Prevalence and Outcomes of High versus Low Ratio Plasma to Red Blood Cell Resuscitation in a Multi-Institutional Cohort of Severely Injured Children.

BACKGROUND: The benefit of targeting high ratio fresh frozen plasma (FFP):red blood cell (RBC) transfusion in pediatric trauma resuscitation is unclear as existing studies are limited to patients who retrospectively met criteria for massive transfusion. The purpose of this study is to evaluate the use of high ratio FFP:RBC transfusion and the association with outcomes in children presenting in shock. METHODS: A post-hoc analysis of a 24-institution prospective observational study (4/2018-9/2019) of injured children <18 years with elevated age-adjusted shock index was performed. Patients transfused within 24 hours were stratified into cohorts of low (<1:2) or high (>1:2) ratio FFP:RBC. Nonparametric Kruskal-Wallis and chi-square were used to compare characteristics and mortality. Competing risks analysis was used to compare extended (≥75th percentile) ventilator, intensive care, and hospital days while accounting for early deaths. RESULTS: Of 135 children with median (IQR) age 10 (5,14) years and weight 40 (20,64) kg, 85 (63%) received low ratio transfusion and 50 (37%) high ratio despite similar activation of institutional massive transfusion protocols (MTP; low-38%, high-46%, p = .34). Most patients sustained blunt injuries (70%). Median injury severity score was greater in high ratio patients (low-25, high-33, p = .01); however, hospital mortality was similar (low-24%, high-20%, p = .65) as was the risk of extended ventilator, ICU, and hospital days (all p > .05). CONCLUSION: Despite increased injury severity, patients who received a high ratio of FFP:RBC had comparable rates of mortality. These data suggest high ratio FFP:RBC resuscitation is not associated with worst outcomes in children who present in shock. MTP activation was not associated with receipt of high ratio transfusion, suggesting variability in MTP between centers. LEVEL OF EVIDENCE: Prospective cohort study, Level II.

Crystalloid volume is associated with short-term morbidity in children with severe traumatic brain injury: An Eastern Association for the Surgery of Trauma multicenter trial post hoc analysis.

OBJECTIVE: This study examined differences in clinical and resuscitation characteristics between injured children with and without severe traumatic brain injury (sTBI) and aimed to identify resuscitation characteristics associated with improved outcomes following sTBI. METHODS: This is a post hoc analysis of a prospective observational study of injured children younger than 18 years (2018-2019) transported from the scene, with elevated shock index pediatric-adjusted on arrival and head Abbreviated Injury Scale score of ≥3. Timing and volume of resuscitation products were assessed using χ 2t test, Fisher's exact t test, Kruskal-Wallis, and multivariable logistic regression analyses. RESULTS: There were 142 patients with sTBI and 547 with non-sTBI injuries. Severe traumatic brain injury patients had lower initial hemoglobin (11.3 vs. 12.4, p < 0.001), greater initial international normalized ratio (1.4 vs. 1.1, p < 0.001), greater Injury Severity Score (25 vs. 5, p < 0.001), greater rates of ventilator (59% vs. 11%, p < 0.001) and intensive care unit (ICU) requirement (79% vs. 27%, p < 0.001), and more inpatient complications (18% vs. 3.3%, p < 0.001). Severe traumatic brain injury patients received more prehospital crystalloid (25% vs. 15%, p = 0.008), ≥1 crystalloid boluses (52% vs. 24%, p < 0.001), and blood transfusion (44% vs. 12%, p < 0.001) than non-sTBI patients. Among sTBI patients, receipt of ≥1 crystalloid bolus (n = 75) was associated with greater ICU need (92% vs. 64%, p < 0.001), longer median ICU (6 vs. 4 days, p = 0.027) and hospital stay (9 vs. 4 days, p < 0.001), and more in-hospital complications (31% vs. 7.5%, p = 0.003) than those who received <1 bolus (n = 67). These findings persisted after adjustment for Injury Severity Score (odds ratio, 3.4-4.4; all p < 0.010). CONCLUSION: Pediatric trauma patients with sTBI received more crystalloid than those without sTBI despite having a greater international normalized ratio at presentation and more frequently requiring blood products. Excessive crystalloid may be associated with worsened outcomes, including in-hospital mortality, seen among pediatric sTBI patients who received ≥1 crystalloid bolus. Further attention to a crystalloid sparing, early transfusion approach to resuscitation of children with sTBI is needed. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma.

Secreted frizzled-related protein 2 (SFRP2) promotes the migration/invasion of metastatic osteosarcoma (OS) cells and tube formation by endothelial cells. However, its function on T-cells is unknown. We hypothesized that blocking SFRP2 with a humanized monoclonal antibody (hSFRP2 mAb) can restore immunity by reducing CD38 and PD-1 levels, ultimately overcoming resistance to PD-1 inhibitors. Treating two metastatic murine OS cell lines in vivo, RF420 and RF577, with hSFRP2 mAb alone led to a significant reduction in the number of lung metastases, compared to IgG1 control treatment. While PD-1 mAb alone had minimal effect, hSFRP2 mAb combination with PD-1 mAb had an additive antimetastatic effect. This effect was accompanied by lower SFRP2 levels in serum, lower CD38 levels in tumor-infiltrating lymphocytes and T-cells, and lower PD-1 levels in T-cells. In vitro data confirmed that SFRP2 promotes NFATc3, CD38 and PD-1 expression in T-cells, while hSFRP2 mAb treatment counteracts these effects and increases NAD+ levels. hSFRP2 mAb treatment further rescued the suppression of T-cell proliferation by tumor cells in a co-culture model. Finally, hSFRP2 mAb induced apoptosis in RF420 and RF577 OS cells but not in T-cells. Thus, hSFRP2 mAb therapy could potentially overcome PD-1 inhibitor resistance in metastatic osteosarcoma.

High-Fat Diet Drives an Aggressive Pancreatic Cancer Phenotype.

BACKGROUND: Emerging evidence indicates associations between high-fat diet (HFD), metabolic syndrome (MetS), and increased risk of pancreatic cancer. However, individual components of an HFD that increase cancer risk have not been isolated. In addition, a specific pattern of cytokine elevation by which MetS drives pancreatic tumor progression is not well described. We hypothesized that oleic acid (OA), a major component of HFD, would augment pancreatic neoplastic processes. METHODS: An orthotopic pancreatic cancer model with Panc02 cells was used to compare the effect of low-fat diet to OA-based HFD on cancer progression. Tumors were quantitated, analyzed by immunohistochemistry. In addition, serum cytokine levels were quantitated. Proliferation, migration assays, and expression of epithelial-to-mesenchymal transition factors were evaluated on Panc02 and MiaPaCa-2 pancreatic cancer cells cultured in high concentrations of OA. RESULTS: HFD tumor-bearing mice (n = 8) had an 18% weight increase (P < 0.001) and increased tumor burden (P < 0.05) compared with the low-fat diet tumor-bearing group (n = 6). HFD tumors had significantly increased angiogenesis (P < 0.001) and decreased apoptosis (P < 0.05). Serum of HFD mice demonstrated increased levels of glucagon and glucagon-like peptide-1. Two pancreatic cancer cell lines cultured in OA demonstrated significant increases in proliferation (P < 0.001) and a >2.5-fold increase in cell migration (P < 0.001) when treated with OA. Panc02 treated with OA had increased expression of epithelial-to-mesenchymal transition factors SNAI-1 (Snail) and Zeb-1(P < 0.01). CONCLUSIONS: High-fat conditions in vitro and in vivo resulted in an aggressive pancreatic cancer phenotype. Our data support further investigations elucidating molecular pathways augmented by MetS conditions to identify novel therapeutic strategies for pancreatic cancer.

Resident-Driven Wellness Initiatives Improve Resident Wellness and Perception of Work Environment.

BACKGROUND: Resident burnout is associated with increased adverse patient events and increased incidence of resident depression and suicide when compared to the general population. We hypothesized that resident-driven assessment and implementation of wellness measures would allow implementation of desired interventions and facilitate improvement in wellness. METHODS: A wellness intervention team was established to address resident wellness and job satisfaction. A needs assessment to determine desired interventions as well as a three-part anonymous 5-point Likert scale survey was developed and distributed to general surgery residents. Following implementation of three measures, a postintervention survey was administered at 6 and 15 mo to the same cohort. Analysis of variance test was used to evaluate for significant difference between preintervention and postintervention surveys. RESULTS: Three interventions were implemented: two protected weekday personal days per year, modernization of resident workspace, and additional meal funds. There were statistically significant changes in perceptions of wellness opportunities (3.14 versus 3.88 and 3.7; P < 0.05), time for wellness (2.53 versus 3.42 and 3.2; P < 0.05), work/life balance satisfaction (2.86 versus 3.71 and 3.41; P < 0.05), and improved quality of life (2.67 versus 3.3 and 3.0; P < 0.05) in both 6-mo and 15-mo postintervention responses. CONCLUSIONS: Implementation of resident-selected wellness measures was found to influence overall resident satisfaction and improved perception of the working environment. Several scores of wellness items showed sustained improvement at 15 mo. These results suggest that resident-driven wellness interventions can positively affect working conditions for residents.

Long-term outcomes of pediatric laparoscopic needled-assisted inguinal hernia repair: A 10-year experience.

PURPOSE: Laparoscopic inguinal hernia repair (LIHR) has gained wide acceptance over the past decade, although studies with longer term follow-up are lacking. We present one of the largest cohorts of children undergoing laparoscopic needle-assisted repair (LNAR) with long-term follow-up. METHODS: A clinical quality database was maintained for children ≤14 years of age who underwent laparoscopic needle-assisted repair between 2009 and 2017 with review of follow-up through 2019. De-identified data was reviewed. RESULTS: 1023 patients with 1457 LNAR were included during the 10-year period. Mean age at surgery was 2.56 years (2 days to14 years). The overall hernia recurrence rate was 0.75% (11/1457). A total of four postoperative hydroceles required intervention. Preterm infant repair done <60w post conceptional age had a significantly lower recurrence rate (0.63%) than other patients (0.82%) (p < 0.01). 64.2% of patients had clinical follow-up over a period of 11 years with a mean follow-up of 5.97 years. CONCLUSION: We present a large cohort study of consecutive pediatric laparoscopic hernia repairs followed over an 11-year period. LNAR is safe and effective for term and preterm patients with similar complication rates to other techniques, including open repair. Additionally, our results suggest that preterm infants may have superior outcomes with this method. LEVEL OF EVIDENCE: Level III - Retrospective Comparative Study.

Interhospital variation of inpatient versus outpatient pediatric burn treatment after emergency department evaluation.

BACKGROUND: Approaches to burn care in the pediatric population are highly variable and can be targeted as a potential measure in cost-reduction. We hypothesized that institutions vary significantly in treatment allocation of nonsevere burns to either inpatient or outpatient care. METHODS: We queried the PHIS database for fiscal year 2017 to quantify small pediatric burn admissions and Emergency Department visits (ED). The ICD-10 code T31.0 was used to identify burns involving <10% of total body surface area (TBSA). Centers were categorized by burn center status and length of stay, readmissions, and charges were compared. RESULTS: Inpatient versus outpatient management distribution was significantly different across the included pediatric children's hospitals (n = 34, p < 0.00001). When data were analyzed with respect to outpatient care, a bimodal distribution distinguished two groups: high hospital utilizers with an average of 30% outpatient burn care and low-utilizers averaging 87%. Median inpatient charge per patient was greater than 31-fold compared to ED burn management (p < 0.0001). CONCLUSIONS: Variability of inpatient versus outpatient pediatric burn management in small burns was significant. Compared to outpatient burn care, inpatient care is significantly more costly. Implementing protocols and personnel to provide adequate attention to small burns in the ED could be an important cost-saving measure. TYPE OF STUDY: Retrospective analysis. LEVEL OF EVIDENCE: Level III.

Timing and volume of crystalloid and blood products in pediatric trauma: An Eastern Association for the Surgery of Trauma multicenter prospective observational study.

BACKGROUND: The purpose of this study was to determine the relationship between timing and volume of crystalloid before blood products and mortality, hypothesizing that earlier transfusion and decreased crystalloid before transfusion would be associated with improved outcomes. METHODS: A multi-institutional prospective observational study of pediatric trauma patients younger than 18 years, transported from the scene of injury with elevated age-adjusted shock index on arrival, was performed from April 2018 to September 2019. Volume and timing of prehospital, emergency department, and initial admission resuscitation were assessed including calculation of 20 ± 10 mL/kg crystalloid boluses overall and before transfusion. Multivariable Cox proportional hazards and logistic regression models identified factors associated with mortality and extended intensive care, ventilator, and hospital days. RESULTS: In 712 children at 24 trauma centers, mean age was 7.6 years, median (interquartile range) Injury Severity Score was 9 (2-20), and in-hospital mortality was 5.3% (n = 38). There were 311 patients(43.7%) who received at least one crystalloid bolus and 149 (20.9%) who received blood including 65 (9.6%) with massive transfusion activation. Half (53.3%) of patients who received greater than one crystalloid bolus required transfusion. Patients who received blood first (n = 41) had shorter median time to transfusion (19.8 vs. 78.0 minutes, p = 0.005) and less total fluid volume (50.4 vs. 86.6 mL/kg, p = 0.033) than those who received crystalloid first despite similar Injury Severity Score (median, 22 vs. 27, p = 0.40). On multivariable analysis, there was no association with mortality (p = 0.51); however, each crystalloid bolus after the first was incrementally associated with increased odds of extended ventilator, intensive care unit, and hospital days (all p < 0.05). Longer time to transfusion was associated with extended ventilator duration (odds ratio, 1.11; p = 0.04). CONCLUSION: Resuscitation with greater than one crystalloid bolus was associated with increased need for transfusion and worse outcomes including extended duration of mechanical ventilation and hospitalization in this prospective study. These data support a crystalloid-sparing, early transfusion approach for resuscitation of injured children. LEVEL OF EVIDENCE: Therapeutic, level IV.

Expert Outpatient Burn Care in the Home Through Mobile Health Technology.

Access to care for pediatric burns remsains a major public health problem in the United States. Telemedicine has an opportunity to improve access to care, but current models are expensive and inefficient. They have developed and pilot-tested the TeleBurn App, a novel smartphone application, to treat partial thickness burns while outpatient. The app allows the provision of expert clinical burn care directly in the patient's home through text and image messaging, video conferencing, and instructional videos. They retrospectively reviewed clinical outcomes and usability in pediatric partial thickness burn patients treated using the TeleBurn App compared with standard therapy alone. Standard therapy is considered to be face-to-face delivery of care. Burn wound care was provided to 32 patients via the app and 35 patients with standard therapy. Most (74%) patients offered the app, used it as their primary source of follow-up care. This group had no wound infections or unexpected returns to clinic or hospital. Both TeleBurn App and standard therapy groups had similar burn severity, age, and burn mechanism. Mean healing time was shorter in the app group (mean ± standard deviation: 11.6 ± 4.7 days versus standard therapy: 14.3 ± 5.4 [P = .03]) with fewer clinical encounters (0.93 ± 0.6 vs standard therapy: 3.3 ± 1.0 [P = .001]). Adherence with completion of therapy in patients using the app was 80 vs 64 per cent with standard therapy. They describe a functional, scalable mobile health application in clinical use in a pediatric burn program. Further prospective, randomized studies may validate this mobile health platform, improving access to expert burn care for a vulnerable population.

Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma.

PURPOSE: Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by NanoString nCounter to identify transcripts from the region that are associated with copy-number gain. In addition, expression data from an independent cohort were used to identify candidate genes. RESULTS: Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in both cohorts [adjusted HR, 2.96; 95% confidence interval (CI), 1.35-6.48; P = 0.01 and adjusted HR, 5.03; 95% CI, 1.43-17.73; P < 0.001]. The F11R, PFDN2, PPOX, USP21, and DEDD genes, all located on 1q23.3, were closely associated with poor outcome. CONCLUSIONS: 1q23.3 copy-number gain displayed association with poor survival in two cohorts of metastatic urothelial carcinoma. The identification of the target of this copy-number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of patients with poor-risk urothelial carcinoma. Prospective validation of the survival association is necessary to demonstrate clinical relevance.

BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper.

Optic pathway gliomas represent a specific subtype of astrocytoma with unique clinicopathologic and biologic properties, but studies of tumors in the optic nerve proper have been hampered by limited tissue availability. We analyzed optic nerve gliomas of 59 patients (median age, 9 years; range, 3 months-66 years; 33 female, 26 male) using formalin-fixed paraffin-embedded material in tissue microarrays. Seven patients had the clinical diagnosis of neurofibromatosis type 1 (NF1). Fluorescence in situ hybridization studies were performed for BRAF, PTEN, CDKN2A (p16), and NF1. Immunohistochemistry was performed for glial fibrillary acidic protein, phospho-ERK, and mutant IDH1 protein. The BRAF duplication was present in 11 (73%) of 15 evaluable tumors, including 1 NF1 patient (1 of 4 tested; 25%). The single tumor lacking BRAF duplication or NF1 association had histologic features of a ganglioglioma. Conversely, heterozygous PTEN deletions were present in 2 (8%) of 25 evaluable cases, one of which was BRAF duplicated and the other was NF1 associated. CDKN2A and NF1 deletions were absent in all tumors tested. Phospho-ERK immunoreactivity was present in 55 (96%) of 57 tumors and was mostly strong and diffuse (80%). Only 1 case of 53 expressed IDH1. Thus, optic nerve gliomas demonstrated molecular alterations typical of pilocytic astrocytomas, including the universal presence of either BRAF duplication or NF1 association and common mitogen-activated protein kinase pathway activation but very rare mutant IDH1 expression.