Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer, is a devastating disease predicted to be the second leading cause of cancer deaths in the next 15 years. Thus, there is an urgent need to develop new treatment approaches based on a better understanding of cellular and molecular mechanisms controlling this dismal progression. PDAC development is marked by nuclear morphological changes likely resulting in changes in chromatin organization and gene expression. Oncogenic KRAS, present in more than 90% of tumors, plays a key role in disease initiation and progression and is sufficient to induce these nuclear morphology changes. Work from our lab has identified the nuclear lamina protein Emerin as a mediator of KRAS-induced nuclear morphology changes. Further, a BioID experiment identified a KRAS-induced interaction of Emerin with a group of nuclear kinases belonging to the ribosomal S6 kinase (RSK) and mitogen- and stress- activated protein kinase (MSK) families. In silico analysis identified candidate MSK and RSK phosphorylation sites in Emerin. Thus, we hypothesize that the nuclear kinase families RSK and MSK can act as effectors of the KRAS-Emerin axis to regulate PDAC nuclear morphology. Further studies will be done to confirm if Emerin can be phosphorylated by RSK and MSK, and to validate that this relationship is dependent on oncogenic KRAS signaling and if its nuclear morphological changes are regulated by this GTPase. Overall, this work aims to define a novel signaling axis for RSK and MSK in controlling nuclear dynamics that play a role in disease progression of PDAC, which can lead to the identification of new therapeutic targets. Citation Format: Kayla LaRue, Ashley Sigafoos, Luis Flores, Brooke Tader, Martin Fernandez-Zapico. The role of nuclear kinases in pancreatic carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3154.

Abstract Craniofacial dermoid cysts are congenital anomalies that rarely have intracranial extension and can be associated with other anomalies. Common sites of these lesions are the lateral brow and parietal scalp. Presentation of the dermoid cyst in the occipital region with intracranial extension is extremely rare. We report a 2-year-old female with a presentation of an occipital dermoid cyst with intracranial extension and secondary cerebellar abscess. This case highlights the rarity of the presentation of an occipital dermoid cyst with intracranial extension and secondary infection and the importance of early imaging for suspected dermoid cysts in the occipital region for identification of intracranial extension.

AbstractPurposePerfusion MRI reveals important tumor physiological and pathophysiologic information, making it a critical component in managing brain tumor patients. This study aimed to develop a dual‐echo 3D spiral technique with a single‐bolus scheme to simultaneously acquire both dynamic susceptibility contrast (DSC) and dynamic contrast‐enhanced (DCE) data and overcome the limitations of current EPI‐based techniques.MethodsA 3D spiral‐based technique with dual‐echo acquisition was implemented and optimized on a 3T MRI scanner with a spiral staircase trajectory and through‐plane SENSE acceleration for improved speed and image quality, in‐plane variable‐density undersampling combined with a sliding‐window acquisition and reconstruction approach for increased speed, and an advanced iterative deblurring algorithm. Four volunteers were scanned and compared with the standard of care (SOC) single‐echo EPI and a dual‐echo EPI technique. Two patients were scanned with the spiral technique during a preload bolus and compared with the SOC single‐echo EPI collected during the second bolus injection.ResultsVolunteer data demonstrated that the spiral technique achieved high image quality, reduced geometric artifacts, and high temporal SNR compared with both single‐echo and dual‐echo EPI. Patient perfusion data showed that the spiral acquisition achieved accurate DSC quantification comparable to SOC single‐echo dual‐dose EPI, with the additional DCE information.ConclusionA 3D dual‐echo spiral technique was developed to simultaneously acquire both DSC and DCE data in a single‐bolus injection with reduced contrast use. Preliminary volunteer and patient data demonstrated increased temporal SNR, reduced geometric artifacts, and accurate perfusion quantification, suggesting a competitive alternative to SOC‐EPI techniques for brain perfusion MRI.

A liver-specific Alb-FlpO mouse line was generated. By coupling it with other existing CreERT or Cre lines, the dual recombinase approach can enable sequential gene modifications within the same cell or across various cell types in an organism for liver research through temporal and spatial gene manipulations.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Abstract The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Background: Despite decades long adoption as the standard-of-care for ischemic stroke, the majority of eligible patients do not receive intravenous thrombolysis (IVT), with underutilization especially pronounced in rural areas. Telestroke, however, may help alleviate this geographical healthcare disparity. The current study aims to identify the impact of implementing a mature telestroke network within a rural setting. Methods: Retrospective review of a prospectively maintained telestroke database from a large rural tertiary care comprehensive stroke center covering 31 spoke hospitals spanning critical access hospitals to primary stroke centers between 10/2021-02/2023. Data was compared to a previous review period (01/2016-12/2018; comprised of 8 spokes) and the statewide IVT rates recorded in GWTG. Data analysis conducted via descriptive statistics and Fisher’s (two-tailed) exact test. Results: 1801 telestroke consults were performed; 41.4% (746/1801) were ineligible for acute stroke intervention. 39% (410/1055) of eligible patients were treated with IVT (vs. 33% [317/959] previously, p = 0.068), representing 58% (410/708; vs 24% [107/448] previously, p < 0.001) of statewide total IVT administration. Symptomatic hemorrhage (sICH) was 3.0%, overall 30-day mortality was 5.6%, and sICH mortality was 1.0%. IVT deferred most commonly: low NIH (44%), mimics (21%), coagulopathy (8%), followed by other. 22% (396/1801) of total consults were transferred from the originating site (vs. 34% [305/890] previously, p < 0.0001) of which 10% (42/396) underwent EVT. Discussion: The impact of expanding a rural telestroke network continued to produce high IVT rates (nearly double the national average) with safety outcomes (sICH, mortality) at or below national standards. Additionally, a large network has significantly increased the proportion of patients remaining at originating sites, optimizing both tertiary and local centers’ resources. The value of a regional telestroke hub is further underscored by the significant increase in statewide IVT attributed to network consults. However, further strategies are needed to better educate rural providers on acute stroke to reduce the rate of ineligible consults and streamline use of telestroke services.

SummaryThis phase II study evaluated time‐limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow‐up time of 25.7 months, the median progression‐free survival (PFS) was 22.9 months. While the primary end‐point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.

31 Background: Incidence of early-onset colorectal cancer (eoCRC, <50 years of age at diagnosis) is increasing globally. However, little is known regarding symptom burden in this sub-population. We compared symptoms in patients with eoCRC to those of patients with average-onset CRC (aoCRC, diagnosed at age ≥ 50). Methods: E2C2 is a stepped-wedge, cluster-randomized pragmatic trial evaluating a collaborative care model for the assessment and management of six symptoms [Sleep disturbance, Pain, Physical function impairment, Anxiety, emotional Distress, and Energy deficit (SPPADE)]. Patients were asked to complete assessments rating each of these symptoms on an 11-point numerical rating scale. Symptom severity was classified as mild (0-3), moderate (4-6), or severe (7-10). We conducted a subgroup analysis of patients with CRC, comparing SPPADE symptoms on an initial survey, regardless of timing in treatment course, between patients with eoCRC and aoCRC. Results: Patients with CRC (n=4281) completed a survey between March 2019 and December 2022. Patient demographics and SPPADE symptoms are reported in the table. Patients with eoCRC were more likely to report severe sleep disturbance ( p<0.0001), pain ( p=0.03485), anxiety ( p<0.0001), emotional distress ( p<0.0001), and fatigue ( p=0.01083). In patients with eoCRC, women were more likely to report severe pain (12.6% vs 6.9%, p=0.0069), anxiety (16.1% vs 10.0%, p=0.012), emotional distress (12.1% vs 5.4%, p=0.00066), fatigue (18.9% vs 13.4%, p=0.038), and physical function impairment (10.1% vs 5.8%, p=0.026) compared to men. Conclusions: Patients with eoCRC reported higher symptom severity than patients with aoCRC. This suggests unique needs for symptom management in patients with eoCRC. Additional research is needed to evaluate how time since diagnosis, disease characteristics, cancer-directed treatment patterns, and co-occurring symptoms are associated with specific symptoms in this population. [Table: see text]