Citations

345 Background: Pediatric febrile neutropenia (PFN) requires emergent evaluation due to risk of invasive bacterial infection. In the management of PFN, there are varying, accepted definitions for fever requiring emergency evaluation and neutropenia requiring admission. Problem statement: From September 1, 2022 - May 31, 2023, 15.1% (n = 11/73) of emergency department (ED) visits and 17.1% (n = 6/35) of admissions for PFN at Mayo Clinic Rochester may be considered unnecessary due to patients not meeting updated clinical criteria. Aim: Decrease unnecessary ED visits and hospitalizations for PFN by 50% from 15.1% to 7.5% (for ED visits) and from 17.1% to 8.6% (for hospitalizations) by 02/29/2024 without adversely impacting mortality from invasive bacterial infection. Methods: We used the DMAIC framework for process improvement. Interventions included (1) adoption of a higher fever definition for PFN, (2) adoption of a risk-stratified neutropenia definition for hospital admission, (3) provided electronic fever plans with definitions to all families, (4) re-iterated that parents call on-call provider with any concern for fever, (5) educated pediatric oncology staff on definition and management of fevers in pediatric oncology patients, and (6) educated pediatric emergency department staff on definition and management of fevers in pediatric oncology patients. Interventions were tested with rapid tests of change. Relevant clinical characteristics, variables, and outcomes for all patients from pediatric oncology were tracked for all encounters of pediatric oncology patients presenting to the ED for acute illnesses. Results: At baseline,15.1% (n = 11/73) of ED visits for PFN were considered unnecessary due to patients not meeting clinical criteria for emergency evaluation. Post-interventions, unnecessary ED visits for PFN had decreased to 3.4% (n = 1/32). At baseline, 17.1% (n = 6/35) of hospitalizations were considered unnecessary due to patients not meeting clinical criteria for admission. Post-interventions, 7.7% (n = 2/26) of hospitalizations were considered unnecessary. There were no patient deaths from invasive bacterial infection among this cohort at baseline or after interventions. Conclusions: Multiple interventions including adoption of a higher, accepted fever threshold and risk stratified neutropenia definition for PFN was associated with a reduction of unnecessary ED visits and hospitalizations for PFN without an increase in mortality from invasive bacterial infection. The projected medical expense savings of approximately $144,000-$210,000 per year.

566 Background: Video telemedicine visits (VTVs) have the potential to overcome disparities in access to cancer care for many socially, geographically, and economically disadvantaged populations. Internet connectivity, digital literacy, and socioeconomic factors are traditionally cited as influencing VTV utilization. However, digital diffusion has occurred rapidly across several sectors, including healthcare, since the onset of the COVID-19 pandemic, and less is known about how these factors have evolved to influence VTV utilization behavior over this time. Through a qualitative approach, we aimed to: (1) explore the lived experiences of cancer patients who transitioned to VTV use as compared to those who persistently did not, and (2) identify similarities and differences between these two groups that could inform targeted interventions to support access and patient acceptance of VTVs in the setting of cancer care. Methods: During June 2024, we conducted semi-structured interviews with 24 patients (Mean age 71.3 years, range 42-88; female 50%) receiving ongoing, longitudinal cancer care at our academic medical center since July 2021 who had not used VTVs through at least October 2022. Using purposeful sampling, patients were equally divided according to VTV utilization behaviors defined as “transitioned users” (TU; i.e. those who transitioned to VTV utilization after October 2022) and “persistent non-users” (PNU). Transcripts were analyzed using a combined deductive–inductive thematic approach and categorized into themes of barriers and facilitators across three domains consistent with the COM-B model: capabilities (C), opportunities (O), and motivations (M). Results: TU patients frequently cited a reduction in travel and logistical considerations as a primary reason for uptake of VTVs. PNU patients frequently reported digital literacy barriers, particularly among older patients, as primary reasons for lack of VTV utilization. TU patients reported more experience and comfort in technical skills as compared to PNU participants. PNU patients also reported less frequent offering of VTV as an option by their care teams over time, implying they may have transitioned to VTV utilization if it had been offered with more regularity. Both study groups desired improved internet access and technical support to enhance (or, in the case of PNU patients, enable) VTV utilization. Conclusions: These findings suggest that multi-modal care delivery may best serve current patient populations, not requiring, yet offering VTV services as an adjunct to in-person care. Longer term, individual barriers to VTV use will also need to be addressed to further optimize access for patients who desire to incorporate this care modality.

55 Background: Prior authorization (PA) processes are known to create administrative burdens and delays in care, but little is known about how these challenges impact rural oncology patients and practice settings. Methods: To understand the broad impact of prior authorization on rural oncology patients and practices, we conducted this study across three community oncology practices serving majority rural patient populations with distinct geography, healthcare infrastructure, and models of care. Sites included one critical access hospital system located in a highly-rural community (Lakewood Health System; Staples, Minnesota), a community-based hub-and-spoke hospital system-based practice located in a mid-sized community (Mayo Clinic Health System – Northfield; Northfield, Minnesota), and a standalone referral level III trauma center serving a highly rural patient base (Self Regional Healthcare; Greenwood, South Carolina). This retrospective cohort study examined all intravenous and subcutaneous cancer-directed therapy plans (no oral therapy) that required PA submission at these locations over a three-month period from October 1, 2024 to December 31, 2024. Results: 129 PA submissions were required during the study period. 82 were due to cancer-directed therapy agents (of which 14 were immunotherapy agents), and 47 were due to adjunctive therapies (of which 22, 16, and 9 were due to granulocyte stimulation, bone preservation, and anti-emesis agents, respectively). All 129 PA submissions ultimately resulted in approval of the desired medication or formulary-approved biosimilar. Delays from PA submission to approval ranged from 0 to 18 days. A total of 209 patient-days were delayed due to PA during the study period, which did not ultimately result in change of care or denial of care in any instance. Conclusions: At all sites included in this study, all PA submissions were eventually authorized. The PA process was found to introduce inconsistent and potentially avoidable delays for hundreds of patients and their care teams. These findings highlight the inefficiency of current PA processes among rural cancer populations and the practices that care for them, underscoring the need for ongoing efforts directed at state and federal PA reform.

Abstract While many postmitotic cells in the body harbor cilia, certain aggressive cancers such as glioblastoma (GBM) display low frequencies of cells harboring a primary cilium. Ciliated GBM cells that plan to multiply have to disassemble their cilium in order for centrioles to duplicate and re-purpose for mitosis. Little is known about the molecular mechanisms underlying cilia disassembly in GBM, or whether this may represent a driving factor in disease onset, progression, or recurrence. In many cell types, ciliary disassembly is thought to be orchestrated by the aurora kinase A (AURKA) and histone deacetylase 6 (HDAC6) signaling axis. These molecules are often overexpressed in GBM, perhaps owing to the less frequent observation of ciliated GBM cells. Here, we review regulators of the core pathway, and discuss recent studies attempting to inhibit AURKA and HDAC6 in patient and mouse models of GBM and resulting effects on cilia. In the face of potent inhibitors, GBM cells appear to engage pathways independent of the core axis to promote cilia disassembly and/or engage other forms of modified axonemal tubulin to ensure persistence of cilia on GBM cells. GBMs upregulate a host of proteins implicated to drive cilia disassembly. Thus, clarifying these alternate mechanisms may be important as the roles of cilia in tumor formation and propagation, angiogenesis, and treatment resistance are increasingly reported. A deeper understanding of the role of cilia in these hallmarks of glioma may hold clues to the high recurrence rate of GBM.

Abstract Background Obstructive sleep apnea (OSA) is a risk factor for hypertension and some evidence suggests this risk may not be mitigated with positive airway pressure. Low-intensity statin therapy can modestly reduce blood pressure (BP). In this exploratory analysis, we examined if six months of high-intensity statin therapy could lower resting or ambulatory BP in patients with OSA. Methods 39 patients with OSA (13F, age = 49 ± 9yrs, body mass index = 32.9 ± 4.2kg/m2, apnea-hypopnea index = 22.2 ± 12.4 events/hour) were randomized to high-intensity atorvastatin or placebo. BP was assessed using seated, “office” measurements and in 20-minute intervals over 24 consecutive hours at three timepoints (baseline, three- and six-months post-randomization). Participants maintained a diary denoting sleep and wake times for analysis. Changes (Δ) in BP from baseline were assessed and adjusted for adherence to participants’ intervention (atorvastatin or placebo) as well as to their treatment for OSA (yes or no). Results There were no between-group differences in baseline BP variables (P = .09-.96). At three months, the changes in resting (P = .74-.87), 24 hour mean (P = .54-.96), daytime (P = .70-.96), nor nighttime (P = .74-.96) BP did not differ between groups. Similarly, the changes in resting (P = .23-.92), 24 hour mean (P = .51-.82), daytime (P = .17-.78), and nighttime (P = .51-1.00) BP did not differ between groups following six months of their respective intervention. Conclusions Our data suggest that high-intensity atorvastatin does not lower resting or ambulatory BP in patients with OSA relative to a placebo. Thus, it does not appear that atorvastatin is a viable adjunct intervention for BP reduction in patients with OSA. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03308578.

Abstract Chimeric antigen receptor (CAR) T-cell (CAR-T) treatment for B-cell acute lymphoblastic leukemia (ALL) induces high initial response rates, but most patients relapse. Low disease burden (often defined as <5% blasts in the bone marrow) is associated with better outcomes. CAR HEMATOTOX (HT) is a score using prelymphodepletion hematologic and inflammatory parameters to predict outcomes in lymphoma. Here, we assess its prognostic utility in a large multicenter adult B-cell ALL cohort. Patients who received brexucabtagene autoleucel across 33 centers in North America were included as part of the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium. An independent cohort of 61 patients with ALL treated with an investigational CD19 CAR-T therapy at 1 center was also described. Among 199 ROCCA consortium patients, 43 (22%) patients with HTlow scores had lower rates of delayed neutrophil recovery than those with HThigh scores (26% vs 52%, P = .002) and fewer severe infections (2.5% vs 18.8%, P = .011). They also had higher response rates, overall survival (OS), and event-free survival (EFS), as well as lower nonrelapse mortality and cumulative incidence of relapse. The survival differences remained significant after multivariable adjustment for disease burden and other covariates. In the investigational cohort of 61 patients, patients with HTlow scores had improved OS and EFS, as well as higher peak CAR-T expansion. In summary, CAR HT score is a prognostic factor independent of disease burden in adult ALL. HTlow score is associated with superior outcomes after CD19 CAR-Ts and higher CAR-T expansion in a single-center cohort. These trials were registered at www.clinicaltrials.gov as #NCT01044069 and #NCT01860937.

Abstract Aims To assess the potential for artificial intelligence-enabled electrocardiogram (AI-ECG) to serve as a long-term cardiac surveillance tool and predict left ventricular systolic dysfunction in childhood cancer patients. Methods and results We assessed performance of our previously established AI-ECG model to predict left ventricular ejection fraction (LVEF) ≤50% and ≤40% in patients with childhood cancer during internal testing (Boston Children’s Hospital) and external validation (Children’s Hospital of Philadelphia). The internal test cohort comprised 447 patients [57% male; age at cancer diagnosis 11.2 (5.4–15.7) years; 1553 ECG–echo pairs at median age 13.5 (IQR 7.7–17.9) years; 6.4% with LVEF ≤50%; 1.3% with LVEF ≤40%], 28% with leukaemia, 16% with lymphoma, 8% with neuroblastoma, 8% with sarcoma, 2% with gastrointestinal cancers, 3% with genitourinary cancers, 6% with central nervous system cancers, 11% with other/unspecified cancers, and 18% with missing/unknown cancer labels. Treatment strategies included anthracyclines (35%), bone marrow transplant (7%), and radiation (1%). The external test cohort comprised 2964 patients [55.4% male; 7054 ECG–echo pairs at median age 11.6 (IQR 6.8–15.1) years; 2.5% with LVEF ≤50%; 0.9% with LVEF ≤40%]. Similar AUROCs (0.80–0.85), sensitivities (0.75–0.82), NPVs (0.986–0.996), and percent predicted negative (51–65%) were obtained across institutions to predict LVEF ≤50%, outperforming a biomarker-based model benchmark. Patients with high AI-ECG risk scores for LVEF ≤50% had higher rates of mortality [hazard ratio 3.1 (95% CI 1.8–5.3), P < 0.001] compared to patients with low AI-ECG risk scores. Conclusion AI-ECG shows promise as a digital biomarker for cardiac surveillance in the vulnerable childhood cancer survivor population.

Abstract BACKGROUND Ovarian cancer rarely metastasises to the brain, thus studies reporting the outcomes of affected patients are lacking. Stereotactic radiosurgery (SRS) is now the mainstay of management for patients with brain metastases (BM) from most primary sites, but little evidence of its efficacy in ovarian cancer is available. The current study was undertaken to provide guidance for SRS management using pooled data from multiple institutions. MATERIAL AND METHODS Centers participating in the IRRF (International Radiosurgery Research Foundation) were asked to provide outcome data for patients who had SRS for ovarian cancer brain metastases between 2020 and 2024 and at least one clinical and imaging follow-up after the procedure. Primary endpoints included survival from SRS, local tumor response according to RANO-BM criteria and occurrence of adverse radiation effects (ARE). Cox regression analyses were performed to identify variables impact each endpoint. RESULTS 128 patients had SRS for a total of 532 BM treated. Epithelial histology was the most common (91%). Median age at SRS was 62 years (IQR 56-70). Median KPS was 80% (IQR 80-90%) and 71.9% of patients had neurological symptoms at presentation. Other active systemic metastases were present in 41.4%. The median number of treated BM was 2 (IQR1-3) and the median cumulative treatment volume was 6 cc (IQR 2-12.9). The median margin dose was 18 Gy (IQR 16-20). At last follow-up, 19.5% of patients were still alive. The median overall survival (OS) after SRS was 27 months, and 6-, 12- and 24-month OS was 83.8%, 74.2% and 52.2%, respectively. Multivariate analyses revealed that increasing age at SRS (HR 1.02, p=0.05), active systemic metastases (HR 2, p=0.005) and increasing number of brain metastases (HR 1.05, p=0.04) were associated with worse survival, while repeating SRS (HR 0.4, p=0.002) led to improved survival. Local failure occurred in 12.8% of treated BM. Actuarial progression-free survival (PFS) at 6, 12 and 24 months was 92.3%, 86.6% and 70.3%, respectively. Only prior WBRT (HR 4.36, p=0.03) led to worse local control on multivariate analyses. New remote BM appeared in 49.5% of patients and 14.5% suffered from leptomeningeal dissemination. ARE were seen in 12.1% of BM but were symptomatic in only 3.2%. On multivariate analyses, prior SRS (HR 3.13, p=0.002) was associated with increased risk of ARE. CONCLUSION Ovarian cancer brain metastases can be safely and effectively managed with SRS as the primary treatment modality in most patients.

Abstract Background Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, including the Aß42/40 and p-tau181/Aß42 ratios, are used in clinical practice to detect the presence of amyloid pathology for the diagnosis of AD. However, in some instances, discrepancies between Aß42/40 and p-tau181/Aß42 are observed. Such discrepancies may introduce uncertainties in the clinical management of patients presenting with cognitive decline. Identifying the underlying causes of these discrepancies and determining which biomarker abnormalities better predict disease progression is crucial to enhancing confidence in the use of these CSF biomarkers for the diagnosis of AD. This study aims to investigate the discordance between the Aß42/40 and p-tau181/Aß42 ratios, evaluate the frequency of these discrepancies, and identify potential causes. Methods Data from 958 individuals who had both CSF Aß42/40 and p-tau181/Aß42 tested at Mayo Clinic Laboratories between 2022 and 2024 and where the tests were ordered in CSF collected during the same lumbar puncture procedure were included. Cases with an inadequate sample collection, which could cause a false decrease in Aß42 concentrations, were excluded from the analysis. Aß42/40 was measured using the Fujirebio LUMIPULSE assays and reported as negative, likely positive, or positive. For this analysis, likely positive and positive results were combined and considered as positive (<0.072). P-tau181/Aß42 was measured using the Roche Elecsys assays and above 0.028 was considered positive. Statistical analyses were conducted using R Studio. Results Aß42/40 was positive in 69.1% of cases (n=661), while p-tau181/Aß42 was positive in 62.1% (n=594). There were 8.0% discordant cases (n=77). Most frequently, the discordant cases had an abnormal Aß42/40 with a normal p-tau181/Aß42 (Aß42/40+/p-tau181/Aß42-; n=72, 94%). Compared to the concordant Aß42/40+/p-tau181/Aß42+ group, the discordant Aß42/40+/p-tau181/Aß42- group showed significantly higher Aß42 concentrations (p <0.001, median [pg/mL]: 878.5 vs 587.0, respectively); whereas p-tau181 concentrations were significantly lower (p <0.001, median [pg/mL]: 19.3 vs 32.1, respectively). Among the Aß42/40+/p-tau181/Aß42- group, 30 cases exhibited abnormally low Aß42 and normal p-tau181, possibly reflecting early-stage AD. There were 41 cases with a normal Aß42 concentration despite an abnormal Aß42/40, possibly reflecting an overall higher production of Aß peptides resulting in an increased Aß40 peptide (median [pg/mL]: 12627 compared to 9487 in the low Aß42 and normal p-tau181 cases (n=30); p <0.001). Of these 41, 19 showed normal Aß42 but elevated p-tau181 concentrations where the use of Aß42/40 compensated for the overall higher production of Aß peptides, resulting in an abnormal ratio. In contrast, the p-tau181/Aß42 ratio was not able to normalize for these differences, leading to a normal ratio. Conclusion While overall concordance was 92.0%, our findings suggest that discrepancies between CSF Aß42/40 and p-Tau181/Aß42 are more often due to the presence of an abnormal Aß42/40 and a normal p-Tau181/Aß42. Two potential explanations for these discrepancies are early-stage AD or higher production of Aß peptides in some individuals. In the latter, differences in amyloid production would be normalized by ratios of the same biomarker (i.e. Aß42/40) but not by ratios of different biomarkers (i.e. p-Tau181/Aß42).

Abstract Background Insulin resistance leads to changes in lipid and lipoprotein metabolism prior to developing prediabetes, including an increase in the concentration of large very-low-density lipoprotein particles (LVLDL-p), the mean size of VLDL (VLDL-s), and the concentration of small low-density lipoprotein particles (sLDL-p). Conversely, there is a decrease in the concentration of large high-density lipoprotein particles (LHDL-p), mean size of HDL (HDL-s), and mean size of LDL (LDL-s). Clinically validated studies show that proton nuclear magnetic resonance (NMR) can measure these six parameters and derive a lipoprotein insulin resistance (LP-IR) score, ranging from 0 to 100, with higher scores indicating greater risk for insulin resistance. The reference method for calculating LP-IR relies on a proprietary NMR spectrometer, spectral deconvolution method, and algorithm. This study seeks to determine if lipoprotein subfraction parameters measured from a commercially available NMR system can produce LP-IR scores comparable to the reference method. Methods Serum lipoprotein NMR spectra were collected using a Bruker Ascend 600 MHz magnet, Bruker Avance NEO 500 spectrometer, and the Numares AXINON lipoFIT System to report the six LP-IR score parameters between January 2023 and January 2025 (Cohort A, n = 2,474). During the same period, LP-IR score and parameters were collected using the Vantera Clinical Analyzer (400 MHz) with the LipoProfile LP4 method (Cohort B, n = 2,959). Linear regression of decile-matched data for each parameter yielded adjustment equations to align lipoFIT values with the LipoProfile method. LP-IR scores were then calculated for both adjusted and unadjusted values using a previously published LP-IR scoring algorithm. Finally, LP-IR scores were compared for sera with measures from both instruments was (Cohort C, n = 108). Results The median concentrations of sLDL-p, LDL-s, VLDL-s, HDL-S matched between Cohort A and B (<1% difference). Significant differences were noted for LVLDL-p and LHDL-p, with percent differences of 21.5% and 23.5%, respectively. Despite closely matching medians, the distributions varied greatly, with a mean interquartile range (IQR) percent difference across measures of 31.2% (Table 1). After distribution matching, all parameter median and mean IQR percent differences fell to <5% and <10%, respectively, between Cohort A and Cohort B. In Cohort C the LP-IR score matched well (y=1.1x-15, r=0.92; 95%CI 0.88, 0.94). Following distribution matching adjustment of lipoFIT values for Cohort C, new calculated LP-IR scores matched with reduced bias (y=0.94x-1.2) while correlation was slightly reduced (r=0.88 [0.83, 0.92]). By comparison, adjustments made via scaling lipoFIT values proportionally by the ratio of the medians between Cohort A and Cohort B yielded calculated LP-IR scores in Cohort C that maintained a similar bias prior to adjustments (y=1.2x-21), highlighting the ability of distribution matching to reduce bias. Conclusion Adjustments to measured lipoprotein parameters from a commercially available NMR spectrometer can be achieved via distribution matching. These adjustments greatly reduce the bias between a commercially available method and algorithm compared to the reference method, allowing for wider adoption of LP-IR score reporting.