Citations

Abstract Intrinsic brainstem tumors arising in pediatric, adolescent, and young adult patients comprise a spectrum of entities, predominantly diffuse midline gliomas (DMG) and IDH mutant astrocytomas. Accurate molecular diagnosis is essential for prognostication and optimal therapy. Therapeutic considerations include inclusion (in IDH mutant) or exclusion (in H3K27M) of adjuvant Temozolomide post radiotherapy and use of molecular targeted therapy (IDH inhibitors). Surgical biopsy, however, is associated with increased risk of permanent neurological deficits and may yield insufficient or non-diagnostic tissue. We hypothesized that minimally-invasive “liquid biopsy” of cerebrospinal fluid (CSF) could represent a superior diagnostic modality in this patient population, employing molecular analysis of cell free DNA (cfDNA). We analyzed 44 CSF samples from 38 unique patients for recurrent driver mutations in brainstem gliomas, including H3K27M, IDH1, and IDH2. MSK-IMPACT, a NY state-authorized hybridization capture-based next-generation panel DNA sequencing assay, was used for analysis. Samples without a detectable driver mutation by MSK-IMPACT testing were further subjected to gene targeted testing by droplet digital PCR. In all, 10/44 (22.7%) samples had mutations detected by MSK-IMPACT using standard calling criteria and 13 of the remaining 34 samples (38.2%) had supporting evidence of a mutation based on manual review. Further testing by ddPCR was performed on a subset of cases (based on DNA availability) which confirmed 7 of the previous low-level mutations and uncovered 4 additional mutations. Overall, 27/44 (61.4%) of cases had detectable evidence of a mutation, and of the 23 patients without a known tissue diagnosis, a driver in the CSF was identified for 47.8% of patients (11/23). Minimally-invasive analysis of CSF cfDNA in patients with intrinsic brainstem tumors has a high diagnostic yield and may obviate the need for tissue biopsy in a majority of patients. Testing with high sensitivity assays is valuable to maximize the rate of detection.

7520 Background: With goal of simplifying clinical trials in lymphomas, we reported that bone marrow biopsies are irrelevant for response assessment in most patients (pts) with follicular lymphoma (FL) on trials (Rutherford JCO 2023). We then investigated impact of imaging frequency in FL clinical trials. We hypothesized that progression free survival (PFS) would not be different when imaging is performed less frequently than required by trials. Methods: We identified all trials through Alliance for Clinical Trials in Oncology that enrolled untreated pts with FL from 2008-2016. We considered 2 imaging schedules: protocol specified (control) vs relaxed (X) in which response assessments at every other required time point were omitted. For each trial, we estimated PFS using Kaplan Meier methods for the 2 schedules then determined difference in PFS between schedules as % change from control schedule in 2 year (yr) PFS rate. We performed simulation studies to approximate impact of less frequent imaging on PFS estimation using 50901 (low-intermediate risk FL) and 50904 (intermediate-high risk FL, control arm). We assumed exponential distribution for PFS, where rate parameter was calculated based on observed median PFS with uniform censoring distribution. Protocols for 50901 and 50904 mandated imaging every 4 months (mos) for 2 yrs then every 6 mos (S0). We ran 1000 iterations of 100 observations using 3 tumor assessment follow up schedules: every 6 mos for 2 yrs then yearly (S1), every 8 mos for 2 yrs then yearly (S2), or yearly (S3) for simulated progression times. We calculated deviation of PFS using simulated schedules from truth (S0). Results: Across 5 FL trials, median percent change of schedule X from control schedule in estimated 2yr PFS was 2.1% (0.0-30.8%) and in estimated 4yr PFS was 0.9% (-8.6-25.7%). Disparate result in 50901 is due to small shift in events with low number of pts at risk for progression. Simulation study results by trial were: for 50901, true median PFS 1.9 yrs and average median PFS for S1, S2, and S3 of 2.05, 2.11, and 2.21 yrs; for 50904 (control arm), true median PFS 4.1 yrs and average median PFS for S1, S2, and S3 of 4.16, 4.12, and 4.05 yrs. Conclusions: Our findings support decreased frequency of imaging studies in FL clinical trials, which would improve resource use and decrease pt burden. We plan a larger analysis to confirm results. https://acknowledgments.alliancefound.org . Clinical trial information: NCT00553501 , NCT01145495 , NCT01190449 , NCT01286272 , NCT01829568 .[Table: see text]

Abstract Introduction People with heart failure (HF) have frequent hospitalizations, and emergency department (ED) visits. We examined the effects of insomnia and rest-activity rhythms (RARs) on time to hospitalizations and ED visits after controlling for other known risk factors among participants in a randomized controlled trial of cognitive behavioral therapy for insomnia compared to heart failure self-management education (attention control). Methods The analysis included 168 HF patients who had available medical records for dates of hospitalization, ED visit, transplant, and death from a randomized clinical trial for insomnia of people with HF and insomnia. The known risk factors included age, sex, New York Heart Association (NYHA) Class, ejection fraction, and comorbid conditions. We used the insomnia severity index (ISI) and evaluated the strength of RAR using the ratio of the amplitude to the MESOR estimated with cosinor analysis with activity counts from a wrist-actigraph worn for at least five consecutive days. Cox proportional hazard models were used to examine ­insomnia and the RAR metrics with the known risk factors on time to first hospitalization, ED visit, transplant, and death. Results Eighty-five (50.1%) had at least one hospitalization, and ninety-one (54.2%) participants had an ED visit. Approximately 42% of the participants were admitted to the hospital due to cardiac events. Older age, male sex, higher NYHA, and greater comorbidity were associated with earlier hospitalization or ED visits. After controlling for those risk factors, stronger RAR was associated with later time to hospitalization, and ED visit with hazard ratios (HRs) of 0.26 (95% CI=[0.07, 0.91]) and 0.25 (95% CI=[0.07, 0.89]); higher insomnia severity (ISI ≥22) was associated with shorter time to ED visits, with an HR of 2.28 (95% CI=[1.19, 4.38]). Conclusion In addition to known demographic and clinical risk factors, insomnia severity and RAR predict hospitalizations and ED visits in people with HF. Further research is necessary to assess the biological mechanism of the associations and examine whether the effects of the risk factors could be modified by improving insomnia severity and RAR in people with HF. Support (if any) This study was financially supported by grants R01NR016191 and P20NR014126 from NIH/NINR.

Abstract Introduction Cognitive behavioral therapy for insomnia (CBT-I) improves individual symptoms of fatigue and daytime sleepiness; however, little is known how CBT-I improves multiple co-occurring daytime symptoms. The purposes of this study are to (1) identify daytime symptom trajectories in adults with insomnia and stable chronic heart failure (HF) over one year, and (2) determine how symptom trajectories vary based on participation in CBT-I or HF self-management education (attention control condition). Methods We conducted a retrospective analysis of data from a randomized controlled trial that looked the sustained effects of CBT-I compared to HF self-management over one year (NCT02660385). We measured daytime symptoms (fatigue, depression, anxiety, dyspnea, pain, and daytime sleepiness) at baseline (pre-treatment) and 3, 6 and 12 months. Symptom cluster trajectory were identified using group-based trajectory modeling, and the association with CBT-I was examined using logistic regressions. Results We randomized 175 participants (M age=63.0 (12.9) years, 57% men). We found four daytime symptom cluster trajectories, (A) low improving symptoms (N = 67, 38.3%); (B) low psychological symptoms and high improving physical symptoms (N = 40, 22.8%); (C), high improving symptoms (N = 42, 24.0%); and (D) high not improving symptoms (N = 26, 14.9%). There was no statistically significant difference between CBT-I and HF self-management across 4 symptom trajectories (p = .2509). However, people who received CBT-I vs. HF self-management education had higher odds of belonging to trajectory A compared to B/C/D after controlling for baseline fatigue (OR = 3.27 95% Confidence Intervals [1.39, 7.68]). Conclusion Most participants experienced improved daytime symptom profiles over 12 months after both interventions. Participants in the CBT-I group experienced symptom improvement even when they started with low symptoms. Support (if any) National Institute of Nursing Research [R01NR016191 and P20NR014126].

Abstract Health-related quality of life (HRQoL) and vulnerability are variably affected in patients with myelodysplastic syndromes (MDS) and other cytopenic states; however, the heterogeneity of these diseases has limited our understanding of these domains. The National Heart, Lung, and Blood Institute-sponsored MDS Natural History Study is a prospective cohort enrolling patients undergoing workup for suspected MDS in the setting of cytopenias. Untreated patients undergo bone marrow assessment with central histopathology review for assignment as MDS, MDS/myeloproliferative neoplasm (MPN), idiopathic cytopenia of undetermined significance (ICUS), acute myeloid leukemia (AML) with <30% blasts, or “At-Risk.” HRQoL data are collected at enrollment, including the MDS-specific Quality of Life in Myelodysplasia Scale (QUALMS). Vulnerability is assessed with the Vulnerable Elders Survey. Baseline HRQoL scores from 449 patients with MDS, MDS/MPN, AML <30%, ICUS or At-Risk were similar among diagnoses. In MDS, HRQoL was worse for vulnerable participants (eg, mean Patent-Reported Outcomes Management Information Systems [PROMIS] Fatigue of 56.0 vs 49.5; P < .001) and those with worse prognosis (eg, mean Euroqol-5 Dimension-5 Level [EQ-5D-5L] of 73.4, 72.7, and 64.1 for low, intermediate, and high-risk disease; P = .005). Among vulnerable MDS participants, most had difficulty with prolonged physical activity (88%), such as walking a quarter mile (74%). These data suggest that cytopenias leading to MDS evaluation are associated with similar HRQoL, regardless of eventual diagnosis, but with worse HRQoL among the vulnerable. Among those with MDS, lower-risk disease was associated with better HRQoL, but the relationship was lost among the vulnerable, showing for the first time that vulnerability trumps disease risk in affecting HRQoL. This study is registered at www.clinicaltrials.gov as NCT02775383.

Abstract Background Producing scholarship in education is essential to the career development of a clinician-educator. Challenges to scholarly production include a lack of resources, time, expertise, and collaborators. Objective To develop communities of practice for education scholarship through an international society to increase community and academic productivity. Methods We developed multi-institutional scholarship pods within the American Thoracic Society through the creation of a working group (2017–2019). Pods met virtually, and meetings were goal focused to advance education scholarship within their area of interest. To understand the impact of these scholarship pods, we surveyed pod leaders and members in 2021 and analyzed the academic productivity of each pod via a survey of pod leaders and a review of the PubMed index. Results Nine pods were created, each with an assigned educational topic. The survey had a response rate of 76.6%. The perceived benefits were the opportunity to meet colleagues with similar interests at other institutions, production of scholarly work, and engagement in new experiences. The main challenges were difficulty finding times to meet because of competing clinical demands and aligning times among pod members. Regarding academic productivity, eight publications, four conference presentations, and one webinar/podcast were produced by six of the nine pods. Conclusion The development of communities of practice resulted in increased multi-site collaboration, with boosted academic productivity as well as an enhanced sense of belonging. Multiple challenges remain but can likely be overcome with accountability, early discussion of roles and expectations, and clear delegation of tasks and authorship.

Abstract Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.