Citations

2616 Background: Non-small cell lung cancer (NSCLC) tissue is a valuable resource for diagnosis, treatment planning, and drug development. Current 2D histopathological techniques introduce under-sampling error (i.e., a single 5 µm section represents 0.5% of a 1 mm thick biopsy), interobserver variability, and failure to capture the biology contained within the entire tissue sample. We have developed a suite of technologies to stain, chemically clarify, image, visualize, and analyze entire, intact lung tissue samples. Herein, we present analysis methods for comprehensive 3D assessment of intact NSCLC tissue. Methods: Human NSCLC tissue, stored frozen in optimal cutting temperature (OCT) compound, was fixed in 4% paraformaldehyde, stained with nuclear (TOPRO-3) and general protein (Eosin) fluorescent dyes, and optically cleared using a modified iDISCO protocol with ethyl cinnamate as the refractive index matching solution. Twenty tissue samples measuring 1-5 mm3 in volume were imaged at 2 µm/pixel resolution with a hybrid open-top light-sheet microscope. Smaller regions of interest (ROIs) with interesting pathologic features were re-imaged at higher resolution, 0.17 µm/pixel. Visualization and analysis was performed using Aivia software, custom spatial analysis software and python scripts. Results: All NSCLC tissue samples were successfully imaged in 3D at both low and high resolution. Computational approaches, such as machine learning, were used to segment and classify tumor cells and lymphocytes within the high resolution ROIs. In one example we quantified a 0.0045 mm3 ROI containing 1x109 voxels. We segmented 1,474 unique objects, and classified 683 (46%) of the objects as lymphocytes and 309 (20%) of the cells as tumor cells. We found that on average the lymphocytes were within 12 µm of the nearest tumor cell. Additionally the tissue was broken into separate lymphocyte dense (58% of volume) and tumor dense regions (42% of volume). Further analysis is in progress to quantify more features, such as tertiary lymphoid structures, stromal cells, and fibrosis over the full 20 sample dataset. Conclusions: We successfully implemented 3D machine learning analysis pipelines using images from intact NSCLC tissue samples measuring up to 5 mm3. The imaging was performed using our custom hybrid open-top light-sheet microscope. This novel method enables us to identify and quantify key histological features such as tumor cells and lymphocytes within the tumor microenvironment. In addition, machine learning driven algorithms clustered cells into distinct tissue regions in 3D which enables a more precise assessment of disease state and heterogeneity. Further investigation is ongoing to link these results to patient outcomes.

1535 Background: Ambulatory management of select patients with febrile neutropenia (FN) may substantially decrease patients’ burden of illness and improve their quality of life, and is recommended by American Society of Clinical Oncology (ASCO) guidelines. However, in the United States, inpatient management remains the universal standard. We hereby report the health care utilization associated with the DEFeNDR remote patient monitoring (RPM) program, which leverages technology and virtual centralized nurse monitoring to facilitate ambulatory management of FN as an alternative to hospital-based care. Methods: Adult patients with cancer hospitalized with FN were assessed daily for eligibility to participate in the DEFeNDR program. Eligibility criteria included MASCC score >21 (per ASCO guidelines), and clinical judgment of the attending provider. Patients receiving cellular therapy (CAR-T, BMT) in the prior 100 days were excluded. Eligible patients agreeing to participate in the 30-day program were provided a kit containing cellular-enabled, pre-connected devices to facilitate monitoring, including twice-daily vital signs and electronic symptom questionnaires. Data were EHR-integrated in real-time and embedded decision trees facilitated alerts for adverse trends. RPM nurses responded to alerts and escalated care as indicated by pre-specified care pathways. Program assessment was performed at 20 weeks after full implementation. The primary outcome was the mean proportion of evaluable days spent inpatient (mPEDI) within 30 days of eligibility compared between those who participated in the program vs. those who declined. Results: 35 patients were offered participation in the DEFeNDR program. Of these, 17 participated and 18 declined. Baseline characteristics are provided. Participating patients experienced mPEDI of 6.9% (Standard Error [SE], 3.7%), compared with 17.7% (SE, 3.6%) for patients who declined participation. Due to small sample size, this difference (10.8%) did not reach statistical significance (Wilcoxon Rank Sums p-value, 0.15). 30-day mortality did not differ between groups. Mean inpatient days were also lower for patients participating in the program. Additionally, when readmitted, patients participating in RPM experienced a trend toward shorter length of stay and lower rates of intensive care unit utilization. Conclusions: A trend towards decreased burden of inpatient care is evident among patients participating in the DEFeNDR program. Further studies are warranted to assess comparative effectiveness of this model vs usual care.[Table: see text]

Background Thromboelastography is a viscoelastic test with multiple potential advantages over conventional coagulation tests in various disease states. Thromboelastography rapidly provides qualitative and quantitative information related to a patient’s coagulation status. Objective To describe recent studies of the use of thromboelastography in various clinical states and how thromboelastography is used in coagulation management. Methods A literature review using the MEDLINE and PubMed databases was conducted. The updated methodology for integrated reviews by Whittemore and Knafl was followed. Coauthors evaluated separate areas that were independently reviewed by other coauthors to ensure appropriateness for inclusion. Results The use of thromboelastography for various clinical conditions with challenging hemostatic profiles has increased. This integrative review covers the use of thromboelastography in patients with trauma, medication-induced coagulopathy, acute and chronic liver failure, and cardiothoracic surgery. Potential future directions are also discussed. Discussion Thromboelastography has numerous potential benefits over conventional coagulation tests for assessing coagulation status in patients in various clinical states. Nurses can support clinical decisions to use the most appropriate test for their patients. Conclusions Each team member should be involved in assessing the usefulness of thromboelastography. Critical care nurses and the multidisciplinary team must identify patients in whom its use is warranted, interpret the results, and provide appropriate interventions in response to the results and clinical status of the patient.

Abstract Two inherited autosomal dominant cancer predisposition conditions - BRCA related hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) - are termed Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a positive impact on public health. Selection of individuals for genetic testing for these conditions is based on personal and family history. The goal of this study was to evaluate whether screening in a tertiary medical center using exome sequencing could efficiently identify carriers of HBOC and LS and to determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines. Participants from three geographically diverse Mayo Clinic practices in the USA (Rochester MN, Phoenix AZ, Jacksonville FL) consented to clinical “Exome+” sequencing (Helix, San Mateo, CA; Mayo GeneGuide, Rochester, MN) in the TAPESTRY study (NCT05212428), which links sequencing data with electronic health records and the return of CDCT1 genetic findings. For this study we focused on two inherited cancer predisposition conditions: BRCA-related HBOC (BRCA1 and BRCA2) and LS (MLH1, MSH2, MSH6, PMS2 and EPCAM). Detailed chart review to collect demographic information, personal and family history, and assessment of clinical practice guidelines for genetic evaluation (National Cancer Control Network 2021). To date, 44,306 patients have enrolled and sequenced in TAPESTRY. Annotation and interpretation of all variants in 7 genes for HBOC and LS resulted in identification of 550 carriers (prevalence 1.24%) which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2 and 0.2% EPCAM). Demographics of the cohort included: 62.7% female, mean age 55.2 years, non-white race 9.6% and 3.8% Hispanic/Latino ethnicity. A personal history of cancer was present in 46.4% of test positive patients, including 22.5% of HBOC patients with breast or ovarian cancer and 20.9% of LS patients with colorectal or uterine cancer. More than half of the patients (52.1%) were newly diagnosed with HBOC and LS based on the results of this study. Overall, 39.2% of HBOC/LS carriers identified through Exome+ sequencing did not satisfy NCCN criteria for genetic evaluation, this was higher for LS (56.2%) compared to HBOC (32%). Amongst those newly diagnosed with HBOC/LS (n=286), NCCN criteria were not satisfied in 60% of cases (78% for LS and 51% for HBOC). Of the pathogenic germline variant carriers who met NCCN guidelines for testing, 34.2% were not aware of their diagnosis prior to participation in this study. Our results emphasize the need for wide genomic screening for CDCT1 cancer predisposition syndromes. Such screening could identify at-risk carriers of HBOC and LS, who would not otherwise be identified through clinical practice guidelines. Citation Format: Emily Gay, Niloy Jewel Samadder, Michelle L. Bublitz, Melanie M. Peterson, Tammy A. Wilson, Lorelei A. Bandel, Sebastian M. Armasu, Robert A. Vierkant, Matthew J. Ferber, Eric W. Klee, Nicholas B. Larson, Teresa M. Kruisselbrink, Timothy B. Curry, Jan B. Egan, Jennifer L. Kemppainen, Jessa S. Bidwell, Jennifer L. Anderson, Tammy M. McAllister, T'Nita S. Walker, Katie L. Kunze, Vanda Lindpere, Michael A. Golafshar, Margaret Klint, Richard J. Presutti, William V. Bobo, Aleksander Sekulic, Jolene M. Summer Bolster, Cheryl L. Willman, Konstantinos N. Lazaridis. Genetic screening in a tertiary medical center identifies carriers of cancer predisposition diseases that would be missed by clinical guidelines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5768.

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.

Abstract Introduction A new three-piece inflatable penile prosthesis was introduced in 2019. The Rigicon Infla10® has been implanted in 26 centers by 103 physicians. Clinical investigation for FDA approval in United States will begin in late 2022. Objective We report initial survival from explantation and revision rates for infection, mechanical failure and medical problems. Data was obtained from analysis of Patient Information Forms (PIFs) submitted to the manufacturer. Patient information data was omitted prior to analysis. Methods 319 patients implanted from 1/06/2019 to 12/31/2021 were followed to analyze device durability from revision/removal and rates of reoperation for infection, mechanical failure or medical reason. Results Mean follow-up was 21.2 months with a range of 5-36 months. Mean age was 58.5. 4.38% required removal/revision. Mechanical failure was 2.5%. There were no infections reported and only two (0.6%) medical problems (component out of place). One Peyronie's patient required revision for inadequate straightening (0.03% Three patients (0.9%) requested device removal for dissatisfaction. A total of 95.6% of Rigicon Infla10® was free from explant or revision 13 months from the original implant date. Kaplan Meier analysis revealed cumulative survival of the device at 12, 24 and 36 months was 95.6%, 94.7% and 95.7% until surgical invention. Conclusions While this is a retrospective study derived from volunteered Patient Information Forms, we believe the vast majority of the early Rigicon Infla10® performed prior to 1/2022 were included in the analysis. Early results show initial durability from re-operation equivalent to contemporary, devices. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Rigicon, Boston Scientific, Coloplast.

AbstractCardiac physiologic pacing (CPP), encompassing cardiac resynchronization therapy (CRT) and conduction system pacing (CSP), has emerged as a pacing therapy strategy that may mitigate or prevent the development of heart failure (HF) in patients with ventricular dyssynchrony or pacing‐induced cardiomyopathy. This clinical practice guideline is intended to provide guidance on indications for CRT for HF therapy and CPP in patients with pacemaker indications or HF, patient selection, pre‐procedure evaluation and preparation, implant procedure management, follow‐up evaluation and optimization of CPP response, and use in pediatric populations. Gaps in knowledge, pointing to new directions for future research, are also identified.

AbstractDaratumumab is an anti‐CD38 antibody that is increasingly incorporated in induction regimens for treating patients with newly diagnosed multiple myeloma (NDMM). Previous reports have demonstrated a lower yield of hematopoietic stem cells (HSCs) after induction with daratumumab; however, none of them reported a failure to collect an adequate number of HSCs. We describe a case of adequate HSC mobilization failure in a patient who inadvertently received excessive doses of daratumumab and was confirmed by higher‐than‐expected circulating levels of daratumumab by mass spectrometry. Eventual clearance of circulating daratumumab was associated with the successful mobilization and harvesting of HSCs.

Abstract Introduction Transthyretin–mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild–type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO–B study. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6–MWT at Month 12 (M12) with patisiran vs placebo. Results APOLLO–B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6–MWT (median [95% CI] change from baseline: patisiran, –8.15 [–16.42, 1.50]; placebo, –21.35 [–34.05, –7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ–OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, –3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6–MWT and KCCQ–OS were observed across predefined patient subgroups. Time to first event of all–cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all–cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns. Conclusions Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO–B open–label extension.

Objective: Our study aimed to assess the impact of pharmacogenomic panel testing in people with HIV (PWH). Design: Prospective, observational intervention assessment Methods: One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants’ current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes. Results: Ninety-six participants (median age 53 years, 74% white, 84% men, 89% viral load <50 copies/ml) completed panel testing, yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild–moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in one participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants. Conclusion: Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.