MacArthur, Taleen A.

Introduction: Calibrated automated thrombogram assay parameters have been shown to assess hypercoagulation state and, therefore, may independently predict posttrauma, symptomatic venous thromboembolism (VTE). Yet, calibrated automated thrombogram lacks high throughput and standardization, limiting diagnostic potential. This study analyzed thrombin generation (TG) profiles in trauma patients using a high-throughput assay, processing up to 10 samples at once, providing batch testing capabilities. We hypothesized that trauma patients who developed VTE would show distinct TG profiles compared with those who did not. Methods: Trauma patients presenting to a Level I Trauma Center had samples collected within 12 hours postinjury prospectively. Follow-up was conducted to 90 days, time to symptomatic VTE diagnosis or death, confirmed via autopsy or imaging. TG profiles were measured from the ST Genesia assay. Data were presented as median (interquartile ranges) or n (%), with the Wilcoxon rank-sum or chi-squared test. Associations between TG parameters and clinical risk factors were assessed using Spearman correlation analysis or the Wilcoxon rank-sum test. Results: Two hundred and fifty-four trauma patients were analyzed [48.5 years (31.0, 62.0), 72.0% male]: 64 patients with VTE (25.2%) to 190 with non-VTE. VTE pts had a median time to VTE of 8 days, with 29 developing deep venous thrombosis, 24 with pulmonary embolism, and 11 with deep venous thrombosis/pulmonary embolism. No significant differences were found in age, sex, or body mass index; significantly more VTE patients underwent surgery and blood transfusions within 24 hours. TG profiles demonstrated accelerated TG in patients who developed VTE compared with non-VTE, with significant differences in peak height ( P = 0.001), time to peak ( P = 0.021), endogenous thrombin potential ( P < 0.001), and velocity index ( P = 0.001). Conclusion: TG profiles using ST Genesia can differentiate trauma patients at high risk of developing VTE. The platform suits clinical labs needing high throughput by providing batch testing capabilities. Study type: Prospective study with less than large effect and no negative criteria. Level of evidence: II.

ABSTRACT Background: Neutrophil extracellular traps (NETs), and its formation and release, known as NETosis, may play a role in the initiation of thrombin generation (TG) in trauma. The objective of this study was to assess whether trauma patients, who develop symptomatic venous thromboembolism (VTE), have increased levels of plasma citrullinated histone H3 (CitH3) and accelerated TG kinetics. Methods: Patients presenting to a level I trauma center as trauma activations had samples collected within 12 h of time of injury, alongside healthy volunteers (HV). CitH3 was measured by enzyme-linked immunosorbent assay, and TG data were measured using a TG analyzer, comparing results between patients developing symptomatic VTE versus those who did not, within 90 days of injury. Data were expressed as median and quartiles (Q1, Q3), and tested using Wilcoxon rank-sum or Fisher’s exact test, or 1-sample test of Spearman’s correlation, P < 0.05 considered significant. Results: 39 trauma patient samples were analyzed (10 with and 29 without VTE), and compared to 15 HV samples. CitH3 levels in patients who developed VTE were significantly greater as compared to those who did not (12.8 ng/mL [7.1, 30.8]; 3.0 ng/mL [1.8,6.8], P = 0.024), with levels in both groups greater compared to HV (1.2 [0.3, 4.1], P = 0.003, P = 0.012), respectively. TG profiles were accelerated in patients developing VTE, with differences in peak height (337.6 nM [304.4, 356.0]; 231.8 nM [180.2, 281.8], P = 0.008), endogenous thrombin potential (1718.5 nM*min [1,500, 1794]; 1208.5 nM*min [1,072, 1,417], P = 0.003) and velocity index (213.2 nM/min [162.3, 260.5]; 124.3 nM/min [93.2, 223.1], P = 0.03), respectively. Conclusion: Trauma patients developing VTE exhibit increased NETosis, measured by increased CitH3 levels and accelerated TG early after injury, outlining an area for further understanding VTE after trauma.

Abstract Purpose Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non‐RCR). Patients and methods This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi‐square tests were conducted for differences among groups. Kaplan–Meier curves were generated for OS and pulmonary relapse. Results Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five‐year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR ( p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17–0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16–0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non‐RCR groups ( p = .14). Five‐year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non‐RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). Discussion Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.

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.

Background:The coronavirus disease 2019 (COVID-19) pandemic provoked rapid changes in clinical practice to accommodate mandated restrictions within healthcare delivery. This study reviewed patient-reported experiences and clinical outcomes after implementation of a same-day discharge protocol after mastectomy with immediate alloplastic breast reconstruction compared with our historical overnight stay protocol.Methods:This is a retrospective single-institution study of consecutive patients who underwent mastectomy and immediate alloplastic reconstruction between July 2019 and November 2020. A postoperative survey was completed by patients to evaluate satisfaction with perioperative communications, recovery, and their overall experience.Results:A total of 302 patients (100% women) underwent mastectomy and immediate alloplastic reconstruction (174 pre-COVID-19, 128 during COVID-19). During COVID-19, 71% of patients were scheduled for a same-day discharge, among which 89% were successfully discharged the same day. Compared with pre-COVID-19, there were no differences in type of surgery, operative times, pain scores, 30-day readmission, or unplanned visits (allP> 0.05) during the COVID-19 pandemic. Compared with pre-COVID-19, patients during the pandemic reported comparable satisfaction with their care experience and postoperative recovery (56% survey response rate). Patient satisfaction was also similar between those discharged the same day (n = 81) versus the next day (n = 47) during COVID-19.Conclusions:Same-day discharge is feasible, safe, and can provide similar patient-reported satisfaction and outcomes compared with traditional overnight stay. These data highlight the ability to deliver adaptable, high-quality breast cancer care, within the constraints of a global pandemic.

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.

ABSTRACT Introduction: Neutrophil extracellular traps (NETs) trigger thrombin generation. We aimed to characterize the effects of deoxyribonuclease (DNAse) on NET components (cell-free DNA [cfDNA] and histones) and thrombin generation after trauma. Methods: Citrated plasma samples were collected from trauma patients and healthy volunteers. Thrombin generation (calibrated automated thrombogram) was measured as lag time (LT, in minutes), peak height (in nM), and time to peak thrombin generation (in minutes). Citrullinated histone 3 (CitH3) and 4 (CitH4) were measured by enzyme-linked immunosorbent assay; cfDNA by PicoGreen (all in nanograms per milliliter). Samples analyzed +/− DNAse (1,000 U/mL). Results expressed as median and quartiles [Q1, Q3], Wilcoxon testing, P < 0.05 significant. Results: We enrolled 46 patients (age, 48 [31, 67] years; 67% male) and 21 volunteers (age, 45 [28, 53] years; 43% male). Deoxyribonuclease treatment of trauma plasma led to shorter LT (3.11 [2.67, 3.52] min; 2.93 [2.67, 3.19] min), shorter time to peak thrombin generation (6.00 [5.30, 6.67] min; 5.48 [5.00, 6.00] min), greater peak height (273.7 [230.7, 300.5] nM; 288.7 [257.6, 319.2] nM), decreased cfDNA (576.9 [503.3, 803.1] ng/mL; 456.0 [393.5, 626.7] ng/mL), decreased CitH3 (4.54 [2.23, 10.01] ng/mL; 3.59 [1.93, 7.98] ng/mL), and increased H4 (1.30 [0.64, 6.36] ng/mL; 1.75 [0.83, 9.67] ng/mL), all P < 0.001. The effect of DNAse was greater on trauma patients as compared with volunteers for LT (ΔLT, −0.21 vs. −0.02 min, P = 0.007), cfDNA (ΔcfDNA −133.4 vs. −84.9 ng/mL, P < 0.001), and CitH3 (ΔCitH3, –0.65 vs. −0.11 ng/mL, P = 0.004). Conclusion: Deoxyribonuclease treatment accelerates thrombin generation kinetics in trauma patient samples as compared with healthy volunteers. These findings suggest that NETs may contribute to the hypercoagulable state observed in trauma patients.

Background. Early-onset gastric cancer (EOGC,age≤60years at diagnosis) now comprises >30% of new gastric cancers in the United States. It is hypothesized that chronic acid suppression with proton-pump inhibitors (PPIs) may promote tumorigenesis, while other medications including statins, nonsteroidal anti-inflammatory drugs (NSAIDs), metformin, and cyclooxygenase-2 (COX-2) inhibitors have been proposed as protective. We aimed to assess for an association between use of the aforementioned commonly prescribed medications and EOGC development. Methods. We used a population-based medical record linkage system, to identify cases of EOGC in Olmsted County, Minnesota, between January 1, 1995, and December 31, 2020. Patients were matched 1 : 1 with controls based on age at diagnosis, sex, smoking status, and body mass index (BMI). Conditional logistic regression was used to examine associations with the odds of EOGC development. Results. Ninety-six cases of EOGC were identified during the study period. On both univariate and multivariate regression analysis, there was no significant association between use of PPIs, statins, NSAIDs, or metformin and EOGC development. In a final multivariable model, there was a significant reduction in odds of EOGC with COX-2 inhibitor use for six months or more prior to cancer diagnosis (OR=0.39, 95% CI 0.16-0.94). Conclusion. In this retrospective, population-based study of individuals in Olmsted County, MN, we found significantly reduced odds of EOGC development associated with COX-2 inhibitor use for six months or more prior to diagnosis, but no association between EOGC development and use of PPIs and other commonly prescribed medications.

Background Talimogene laherparepvec (TVEC) is an injectable attenuated oncolytic herpes simplex virus (HSV-1) used in the treatment of loco regionally metastatic melanoma. Lesions managed by TVEC are generally considered unresectable at time of initiation of intralesional therapy; however, a subset of patients go on to have surgical resection of loco regionally controlled disease. We sought to review our experience with surgical excision of treated lesions to offer an insight into the radiologic correlate, treatment effect, and pathological findings of intralesional TVEC therapy. Methods This is a retrospective descriptive case series of patients who underwent TVEC injection at Mayo Clinic, Rochester, MN, between October 2016 and July 2020. Institutional Institutional Review Board approval was obtained. Results Twenty-one patients underwent intralesional TVEC, met inclusion criteria, and were included in this series. Seven went on to surgical excision of the injected lesions after an initial course of TVEC. Of those 7 patients, 4 had residual melanoma in the specimen on final pathology, while 3 had a complete pathologic response. All 3 patients who had no residual disease on pathology continued to have fluorodeoxyglucose (FDG) avidity on preoperative positron emission tomography scan of the excised lesions. Discussion Despite ongoing FDG avidity on PET scan, patients who have well-controlled disease and stability over time of the injected lesions may benefit from surgical excision following a course of TVEC. This may render the patient clinically disease free and/or allow them a reprieve from TVEC treatment.