Citations

Abstract Background and Aims Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. Methods This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%–25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. Results One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. Conclusions North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

AbstractBackgroundThe brainstem nucleus incertus (NI) or ‘uncertain nucleus’, was originally described by Streeter in 1903 as a midline region in the floor of the fourth ventricle of the human brain with an ‘unknown’ function. A century later, the NI has been shown to play a key role in memory formation in rodents, through direct and indirect inhibition of the hippocampus; and the anatomy of the NI and its projections throughout the brain have been systematically mapped in rats, mice, and primates, but not in humans. In these novel studies, we mapped the human NI using the neuropeptide, relaxin‐3 (RLN3), as neurochemical marker. In rodents, RLN3 is produced mostly in NI neurons with some subsidiary positive cells in the periaqueductal gray and an area dorsal to the substantia nigra.MethodsSerial, free‐floating coronal sections of formalin‐fixed postmortem tissue were prepared from the pons of an adult female (aged 96 years) without a history of dementia or other neurological disorders, provided by the Banner Brain and Body Donation Program, Sun City, Arizona, USA. Using immunohistochemistry, we first identified the NI by mapping the distribution of microtubule‐associated protein‐2 (MAP2) and RLN3. The specificity of the RLN3 antibody used was verified in a dot‐blot using native RLN3 peptide. We also investigated the presence of markers detected in the NI of rats ‐ glutamic acid dehydrogenase‐65/67 (GAD65/67) and corticotropin‐releasing factor type 1 receptor (CRF1); and used a phosphorylated‐tau (AT8) to determine if the NI displayed tau accumulation.ResultsDetection of MAP2‐immunoreactivity revealed the neuronal distribution throughout the pons. RLN3‐immunoreactivity was detected in neurons in the dorsal, anterior‐medial region, revealing the broad anatomy of the human NI. Neurons within this same area were also positive for GAD65/67‐ and CRF1‐immunoreactivity, in line with previous studies; and AT8‐immunoreactivity was also detected.ConclusionsRLN3 is present in neurons of the human NI and aspects of its anatomy are shared across species, including the macaque. Accumulation of phosphorylated‐tau in the NI suggests its possible involvement in the pathology of Alzheimer’s disease and related dementias. Further comparative studies are required to better understand the neurochemical anatomy of the human NI.

Abstract Purpose: The 2024 ASHP Pharmacy Forecast identifies and contextualizes emerging issues and trends that will influence healthcare, health systems, and the pharmacy profession and provides recommendations to inform long-term strategic planning that should prompt action by pharmacists and health-system leaders. Methods: Drawing on the “wisdom of crowds” concept, a survey was constructed with 6 general themes, each with 6 to 9 focused statements and a seventh theme on preparedness (58 survey items in total). The size of and representation within the survey panel were intended to capture opinions from a wide range of pharmacy leaders. The survey instructed panelists to consider the likelihood of the events/scenarios described in the statements occurring in the next 5 years as being likely, somewhat likely, somewhat unlikely, or very unlikely. Then, survey panelists assessed the preparedness (from very unprepared to very prepared) for 12 of the statements. Results: The 6 survey themes identified were Urgent Public Health Priorities, Responding to the Mental Health Crisis, Achieving Care Equity, New Disease Paradigms and Treatment Innovations, Workforce: Focus on Culture for the Future, and Artificial Intelligence: Can Ethics and Regulators Catch Up? The survey was completed by 250 respondents, yielding an 88% response rate. Analysis of survey results was provided by chapter authors along with strategic recommendations to guide actions for each theme. Conclusion: The focus of the Pharmacy Forecast is on large-scale, long-term trends that will influence healthcare and the pharmacy profession over months and years and not on day-to-day situational dynamics. The report provides insight to stimulate thinking and discussion and provides a starting point to proactively position leaders, their teams, and departments for potential future events and trends.

Abstract INTRODUCTION Disparities in breast cancer (BC) screening are observed between Hispanic and non-Hispanic White women and stronger amongst Hispanic women with under- and uninsured statuses.1-2 Risk-based screening has been recommended by professional societies, including American Cancer Society, starting at age 30 and may be an important strategy for reducing disparities.3 The purpose of the study was to characterize whether women had been told their personal risk of BC and to identify differences in characteristics of patients informed of their personal risk. METHODS This is a cross-sectional analysis of data from a supplemental self-reported survey to an NIH-funded randomized trial conducted at a large Federally Qualified Health Center (FQHC) in Arizona (R01 MD09682-05). The survey was sent to a randomized 600 of the 1,356 participants. Between November 2022 and April 2023, 177 women completed the survey (response rate 29.5%). Participants were asked if a doctor or other healthcare provider had ever talked to them about their personal risk for BC. Differences between those who recalled being told their personal risk for BC and those who did not were assessed using Fisher exact test. RESULTS Overall, 66.3% were 50 years or older, 81.8% who speak primarily Spanish, and 64.8% of respondents had less than a high school education. Also, 22.4% reported a family history of BC, 27.4% have been previously recalled for additional imaging, 10.8% have had a history of prior breast biopsy, 59.9% stated having a regular provider, and 53.1% were found to have dense breast category C or D at screening visit. 40% did not report having a regular doctor although all participants received care at an FQHC. 30.5% of respondents stated that a healthcare professional had ever talked to them about their personal risk for BC. There was a trend toward women with a main doctor being more likely to recall being told their personal risk for BC as compared to those without a main doctor (38.5% vs 22.5%, p=0.06). CONCLUSIONS In this cohort of primarily Spanish-speaking Hispanic women who have had mammography screening and written report of their breast density, about a third of respondents recall being informed of their personal BC risk. These observations need to be confirmed in a larger population with greater response rate, but these results suggest that there is a cohort of patients who need different approaches for conveying risk. REFERENCES 1. Jadav, S., Rajan, S. S., Abughosh, S., & Sansgiry, S. S. (2015). The Role of Socioeconomic Status and Health Care Access in Breast Cancer Screening Compliance Among Hispanics. Journal of Public Health Management and Practice, 21(5), 467–476. https://www.jstor.org/stable/48517175 2. American Cancer Society. (2017). Breast cancer facts & figures 2017-2018. Atlanta, GA: American Cancer Society, Inc. 3. ACS Breast Cancer Screening Guidelines. (2022, January 14). https://www.cancer.org/cancer/types/breast-cancer/screening-tests-and-early-detection/american-cancer-society-recommendations-for-the-early-detection-of-breast-cancer.htm Citation Format: Jhenitza P. Raygoza Tapia, Sarah M. Jenkins, Jennifer L. Ridgeway, Aaron D. Norman, Crystal R. Gonzalez, Valentina Hernandez, Bhavika K. Patel, Celine M. Vachon, Jessica D. Austin. Communicating breast cancer risk to Spanish-speaking Hispanic women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C126.

Dent disease I is a rare X‐linked recessive chronic kidney disorder caused by mutations of the CLCN5 gene, which encodes the electrogenic Cl−/H+ exchanger (transporter) ClC‐5. CLC‐5 protein has been localized to the apical membrane and endosomal vesicles of the kidney in the proximal tubule as well as other tubule segments. Clinical manifestations of patients with Dent disease include low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis, nephrolithiasis, bone disease (rickets), and often progressive renal failure. While it is known that the CLC‐5 protein functions in the formation and maturation of endosomes, the etiology of the nephrocalcinosis and kidney stones often observed in Dent disease patients is not known. Therefore, in this project we investigated the effects of several CLC‐5 mutations identified in Dent disease patients, including S244L, Q629X, and R345W, on cellular processing of calcium oxalate (CaOx) crystals. Monolayers of renal proximal tubular cells (LLC‐PK1) and renal cortical tubular epithelial cells (RCTE) transfected with GFP tagged WT and mutated CLC‐5 were subjected to a CaOx crystal adhesion/agglomeration assay for thirty minutes then imaged by DIC and epifluorescence microscopy. The total area of CaOx crystal formation around each transfected cell within a 35, 55, and 75 μm diameter concentric circle was analyzed using ImageJ, and compared to adjacent un‐transfected cells which served as an internal control. A significant increase in CaOx aggregation was observed around cells expressing CLC‐5 mutants compared to wild type cells, especially for S244L. In LLC‐PK1 cells crystal adhesion/agglomeration decreased in this order: S224L > R345W > Q629X = WT; while in RCTE it decreased in this order: S224L = Q629X > R345W = WT. These findings support the hypothesis that mutated CLC‐5 proteins alter the apical surface of epithelial nephron cells and encourage CaOx aggregation/adhesion. It is also possible that decreased internalization and dissolution of CaOx crystals which form on the cell surface plays a role, as the greatest crystal adhesion/agglomeration was found within the 35 μm diameter circle around cells transfected with mutated CLC‐5 (35 μm > 55 μm > 75 μm). Further investigation into the impact of specific CLC‐5 mutation of protein structure and function, including protein‐protein interactions, is needed. Support or Funding Information Supported by O'Brien Urology Research Center U54‐DK100227 summer student supplement and the Rare Kidney Stone Consortium (U54‐DK083908)

Objective: Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage 131 I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT. Methods: This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF -MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose 131 I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose 131 I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received 131 I therapy. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following 131 I therapy in select patients with RAIR-DTC, particularly those with RAS -driven “follicular” phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic anaplastic transformation.

Abstract Disclosure: D. Toro-Tobon: None. J.C. Morris: None. C. Hilger: None. C.S. Peskey: None. D.M. Jolanta: None. M.M. Ryder: None. Objective: Patients with metastatic differentiated thyroid cancer (DTC) that are radioactive iodine (RAI) refractory (RAIR) have a poor prognosis. Redifferentiation therapy (RDT) has emerged as a potential approach to restore RAI avidity in this disease. The aim of this study was to examine the efficacy and predictors of RAI restoration in RAIR disease, as well as examine the outcomes of patients re-treated with high dose RAI following RDT. Methods: A retrospective review was conducted of 33 patients with RECIST-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic. All patients underwent genomic profiling, and either MEK inhibitor alone or combination BRAF-MEK inhibitors were prescribed for 4 weeks. At week 3, Thyrogen-stimulated I-123 whole body scans were performed. Those with increased RAI avidity in metastatic foci received high dose I-131 therapy using a previously published modified dosimetry protocol. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 12 of 23 (52%) with papillary thyroid cancers (PTC), 4 of 4 (100%) with follicular variant PTCs (FV-PTC), and 7 of 7 (100%) with follicular thyroid cancers (FTC) had restored RAI avidity following RDT using dabrafenib/trametinib (7 for BRAF mutant disease) or trametinib monotherapy (12 for RAS mutant disease). All 11 (100%) RAS mutant tumors (2 PTC, 3 FV-PTC, and 6 FTC) had RAI avidity restoration compared to 7 (36%) with BRAF mutant disease (6 PTC, and 1 FV-PTC). Of the 19 patients (57%) with restored RAI avidity (responders), 18 (94%) received I-131 with a median dose of 294 mCi. The median thyroglobulin (Tg) in responders was 294 mIU/L as compared to 29 mIU/L in non-responders. Following RDT-facilitated I-131 treatment, 94.7% achieved RECIST defined objective response (complete or partial response, stable disease, non-complete response/non-progressive disease) with a median progression free survival of 18 months and an overall survival of 30 months. Overall, patients with FTC (p=0.01), RAS mutation (p<0.001), Tg of 294 mIU/L or more (p=0.03), largest tumor diameter of 1.7 cm or less (p=0.05), bone metastasis (p=0.007), and without locoregional nodal disease (p=0.04), were more likely to demonstrate restored RAI avidity following RDT. Of the entire cohort, 2 (6%) patients experienced histologic transformation to anaplastic thyroid cancer and 5 (15%) patients died, all had had RAI restoration and received high-dose RAI following RDT. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following I-131 therapy in select patients with RAIR-DTC, particularly those with RAS mutations and ‘follicular’ phenotypes. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic transformation. Presentation Date: Saturday, June 17, 2023

SummaryBackgroundThe Th2 allergic pathway in eosinophilic oesophagitis (EoE) responds to food antigen exposure.AimTo compare the presence and temporal pattern of food antigen penetration in oesophageal mucosa in active and inactive EoE and controlsMethodsThirty‐two patients with EoE (20 active) and 10 controls were asked to eliminate all wheat and/or dairy 12, 24, 48, 72 or 96 hours before endoscopy. Immunostaining on endoscopic biopsies was performed for gliadin, casein and whey.ResultsGluten, casein and whey were detected by positive staining in 17/32 (53.1%), 21/32 (65.6%), and 30/32 (92.0%) of patients, respectively. In active vs inactive EoE, 70.0% vs 25.0% (P < 0.05), 80.0% vs 41.5%, and 90.0% vs 90.9% patients had detectable gliadin, casein and whey, respectively. Casein and whey (20.0% and 100%, respectively) but not gliadin, were present in controls. The gliadin staining density was greater in active compared to inactive disease at ≤ 24 vs >24 hours after exposure (P = 0.05) but no differences were detected when comparing active and inactive patients for casein and whey. There was greater staining density for whey than casein for all patients at ≤24 hours (mean 2.14 ± 0.91 and 1.07 ± 1.33, P = 0.02). In active EoE, IgG4 was present in 14/20 compared to one inactive patient.ConclusionThe oesophageal epithelium is selectively permeable and has relatively long dwell times for food antigens known to trigger EoE. The precise mechanism of antigen‐specific mucosal entry and the factors that determine the induction or effector trigger of the Th2 pathway activation merit further study.