3.5 recurrence. Median treatment duration was 6 cycles (n=6, 150-200 mg/m2 days 1-5, 28-day cycles; n=1, 75 mg/m2, days 1-21, 28-day cycles). Seven patients experienced progression after temozolomide treatment, median progression-free survival (PFS) was 4 months. One patient remains on treatment, progression-free at 5 months. MGMT methylation status was assessed for 3 tumors. Among 2 patients with MGMT promoter methylated tumors, PFS was 4 months for one patient, the other remains on treatment. For one patient with MGMT promoter unmethylated corticotroph adenoma, PFS was 9 months. No ≥ grade 4 toxicities were noted. Most common toxicities were nausea (n=5), thrombocytopenia (n=3), and fatigue (n=2). CONCLUSION In this group of heavily pretreated patients, temozolomide monotherapy was well-tolerated and associated with median PFS of 4 months. Interestingly, PC patients had longer PFS at 9 months and 24 months. Our findings support use of single-agent temozolomide chemotherapy for patients with APT/PC, but further prospective analysis is needed to identify patients more likely to benefit from treatment and optimal timing of chemotherapy initiation.

ABSTRACT Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host’s immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428–e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8 ], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, “rhinocerebral mucormycosis.” A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.