Spears, Grant M.

ABSTRACT Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Abstract Objectives Free light chain (FLC) assays and the ratio of κ/λ are recommended for diagnosis, prognosis and monitoring of plasma cell dyscrasias (PCD). Limited data exists on FLC clinical specificity in patients diagnosed with other conditions. Methods We assessed the κ, λ, and κ/λ FLC ratio using the FreeLite assay and the Sebia FLC ELISA assay in 176 patients with clinical presentations of fatigue, anemia, polyclonal hypergammaglobulinemia, joint disorders, kidney disease and non PCD-cancers with no monoclonal protein observed on serum protein electrophoresis or MASS-FIX immunoglobulin isotyping. Manufacturer defined reference intervals (RI) and glomerular filtration rate (GFR) specific RI (renal RI) were utilized. Results For the κ/λ ratio, 68.7 % (121/176) of specimens on the FreeLite and 87.5 % (154/176) of specimens on the Sebia assay were within RI. For κ, 68.2 % (120/176) and 72.2 % (127/176) of results were outside RI for FreeLite and Sebia respectively. For λ, 37.5 % (66/176) and 84.1 % (148/176) of FreeLite and Sebia results were outside RI. With FreeLite and Sebia, patients with kidney disease (n=25) had the highest κ/λ ratios. 44 patients (25.0 %) had GFR <60 mL/min/BSA. When renal RI were applied, 13.6 % had a FLCr outside the renal RI with FreeLite, and 4.5 % with Sebia. Conclusions In a cohort of patients with signs and symptoms suggestive of PCDs, but ultimately diagnosed with other conditions, Sebia FLC had improved clinical specificity relative to FreeLite, if one was using an abnormal κ/λ ratio as a surrogate for monoclonality.

OBJECTIVE Arginine vasopressin deficiency (AVD) following neurosurgical procedures for pituitary disorders is common and can delay discharge. Copeptin, a stable surrogate marker of arginine vasopressin, may predict postoperative AVD. The authors’ aim was to assess the optimal postoperative sampling time and cut-point concentration of copeptin to predict the development of postsurgical AVD. METHODS Adults without preexisting AVD who were undergoing surgery for a pituitary lesion between February 2020 and April 2022 were eligible for study inclusion. Two samples were drawn from each patient postoperatively to assess the copeptin concentration using an immunofluorescent assay. Samples were denoted as "early" (within 6 hours of extubation) or "postoperative day 1" (POD1; within 10–30 hours of extubation). Patients were evaluated for the development of AVD. RESULTS One hundred ninety-two patients (54.2% female) with a median age of 54.5 years (IQR 39.8–67.0 years) were included in the study. The median copeptin concentration at both time points was significantly lower in those with AVD (transient or permanent; n = 22, 11.5%) than in those without (early: 4.9 vs 18.7 pmol/L, p < 0.001; POD1: 3.4 vs 4.9 pmol/L, p < 0.001) but did not differ in those who developed transient versus permanent AVD. The optimal copeptin cut point for the prediction of AVD was < 8.5 pmol/L for early samples (sensitivity 0.70, specificity 0.80, positive predictive value [PPV] 0.29, negative predictive value [NPV] 0.96) and < 4.3 pmol/L for POD1 samples (sensitivity 0.82, specificity 0.63, PPV 0.22, NPV 0.96). In early samples, a copeptin cutoff of 22.9 pmol/L increased the sensitivity for the detection of AVD to 95% with an NPV of 99%. The proportion of patients who had AVD was higher (60.0% vs 8.8%, p < 0.001) and the copeptin concentration lower (early: 4.3 vs 17.0 pmol/L, p < 0.001; POD1: 2.7 vs 4.9 pmol/L, p < 0.001) among those who had undergone surgery for a craniopharyngeal duct pathology versus a pituitary adenoma. Although copeptin was lower in patients with persistent Cushing’s disease than in those in remission, the difference did not reach statistical significance (early p = 0.11, POD1 p = 0.52). Furthermore, the copeptin concentration could not predict the development of syndrome of inappropriate secretion of antidiuretic hormone. Patients without AVD who had received stress dose steroids intraoperatively had lower median early copeptin (11.7 vs 19.1 pmol/L, p = 0.027). CONCLUSIONS In early postoperative copeptin samples, the optimal copeptin cut point for AVD diagnosis was < 8.5 pmol/L, and a level > 22.9 pmol/L had predicative utility in excluding AVD. Caution should be used when interpreting copeptin results, as patients administered glucocorticoids intraoperatively without AVD had lower median copeptin concentrations.

Objective A follow-up of women 50 years or older with concomitant positive high-risk human papillomavirus (HPV) genotypes other than 16 and 18 (hrHPVO) and negative Pap test (NILMPap) was conducted to better understand the implications of hrHPVO positivity on potential risk of developing significant high-grade lesions. Material and Methods A retrospective review of 2014 cytology data of patients with co-testing (Pap test and HPV DNA) identified 85 women 50 years or older with NILMPap and hrHPVO+. Results Most patients (63) had repeat co-testing on next follow-up. Of these, 41 patients with persistent hrHPVO+ status, 3 developed cervical intraepithelial neoplasia 2 (CIN2), and 1 CIN3. Nineteen patients were followed with biopsies. Of these, 7 biopsies were abnormal, 5 of which showed low-grade (CIN1) and 2 high-grade (CIN3) histology; none progressed on further follow-up. Three patients were followed with Pap test only, all had NILMPap, and none progressed on further follow-up. In summary, of the 85 patients, 26 developed abnormal histology during follow-up, 6 of whom had high-grade histology (CIN2 and CIN3, 3 each). The 5-year risk of CIN1+ in this cohort was 43.8% and for CIN2+ was 12.3%. The risk of abnormal histology did not differ significantly by prior history of Pap tests, histology, and/or HPV results. Conclusions A persistent positivity for hrHPVO indicated higher likelihood to develop a lesion, and this risk was not reduced for patients 50 and older compared with the published screening population risk.

191 Background: ANC is used to determine the dosing of chemotherapy and eligibility in clinical trials. Duffy-null phenotype is associated with a lower ANC and present in 2/3 of the Black population. Therefore, ANC reference intervals from hospitals serving a larger percentage (%) of Black population are expected to be lower. Ideally, reference intervals should represent the normal values of the population served. The objective of this study is to determine if the ANC reference intervals of hospitals in the US are representative of the population served based on racial diversity. Methods: We obtained hospital ANC reference intervals from the Mayo Clinic EPIC electronic medical records Care Everywhere health information exchange. Reference intervals from 2020-2023 were included. For each hospital, we determined the city where it is located. For each city, the % of Black population was obtained from the 2020 US Census. We studied the correlation (Pearson) between reference ANC values and % of Black population. To determine the expected ANC reference intervals, we obtained ANC data from the 2021-2022 National Health and Nutrition Examination Survey (NHANES) and performed a reference interval simulation study. Individuals with cancer and cirrhosis were excluded. Random samples of 120 individuals were selected, consisting of n samples from Black individuals and 120-n samples from non-Black individuals. This was performed for n from 0 to 120, and repeated 1000 times per n. Results: We collected data from 107 hospitals across 40 states and 81 cities. Fifty-three (49.5%) hospitals were academic. The % of Black populations in the cities served by the hospitals was a mean of 23.4% (range, 0.7%-82.8%). There was no correlation between ANC upper (r = -0.17, p=0.07) and lower (r = 0.01, p=0.88) limits based on the % Black population. This finding was similar in both academic and non-academic hospitals. Assessment of the ANC distribution in the US population based on race by using the NHANES database showed a clear association with race at the 2.5th (p<0.001) and 97.5th (p=0.009) percentiles with an overall estimated mid-95% reference range of 2.0-8.3 for non-Black individuals and 1.3-7.7 for Black individuals. Conclusions: Hospitals serving a higher % of Black population have similar upper and lower ANC reference intervals compared to those serving a lower % of Black population. This contrasts with the findings from NHANES data which showed significant variations in the normal ANC values between Black and non-Black individuals. Therefore, current hospital ANC reference intervals may not represent the diversity of the population served. Potential clinical implications include misdiagnosis of neutropenia, delay or underdosing of chemotherapy, and inappropriate exclusion in clinical trials, especially in areas with a high % of Black population.

Abstract Disclosure: D.Z. Erickson: None. D. Donegan: None. J. Van Gompel: None. J. Atkinson: None. M. Link: None. F. Meyer: None. M. Peris-Celda: None. G. Spears: None. J. Bornhorst: None. M. Hoplin: None. Dysnatremias are common after neurosurgical procedures. Depending on the cohort assessed, transient arginine vasopressin deficiency (AVD) following neurological procedures is seen in up to 46% of patients which can delay discharge. Copeptin (COPEP), a stable surrogate marker of arginine vasopressin, has demonstrated utility in the prediction of postoperative AVD, however COPEP cutoff and sample timing has varied. Aim: To assess the optimal sampling time and cut point concentration of COPEP to predict the development of post-surgical AVD. Method: Adults who had transsphenoidal surgery (TSS) for a sellar or suprasellar mass between February 2020 and April 2022 without pre-existing AVD were prospectively enrolled if agreeable. Two COPEP samples (immunofluorescent assay on B.R.A.H.M.S Kryptor Compact PLUS) included “early” sample 1-6 hours following extubation, and another post-op day 1 (POD1, 10-30 hours of extubation). Patients were assessed for the development of AVD; defined as new onset hypotonic (&lt; 295 mmol/kg) polyuria (&gt;50 ml/kg/d) without other causes. Patient demographics and tumor characteristics were collected. Results: 192 patients (median age 54.5 (39.8-67.0) years with 54.2% female) were included. Surgical indications included non-functioning pituitary adenoma (N=101), functioning pituitary adenoma (N= 78), disorders or the craniopharyngeal duct (N=10) and other (N=3). Median COPEP levels were associated with age, but not sex. Median COPEP levels were significantly lower at both time points in patients who developed AVD (N=20, 10.4%) vs those who did not, (early: 4.9 vs 18.7 pmol/L, P= &lt;0.001; POD1: 3.35 vs 4.9 pmol/L, P=&lt;0.001). Change in median COPEP level between the 2 sample times was lower in those who developed AVD -1.8 pmol/L vs who did not -12.6 pmol/L (P&lt;0.001). ROC curve analysis of early COPEP indicated that a level &gt;20.3 pmol/L had a negative predictive value (NPV) of 97% whereas POD1 level &gt;6.7 pmolL had a NPV of 96%. In univariate logistic analysis, lower early COPEP was associated with higher risk of AVD (OR=0.34, CI 0.26 -0.62, p=0.008), with an optimal cut point of 8.5 pmol/L. A similar association was seen for POD1 COPEP (OR=0.19, CI 0.07- 0.53, p= 0.002), which had an optimal cut point of 4.3 pmol/L. In patients with disorders of the craniopharyngeal system vs those who had TSS for other reasons, AVD was more common (60% vs 9%, P&lt;0.001) and median COPEP levels were lower at both time points. Those without AVD who received stress dose steroids intraoperatively had lower median early COPEP (11.7 vs 19.1 pmol/L, P=0.27). Conclusion: In early samples taken following extubation, the optimal COPEP cut point for AVD diagnosis was 8.5 pmol/L and a level of &gt;20.3 pmol/L has predicative utility in excluding AVD. However, caution should be used in patients who are administered glucocorticoids intra-operatively as this was associated with a lower median COPEP level. Presentation: Thursday, June 15, 2023

Abstract Background Analytical outliers (fliers) occur with most troponin methods and can adversely affect patient management. We compared the analytical outlier rates for the Roche 5th generation Troponin T STAT (cTnT) reformulated (biotin-insensitive) reagent using a Cobas e601 analyzer (Indianapolis, IN) to rates observed in a previous study using the biotin-sensitive reagent on a Cobas e411 analyzer. Methods Plasma separator tubes (PST) were collected from hospital patients with orders for clinical cTnT testing. PST samples were centrifuged for 3 min at 4000g and analyzed using the biotin-insensitive cTnT Gen 5 assay on a Roche Cobas e601 immunoassay system. If samples displayed measurable cTnT Gen 5 (≥6 ng/L), samples were stored at 2–8 °C within 2 h of initial measurement (N = 2555). Within 24 h of initial analysis, samples were warmed to room temperature, aliquoted, re-centrifuged at 4000g for 3 min, and cTNT was re-measured on the same analyzer. Outlier rates were compared to a previous study (N = 1997) using nearly identical study design but using biotin-sensitive Roche 5th Gen cTnT reagent on an e411 analyzer. We defined analytical outliers by three methods: Repeat value (after aliquoting and re-centrifugation) that differed from the initial value for all samples with measurable cTnT by a critical difference (CD): where CD = z × √2 × SDanalytical, with a z-value of 3.719 and using SD from best fit line of precision vs cTnT concentration. Precision experiments were performed using four plasma pools in 5 × 5 precision experiment on the e411 analyzer. Using the same CD but considering only initial cTnT values &lt;100 ng/L, those are most likely to be clinically significant or lead to misinterpretation. Using CD for initial values &lt;100 ng/L, and a fixed 10% difference between replicates for initial values ≥100 ng/L, accounting for our practice of reporting the cTnT “delta” in percent (rather than absolute) for values ≥100 ng/L. Comparisons of outlier rates between the biotin-sensitive and biotin-insensitive reagents were performed using Pearson’s chi-squared test. Results Using the CD the total number of outliers that were observed for the biotin-insensitive reagent on the e601 was 208/2555 (8.1%), compared to 68/1997 (3.4%) on the biotin-sensitive reagent measured on the e411 (P &lt; 0.0001). Outliers were observed in 138 (6.4%) of samples with initial values &lt; 100 ng/L using the biotin-insensitive reagent on the e601 compared to 45 (2.6%) of such samples on the e411 (P &lt; 0.0001). Using the Z score method to define outliers for initial values &lt;100 ng/L and a fixed 10% to define outliers for initial values ≥100 ng/L, the outlier rate was 151 (5.9%) for the biotin-insensitive reagent on the e601 compared to 53 (2.7%) on the e411 (P &lt; 0.0001). Conclusions Analytical outliers occurred more frequently using the reformulated (biotin-insensitive) reagent on the Roche Cobas e601 analyzer, compared to outlier rates observed for biotin-sensitive reagent on the Cobas e411.

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Mayo Clinic Department of Laboratory Medicine and Pathology. Background Elevated lipoprotein(a) [Lp(a)] is associated with increased risk for atherosclerotic cardiovascular disease (ASCVD). Treatment of patients with elevated Lp(a) usually includes marked reduction in low density lipoprotein cholesterol (LDL-C). However, there are uncertainties about whether all increases in Lp(a) are equivalent in there risk relationship. Purpose The aim of this investigation was to risk stratify patients with elevated Lp(a) mass [Lp(a)-M] based on Lp(a) cholesterol (Lp(a)-C) measurements. We assessed coronary artery disease (CAD) by coronary angiogram and major adverse cardiac events (MACE) in a cohort of patients with elevated Lp(a) mass (≥30mg/dL) over a 15 year followup. Methods Electrophoretic and immunologic assays were used to measure Lp(a)-C and Lp(a)-M, respectively. Univariate and multivariate logistic regression analysis was employed to test for association between Lp(a) and CAD in a cohort patients with elevated Lp(a)-M (≥30mg/dL). The relationship between Lp(a) and time to major cardiac events was evaluated using cox regression analysis. Receiver operator curve (ROC) analyses were used to identify optimal cutoff values for Lp(a)-M and C for predicting CAD in our model. Results We analyzed 179 patients with elevated Lp(a)-M. Cutoff values of 3.3mg/dL for Lp(a)-C and 42.1mg/dL for Lp(a)-M optimally predicted CAD in an ROC analysis. Of these patients, 84 were found to have Lp(a)-C &lt; 3.3mg/dL (low Lp(a)-C), while 95 patients had Lp(a)-C levels ≥ 3.3mg/dL (high Lp(a)-C). High Lp(a)-C was associated with CAD identified on coronary angiography in univariate (OR = 2.17, 95% CI = 1.18 – 4.00, p = 0.013) and multivariate (OR = 3.36, 95% CI = 1.64 – 6.89, p &lt; 0.001) models controlling for traditional risk factors. In univariate analyses high Lp(a)-C was also associated with MACE (HR = 2.38, 95% CI = 1.19 – 4.75, p = 0.01) while Lp(a)-M ≥ 42.1mg/dL (high Lp(a)-M) was not (HR = 1.68, 95% CI = 0.82 – 3.44, p = 0.15) (Table 1, Figure 1). Lp(a)-C remained significantly correlated with MACE after adjusting for traditional risk factors. When included in a model together, Lp(a)-C maintained its significance while Lp(a)-M failed to predict MACE, indicating that Lp(a)-C is a stronger predictor of MACE than Lp(a)-M. Conclusion This study demonstrates that patients with elevated Lp(a)-M and high Lp(a)-C are approximately 2.5 times more likely to encounter MACE over time when compared to patients with elevated Lp(a)-M and low Lp(a)-C. Our investigation suggests that Lp(a)-C can be used to risk stratify patients with elevated Lp(a)-M and identify those at higher risk.

AbstractBackgroundThis study was aimed at developing and validating a decision‐making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases.MethodsThree hundred sixty‐one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies.ResultsThe final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21 months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p < .001), and each 1‐point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79–2.25; p < .0001). The concordance value was 0.75 (95% CI, 0.71–0.78). The scores were discretized into three groups—favorable (score = 0–1), intermediate (score = 2), and poor survival (score = 3–5)—with 2‐year OS rates of 84% (95% CI, 79%–90%), 46% (95% CI, 36%–59%), and 21% (95% CI, 14%–32%), respectively (p < .0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p < .0001). Increasing SINS<zaq;6> was predictive of decreased OS as a continuous variable (p < .0001).ConclusionsThis novel score is proposed as a decision‐making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

ABSTRACT Introduction: Little is known regarding peripheral blood mononuclear cell telomere length (PBMC-TL) and response to traumatic injury. The objective of this study was to characterize the role of PBMC-TL in coagulation and clinical outcomes after injury. Methods: Plasma and buffy coats were prospectively collected from trauma patients and healthy volunteers. DNA was purified and PBMC-TL quantified by quantitative polymerase chain reaction. Thrombin generation kinetics were expressed as lag time (in minutes), peak height (in nanometers), time to peak (in minutes), and endogenous thrombin potential (in nM × min). Results are in median and quartiles [Q1, Q3]. P < 0.05 was considered significant (Wilcoxon rank sum testing). Results: Forty-two younger patients (21 [20, 22] years, 69% were male) and 39 older patients (62 [61, 64] years, 79% were male) were included. There was no significant difference in Clinical Frailty Scores between groups. Younger patients had longer total PBMC-TL (0.40 Mb [0.30, 0.49] vs. 0.29 Mb [0.23, 0.33], P < 0.001) and longer average PBMC-TL per chromosome (4.3 kb [3.3, 5.3] vs. 3.2 kb [2.5, 3.7], P < 0.001). When older patients were stratified by 50th percentile of PBMC-TL, there were no differences in thrombin generation; however, those with shorter telomeres were less likely to be discharged home (29% vs. 77%, P = 0.004). Older patients in the bottom quartile of PBMC-TL had shorter lag time (2.78 min [2.33, 3.00] vs. 3.33 min [3.24, 3.89], P = 0.030) and were less likely to be discharged home (22% vs. 90%, P = 0.006) than those in the top quartile of PBMC-TL. Multivariable logistic regression models revealed both increased age and shorter PBMC-TL to be independent predictors of discharge disposition other than home. Conclusion: In older trauma patients, shorter PBMC-TL is associated with accelerated initiation of thrombin generation and lower likelihood of being discharged to home.