Citations

Introduction: The main goal of Clinical Decision Support (CDS) is to provide timely and useful information for providers to deliver high-quality and safe care. Issues, like alert fatigue and provider burnout are commonly cited as unintended consequences of the CDS systems. Herein, we describe leveraging electronic health record (EHR) self-service reporting tools to gain insights on a CDS rule designed to avoid providers from ordering QT-prolonging medication in patients with history of QT-prolongation. Methods: Our EHR (Epic) SlicerDicer reporting tool was used to identify the frequency of QT-prolongation Best Practice Advisory (BPA) triggerings from 1/1/2020 to 12/31/2020 across Mayo Clinic sites. Additionally, associated patient encounter and BPA-specific data were queried. Text from acknowledgement comments to the BPA were reviewed and central themes and comments were categorized. Epic Clarity Data Warehouse was queried to identify the BPA-triggering medications and frequencies. Comparisons of percent action taken on the BPA were compared internally to Mayo Clinic’s BPA benchmark, and with national benchmarks using Epic BestPractice Pulse dashboard. Results: A total of 17,538 BPAs of interest were triggered across the Mayo Clinic sites in 2020, of which 3,696 (20.1%) were acted upon through either monitoring or medication discontinuation. This is below Mayo Clinic’s median of 29.2% for inpatient BPAs and 45.6% BPAs for outpatient, but above the national median of 10% (IQR 6.1-13.1%) for inpatient and 10% (IQR 4.3-19.5%) for outpatient BPAs actioned upon. A total of 30 different medications triggered the BPA, with the most common being ondansetron (41.5%), amiodarone (11.3%), and haloperidol (10.1%). User comments were left on 2,382 orders (13.5%) that acknowledged the BPA, but provided argument to prescribe drug. Three most common themes identified from comments on overridden BPAs: patient previously tolerated medication (19.0%), QT interval not prolonged on recent ECG (14.2%), and patient on hospice care (5.2%). Conclusion: Analysis of free text comments of CDS can be and should be performed to reveal opportunities for further improvement of CDS. Providers should be encouraged to provide comments when encountering CDS interventions.

Abstract Observational studies and stand-alone trials indicate that patients with follicular lymphoma (FL) who experience disease progression within 24 months of front-line chemoimmunotherapy (POD24), have poor outcomes. We performed a pooled analysis of 13 randomized clinical trials of patients with FL in the pre- and postrituximab eras to identify clinical factors that predict POD24. Logistic regression models evaluated the association between clinical factors and POD24. Cox regression evaluated the association between POD24 as a time-dependent factor and subsequent overall survival (OS). A landmark analysis evaluated the association of POD24 with OS for the subset of patients who were alive at 24 months after trial registration. Patients without progression at 24 months at baseline had favorable performance status (PS), limited-stage (I/II) disease, low-risk FL International Prognostic Index (FLIPI) score, normal baseline hemoglobin, and normal baseline β2 microglobulin (B2M) level. In a multivariable logistic regression model, male sex (odds ratio [OR], 1.30), PS ≥2 (OR, 1.63), B2M (≥3 mg/L; OR, 1.43), and high-risk FLIPI score (3-5; OR, 3.14) were associated with increased risk of progression before 24 months. In the time-dependent Cox model and the 24-month landmark analysis, POD24 was associated with poor subsequent OS (hazard ratio, 4.85 and 3.06, respectively). This is the largest pooled analysis of clinical trials data validating POD24 as a robust indicator of poor FL survival and identified clinical predictors of early death and progression that can aid in building comprehensive prognostic models incorporating clinical and molecular predictors of POD24.

AbstractPurposeAs a typical chronic kidney disease (CKD), hypertensive nephrosclerosis (HN) is a common syndrome of hypertension, characterized by chronic kidney microvascular damage. Early diagnosis of microvascular damage using conventional ultrasound imaging encounters challenges in sensitivity and specificity owing to the inherent diffraction limit. Ultrasound localization microscopy (ULM) has been developed to obtain microvasculature and microvascular hemodynamics within the kidney, and would be a promising tool for the early diagnosis of CKD.MethodsIn this study, the advantage of quantitative indexes obtained by using ULM (mean arterial blood flow speeds of different segments of interlobular arteries) over indexes obtained using conventional clinical serum (β2‐microglobulin, serum urea nitrogen, and creatinine) and urine (24‐h urine volume and urine protein) tests and ultrasound Doppler imaging (peak systolic velocity [PSV], end‐diastolic velocity [EDV], and resistance index [RI]) and contrast‐enhanced ultrasound imaging (CEUS; rise time [RT], peak intensity [IMAX], mean transit time [mTT], and area under the time‐intensity curve [AUC]) for early diagnosis of HN were investigated. Examinations were carried out on six spontaneously hypertensive rats (SHR) and five normal Wistar–Kyoto (WKY) rats at the age of 10 weeks.ResultsThe experimental results show that the indicators derived from conventional clinical inspections (serum and urine tests) and ultrasound imaging (PSV, EDV, RI, RT, IMAX, mTT, and AUC) do not show significant difference between hypertensive and healthy rats (p > 0.05), while the TTP of the SHR group (28.52 ± 5.52 s) derived from CEUS is significantly higher than that of the WKY group (18.68 ± 7.32 s; p < 0.05). The mean blood flow speed in interlobular artery of SHR (12.47 ± 1.06 mm/s) derived from ULM is significantly higher than that of WKY rats (10.13 ± 1.17 mm/s; p < 0.01).ConclusionThe advantages of ULM over conventional clinical inspections and ultrasound imaging methods for early diagnosis of HN were validated. The quantitative results show that ULM can effectively diagnose HN at the early stage by detecting the blood flow speed changes of interlobular arteries. ULM may promise a reliable technique for early diagnosis of HN in the future.

Abstract Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged &gt;70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status &gt;0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

AbstractPurposeThe Leksell Gamma Knife Icon unit (IU) was introduced recently as an upgrade to the Perfexion unit (PU) at our Gamma Knife practice. In the current study, we sought mainly to characterize dosimetry and targeting accuracy of the IU treatment deliveries using both invasive frame and frameless treatment workflows.MethodsRelative output factors were measured by delivering single‐shot 4, 8 and 16 mm radiation profiles in the manufacturer's acrylonitrile butadiene styrene spherical phantom in coronal and sagittal planes using EBT3 film. Resultant dosimetry was compared with the manufacturer's dose calculation and derived output factors were compared with the manufacturer's published value. Geometric consistency of stereotactic coordinates based on cone‐beam computed tomography (CBCT) versus the traditional conventional CT‐based method was characterized using a rigid phantom containing nine fiducial indicators over four separate trials. End‐to‐end (E2E) testing using EBT3 film was designed to evaluate both dosimetric and geometric accuracy for hypothetical framed and frameless workflows.ResultsRelative output factors as measured by the manufacturer were independently confirmed using EBT3 film measurements to within 2%. The mean 3D radial discrepancy in stereotactic space between CBCT and CT‐based definition over the sampled locations in our rigid geometry phantom was demonstrated to be between 0.40 mm and 0.56 mm over the set of trials, larger than prior reported values. E2E performed in 2D demonstrates sub‐mm (and typically < 0.5 mm) accuracy for framed and frameless workflows; geometric accuracy of framed treatments using CBCT‐defined stereotactic coordinates was shown to be slightly improved in comparison with those defined using conventional CT. Furthermore, in phantom, frameless workflows exhibited better accuracy than framed workflows for fractionated treatments, despite large magnitudes of introduced interfraction setup error. Accuracy of dosimetric delivery was confirmed in terms of qualitative comparisons of dose profiles and in terms of 2D gamma pass rates based on 1%/1 mm criteria.ConclusionThe IU was commissioned for clinical use of frameless and framed treatment protocols. The present study outlines an extensive E2E methodology for confirmation of dosimetric and geometric treatment accuracy.

Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p&lt;0.001), RBS of 0 (p&lt;0.05), and SFS of 0 (p&lt;0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p&lt;0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

344 Background: ICI with anti-PD-1 therapy was approved by the US FDA as 1st/2nd-line treatment of advanced GEC regardless of PD-L1 status. It is argued that patients (pts) with PD-L1-low GEC do not benefit from ICI. To avoid spurious exclusion of pts, we systematically reviewed phase 3 trials to assess the magnitude and consistency of PD-L1 to predict benefit from ICI. We also examined other potential predictive factors to understand their magnitude and consistency in comparison with PD-L1 status. Methods: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register were searched for all randomized clinical trials (RCT; 2000-2021) in advanced GEC comparing ICI, alone or with chemotherapy, vs standard of care (SOC). The primary endpoint was overall survival (OS). Study screening, data abstraction, and bias assessment were done independently by two reviewers per PRISMA guidelines. The mean HR for ICI vs SOC was calculated by random effects model. The predictive value of a factor was quantified using relative magnitude and consistency (table). Results: 14 RCTs at low risk of bias were included (N = 9,210 pts; KN62, CM649, CM648, ESCORT1st, KN590, ATT4, JAV100, KN181, KN61, ATT3, ESCORT, RATIONALE302, JAV300, ATT2). 6 trials were 1st-line, 8 were after 1st-line. Treatment comparisons were ICI + chemo vs chemo (6 trials), ICI vs chemo (9 trials), and ICI vs placebo (1 trial). ICI was always anti-PD-1/-L1 (1 trial also had anti-CTLA-4). Table shows primary results. To enable head to head comparisons, subgroup analyses of trials containing both levels of a factor or having similar design were done and generally yielded consistent results. Conclusions: PD-L1 CPS is the strongest predictive biomarker, after MSI, for OS benefit from ICI-containing therapy vs SOC. Additional research on gender is warranted.[Table: see text]

101 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (20-49 years, named early-onset CRC, eoCRC) has been increasing. eoCRC patients with metastatic disease are treated with the same standard regimens as late-onset CRC (loCRC, age ≥ 50 years) although detailed response data for eoCRC are largely missing. Methods: Individual patient data on 7,604 subjects with metastatic eoCRC from 11 first line randomized bevacizumab studies between 2000 and 2012 in the ARCAD advanced colorectal cancer database were pooled. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were summarized by age groups. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier curves and Cox models stratified by treatment arms within studies, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables. Results: Female eoCRC are more commonly seen compared to loCRC (46.8% vs. 38.7%, p<0.0001). Patients with eoCRC (n=1,289) were significantly more likely to have had prior metastasectomy (17.5% vs. 13.5%, p=0.043) and lung metastatic disease (67% vs. 59.8%, p<0.001), but less likely to have distant lymph node metastatic disease (58.8 vs. 62.9%, p=0.036) or KRAS mutation (29.2% vs. 34.4%, p=0.042) compared to those with loCRC (n=6,315). eoCRC and loCRC patients had similar distributions according to PS, primary tumor sidedness, prior primary tumor resection, liver involvement, peritoneal involvement, number of metastatic sites, NRAS and BRAF. Age of disease onset was not a statistically significant prognostic factor for PFS in univariate and multivariate analysis (seen in table). Bevacizumab in addition to chemo improved PFS in eoCRC population (9.9 vs. 6.8 months, HR = 0.66, p<0.001), which was similar to the findings in loCRC population (9.4 vs. 7.3 months, HR= 0.73, p<0.001, interaction p=0.54). By multivariate analysis, a greater improvement in PFS was noted for the addition of bevacizumab in eoCRC relative to LoCRC patients (HR = 0.62 vs. HR = 0.82). Conclusions: Treatment naive eoCRC patients with metastatic disease derive similar benefit from bevacizumab relative to their average age counterparts.[Table: see text]