Citations

9022 Background: High quality education is crucial for hematology/oncology (H/O) training and lifelong learning. However, H/O has historically prioritized clinical and research careers over medical education careers. Consequently, few programs support H/O educators. A CoP is a group that shares “a concern or passion for something they do and learn how to do it better as they interact regularly.” We formed the ASCO Med Ed CoP in 2021 to provide a collaborative network and professional development venue for H/O educators. Methods: Following a published framework for developing a global health professions educator community (Establish-Grow-Sustain), we (ASCO Education Scholars Program graduates) developed CoP mission and vision statements and a leadership structure (Establish), formed committees and projects (Grow), and gathered at the ASCO Annual Meeting and via virtual Town Halls (Sustain). In 2023, we collected demographics and evaluated the CoP using a logic model focused on inputs, activities, outputs, and impact. Results: As of December 2023, the CoP includes 238 members from 143 institutions (38 [27%] non-U.S.): 207 (87%) ASCO members; 127 (53%) women, 106 (45%) men, 5 (2%) no response (NR); 111 (47%) White, 88 (37%) Asian/Pacific Islander, 27 (11%) Latinx/Hispanic, 12 (5%) Black/African-American, 8 (3%) Middle Eastern, 1 (0.4%) African, 16 (7%) NR; 146 (61%) hematologist/oncologists, 68 (29%) trainees, 6 (3%) radiation oncologists, 3 (1%) surgical oncologists, and 15 (6%) other professionals. The logic model is displayed (Table). Conclusions: The CoP has had an impact on its members, ASCO, and beyond and continues to grow and sustain itself by recruiting broadly, driving projects forward, and making structural adjustments for long-term sustainability. Upcoming projects include providing more educational resources and measuring outcomes such as changes in members’ knowledge, skills, and attitudes. Membership diversity continues to be a challenge and a priority. [Table: see text]

Abstract Background Few antiviral therapies have been studied in patients with coronavirus disease 2019 (COVID-19) and kidney impairment. Herein, the efficacy, safety, and pharmacokinetics of remdesivir, its metabolites, and sulfobutylether-β-cyclodextrin excipient were evaluated in hospitalized patients with COVID-19 and severe kidney impairment. Methods In REDPINE, a phase 3, randomized, double-blind, placebo-controlled study, participants aged ≥12 years hospitalized for COVID-19 pneumonia with acute kidney injury, chronic kidney disease, or kidney failure were randomized 2:1 to receive intravenous remdesivir (200 mg on day 1; 100 mg daily up to day 5) or placebo (enrollment from March 2021 to March 2022). The primary efficacy end point was the composite of the all-cause mortality rate or invasive mechanical ventilation rate through day 29. Safety was evaluated through day 60. Results Although enrollment concluded early, 243 participants were enrolled and treated (remdesivir, n = 163; placebo, n = 80). At baseline, 90 participants (37.0%) had acute kidney injury (remdesivir, n = 60; placebo, n = 30), 64 (26.3%) had chronic kidney disease (remdesivir, n = 44; placebo, n = 20), and 89 (36.6%) had kidney failure (remdesivir, n = 59; placebo, n = 30); and 31 (12.8%) were vaccinated against COVID-19. Composite all-cause mortality or invasive mechanical ventilation rates through day 29 were 29.4% and 32.5% in the remdesivir and placebo group, respectively (P = .61). Treatment-emergent adverse events were reported in 80.4% for remdesivir versus 77.5% for placebo, and serious adverse events in 50.3% versus 50.0%, respectively. Pharmacokinetic plasma exposure to remdesivir was not affected by kidney function. Conclusions Although the study was underpowered, no significant difference in efficacy was observed between treatment groups. REDPINE demonstrated that remdesivir is safe in patients with COVID-19 and severe kidney impairment. Clinical Trials Registration EudraCT 2020-005416-22; Clinical Trials.gov NCT04745351.

Key Points Measuring blood potassium has always required access to blood. The surface electrocardiogram, analyzed using an artificial intelligence algorithm, can detect hyperkalemia bloodlessly. The artificial intelligence-analyzed electrocardiogram exhibited a high negative predictive value but substantially lower positive predictive value. Background Artificial intelligence (AI) electrocardiogram (ECG) analysis can enable detection of hyperkalemia. In this validation, we assessed the algorithm's performance in two high acuity settings. Methods An emergency department (ED) cohort (February to August 2021) and a mixed intensive care unit (ICU) cohort (August 2017 to February 2018) were identified and analyzed separately. For each group, pairs of laboratory-collected potassium and 12 lead ECGs obtained within 4 hours of each other were identified. The previously developed AI ECG algorithm was subsequently applied to leads 1 and 2 of the 12 lead ECGs to screen for hyperkalemia (potassium >6.0 mEq/L). Results The ED cohort ( N =40,128) had a mean age of 60 years, 48% were male, and 1% ( N =351) had hyperkalemia. The area under the curve (AUC) of the AI-enhanced ECG (AI-ECG) to detect hyperkalemia was 0.88, with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive likelihood ratio (LR+) of 80%, 80%, 3%, 99.8%, and 4.0, respectively, in the ED cohort. Low-eGFR (<30 ml/min) subanalysis yielded AUC, sensitivity, specificity, PPV, NPV, and LR+ of 0.83, 86%, 60%, 15%, 98%, and 2.2, respectively, in the ED cohort. The ICU cohort ( N =2636) had a mean age of 65 years, 60% were male, and 3% ( N =87) had hyperkalemia. The AUC for the AI-ECG was 0.88 and yielded sensitivity, specificity, PPV, NPV, and LR+ of 82%, 82%, 14%, 99%, and 4.6, respectively in the ICU cohort. Low-eGFR subanalysis yielded AUC, sensitivity, specificity, PPV, NPV, and LR+ of 0.85, 88%, 67%, 29%, 97%, and 2.7, respectively in the ICU cohort. Conclusions The AI-ECG algorithm demonstrated a high NPV, suggesting that it is useful for ruling out hyperkalemia, but a low PPV, suggesting that it is insufficient for treating hyperkalemia.

Importance Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS ( P &amp;lt; .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases ( P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

Introduction: Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction. Migraine headache has been reported to be common among patients with SCAD, but the degree of migraine-related disability has not been quantified. Methods: Clinical data and headache variables were obtained from the baseline assessment of the prospective, multicenter iSCAD Registry. Migraine-related disability was quantified using the self-reported Migraine Disability Assessment (MIDAS). Demographic, clinical, psychosocial, and medical characteristics from data entry forms were compared between patients with and without migraine. Results: Of the 773 patients with available data, 46% reported previous or current migraines. Those with migraines were more likely to be women (96.9% vs 90.3%, p = 0.0003). The presence of underlying carotid fibromuscular dysplasia was associated with migraine (35% vs 27%, p = 0.0175). There was not a significant association with carotid artery dissection and migraine. Current migraine frequency was less than monthly (58%), monthly (24%), weekly (16%), and daily (3%). Triptan use was reported in 32.5% of patients, and 17.5% used daily migraine prophylactic medications. Using the MIDAS to quantify disability related to migraine, 60.2% reported little or no disability, 14.4% mild, 12.7% moderate, and 12.7% severe. The mean MIDAS score was 9.9 (mild to moderate disability). Patients with SCAD had higher rates of depression and anxiety (28.2% vs 17.7% [ p = 0.0004] and 35.3% vs 26.7% [ p = 0.0099], respectively). Conclusions: Migraines are common, frequent, and a source of disability in patients with SCAD. The association between female sex, anxiety, and depression may provide some insight for potential treatment modalities.

AbstractBackground and ObjectivesThe SARS‐COVID‐19 pandemic significantly limited healthcare access. We sought to evaluate whether California's lockdown in March 2020 affected staging and time to treatment of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that patients diagnosed after the lockdown would have longer time to treatment and higher stage at presentation.MethodsWe retrospectively identified and categorized 1294 patients presenting to five University of California healthcare systems with a new diagnosis of PDAC into “pre‐lockdown” and “post‐lockdown” groups based on timing of pathologic diagnosis.ResultsIn the 12 months pre‐lockdown, 835 patients were diagnosed with PDAC, and 459 patients in the 6 months post‐lockdown. Demographics, staging, and treatment type were similar between eras. There was a decreased male:female ratio post‐ versus pre‐lockdown (0.97 vs. 1.25; p = 0.03). Time from symptom onset to first treatment was significantly increased among females post‐lockdown (p = 0.001). However, overall time from diagnosis to first treatment was shorter in the post‐lockdown era (median 23 vs. 26 days, p < 0.001).ConclusionsThe COVID‐19 lockdown did not significantly delay initial presentation, diagnosis, or treatment of newly diagnosed PDAC patients. Time from diagnosis to first treatment was shorter post‐lockdown. Reduced healthcare utilization for minor complaints and increased telehealth utilization may have contributed.

Abstract BACKGROUND Medulloblastoma (MB) is a highly malignant childhood cerebellar tumor comprising a collection of molecularly and clinically distinct entities. Group 3 and Group 4-MB subgroups originate from overlapping progenitor pools of the developing rhombic lip when neuronal differentiation hierarchies are subverted through somatic alterations. Mutations suspected to deregulate the activity of chromatin-modifying genes are pervasive in Group 3 and Group 4-MB. However, the molecular consequences of these alterations remain largely undefined. METHODS We characterized the chromatin landscape of fifty-two primary MBs using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for six histone modifications and performed multi-modal integration with sample-matched somatic lesions, genome-wide DNA methylation, and transcriptomic profiles. RESULTS Analysis of differential chromatin states across MB subgroups using a Hidden Markov Model revealed a significant enrichment of the bivalent enhancer state (EnhBiv; marked by coincident H3K4me1 and H3K27me3) in Group 4-MB which localized to promoters of neurodevelopmental genes and transcription factors. To functionally dissect the pathogenetic significance of the enriched EnhBiv state in Group 4-MB, we sought to identify key regulators that confer this state. Integrative bioinformatics coupled with CUT&RUN analysis revealed significant enrichment of KDM2B, a histone lysine demethylase overexpressed in Group 4-MB, in gene promoters marked by the EnhBiv state. CRISPR gene targeting or targeted protein degradation of KDM2B selectively suppressed growth of Group 3 and Group 4-MB models in vitro and in vivo. Mechanistically, inhibition of KDM2B disrupted chromatin bivalency by blocking PRC2 complex recruitment and reducing H3K27me3 deposition, profoundly derepressing PRC2 targets involved in neuronal differentiation. CONCLUSIONS Our comprehensive characterization of the MB chromatin landscape in a large cohort of primary tumors provides unprecedented insights into the epigenetic basis of MB subgroups, implicating novel mechanisms of tumorigenesis, and nominating KDM2B as a selective dependency in Group 3/4-MB that should be prioritized as an attractive therapeutic target.

Abstract BACKGROUND Atypical teratoid/rhabdoid tumor (ATRT) is a malignant, highly aggressive embryonal tumor of the central nervous system. Long-term survival remains dismal despite aggressive multimodal therapy, including a maximal safe surgical resection and intensive systemic chemotherapy +/- radiation therapy. While these tumors typically present in infancy or early childhood, there are scattered case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. CASE REPORT A 25-year-old female with Down syndrome presented with nausea, vomiting, dysphagia, and facial droop and was found to have an avidly enhancing, left cerebellopontine angle mass. There was initial clinical suspicion for leukemic chloroma given the patient’s Down syndrome status and known association with higher rates of hematologic malignancy concurrent with a dramatic scarcity of solid tumors in the Down syndrome population. However, histology demonstrated sheets of high-grade rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing defined a frameshift mutation in SMARCB1 (p.C298), and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton radiation, followed by chemotherapy on a modified regimen based on the Children’s Oncology Group protocol, ACNS0333. Systemic methotrexate and all consolidative high-dose chemotherapy with stem cell rescue were omitted due to concern for heightened risk of treatment-related toxicity. The patient remains alive and clinically asymptomatic 19 months from diagnosis. CONCLUSION This report represents the first known case of ATRT in an adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Adult ATRT is a rare entity without standardized treatment or established prognostic understanding. Further studies are needed to define an appropriate risk-adapted therapeutic approach for this patient population.