Citations

Background. Solid organ transplant recipients are at risk of severe coccidioidomycosis and are given prophylaxis to mitigate the risk. Patients with seropositive testing typically receive lifelong prophylaxis; currently, this prophylaxis strategy includes patients who are positive only for IgM by enzyme immunoassay (EIA-IgM-only), although this result may be falsely positive. Methods. We conducted a retrospective study at a large-volume transplant center in an endemic coccidioidomycosis region to compare outcomes of non–lung transplant recipients who were seropositive for Coccidioides but discontinued prophylaxis (case patients) to outcomes of patients who continued prophylaxis (controls). Results. No case or control patients developed active coccidioidomycosis during the follow-up period. Before transplant, 62 of 77 case patients (80.5%) had a single positive serologic test, of whom 27 of 62 were EIA-IgM-only positive (43.5%). In contrast, 57 of 77 controls (74.0%) had a single seropositive result (16/57 [28.1%] were EIA-IgM-only). The single EIA-IgM-only result was classified as falsely positive by infectious disease consultants in 20 of 43 patients (46.5%) compared with all other Coccidioides serologic results (13/111 [11.7%], P < 0.001). Lifetime antifungal prophylaxis was felt to be unnecessary for 28 of 43 patients (65.1%) who were EIA-IgM-only versus 31 of 111 patients (27.9%) with other serologic results (P < 0.001). Conclusions. For patients repeatedly positive for EIA-IgM-only and no evidence of seroconversion, compatible clinical illness, or radiographic findings, discontinuing antifungal prophylaxis may be reasonable after the first posttransplant year.

Background: Cardiovascular disease remains the most common cause of death among kidney transplant recipients, with hypertension being one of the most prevalent risk factors. Understanding the current prevalence of hypertension in this population is critical to help shape post-transplant care policies and guidelines and ensure proper management of CVD risk. Methods: We included all kidney transplant recipients who received their transplant between 2019 and 2023 at our center and who completed 24-hour ABPM at 12 months post-transplant. We reported data in mean (SD) unless noted otherwise. BP was categorized per AHA guidelines. This study was deemed exempt by the IRB. Results: A total of 940 patients were included in this study. Detailed results are seen in Figure 1 and Table 1. Notable to mention that 60% of the patients had blood pressure > 130/80 mmHg at 12 months post kidney transplant, with the majority being stage 1. Patients with more severe hypertension tended to be older, had lower eGFR, and had more comorbidities. They also had lower diastolic blood pressure than stage 1 HTN patients, consistent with older age. Night-time BP was significantly higher among stage 2 HTN patients. Conclusion: Hypertension remains a prevalent condition post-kidney transplant despite the majority of patients having satisfactory kidney allograft function. Ongoing BP monitoring and assessment of out-of-office BP post-kidney transplantation is critical to ensure control of this important cardiovascular risk factor. 24-hour ABPM has several advantages in this group, including accurate measurement of out-of-office BP and detection of nocturnal hypertension, an independent risk factor for cardiovascular events. Additional studies are needed to describe the hypertension subphenotypes (e.g., sustained vs. masked) and to identify predictors of severe uncontrolled hypertension in this patient population.

Abstract Context Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. Objective We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). Methods The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished the kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Results Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous but not ingested origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Conclusion Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

In the Spring of 2020, the United States of America (USA) deployed COVID-19 convalescent plasma (CCP) to treat hospitalized patients. Over 500,000 patients were treated with CCP during the first year of the pandemic. In this study, we estimated the number of actual inpatient lives saved by CCP treatment in the United States of America based on CCP weekly use, weekly national mortality data, and CCP mortality reduction data from meta-analyses of randomized controlled trials and real-world data. We also estimate the potential number of lives saved if CCP had been deployed for 100% of hospitalized patients or used in 15 to 75% of outpatients. Depending on the assumptions modeled in stratified analyses, we estimated that CCP saved between 16,476 and 66,296 lives. The CCP ideal use might have saved as many as 234,869 lives and prevented 1,136,133 hospitalizations. CCP deployment was a successful strategy for ameliorating the impact of the COVID-19 pandemic in the USA. This experience has important implications for convalescent plasma use in future infectious disease emergencies.

Tools used for the identification, evaluation, and monitoring of concussion have not been sufficiently studied in youth or real-world settings. Normative and reliability data on sideline concussion assessment measures in the youth athlete population is needed. Pre-season normative data for 515 athletes (93.5% male) aged 5 to 16 on the Standardized Assessment of Concussion (SAC/SAC-Child), modified Balance Errors Scoring System (mBESS), Timed Tandem Gait (TTG), and the King–Devick Test (KDT) are provided. A total of 212 non-injured athletes repeated the measures post-season to assess test–retest reliability. Mean performance on the SAC-C, mBESS, TTG, and KDT tended to improve with age. KDT was the only measure that demonstrated good to excellent stability across age ranges (ICC = 0.758 to 0.941). Concentration was the only SAC/SAC-C subtest to demonstrate moderate test–retest stability (ICC = 0.503 to 0.706). TTG demonstrated moderate to good (ICC = 0.666 to 0.811) reliability. mBESS demonstrated poor to moderate reliability (ICC = −0.309 to 0.651). Commonly used measures of concussion vary regarding test–retest reliability in youth. The data support the use of at least annual sport concussion baseline assessments in the pediatric population to account for the evolution in performance as the child ages. Understanding the variation in the stability and the evolution of baseline performance will enable improved identification of possible injury.

ImportanceMeasurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.ObjectiveTo assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.Data SourcesClinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.Study SelectionProspective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.Data Extraction and SynthesisStudy sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.Main Outcomes and MeasuresAnalyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.ResultsA total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P &amp;lt; .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P &amp;lt; .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).Conclusions and RelevanceThe findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.

11118 Background: Lung cancer survivors experience more physical and mental challenges, heavier symptom burden, and poorer quality of life than survivors of other cancers. Many symptoms persist or worsen for survivors beyond 5 years of cancer diagnosis, referred as long-term lung cancer survivors (LTLCS). Social determinants of health (SDoH) factors negatively impact patient reported outcomes (PROs) among cancer survivors, but their role in outcomes is under reported in lung cancer survivors and unknown in LTLCS. We investigated the impact of SDoH on PROs in a 20-year prospective lung cancer cohort. Methods: Our cohort includes 19,251 lung cancer patients (cases) diagnosed from 1997 through 2016 and followed up to 27 years, of whom 4799 (25%) became LTLCS. SDoH information was obtained by a lung cancer study PRO questionnaire or an institution SDoH questionnaire. Analyzed in this report are 2982 cases and 480 controls who had a low-dose chest CT scan and were ruled out for cancer, all answered at least one PRO questionnaire (first response); and 1366 LTLCS answered 5 years after diagnosis (long-term response). Along with fatigue and dyspnea, 5 SDoH variables, i.e., financial concerns, legal concerns, family and friends support, spiritual well-being, and social activity were scored on a 0 (worst) - 10 (best) scale and dichotomized as 0-5 (deficit/worse/lower) or 6-10 (no deficit/better/higher). We also assessed employment and health-related work experience. A difference of 1.0 unit or more in score was considered clinically meaningful along with a 2-sided test P-value less than 0.05; Chi-square or Fisher’s Exact Test and Kruskal-Wallis test were used accordingly. Results: Compared to controls, cases were younger (mean age: 62 vs. 65 years, P<0.05); more women than men reported worse financial concerns (56% vs. 38%, P<0.01) and lower spiritual well-being (43% vs. 26%, P=0.04) at first response; this sex disparity reduced but remained significant at long-term. Worse dyspnea (4.4-4.8 vs. 5.6) and fatigue (4.7-4.8 vs. 5.8-5.9) were seen in cases with more financial and legal concerns compared to those with fewer concerns (Ps<0.01). Cases with higher family and friends support, spiritual well-being and social activity had less dyspnea (5.7-6.0 vs. 4.2-4.5) and fatigue (5.5-5.9 vs. 3.9-4.4) than those with lower scores (Ps<0.04). Employment and health-related work experience data were provided by 2213 responders: Comparing 1735 cases to 478 controls, a lower proportion of cases was employed (28% vs. 39%), more cases “often felt tired after work” (49% vs. 28%), and more cases had “quite a lot” of difficulty in daily work or could not work at all” (26% vs. 9%, Ps<0.01). Conclusions: We found that in lung cancer survivors, more women than men reported worse financial concerns, and lower SDoH status was correlated with worse dyspnea and fatigue, indicating SDoH-driven interventions are important to improve lung cancer survivors’ PROs.

Abstract Introduction The ICSD-3-TR defines idiopathic hypersomnia in terms of objective sleep times as sleeping at least 11 hours using 24-hour polysomnography or wrist actigraphy averaged over at least 7 days. Published studies on sleep duration are generally limited by lower sleep duration cut-offs (e.g., ≥ 9 hours), so prevalence data on longer sleep durations are missing. This study used clinical questionnaire data from Mayo Clinic patients to characterize longer sleep times and excessive daytime sleepiness in this population. Methods We retrospectively identified patients who answered questions about subjective sleep times and excessive daytime sleepiness, using the Epworth Sleepiness Scale (ESS), as part of their evaluation in a sleep clinic across the Mayo Clinic Enterprise from 2017 to 2023. Demographic data and sleep disorder diagnoses were then analyzed. Results Patients (N=25,480) with subjective nocturnal sleep times of ≥ 9 (n=2721, 10.7%), ≥ 10 (n=1059, 4.2%), and ≥ 11 hours (n=349, 1.4%) had an ESS ≥ 10 in 33.5%, 41.0%, and 51.3% of the time, respectively. 3.6% (age 53.2±19.7; 58.9% female), 1.7% (age 53.1±20.4; 58.1% female), and 0.7% (age 49.8±19.9; 58.1% female) of the patients reported an ESS ≥ 10 and subjective nocturnal sleep times of ≥ 9, ≥ 10, and ≥ 11 hours per night, respectively. After adjusting for age and sex, patients with more than one diagnostic entry compared to those with one or fewer diagnostic entries for idiopathic hypersomnia with long sleep time (OR=12.75, 95% CI [6.09, 24.52], p&lt; 0.001) and narcolepsy with cataplexy (OR=5.53, 95% CI [1.31, 15.84], p=0.005) were significantly more likely to report ESS ≥ 10 and subjective nocturnal sleep times ≥ 11 hours per night. Conclusion Less than 1% of patients presenting to a Mayo Clinic sleep specialist have self-reported metrics (i.e., ESS ≥ 10 and subjective nocturnal sleep times ≥ 11 per night) consistent with basic clinical features of idiopathic hypersomnia with long sleep time. Additional data analyses (e.g., comorbid conditions, social history, and laboratory results) are underway. Support (if any)

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC &lt; 100 μL, 0 vs 2 days, p &lt; 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p &lt; 0.0001) as well as incidence of protracted profound neutropenia (&gt; 7 days, 3.8% vs 22.8%, p &lt; 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC &lt; 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb &lt; 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt &lt; 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [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 6327.

Introduction: Achieving undetectable measurable residual disease (uMRD) following treatment has shown significant prognostic value in several hematological malignancies. In chronic lymphocytic leukemia (CLL), uMRD is associated with improved outcomes in the era of chemoimmunotherapy (CIT). However, the role of measurable residual disease (MRD) in the context of novel agents such as Bruton tyrosine kinase inhibitors (BTKi) and/or BCL2 inhibitors (e.g. venetoclax) is uncertain. To address this question, we conducted a systematic review of the literature and performed a comprehensive meta-analysis of trials that included novel agents to evaluate the association between MRD status after treatment and PFS in patients with CLL. Methods: We conducted a comprehensive search of PubMed, EMBASE, Scopus, and Web of Science focusing on CLL trials reporting MRD and its association with PFS. Results were independently screened by two reviewers. Inclusion criteria included prospective phase 3 trials involving a novel agent in one of the treatment arms, while studies with incomplete information on MRD status related to PFS, reviews, abstracts, and retrospective analyses were excluded. The initial search identified 185 studies in PubMed and 402 studies in EMBASE. After applying prespecified criteria, a total of 10 phase 3 trials were included in our analysis. We extracted sample size, patient age, follow-up time, time point and tissue of MRD assessment, MRD cut-off and rate, performance status and molecular status when available. We only considered treatment arms with complete MRD information. The comparison involved patients who achieved uMRD with those exhibiting detectable MRD. When available, hazard ratios (HR) and confidence intervals (CI) were used to evaluate the relationship between MRD status and PFS. If not, we used Kaplan-Meier (KM) curves from both uMRD and MRD subgroups and extracted the coordinates points of the curves using DigitizeIt software (version 2.5.10, I. Bormann) and using the number at risk provided we estimated the HRs and CIs. A meta-analysis was performed using a random effects model from the R package metafor (Viechtbauer, W. (2010). Conducting meta-analyses in R with the metafor package. Journal of Statistical Software, 36(3), 1-48). The pooled hazard ratio estimates, and the corresponding 95% CI and prediction intervals (PI) were reported. Funnel and Baujat plots were generated to assess study heterogeneity and bias. All analysis was performed using R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria). Results: A total of 10 phase 3 trials, encompassing 14 treatment arms and involving 3152 patients, met the stringent inclusion criteria. All but one study used a uMRD cut-off of &lt; 0.01%. Detailed information on the treatment arms and key trial characteristics is presented in Table 1. Notably, ten treatment arms were derived from first-line treatment trials, while the remaining arms pertained to the relapsed/refractory population. Only two trials (4 treatment arms) assessed MRD using next generation sequencing (NGS), while the rest used multicolor flow cytometry (MFC) (9 treatment arms) and allele-specific oligonucleotides polymerase chain reaction (ASO-PCR) (2 treatment arms). All but 3 trials assessed MRD in both bone marrow (BM) and peripheral blood (PB). One trial (2 treatment arms) was excluded from the met-analysis due to higher MRD cut-off. All studies included in the meta-analysis measured uMRD (&lt;0.01) versus MRD. The PFS pooled HR estimate for achieving uMRD at 0.01 cut off from the meta-analysis was 0.32 (95% CI [0.22, 0.45]), with minimal bias observed on the Funnel Plot. Conclusions: In this comprehensive meta-analysis, comprising 9 phase 3 trials, achieving uMRD was strongly associated with PFS. These findings further establish the prognostic role of MRD in CLL management and its potential use as a surrogate marker in clinical trials. As the body of evidence on MRD in CLL continues to grow, it becomes imperative to standardize the optimal time point, methodology, and tissue for MRD assessment. Substantial heterogeneity in these aspects underscores the necessity for unified guidelines to ensure the accurate and consistent evaluation of MRD status in clinical practice.