Citations

Background and purpose Deep brain stimulation of the thalamus is an effective treatment for multiple neurological disorders. The centromedian and parafascicular nuclei are recently emerging targets for multiple conditions, such as epilepsy and Tourette syndrome; however, their limited visibility on conventional magnetic resonance imaging sequences has been a major obstacle. The goal of this study was to demonstrate the feasibility of a high-resolution and high-contrast targeting sequence for centromedian-parafascicular deep brain stimulation using a recently described magnetic resonance imaging sequence, three-dimensional edge-enhancing gradient echo. Methods The three-dimensional edge-enhancing gradient echo sequence was performed on a normal volunteer for a total of six acquisitions. Multi-image co-registration and averaging was performed by first co-registering each of the six scans and then averaging to produce an edge-enhancing gradient echo-multi-image co-registration and averaging scan. The averaging was also performed for two, three, four and five scans to assess the change in the signal-to-noise ratio and identify the ideal balance of image quality and scan time. Results The edge-enhancing gradient echo-multi-image co-registration and averaging scan allowed clear boundary delineation of the centromedian and parafascicular nuclei. The signal-to-noise ratio increased as a function of increasing scan number, but the added gain was small beyond four scans for the imaging parameters used in this study. Conclusions The recently described three-dimensional edge-enhancing gradient echo sequence provides an easily implementable approach, using widely available magnetic resonance imaging technology without complex post-processing techniques, to delineate centromedian and parafascicular nuclei for deep brain stimulation targeting.

4023 Background: Biliary tract cancers (BTC) are increasingly subtyped by molecular alterations, but little is known about the relationship between gain-of-function mutations and the RNA transcript expression of immune-related pathways. Methods: A sample of retrospective, clinicogenomic and transcriptomic data from de-identified records of patients with BTC in the Tempus database was selected. We then investigated the relationship between the mutational landscape and immune-related RNA signatures of different anatomic and genomic BTC subtypes. Results: The cohort included 455 samples of intrahepatic bile duct (IH) (n=267), gallbladder (GB) (n=153), and extrahepatic bile duct (EH) (n=35) cancer subtypes. Across all subtypes, we detected alterations in TP53 (43.8%), ARID1A (19.8%), KMT2C (18.2%), BAP1 (14.6%), KRAS (12.7%), TERT (12.0%), IDH1 (11.4%), KMT2D (11.0%), LRP1B (11.0%), and PBRM1 (10.7%), along with FGFR2 fusions (2.6%). Potentially actionable biomarkers ( FGFR2 and NTRK1-3 fusions, IDH1 and BRAFV600E mutations, tumor mutational burden [TMB]>10, HER2 expression, and/or microsatellite instability) were identified in 21.1% of all BTC and 28.6% of IH samples. Mutually exclusive alterations observed between subtypes were TP53 & BAP1, KRAS & BAP1, TP53 & IDH1, KRAS & IDH1, and SMAD4 & BAP1 ( P < 0.001 for all). GB was more inflamed based on RNA signatures and classical immune biomarkers, including PD-L1 and TMB. RNA signature analyses revealed a higher expression of immune-related pathways in GB than IH ( P = 0.001) with no differences in comparison with EH. PD-L1 expression and continuous TMB were elevated in GB versus the other anatomical subtypes. Significant associations were noted between particular genetic mutations and immune profiling features (table). Conclusions: BTC subtypes are diverse in DNA alterations, RNA inflammatory signatures, and immune markers. Notably, potentially actionable biomarkers were identified in a sizable portion of the cohort and varied significantly between subtypes. These results provide guidance for targeted therapy development and support the use of multimodal immune profiling for BTC. For example, GB-specific clinical trials may be considered due to the relative increase in immune-related biomarkers observed in GB and the historically limited success of BTC trials.[Table: see text]

Abstract Background Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important. Methods PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH, and phosphoproteomics. Results Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment. Conclusions Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20–50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.

Encephalopathy, delirium, and agitation are documented symptoms of coronavirus disease (COVID-19) infection, but research into the management of agitation in the setting of COVID-19 and pre-existing neuropsychiatric disease is ongoing. We present a 55-year-old male patient with early-onset Alzheimer disease and deteriorating mental and functional status who presented to our institution with agitation and persistent COVID-19 positivity on polymerase chain reaction testing. His agitation was improved through pharmacologic optimization including the avoidance of benzodiazepines and initiation of clonidine and prazosin, which temporally coincided with the resolution of his nearly 2-month long COVID-19 positivity.

Introduction: Cardiovascular disease risks are significantly higher in patients with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). There are limited data on the management and outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in patients with HIV/AIDS> Methods: A retrospective cohort of AMI-CS during 2000-2017 from the National Inpatient Sample was evaluated for concomitant HIV and AIDS. Outcomes of interest included in-hospital mortality, use of cardiac procedures, hospital length of stay, hospitalization costs, use of do-not-resuscitate (DNR) status, and palliative care use. A sub-group analysis was performed for those with and without AIDS within the HIV cohort. Results: A total 557,974 AMI-CS admissions were included, with HIV and AIDS in 1,321 (0.2%) and 985 (0.2%), respectively. The HIV cohort was younger (54.1 vs. 69.0 years), more often male, of non-white race, uninsured, from a lower socioeconomic status, and with higher comorbidity (all p <0.001). The HIV cohort had comparable multiorgan failure (37.8% vs. 39.0%) and cardiac arrest (28.7% vs. 27.4%) ( p >0.05). The cohorts with and without HIV had comparable rates of coronary angiography (70.2% vs. 69.0%; p =0.37), but less frequent early coronary angiography (hospital day zero) (39.1% vs. 42.5%; p <0.001). The cohort with HIV had comparable in-hospital mortality compared to those without (26.9% vs. 37.4%; adjusted odds ratio 1.04 [95% confidence interval 0.90-1.21]; p =0.61). The cohort with HIV had longer duration of hospitalization (10.8±10.1 vs 9.9±11.4 days), higher hospitalization costs (158±155 vs. 143±182 x1000 USD) and was discharged home (48.6% vs 41.8%) more often as compared to those without HIV (all p <0.005). In the HIV cohort, AIDS was associated with higher in-hospital mortality (28.8% vs. 21.1%; adjusted odds ratio 4.12 [95% confidence interval 1.89-9.00]; p <0.001). Secondary outcomes were relatively comparable between those with and without AIDS. Conclusions: The cohort with HIV had longer hospital stay and higher hospitalization costs; however these were comparable between those with and without AIDS.

Introduction: Several chemotherapy agents, especially anthracyclines, are associated with the development of non-ischemic cardiomyopathy. When chemotherapy-induced cardiomyopathy (CHIC) is associated with left bundle branch block (QRS >150 ms) and a left ventricular ejection fraction (LVEF) of 35% or lower, cardiac resynchronization therapy (CRT) is often utilized to improve cardiac function and relieve symptoms. Hypothesis: CRT is associated with improvement in left ventricular strain in patients with CHIC. Methods: The study included 22 patients with CHIC and 44 age- and gender-matched controls with other types of NIC who underwent CRT implantation between 2004 and 2017. LVEF, left ventricular global longitudinal strain (GLS), systolic strain rate (SRS), and early diastolic strain rate (SRE) were assessed at baseline and 6-18 months after CRT. CRT response was defined as LVEF improvement by >5% after CRT. Results: CRT responders had a significant improvement in left ventricular GLS as compared to CRT non-responders in the control group, but not in the CHIC group (Table 1). The mean change in LVEF after CRT was similar between the CHIC and control groups (10 ± 10% versus 11 ± 11%, p= 0.67). The mean change in GLS after CRT was also similar between the two groups (-2.15 ± 4.32 versus -3.57 ± 4.02, p= 0.19). The proportion of patients whose LVEF increased by more than 5% was similar between the two groups (59% in the CHIC group versus 68% in the control group, p= 0.46). The mean changes in LV myocardial systolic and early diastolic strain rates were similar between the CHIC and control groups. Mean SRS decreased by 0.13 ± 0.14 in the CHIC group and by 0.34 ± 1.28 in the control group (p=0.45). Mean SRE increased by 0.06 ± 0.18 in the CHIC group and by 0.07 ± 0.22 in the control group (p=0.86). Conclusions: CRT is associated with improvement in left ventricular strain in patients with CHIC. Prospective studies are needed to further evaluate the echocardiographic strain outcomes of CRT in CHIC.