A Rare Case of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Associated With Hemophagocytic Lymphohistiocytosis in a Patient With Recurrent Sinusitis.

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to nasal-type extranodal natural killer/T-cell lymphoma (ENKL). Nasal-type ENKL is a rare subtype of non-Hodgkin's lymphoma usually associated with Epstein-Barr virus (EBV). The patient was a 19-year-old woman who presented with facial numbness, diminished hearing, and dysgeusia. She was febrile with palatal necrosis, loss of gag reflex, and cranial nerve palsies. Labs revealed neutropenia. Broad-spectrum antimicrobials, including amphotericin, were started. Given concern for invasive fungal disease, she underwent surgical debridement, which revealed inflamed fibrous tissue and extensive necrosis. Pathology showed no fungal elements or malignancy. Lack of clinical improvement and worsening palatal necrosis prompted additional debridement. Histology identified an atypical CD3+/CD56+ cellular infiltrate. Bone marrow biopsy showed prominent hemophagocytosis, but no malignancy. She met the criteria for HLH and high-dose dexamethasone was started. Her fevers resolved. Additional labs and nasal tissue sampling with EBV-encoded RNA staining were recommended. Flow cytometry was negative, but histology revealed ENKL nasal-type, with positive EBV-encoded RNA in situ hybridization. Plasma EBV DNA level was 11,518 IU/mL. The M-SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) regimen was initiated; one cycle led to marked improvement. EBV level returned to zero. Subsequent radiation and chemotherapy, followed by autologous stem cell transplant consolidation, led to complete remission. We conclude that ENKL may mimic invasive sinusitis clinically. Fibrinoid necrosis in vessels and surrounding tissues often leads to diagnostic delay. It is important to have a high degree of clinical suspicion for malignancy in cases of HLH and sinusitis unresponsive to appropriate therapy. Obtaining proper tissue, communication with the pathologist, and prompt initiation of therapy are crucial.

The Sensitivity of Limited-Sequence MRI in Identifying Pediatric Cervical Spine Injury: A Western Pediatric Surgery Research Consortium Multicenter Retrospective Cohort Study.

INTRODUCTION: Clinical clearance of a child's cervical spine after trauma is often challenging due to impaired mental status or an unreliable neurologic examination. Magnetic resonance imaging (MRI) is the gold standard for excluding ligamentous injury in children but is constrained by long image acquisition times and frequent need for anesthesia. Limited-sequence MRI (LSMRI) is used in evaluating the evolution of traumatic brain injury and may also be useful for cervical spine clearance while potentially avoiding the need for anesthesia. The purpose of this study was to assess the sensitivity and negative predictive value of LSMRI as compared to gold standard full-sequence MRI as a screening tool to rule out clinically significant ligamentous cervical spine injury. METHODS: We conducted a ten-center, five-year retrospective cohort study (2017-2021) of all children (0-18y) with a cervical spine MRI after blunt trauma. MRI images were re-reviewed by a study pediatric radiologist at each site to determine if the presence of an injury could be identified on limited sequences alone. Unstable cervical spine injury was determined by study neurosurgeon review at each site. RESULTS: We identified 2,663 children less than 18 years of age who underwent an MRI of the cervical spine with 1,008 injuries detected on full-sequence studies. The sensitivity and negative predictive value of LSMRI were both >99% for detecting any injury and 100% for detecting any unstable injury. Young children (age < 5 years) were more likely to be electively intubated or sedated for cervical spine MRI. CONCLUSION: LSMRI is reliably detects clinically significant ligamentous injury in children after blunt trauma. To decrease anesthesia use and minimize MRI time, trauma centers should develop LSMRI screening protocols for children without a reliable neurologic exam. LEVEL OF EVIDENCE: 2 (Diagnostic Tests or Criteria).

A core outcome set for acute necrotizing pancreatitis: An Eastern Association for the Surgery of Trauma modified Delphi method consensus study.

BACKGROUND: The management of acute necrotizing pancreatitis (ANP) has changed dramatically over the past 20 years including the use of less invasive techniques, the timing of interventions, nutritional management, and antimicrobial management. This study sought to create a core outcome set (COS) to help shape future research by establishing a minimal set of essential outcomes that will facilitate future comparisons and pooling of data while minimizing reporting bias. METHODS: A modified Delphi process was performed through involvement of ANP content experts. Each expert proposed a list of outcomes for consideration, and the panel anonymously scored the outcomes on a 9-point Likert scale. Core outcome consensus defined a priori as >70% of scores receiving 7 to 9 points and <15% of scores receiving 1 to 3 points. Feedback and aggregate data were shared between rounds with interclass correlation trends used to determine the end of the study. RESULTS: A total of 19 experts agreed to participate in the study with 16 (84%) participating through study completion. Forty-three outcomes were initially considered with 16 reaching consensuses after four rounds of the modified Delphi process. The final COS included outcomes related to mortality, organ failure, complications, interventions/management, and social factors. CONCLUSION: Through an iterative consensus process, content experts agreed on a COS for the management of ANP. This will help shape future research to generate data suitable for pooling and other statistical analyses that may guide clinical practice. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Predicting high-intensity resuscitation needs in injured patients in the post-hemostasis phase of care following intervention.

BACKGROUND: Best resuscitation practices in the posthemostasis phase of care are poorly defined; this phase of care is characterized by a range of physiologic derangements and multiple therapeutic modalities used to address them. Using a cohort of injured patients who required an immediate intervention in the operating room or angiography suite following arrival to the emergency department, we sought to define high-intensity resuscitation (HIR) in this posthemostasis phase of care; we hypothesized that those who would require HIR could be identified, using only data available at intensive care unit (ICU) admission. METHODS: Clinical data were extracted for consecutive injured patients (2016-2019) admitted to the ICU following an immediate procedure in the operating room or angiography suite. High-intensity resuscitation thresholds were defined as the top decile of blood product (≥3 units) and/or crystalloid (≥4 L) use in the initial 12 hours of ICU care and/or vasoactive medication use between ICU hours 2 and 12. The primary outcome, HIR, was a composite of any of these modalities. Predictive modeling of HIR was performed using logistic regression with predictor variables selected using Least Absolute Shrinkage and Selection Operator (LASSO) estimation. Model was trained using 70% of the cohort and tested on the remaining 30%; model predictive ability was evaluated using area under receiver operator curves. RESULTS: Six hundred five patients were included. Patients were 79% male, young (median age, 39 years), severely injured (median Injury Severity Score, 26), and an approximately 3:2 ratio of blunt to penetrating mechanisms of injury. A total of 215 (36%) required HIR. Predictors selected by LASSO included: shock index, lactate, base deficit, hematocrit, and INR. The area under receiver operator curve for the LASSO-derived HIR prediction model was 0.82. CONCLUSION: Intensive care unit admission data can identify subsequent HIR in the posthemostasis phase of care. Use of this model may facilitate triage, nursing ratio determination, and resource allocation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial.

BACKGROUND: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure. METHODS: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761. FINDINGS: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10). INTERPRETATION: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy. FUNDING: National Institutes of Health.

Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies.

Importance: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. Objective: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. Design, Setting, and Participants: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. Exposures: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. Main Outcomes and Measures: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. Results: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). Conclusions and Relevance: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes.

Long-term health-related quality of life and independence among older survivors of serious injury.

BACKGROUND: Little is known about the recovery experiences of older trauma intensive care unit (TICU) survivors and the relationship between geriatric trauma care and long-term functional ability and health-related quality of life (HRQOL). METHODS: We conducted a prospective cohort study of 218 patients (age, ≥65 years) admitted to a Level 1 regional trauma center TICU before versus after implementation of a geriatric care bundle with protocolized geriatrics consultations (Geri-T). Survivors or their proxies were interviewed approximately 1 year after hospitalization. Outcomes included the Katz Index of Independence in Activities of Daily Living (ADLs), Lawton Instrumental Activities of Daily Living (IADLs), and EQ-5D-5L HRQOL survey. Two investigator-developed questions regarding recovery experiences were included. Differences in outcomes among survivors admitted before versus after Geri-T were analyzed using multivariable linear regression. Responses to questions about recovery experiences were qualitatively assessed using content analysis. RESULTS: We reached 67% (146/218) of hospital survivors or their proxies across both groups; 126 patients were still alive and completed the survey. Mean age was 76 (SD, 8), 36% were female, and 90% were independent with ADLs preinjury. At follow-up, independence with ADLs was 76% and IADLs was 63%. The mean EQ-5D-5L index score was 0.78 (SD, 0.18). Most patients (65%) reported having not returned to preinjury functional status. Neither functional ability or HRQOL differed significantly among patients admitted before versus after Geri-T. Content analysis of open-ended questions revealed themes of activity limitations, persistent pain, and cognitive dysfunction. CONCLUSION: Nearly one-fifth of TICU survivors experienced loss of ADL function 1 year after injury, and most reported having not returned to preinjury functional status. Nonetheless, patient-reported HRQOL was comparable to age-adjusted norms. Geri-T was not associated with differences in HRQOL or functional ability. Survivors reported persistent difficulty with activities beyond those of daily living, pain, and cognition. LEVEL OF EVIDENCE: Prognostic and Epidemiologic, Level III.

Diagnostic Accuracy of Ultrasound in Predicting Extrathyroidal Extension and Its Relation to Body Mass Index in a North American Population.

Detection of extrathyroidal extension (ETE) in patients with papillary thyroid carcinoma (PTC) influences treatment plan and surgical aggressiveness. Ultrasound (US) is the long-standing preoperative imaging method of choice. Recent literature from Asia suggests US accuracy to be influenced by patient characteristics, such as body mass index (BMI). Here, we examine the effect of BMI on the accuracy of US at a North American tertiary referral center. A total of 204 PTC-confirmed patients were retrospectively read by a radiologist blinded to surgical pathology findings. The radiologist recorded multiple sonographic features, including ETE, loss of echogenic capsule, nodule vascularity, capsular abutment, and bulging of contour. When considering all patients, the ultrasonographic feature with the best overall performance was loss of echogenic capsule (diagnostic odds ratio (DOR) = 4.48, 95% confidence interval (CI) = 1.86-10.78). Sub-group analysis by patient BMI found that area under the curve (AUC) for sonographic features was greater in non-obese BMI patients (0.71 ± 0.06) when compared with obese patients (0.43 ± 0.05; p = 0.001). Overall, US diagnostic performance was significantly better in non-obese (DOR = 3.70, 95%CI = 1.53-8.94) patients when compared to those who were obese (DOR = 1.12, 95%CI = 0.62-2.03; p = 0.03). Loss of the echogenic capsule did not differ between the two cohorts with respect to DOR (p = 0.51), specificity (p = 0.52), or sensitivity (p = 0.09). Our work suggests that the diagnostic value of ETE detection by US is impaired in obese patients. Considering that loss of the echogenic capsule did not differ with respect to diagnostic performance, specificity, nor sensitivity between non-obese and obese patients, it could be considered the most important predictor of US-determined ETE.

Neuroendocrine Carcinoma as a Cause of Humoral Hypercalcemia of Malignancy: A Case of a Patient With Elevated Parathyroid Hormone-Related Protein.

Humoral hypercalcemia of malignancy (HHM) is a paraneoplastic syndrome caused by elevations in parathyroid hormone-related protein (PTH-rP). HHM often presents in patients with squamous cell carcinomas of the lung, head, and neck, as well as breast, ovarian, renal, and bladder carcinomas. HHM associated with neuroendocrine carcinoma (NEC) is rarely observed. Here, we report a case of NEC-associated HHM refractory to standard calcium-reducing therapies but improved with the off-label addition of cinacalcet. A 31-year-old male with metastatic NEC presented to the emergency department (ED) with symptoms of nausea, emesis, constipation, and progressive weakness. He was being treated via a clinical trial at a tertiary referral center after failing standard therapies. He had recently been admitted at an outside facility for hypercalcemia, which had been managed with denosumab (120 mg subcutaneously) over the previous four weeks. He was admitted from the ED with a serum calcium of 14.6 mg/dL, potassium of 2.9 mmol/L, and phosphate of 1.2 mg/dL; ionized calcium was elevated at 8.0 mg/dL. Despite hydration and aggressive electrolyte replacement, his calcium increased to 15.5 mg/dL. Further laboratory evaluation revealed parathyroid hormone (PTH) of 6 pg/mL (10-65 pg/mL), 25-hydroxyvitamin D of 25 ng/mL (25-80 ng/mL), 1,25-dihydroxyvitamin D of 513 pg/mL (18-64 pg/mL), and PTH-rP of 25 pmol/L (<2.5 pmol/L), consistent with HHM. Calcitonin was avoided due to a prior hypersensitivity reaction. He received prednisone 10 mg daily and pamidronate 90 mg IV, and his calcium improved to 11.5 mg/dL. He was discharged and investigational therapy was resumed. This therapy failed, and he did not qualify for additional cancer therapy due to refractory hypercalcemia. He was started on cinacalcet, and his calcium decreased enough to permit further cancer treatment. He had multiple hospitalizations with fluctuating calcium levels and ultimately died several months later after sustaining a subarachnoid hemorrhage from a fall. In conclusion, we report a rare case of HHM associated with NEC. While many cases of HHM are effectively managed with hydration, calcitonin, antiresorptive therapies, and glucocorticoids, some are refractory. Our patient was refractory and differed from most patients with HHM in at least two ways. As mentioned previously, NEC causing HHM is quite uncommon (~2% of cases); it is unclear, but this malignancy might predispose to refractory hypercalcemia. Our patient's elevated vitamin D may also have made his HHM more resistant to treatment. Ultimately, while not first line, cinacalcet was an effective treatment in our patient. This provides additional evidence that cinacalcet may be considered for refractory hypercalcemia secondary to malignancy.

Machine learning algorithms to estimate 10-Year survival in patients with bone metastases due to prostate cancer: toward a disease-specific survival estimation tool.

BACKGROUND: Prognostic indicators, treatments, and survival estimates vary by cancer type. Therefore, disease-specific models are needed to estimate patient survival. Our primary aim was to develop models to estimate survival duration after treatment for skeletal-related events (SREs) (symptomatic bone metastasis, including impending or actual pathologic fractures) in men with metastatic bone disease due to prostate cancer. Such disease-specific models could be added to the PATHFx clinical-decision support tool, which is available worldwide, free of charge. Our secondary aim was to determine disease-specific factors that should be included in an international cancer registry. METHODS: We analyzed records of 438 men with metastatic prostate cancer who sustained SREs that required treatment with radiotherapy or surgery from 1989-2017. We developed and validated 6 models for 1-, 2-, 3-, 4-, 5-, and 10-year survival after treatment. Model performance was evaluated using calibration analysis, Brier scores, area under the receiver operator characteristic curve (AUC), and decision curve analysis to determine the models' clinical utility. We characterized the magnitude and direction of model features. RESULTS: The models exhibited acceptable calibration, accuracy (Brier scores < 0.20), and classification ability (AUCs > 0.73). Decision curve analysis determined that all 6 models were suitable for clinical use. The order of feature importance was distinct for each model. In all models, 3 factors were positively associated with survival duration: younger age at metastasis diagnosis, proximal prostate-specific antigen (PSA) < 10 ng/mL, and slow-rising alkaline phosphatase velocity (APV). CONCLUSIONS: We developed models that estimate survival duration in patients with metastatic bone disease due to prostate cancer. These models require external validation but should meanwhile be included in the PATHFx tool. PSA and APV data should be recorded in an international cancer registry.

Nonoperative Management in Blunt Splenic Trauma: Can Shock Index Predict Failure?

INTRODUCTION: Predicting failure of nonoperative management (NOM) in splenic trauma remains elusive. Shock index (SI) is an indicator of physiologic burden in an injury but is not used as a prediction tool. The purpose of this study was to determine if elevated SI would be predictive of failure of NOM in patients with a blunt splenic injury. METHODS: Adult patients admitted to a level-1 trauma center from January 2011 to April 2017 for NOM of splenic injury were reviewed. Patients were excluded if they underwent a procedure (angiography or surgery) prior to admission. The primary outcome was requiring intervention after an initial trial of noninterventional management (NIM). An SI > 0.9 at admission was considered a high risk. Univariate and multivariate analyses were used to identify predicators of the failure of NOM. Findings were subsequently verified on a validation cohort of patients. RESULTS: Five hundred and eighty-five patients met inclusion criteria; 7.4% failed NIM. On an univariate analysis, findings of pseudoaneurysm or extra-arterial contrast on computed tomography did not differentiate successful NIM versus failure (8.1% versus 14.0%, P = 0.18). Age, the American Association for the Surgery of Trauma injury grade, and elevated SI were included in multivariate modeling. Grade of injury (OR 3.49, P = 0.001), age (OR 1.02, P = 0.009), and high SI (OR 3.49, P = 0.001) were each independently significant for NIM failure. The risk-adjusted odds of failure were significantly higher in patients with a high risk SI (OR 2.35, P < 0.001). Validation of these findings was confirmed for high SI on a subsequent 406 patients with a c-statistic of 0.71 (95% CI 0.62-0.80). CONCLUSIONS: Elevated SI is an independent risk factor for failure of NIM in those with splenic injury. SI along with age and computed tomography findings may aid in predicting the failure of NIM. Trauma providers should incorporate SI into decision-making tools for splenic injury management.

Acute intensive care unit resuscitation of severely injured trauma patients: Do we need a new strategy?

BACKGROUND: Unlike recent advances in blood product resuscitation, intravenous crystalloid (IVF) use after intensive care unit (ICU) admission in hemorrhagic shock has received less attention and current recommendations are based on limited evidence. To address this knowledge gap, we aimed to determine associations between IVF administration during acute ICU resuscitation and outcomes. We hypothesized that larger IVF volumes are associated with worse outcomes. METHODS: We linked our trauma registry with electronic health record data (2012-2015) to identify adults with an initial lactate level of ≥4 mmol/L and documented lactate normalization (≤2 mmol/L), excluding those with isolated head Abbreviated Injury Scale score ≥3. We focused on the period from ICU admission to lactate normalization, analyzing duration, volume of IVF, and proportion of volume as 1-L boluses. We used linear regression to determine associations with ICU length of stay and duration of mechanical ventilation in survivors, and logistic regression to identify associations with acute kidney injury and home discharge while adjusting for important covariates. RESULTS: We included 337 subjects. Median time to lactate normalization was 15 hours (interquartile range, 7-25 hours), and median IVF volume was 3.7 L (interquartile range, 1.5-6.4 L). The fourfold difference between the upper and lower quartiles of both duration and volume remained after stratifying by injury severity. Hourly volumes tapered over time but persistently aggregated at 0.5 and 1 L, with 167 subjects receiving at least one 0.5-L bolus for 6 hours after ICU admission. Administration of larger volumes was associated with longer ICU length of stay and duration of mechanical ventilation, as well as acute kidney injury. CONCLUSION: There is substantial variation in volume administered during acute ICU resuscitation, both absolutely and temporally, despite accounting for injury severity. Administration of larger volumes during acute ICU resuscitation is associated with worse outcomes. There is an opportunity to improve outcomes by further investigating and standardizing this important phase of care. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Use of regional analgesia and risk of delirium in older adults with multiple rib fractures: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: Single-center data demonstrates that regional analgesia (RA) techniques are associated with reduced risk of delirium in older patients with multiple rib fractures. We hypothesized that a similar effect between RA and delirium would be identified in a larger cohort of patients from multiple level I trauma centers. METHODS: Retrospective data from seven level I trauma centers were collected for intensive care unit (ICU) patients 65 years or older with ≥3 rib fractures from January 2012 to December 2016. Those with a head and/or spine injury Abbreviated Injury Scale (AIS) score of ≥ 3 or a history of dementia were excluded. Delirium was defined as one positive Confusion Assessment Method for the Intensive Care Unit score in the first 7 days of ICU care. Poisson regression with robust standard errors was used to determine the association of RA (thoracic epidural or paravertebral catheter) with delirium incidence. RESULTS: Data of 574 patients with a median age of 75 years (interquartile range [IQR], 69-83), Injury Severity Score of 14 (IQR, 11-18), and ICU length of stay of 3 days (IQR, 2-6 days) were analyzed. Among the patients, 38.9% were women, 15.3% were non-White, and 31.4% required a chest tube. Regional analgesia was used in 19.3% patients. Patient characteristics did not differ by RA use; however, patients with RA had more severe chest injury (chest AIS, flail segment, hemopneumothorax, thoracostomy tube). In univariate analysis, there was no difference in the likelihood of delirium between the RA and no RA groups (18.9% vs. 23.8% p = 0.28). After adjusting for age, sex, Injury Severity Score, maximum chest AIS, thoracostomy tube, ICU length of stay, and trauma center, RA was associated with reduced risk of delirium (incident rate ratio [IRR], 0.65; 95% confidence interval [CI], 0.44-0.94) but not with in-hospital mortality (IRR, 0.42; 95% CI, 0.14-1.26) or respiratory complications (IRR, 0.70; 95% CI, 0.42-1.16). CONCLUSION: In this multicenter cohort of injured older adults with multiple rib fractures, RA use was associated with a 35% lower risk of delirium. Further studies are needed to standardize protocols for optimal pain management and prevention of delirium in older adults with severe thoracic injury. LEVEL OF EVIDENCE: Therapeutic, level IV; Epidemiologic, level III.

The fine line of defensive medicine.

Defensive medicine is a practice that has been utilized by clinicians in efforts of preventing patient dissatisfaction and malpractice claims and may be done through either omission or commission. As much as 57% of physicians have disclosed that they practice defensive medicine. However, this practice does not necessarily prevent malpractice claims and more importantly, neither does it equate to good medical practice, with some leading to poor outcomes. Unfortunately, there is a high percentage of malpractice claims lodged against clinicians in both primary care and hospital settings. Specialists such as surgeons, obstetricians, and gynecologists face the highest claims. In particular, during the SARS CoV-2 pandemic, with new challenges and limited treatment algorithms, there is an even greater concern for possible bourgeoning claims. Counteracting defensive medicine can be accomplished through decriminalizing malpractice claims, leaving physician oversight up to state medical boards and hospital claims management committees. Additional tort reform measures must also be taken such as caps on noneconomic damages to ensure emphasis on beneficence and nonmaleficence. Once these are in place, it may well serve to increase clinician-patient trust and improve patient independence in the shared decision-making process of their treatment, allowing clinicians to practice their full scope of practice without feeling wary of potential malpractice claims.

Low-Dose Radiation Potentiates the Propagation of Anti-Tumor Immunity against Melanoma Tumor in the Brain after In Situ Vaccination at a Tumor outside the Brain.

Brain metastases develop in over 60% of advanced melanoma patients and negatively impact quality of life and prognosis. In a murine melanoma model, we previously showed that an in situ vaccination (ISV) regimen, combining radiation treatment and intratumoral (IT) injection of immunocytokine (IC: anti-GD2 antibody fused to IL2), along with the immune checkpoint inhibitor anti-CTLA-4, robustly eliminates peripheral flank tumors but only has modest effects on co-occurring intracranial tumors. In this study, we investigated the ability of low-dose radiation to the brain to potentiate anti-tumor immunity against a brain tumor when combined with ISV + anti-CTLA-4. B78 (GD2+, immunologically "cold") melanoma tumor cells were implanted into the flank and the right striatum of the brain in C57BL/6 mice. Flank tumors (50-150 mm3) were treated following a previously optimized ISV regimen [radiation (12 Gy × 1, treatment day 1), IT-IC (50 µg daily, treatment days 6-10), and anti-CTLA-4 (100 µg, treatment days 3, 6, 9)]. Mice that additionally received whole-brain radiation treatment (WBRT, 4 Gy × 1) on day 15 demonstrated significantly increased survival compared to animals that received ISV + anti-CTLA-4 alone, WBRT alone or no treatment (control) (P < 0.001, log-rank test). Timing of WBRT was critical, as WBRT administration on day 1 did not significantly enhance survival compared to ISV + anti-CTLA-4, suggesting that the effect of WBRT on survival might be mediated through immune modulation and not just direct tumor cell cytotoxicity. Modest increases in T cells (CD8+ and CD4+) and monocytes/macrophages (F4/80+) but no changes in FOXP3+ regulatory T cells (Tregs), were observed in brain melanoma tumors with addition of WBRT (on day 15) to ISV + anti-CTLA-4. Cytokine multiplex immunoassay revealed distinct changes in both intracranial melanoma and contralateral normal brain with addition of WBRT (day 15) to ISV + anti-CTLA-4, with notable significant changes in pro-inflammatory (e.g., IFNγ, TNFα and LIX/CXCL5) and suppressive (e.g., IL10, IL13) cytokines as well as chemokines (e.g., IP-10/CXCL10 and MIG/CXCL9). We tested the ability of the alkylphosphocholine analog, NM600, to deliver immunomodulatory radiation to melanoma brain tumors as a targeted radionuclide therapy (TRT). Yttrium-86 (86Y) chelated to NM600 was delivered intravenously by tail vein to mice harboring flank and brain melanoma tumors, and PET imaging demonstrated specific accumulation up to 72 h at each tumor site (∼12:1 brain tumor/brain and ∼8:1 flank tumor/muscle). When NM600 was chelated to therapeutic ß-particle-emitting 90Y and administered on treatment day 13, T-cell infiltration and cytokine profiles were altered in melanoma brain tumor, like that observed for WBRT. Overall, our results demonstrate that addition of low-dose radiation, timed appropriately with ISV administration to tumors outside the brain, significantly increases survival in animals co-harboring melanoma brain tumors. This observation has potentially important translational implications as a treatment strategy for increasing the response of tumors in the brain to systemically administered immunotherapies.

Update on First-Line Combination Treatment Approaches in Metastatic Clear-Cell Renal Cell Carcinoma.

OPINION STATEMENT: The treatment for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years with a deeper understanding of the molecular make-up of the disease and the clinical development of therapies with novel mechanisms of action. While some patients with more indolent disease may benefit from local therapy such as metastasectomy or cytoreductive nephrectomy, others may safely embark on an active surveillance program or be offered targeted therapy. Yet, a combination regimen including an ICI is the most effective regimen and should be considered in most mRCC cases. Ongoing studies will help determine which factors can be further used to optimize treatment selection and personalize disease management.

Characteristics of survivors of civilian public mass shootings: An Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: Firearm injury remains a public health crisis. Whereas there have been studies evaluating causes of death in victims of civilian public mass shootings (CPMSs), there are no large studies evaluating injuries sustained and treatments rendered in survivors. The purpose of this study was to describe these characteristics to inform ideal preparation for these events. METHODS: A multicenter, retrospective study of CPMS survivors who were treated at designated trauma centers from July 1, 1999 to December 31, 2017, was performed. Prehospital and hospital variables were collected. Data are reported as median (25th percentile, 75th percentile interquartile range), and statistical analyses were carried out using Mann-Whitney U, χ2, and Kruskal-Wallis tests. Patients who died before discharge from the hospital were excluded. RESULTS: Thirty-one events involving 191 patients were studied. The median number of patients seen per event was 20 (5, 106), distance to each hospital was 6 (6, 10) miles, time to arrival was 56 (37, 90) minutes, number of wounds per patient was 1 (1, 2), and Injury Severity Score was 5 (1, 17). The most common injuries were extremity fracture (37%) and lung parenchyma (14%). Twenty-nine percent of patients did not receive paramedic-level prehospital treatment. Following arrival to the hospital, 27% were discharged from the emergency department, 32% were taken directly to the operating room/interventional radiology, 16% were admitted to the intensive care unit, and 25% were admitted to the ward. Forty percent did not require advanced treatment within 12 hours. The most common operations performed within 12 hours of arrival were orthopedic (15%) and laparotomy (15%). The most common specialties consulted were orthopedics (38%) and mental health (17%). CONCLUSION: Few CPMS survivors are critically injured. There is significant delay between shooting and transport. Revised triage criteria and a focus on rapid transport of the few severely injured patients are needed. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Splenic artery angioembolization for high-grade splenic injury: Are we wasting money?

BACKGROUND: Non-operative management (NOM) is accepted treatment of splenic injury, but this may fail leading to splenectomy. Splenic artery embolization (SAE) may improve rate of salvage. The purpose is to determine the cost-utility of the addition of SAE for high-grade splenic injuries. METHODS: A cost-utility analysis was developed to compared NOM to SAE in patients with blunt splenic injury. Sensitivity analysis was completed to account for uncertainty. Utility outcome was quality-adjusted life years (QALY). RESULTS: For patients with grade III, IV and V injury NOM is the dominant strategy. The probability of NOM being the more cost-effective strategy is 87.5% in patients with grade V splenic injury. SAE is not the favored strategy unless the probability of failure of NOM is greater than 70.0%. CONCLUSION: For grade III-V injuries, NOM without SAE yields more quality-adjusted life years. NOM without SAE is the most cost-effective strategy for high-grade splenic injuries.

Tumor-Specific Antibody, Cetuximab, Enhances the In Situ Vaccine Effect of Radiation in Immunologically Cold Head and Neck Squamous Cell Carcinoma.

In head and neck squamous cell carcinoma (HNSCC) tumors that over-expresses huEGFR, the anti-EGFR antibody, cetuximab, antagonizes tumor cell viability and sensitizes to radiation therapy. However, the immunologic interactions between cetuximab and radiation therapy are not well understood. We transduced two syngeneic murine HNSCC tumor cell lines to express human EGFR (MOC1- and MOC2-huEGFR) in order to facilitate evaluation of the immunologic interactions between radiation and cetuximab. Cetuximab was capable of inducing antibody-dependent cellular cytotoxicity (ADCC) in MOC1- and MOC2-huEGFR cells but showed no effect on the viability or radiosensitivity of these tumor cells, which also express muEGFR that is not targeted by cetuximab. Radiation enhanced the susceptibility of MOC1- and MOC2-huEGFR to ADCC, eliciting a type I interferon response and increasing expression of NKG2D ligands on these tumor cells. Co-culture of splenocytes with cetuximab and MOC2-huEGFR cells resulted in increased expression of IFNγ in not only NK cells but also in CD8+ T cells, and this was dependent upon splenocyte expression of FcγR. In MOC2-huEGFR tumors, combining radiation and cetuximab induced tumor growth delay that required NK cells, EGFR expression, and FcγR on host immune cells. Combination of radiation and cetuximab increased tumor infiltration with NK and CD8+ T cells but not regulatory T cells. Expression of PD-L1 was increased in MOC2-huEGFR tumors following treatment with radiation and cetuximab. Delivering anti-PD-L1 antibody with radiation and cetuximab improved survival and resulted in durable tumor regression in some mice. Notably, these cured mice showed evidence of an adaptive memory response that was not specifically directed against huEGFR. These findings suggest an opportunity to improve the treatment of HNSCC by combining radiation and cetuximab to engage an innate anti-tumor immune response that may prime an effective adaptive immune response when combined with immune checkpoint blockade. It is possible that this approach could be extended to any immunologically cold tumor that does not respond to immune checkpoint blockade alone and for which a tumor-specific antibody exists or could be developed.

Tranexamic acid administration in the field does not affect admission thromboelastography after traumatic brain injury.

BACKGROUND: No Food and Drug Administration-approved medication improves outcomes following traumatic brain injury (TBI). A forthcoming clinical trial that evaluated the effects of two prehospital tranexamic acid (TXA) dosing strategies compared with placebo demonstrated no differences in thromboelastography (TEG) values. We proposed to explore the impact of TXA on markers of coagulation and fibrinolysis in patients with moderate to severe TBI. METHODS: Data were extracted from a placebo-controlled clinical trial in which patients 15 years or older with TBI (Glasgow Coma Scale, 3-12) and systolic blood pressure of ≥90 mm Hg were randomized prehospital to receive placebo bolus/placebo infusion (placebo), 1 g of TXA bolus/1 g of TXA infusion (bolus maintenance), or 2 g of TXA bolus/placebo infusion (bolus only). Thromboelastography was performed, and coagulation measures including prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, D-dimer, plasmin-antiplasmin (PAP), thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were quantified at admission and 6 hours later. RESULTS: Of 966 patients receiving study drug, 700 had laboratory tests drawn at admission and 6 hours later. There were no statistically significant differences in TEG values, including LY30, between groups (p > 0.05). No differences between prothrombin time, activated partial thromboplastin time, international ratio, fibrinogen, thrombin antithrombin, tissue plasminogen activator, and plasminogen activator inhibitor 1 were demonstrated across treatment groups. Concentrations of D-dimer in TXA treatment groups were less than placebo at 6 hours (p < 0.001). Concentrations of PAP in TXA treatment groups were less than placebo on admission (p < 0.001) and 6 hours (p = 0.02). No differences in D-dimer and PAP were observed between bolus maintenance and bolus only. CONCLUSION: While D-dimer and PAP levels reflect a lower degree of fibrinolysis following prehospital administration of TXA when compared with placebo in a large prehospital trial of patients with TBI, TEG obtained on admission and 6 hours later did not demonstrate any differences in fibrinolysis between the two TXA dosing regimens and placebo. LEVEL OF EVIDENCE: Diagnostic test, level III.