Citations

136 Background: Studies using International Classification of Diseases (ICD) codes have aimed to characterize the safety profile of cancer therapies in the Real-World Data setting, but this approach has limitations including an inability to illustrate patient journey and offer insights into drug-Adverse Event (AE) causality. Using data from a cohort of ~9000 patients treated with immune checkpoint inhibitors (ICI) at Mayo Clinic, we recently demonstrated the feasibility of applying Augmented Curation (AC), a natural language processing (NLP)-based innovation, on unstructured electronic health record (EHR) data to detect and characterize immune related AEs (irAEs). While the ability to identify and extract clinical details from EHRs has been previously demonstrated, our approach focuses on applying these techniques to identify implied textual causality of drug-event pairs. This study aims to build upon our prior findings and compare the accuracy, speed, and resource savings enabled by AC analysis versus manual review of patient notes. Methods: We compared the prevalence of adrenal insufficiency, colitis, and hypophysitis (A.C.H) among ICI patients at Mayo Clinic using ICD codes and AC which leverages SciBERT to perform scientific NLP tasks. AC models trained to identify drug-adverse event relationships were used to assess irAEs and subsequent treatments and demonstrated strong performance with F1 scores of 0.85. Manual curation of relevant clinical data, i.e. medications and adverse events, was employed to create a “gold standard” A.C.H. cohort. Time required for manual review compared to AC was documented for overall comparison. Corticosteroid/immunosuppressant use and ICI discontinuations were used as proxies of severity. Results: In our cohort, 540 unique patients experienced at least one of the A.C.H. irAEs. A.C.H patients were found to receive corticosteroids for their respective irAE 79% of the time and discontinued the ICI due to the irAE 7.7% of the time. 6.1% of Colitis patients were treated with a 2L immunosuppressant. Similar to the previous study, AC showed higher sensitivity, PPV and NPV compared to ICD codes alone within the A.C.H. cohort. Sentence extraction and entity classification using AC models on all 9,000-patients took ~10 minutes, whereas manual review of this cohort would take roughly 9 weeks (~10 minutes per patient). Conclusions: The results from this study reinforce that AC models are a valuable tool to comprehensively extract information and to impute relationships between entities, such as therapies and AEs. The AC models demonstrated better accuracy at a much greater speed compared to manual review of patient EHRs. Leveraging AC models provides the ability to manipulate unstructured clinical text married to structured EHR data at scale while minimizing need for manual curation.

Abstract Rationale Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a “race-neutral” interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.

Abstract Background Genicular nerve radiofrequency ablation (GNRFA) is an effective treatment for chronic knee pain. However, there has been minimal investigation of real-world, long-term outcomes and factors that predict treatment success after GNRFA. Objectives To evaluate the effectiveness of GNRFA for chronic knee pain in a real-world population and identify predictive factors. Methods Consecutive patients who underwent GNRFA at a tertiary academic center were identified. Demographic, clinical, and procedural characteristics were collected from the medical record. Outcome data were numeric rating scale (NRS) pain reduction and Patient Global Impression of Change (PGIC). Data were collected by standardized telephone survey. Predictors of success were evaluated with logistic and Poisson regression analyses. Results Of the 226 total patients identified, 134 (65.6 ± 12.7; 59.7% female) were successfully contacted and analyzed, with a mean follow-up time of 23.3 ± 11.0 months. Of those, 47.8% (n = 64; 95% CI: 39.5%–56.2%) and 61.2% (n = 82; 95% CI: 52.7%–69.0%) reported ≥50% NRS score reduction and ≥2-point NRS score reduction, respectively, and 59.0% (n = 79; 95% CI: 50.5%–66.9%) reported “much improved” on the PGIC questionnaire. Factors associated with a greater likelihood of treatment success (P < .05) were higher Kellgren–Lawrence osteoarthritis grade (2–4 vs 0–1); no baseline opioid, antidepressant, or anxiolytic medication use; and >3 nerves targeted. Conclusion In this real-world cohort, approximately half of the participants experienced clinically meaningful improvements in knee pain after GNRFA at an average follow-up time of nearly 2 years. Factors associated with higher likelihood of treatment success were more advanced osteoarthritis (Kellgren–Lawrence Grade 2–4); no opioid, antidepressant, or anxiolytic medication use; and >3 nerves targeted.

Précis: When comparing patients on systemic immunosuppressive therapy to those without, there was no difference in intraocular pressure (IOP) early after SLT; however, at 1 year following SLT, IOP was higher in the immunosuppression group compared with controls. Purpose: To determine whether patients taking systemic immunosuppressive medications have a different IOP-lowering response to selective laser trabeculoplasty (SLT) compared with a control group of patients. Methods: All patients who underwent SLT at Mayo Clinic 2017–2021 were identified. Patients on systemic immunosuppressive medications at the time of SLT were compared with control patients not receiving systemic immunosuppressive medications. The primary endpoints of this study were the percentage IOP reduction at 1 to 2, 3 to 6, and 12 months. Additional analyses included the percentage of patients who did not require additional therapy at each time point. Results: There were 108 eyes of 72 patients that underwent SLT in the immunosuppressed group and 1997 eyes of 1417 patients in the control group. There was no significant difference in age-adjusted change in IOP between groups at the first postoperative visit 1 to 2 months following SLT (−18.8±20.7% vs. −16.0±16.5%, P=0.256) or 3–6 months following SLT (−15.2±21.6% vs. −18.3±23.2%, P=0.062). However, at 12 months following SLT, the IOP reduction in the immunosuppressive therapy group was significantly less compared with the control group (−15.1±21.2% vs. −20.3±22.9%, P=0.045). There was no difference between groups in the number of additional treatments during the study intervals. Conclusion: Patients in the systemic immunosuppressive therapy group showed equivalent early IOP-lowering after SLT compared with a control group, but the treatment response was diminished at 1 year. Further studies investigating IOP regulation after SLT in immunosuppressed patients are needed.

Macrolides are a mainstay of therapy for infections due to nontuberculous mycobacteria (NTM). Among rapidly growing mycobacteria (RGM), inducible macrolide resistance is associated with four chromosomal 23S rRNA methylase ( erm ) genes.

Introduction: Cardiac sarcoidosis (CS) is a non-ischemic disease which can present with right ventricular (RV) dysfunction, but there is a paucity of research describing RV function and natural history in CS. Methods: We queried a registry of 512 CS patients for those with baseline and follow-up echocardiography (TTE). Demographics, medications, and baseline/follow-up TTE data were collected. RV-pulmonary arterial (RV-PA) coupling was approximated by ratio of tricuspid annular plane systolic excursion to estimated pulmonary artery systolic pressure (TAPSE:ePASP). Results: Our query yielded 343 CS patients with mean age 56y (σ=12y), who were predominantly male (67%) and white (90%) with a median follow-up 4y (interquartile range 4.1y). Most had pulmonary sarcoidosis (68%). Baseline TTE data showed left ventricular ejection fraction 48% (σ=14), abnormal RV function with RV systolic pressure (ePASP) 34 mmHg (σ=11), TAPSE 21mm (σ=5), RV S′ 0.14 m/s (σ=0.07), and RV-PA uncoupling (TAPSE:ePASP 0.69 mm/mm Hg, σ=0.25). Baseline RV function parameters did not differ by pulmonary involvement of sarcoidosis. 92% received immunosuppression and 65% received neurohormonal blockade. In long-term follow-up, the overall cohort demonstrated a trend towards worsening of both RV S’ and RV-PA coupling (P=.02 and P=.003 for linear trend, respectively) but stable ePASP (P=.11). Trends in both non-invasive ePASP and RV-PA coupling were similar in patients with and without pulmonary involvement (P=.48 and P=.79, respectively). Conclusions: In our large CS cohort with extensive follow-up, metrics of RV function and RV-PA coupling are often abnormal at CS diagnosis. Echocardiographic measures of PASP tend to remain stable but markers of RV dysfunction, including RV-PA coupling, tend to worsen throughout the disease course irrespective of pulmonary sarcoidosis. More granular phenotyping of pulmonary hypertension in CS is required to better understand this relationship.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

3595 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 tumor-specific antigens frequently expressed in patients with mCRC. Following early evidence of clinical activity of PolyPEPI1018 in first-line MSS mCRC, here we report the results of a phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-15 of a 28-day cycle. Treatment continued for up to 7 cycles, until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 15 patients started treatment. Median age was 55 years (range 31–71), 73% had liver metastases (mets), 73% had KRAS mutant tumors. The most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events (n = 15) at least possibly related to treatment were fatigue, decreased white blood cell, lymphocyte and neutrophil counts, nausea, diarrhea, myalgia, and maculo-papular rash. There were no Gr 4 or 5 events. The ORR was 0%. The DCR was 53.3% in the overall population and 36% and 100% for the patients with liver mets and without liver mets, respectively. The mPFS was 4 months (95%CI 2.2-6.1) in the overall population and 2.3 months (95%CI 2.1-NE) and 7.6 months (95%CI 4.4-NE) for the patients with liver mets and without liver mets, respectively (HR = 5.73 (95%CI 1.21, 27.06); p = 0.015). At the data cut-off date (Feb 10, 2023), the mOS was 8.7 months (95%CI 6.9-NE; not mature) in the overall population and it was not reached in patients without liver mets. Patients with increased PFS (≥ 24 weeks) had more robust vaccine-specific humoral and T cell responses induced by higher number of vaccine peptides than patients with PFS < 24 weeks. Conclusions: To our knowledge, this is the first study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immunological responses to the improved clinical benefit and the combination warrants further testing. Clinical trial information: NCT05130060 .

3533 Background: The BACCI trial (NCT02873195) randomized 133 mCRC pts to C+B+A (investigational) or C+B+placebo. Longer progression free survival (PFS) was observed in the investigational vs placebo arm. To investigate T-cell functional heterogeneity, we performed single-cell proteomic analyses on pts with either long or short PFS and evaluated T-cell function as a prognostic and predictive biomarker. Methods: Isolated CD8+ and CD4+ cells were analyzed at baseline and first restaging from pts with long ( > 6 mo, N = 14) or short ( < 2 mo, N = 13) PFS. Single-cell, functional proteomic analyses were conducted using the IsoLight system (Isoplexis), which assessed secretion of 32 cytokines from an average of 786 cells per sample. The cumulative readout was polyfunctional strength index (PSI), a composite score of frequency and magnitude of secreted cytokines. Cytokines are organized into effector (E), stimulatory, chemoattractive (CA), regulatory, and inflammatory (I) clusters. Differential expression analyses were done using Wilcoxon rank-sum tests. Potential predictive effects were assessed using logistic regressions with interaction between treatment and biomarkers. No multiple comparison control was done due to the exploratory nature of analyses. Results: Baseline CD8+ and CD4+ cells were stimulated ex vivo and single-cell cytokine analyses performed. Prognostic analyses indicated that CD8+ cells from pts with long PFS had ~3-fold higher PSI compared to pts with short PFS (p = 0.005). Further analysis identified that the E (p = 0.005) and CA clusters (p = 0.005) most impacted PSI, significant individual cytokines are listed in the table. Baseline CD8+ cell function was not predictive of outcome. Baseline CD4+ cell function was not prognostic or predictive of outcome. Analysis of CD8+ cells after treatment identified that changes in CA cluster was prognostic of long PFS (p = 0.024). Cytokine changes from CD4+ cells were not prognostic; however, early changes in the CD4+ CA cluster were predictive of outcome (p-int = 0.055). Similarly, early changes in the CD8+ I cluster were predictive of outcome (p-int = 0.073). Conclusions: These results reveal pts with long PFS had more functional CD8+ T-cells with a higher PSI than pts with short PFS. Predictive analyses suggested that early changes in the CD4+ CA and CD8+ I clusters were associated with benefit from immunotherapy. These preliminary results highlight the importance of single-cell functional proteomic analyses. [Table: see text]

Abstract Background Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring. Methods Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring. Results Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months. Conclusions BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.