Citations

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Abstract Pediatric Acute Myeloid Leukemia (AML) with a FLT3 internal tandem duplication (FLT3-ITD) is a challenging disease due to poor outcomes in many patients. The 4-year progression-free survival is still only 31%. Current biomarkers are insufficient to predict why certain patients with FLT3-ITD AML relapse and others do not. The development of prognostic biomarkers in FLT3-ITD pediatric AML may help improve the outcomes and management of these patients. We acquired a panel of 37 diagnostic samples with 18 samples from FLT3-ITD pediatric AML patients with poor outcomes (relapse within 3 years) and 19 from favorable outcome patients that did not exhibit relapse for at least 5 years. Next, we performed FACS to isolate CD34+CD38dim and CD34+CD38+ cells. These two populations were then sequenced using 10x Genomics 3’ end single-cell RNA sequencing (scRNAseq). Using this scRNAseq dataset comprising over 250k single cells, we first investigated if the frequency of specific RNA clusters of AML cells may predict patient outcome. We found 5 clusters had significantly different frequencies between patients with favorable and poor outcomes (p &lt; 0.05). Using these clusters, we performed CIBERSORTx deconvolution on publicly available FLT3-ITD AML bulk RNAseq samples from TCGA (n = 36), BeatAML (n = 47), and the TARGET project (ntrain = 72; ntest = 26) to identify the inferred cluster composition present in each AML patient from these datasets. Next we built LASSO prediction models using the inferred scRNAseq clusters by CIBERSORTx and incorporating clinical features including leukemic blast percentage, bone marrow leukemic blast percentage, and WBC at diagnosis. We found these prediction models to be highly specific as a prognostic biomarker for pediatric AML (p &lt;&lt; 0.01). We were unable to train a model directly using genes from the publicly available bulk RNAseq data for pediatric FLT3-ITD AML, highlighting the relevance of using our deconvolution based biomarker. Between the high (&gt; median) and low (&lt; median) LASSO score groups, there was ~50% difference in the number of patients relapsing after 4 years. When we included this LASSO score in a multivariate cox regression (likelihood ratio p value = 0.007), the LASSO score (HR = 6.8, p = 0.026, CI = 1.26 - 37.28) showed additional predictive ability when including FLT3-ITD allelic ratio (HR = 1.83, p = 0.38, CI = 0.47 - 7.15) and MRD (HR = 3.95, p = 0.021 CI = 0.051 - 0.79). These results demonstrate that incorporating rare AML cell populations into a prognostic biomarker could add substantial clinical information to existing biomarkers. This indicates single-cell derived prognostic models can and should be explored further for pediatric FLT3-ITD AML and demonstrates a platform that could be used for other malignancies, including non-hematologic tumors, to create cell-type biomarkers. Citation Format: Robert Schauner, Zachary Jackson, Nethrie Idippily, Grace Lee, Sheela Karunanithi, Shivaprasaad Manjappa, Tae Hyun Hwang, David Wald. New platform for novel biomarker discovery using single-cell RNA sequencing on pediatric acute myeloid leukemia samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4080.

Abstract Background Since its emergence in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a risk to healthcare personnel (HCP) and patients in healthcare settings. Although all clinical interactions likely carry some risk of transmission, human actions, such as coughing, and care activities, such as aerosol-generating procedures, likely have a higher risk of transmission. The rapid emergence and global spread of SARS-CoV-2 continues to create significant challenges in healthcare facilities, particularly with shortages of the personal protective equipment (PPE) used by HCP. Evidence-based recommendations for what PPE to use in conventional, contingency, and crisis standards of care continue to be needed. Where evidence is lacking, the development of specific research questions can help direct funders and investigators. The purpose of the current study was to develop evidence-based rapid guidelines intended to support HCP in their decisions about infection prevention when caring for patients with suspected or known coronavirus disease 2019 (COVID-19). Methods The Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel including frontline clinicians, infectious disease specialists, experts in infection control, and guideline methodologists, with representation from the disciplines of public health, medical microbiology, pediatrics, critical care medicine and gastroenterology. The process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then a systematic review of the peer-reviewed and gray literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Results The IDSA guideline panel agreed on 8 recommendations, including 2 updated recommendations and 1 new recommendation added since the first version of the guideline. Narrative summaries of other interventions undergoing evaluations are also included. Conclusions Using a combination of direct and indirect evidence, the panel was able to provide recommendations for 8 specific questions on the use of PPE by HCP providing care for patients with suspected or known COVID-19. Where evidence was lacking, attempts were made to provide potential avenues for investigation. There remain significant gaps in the understanding of the transmission dynamics of SARS-CoV-2, and PPE recommendations may need to be modified in response to new evidence. These recommendations should serve as a minimum for PPE use in healthcare facilities and do not preclude decisions based on local risk assessments or requirements of local health jurisdictions or other regulatory bodies.

Objectives We evaluated the outcomes of metastatic pancreatic cancer (MPC) patients who underwent liver metastases (LMs)–directed ablative radiotherapy (RT) and sought to characterize patients with more favorable prognosis. Methods A retrospective analysis of 76 MPC patients who underwent ablative RT (median dose, 50 Gy) to LM at 3 academic centers between 2008 and 2018 was performed. Endpoints were local control (LC), progression-free survival, and overall survival (OS) since RT. Results Median follow-up was 10.9 months. Liver metastases were metachronous in 68%. Before RT, LM was responsive/stable on chemotherapy (CTX) in 36% whereas progressive in 43%. Median carbohydrate antigen 19-9 (CA 19-9) at RT was 334 U/mL. After RT, 32% had ≥6 months of CTX break. Twelve-month outcomes were: LC, 66%; progression-free survival, 7%; and OS, 38%. On multivariable analysis, Eastern Cooperative Oncology Group 2–3 (hazard ratio [HR], 13.49; P < 0.01), progressive LM on CTX (HR, 3.26; P < 0.01), and higher CA 19-9 (log 10 scale; HR, 1.39; P < 0.01) at RT predicted worse OS. Conclusions Ablative RT to LM in setting of MPC may offer LC of systemic disease and thus quality time off CTX. Selected patients with good performance status, stable/responsive LM on CTX, and lower CA 19-9 have more favorable prognosis.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible virus that can infect healthcare personnel (HCP) and patients in healthcare settings. Specific care activities, in particular, aerosol-generating procedures, may have a higher risk of transmission. The rapid emergence and global spread of SARS-CoV-2 has created significant challenges in healthcare facilities, particularly with severe shortages of personal protective equipment (PPE) used to protect HCP. Evidence-based recommendations for what PPE to use in conventional, contingency, and crisis standards of care are needed. Where evidence is lacking, the development of specific research questions can help direct funders and investigators. Objective Our objective was to develop evidence-based rapid guidelines intended to support HCP in their decisions about infection prevention when caring for patients with suspected or known coronavirus disease 2019 (COVID-19). Methods The Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel that included front-line clinicians, infectious diseases specialists, experts in infection control, and guideline methodologists with representation from the disciplines of preventive care, public health, medical microbiology, pediatrics, critical care medicine, and gastroenterology. The process followed a rapid recommendation checklist. The panel prioritized questions and outcomes. Then, a systematic review of the peer-reviewed and gray literature was conducted. The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess the certainty of evidence and make recommendations. Results The IDSA guideline panel agreed on 8 recommendations and provided narrative summaries of other interventions undergoing evaluations. Conclusions Using a combination of direct and indirect evidence, the panel was able to provide recommendations for 8 specific questions on the use of PPE for HCP who provide care for patients with suspected or known COVID-19. Where evidence was lacking, attempts were made to provide potential avenues for investigation. Significant gaps in the understanding of the transmission dynamics of SARS-CoV-2 remain, and PPE recommendations may need to be modified in response to new evidence.

SummaryDaily self‐weighing is a weight management behaviour that requires a scale; however, scale ownership may be cost‐prohibitive for some patients. Our objective was to understand the proportion of primary care patients with a scale at home, and factors associated with home scale access, to potentially inform future interventions that facilitate scale access. Cross sectional survey of 216 adult patients from three primary care clinics: mixed‐income urban/suburban (n = 68); mixed‐income urban (n = 70); low‐income urban (n = 74). The dependent variable was presence of a home scale; bivariate associations were conducted with variables including demographics, insurance type, clinic setting and self‐reported height/weight. Mean age was 53 years; 71% women; 71% racial minority; mean body mass index 32 kg/m2. Overall, 56% had a home scale. Most (79%) white patients owned a scale, compared to 46% of racial minority patients (P < .01); 33% of low‐income patients owned scale, compared to over 66% of patients at the clinics serving mixed‐income populations (P < .01). Most low‐income urban clinic patients do not own a home scale. Because self‐weighing is an effective weight‐management behaviour, clinicians could consider assessing scale access, and future research should assess the health impact of providing scales to patients with overweight/obesity who desire weight loss or maintenance.

Abstract Abstract 1159 Background. Heparin induced thrombocytopenia (HIT) is an immune disorder where platelets are activated by antibodies to a complex of platelet factor 4 antigen and heparin (PF4/H), leading to thrombocytopenia (HIT) and, potentially, thrombosis (HITT). Documentation of anti-PF4/H antibodies in addition to the appropriate clinical findings is essential for making a diagnosis of HIT. In the post-cardiac bypass surgery setting, however, the frequency of elevated anti-PF4/H antibodies is high, whereas the frequency of clinical HIT or HITT is relatively uncommon. Several studies have shown that the presence of anti-PF4/H antibodies may be associated with an increased frequency of adverse outcomes, even in the absence of clinical HIT. The primary objective of this study was to determine the relationship between a positive PF4/H antibody in the postoperative setting with adverse thromboembolic events occurring up to 3 months after cardiac surgery. Methods. Patients undergoing cardiac surgery who were not going to be treated with chronic anticoagulation postoperatively were eligible for this multi-center prospective cohort study. Data were collected daily during hospitalization, and then at 30 and 90 days after surgery using a structured interview format with a standardized questionnaire that included all thrombotic as well as hemorrhagic events, platelet counts, and utilization of antithrombotics in the postoperative setting. The primary outcome variable was a composite endpoint comprising arterial and venous thrombotic events and other miscellaneous events compatible with HIT, as well as death attributable to an event compatible with HIT. Citrated plasma was collected at baseline, pre-discharge (∼4–5 days after surgery), and the 30 day follow-up visit, processed, and stored at −80°C for testing. Laboratory analyses included an anti-PF4/H antibody ELISA (GTI, Waukesha, WI) on all samples, a high-heparin confirmatory test on samples with an OD reading >0.40, and a serotonin release assay (SRA) on all postoperative samples with an OD reading >0.40. A sample size of 800 patients was estimated in order to detect a 3% difference in thromboembolic events assuming a 2 to 10-fold increase risk attributable to seropositivity. Chi-squared testing was used to test the relationship between the primary outcome and postoperative anti-PF4/H levels. Results. Informed consent was obtained from 1030 eligible patients between August 2006 and May 2009, and laboratory and follow-up data were analyzable for 1016 patients. Thirty-day antibody data were available for 888 patients, and fully complete laboratory and 90-day follow-up data were available for 815 patients. The average age was 62 ± 12 years, and 73% of participants were male. A total of 769 patients underwent coronary artery bypass grafting and 237 underwent valve repair or replacement. During the entire study period, there were 17 (1.7%) deaths, 46 thromboembolic events in 44 patients (4.3%), and 25 hemorrhagic events in 24 patients (2.4%). Using an OD cutoff of 0.40 for the ELISA, 339 patients (33.4%) were positive for anti-PF4/H antibodies at the time of discharge, and 630 patients (62%) were positive by day 30. There was no correlation between seropositivity for anti-PF4/H antibodies at the day of discharge or at day 30 and the primary outcome (p=0.47 and 0.73, respectively). Incorporating the high-heparin confirmatory step did not improve the relationship between positive antibody results and the primary outcome. Using a higher cut-off value for the anti-PF4/H antibody ELISA of 1.0 decreased the number of patients with positive results (96 patients at the time of discharge [9.4%] and 221 patients at the 30-day follow-up visit [21.8%]), but this did not improve the relationship between antibody positivity at the day of discharge or day 30 and the primary clinical endpoint, since most patients with the primary endpoint had an ELISA OD below 1.0 (75th percentile of 0.90; 90th percentile of 1.22). Similarly, using the SRA did not identify a relationship between assay results and outcome. Conclusions. The presence of anti-PF4/H antibodies in the postoperative setting following cardiac bypass surgery is not associated with an increased risk for thromboembolic complications. Positive anti-PF4/H results in this clinical setting should be interpreted with caution and only in the context of clinical suspicion for HIT. Disclosures: Ortel: Instrumentation Laboratory: Consultancy; Eisai: Research Funding; GSK: Research Funding. Welsby:CSL Behring: Speaker; CSL Behring: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Principal Investigator. Heit:Daiichi Sankyo: Honoraria; Ortho-McNeil Janssen: Honoraria; Covidien: Honoraria.

Abstract Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple myeloma cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs, which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant multiple myeloma models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with multiple myeloma standard-of-care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several multiple myeloma disease models and provide the rationale for clinical evaluation as monotherapy and in combination in multiple myeloma. Mol Cancer Ther; 16(11); 2375–86. ©2017 AACR.

AbstractShared decision making (SDM) is essential to advancing patient‐centered care in emergency medicine. Despite many documented benefits of SDM, prior research has demonstrated persistently low levels of patient engagement by clinicians across many disciplines, including emergency medicine. An effective dissemination and implementation (D&I) framework could be used to alter the process of delivering care and to facilitate SDM in routine clinical emergency medicine practice. Here we outline a research and policy agenda to support the D&I strategy needed to integrate SDM into emergency care.

AbstractIntroductionFocused parathyroidectomy in primary hyperparathyroidism (1°HPT) is possible with accurate preoperative localization and intraoperative PTH monitoring (IOPTH). The added benefit of multimodal imaging techniques for operative success is unknown.MethodPatients with 1°HPT, who underwent parathyroidectomy in 2012–2014 at a single institution, were retrospectively reviewed. Only the patients who underwent the standardized multimodal imaging workup consisting of 123I/99Tc‐sestamibi subtraction scintigraphy, SPECT, and SPECT/CT were assessed.ResultsOf 360 patients who were identified, a curative operation was performed in 96 %, using pre‐operative imaging and IOPTH. Imaging analysis showed that 123I/99Tc‐sestamibi had a sensitivity of 86 % (95 % CI 82–90 %), positive predictive value (PPV) 93 %, and accuracy 81 %, based on correct lateralization. SPECT had a sensitivity of 77 % (95 % CI 72–82 %), PPV 92 % and accuracy 72 %. SPECT/CT had a sensitivity of 75 % (95 % CI 70–80 %), PPV of 94 %, and accuracy 71 %. There were 3 of 45 (7 %) patients with negative sestamibi imaging that had an accurate SPECT and SPECT/CT. Of 312 patients (87 %) with positive uptake on sestamibi (93 % true positive, 7 % false positive), concordant findings were present in 86 % SPECT and 84 % SPECT/CT. In cases where imaging modalities were discordant, but at least one method was true‐positive, 123I/99Tc‐sestamibi was significantly better than both SPECT and SPECT/CT (p < 0.001). The inclusion of SPECT and SPECT/CT in 1°HPT imaging protocol increases patient cost up to 2.4‐fold.Conclusion123I/99Tc‐sestamibi subtraction imaging is highly sensitive for preoperative localization in 1°HPT. SPECT and SPECT/CT are commonly concordant with 123I/99Tc‐sestamibi and rarely increase the sensitivity. Routine inclusion of multimodality imaging technique adds minimal clinical benefit but increases cost to patient in high‐volume setting.