Regan F. Williams

Improved Intratumoral Oxygenation Through Vascular Normalization Increases Glioma Sensitivity to Ionizing Radiation

PURPOSE Ionizing radiation, an important component of glioma therapy, is critically dependent on tumor oxygenation. However, gliomas are notable for areas of necrosis and hypoxia, which foster radioresistance. We hypothesized that pharmacologic manipulation of the typically dysfunctional tumor vasculature would improve intratumoral oxygenation and, thus, the antiglioma efficacy of ionizing radiation. METHODS AND MATERIALS Orthotopic U87 xenografts were treated with either continuous interferon-beta (IFN-beta) or bevacizumab, alone, or combined with cranial irradiation (RT). Tumor growth was assessed by quantitative bioluminescence imaging; the tumor vasculature using immunohistochemical staining, and tumor oxygenation using hypoxyprobe staining. RESULTS Both IFN-beta and bevaziumab profoundly affected the tumor vasculature, albeit with different cellular phenotypes. IFN-beta caused a doubling in the percentage of area of perivascular cell staining, and bevacizumab caused a rapid decrease in the percentage of area of endothelial cell staining. However, both agents increased intratumoral oxygenation, although with bevacizumab, the effect was transient, being lost by 5 days. Administration of IFN-beta or bevacizumab before RT was significantly more effective than any of the three modalities as monotherapy or when RT was administered concomitantly with IFN-beta or bevacizumab or 5 days after bevacizumab. CONCLUSION Bevacizumab and continuous delivery of IFN-beta each induced significant changes in glioma vascular physiology, improving intratumoral oxygenation and enhancing the antitumor activity of ionizing radiation. Additional investigation into the use and timing of these and other agents that modify the vascular phenotype, combined with RT, is warranted to optimize cytotoxic activity.

Early vs interval appendectomy for children with perforated appendicitis.

OBJECTIVE To compare the effectiveness and adverse event rates of early vs interval appendectomy in children with perforated appendicitis. DESIGN Nonblinded randomized trial. SETTING A tertiary-referral urban childrens hospital. PATIENTS A total of 131 patients younger than 18 years with a preoperative diagnosis of perforated appendicitis. INTERVENTIONS Early appendectomy (within 24 hours of admission) vs interval appendectomy (6-8 weeks after diagnosis). MAIN OUTCOME MEASURES Time away from normal activities (days). Secondary outcomes included the overall adverse event rates and the rate of predefined specific adverse events (eg, intra-abdominal abscess, surgical site infection, unplanned readmission). RESULTS Early appendectomy, compared with interval appendectomy, significantly reduced the time away from normal activities (mean, 13.8 vs 19.4 days; P < .001). The overall adverse event rate was 30% for early appendectomy vs 55% for interval appendectomy (relative risk with interval appendectomy, 1.86; 95% confidence interval, 1.21-2.87; P = .003). Of the patients randomized to interval appendectomy, 23 (34%) had an appendectomy earlier than planned owing to failure to improve (n = 17), recurrent appendicitis (n = 5), or other reasons (n = 1). CONCLUSIONS Early appendectomy significantly reduced the time away from normal activities. The overall adverse event rate after early appendectomy was significantly lower compared with interval appendectomy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00435032.

Impact of decompressive craniectomy on functional outcome after severe traumatic brain injury.

BACKGROUND The beneficial effect of decompressive craniectomy (DC) in the treatment of traumatic brain injury (TBI) remains controversial. In many centers, it is used as a salvage procedure for uncontrollable intracranial pressure (ICP). It is our contention that DC represents a viable early option for head trauma patients. The purpose of this study was to evaluate the efficacy of DC on functional outcome after severe TBI in the largest single institutional series reported in the literature. METHODS Patients with severe TBI (Abbreviated Injury Score 4-5) treated with DC for the management of increased ICP during 6-year period were identified from the trauma registry. Functional outcome was measured 1 year to 6 years postinjury using the Glasgow Outcome Score Extended (GOSE) via telephone interview and classified as good (GOSE 5-8) or poor (GOSE 1-4, including death). Outcomes were compared using Wilcoxon rank-sum and chi2 tests where appropriate. RESULTS One hundred and seventy-one patients were identified: 137 (80%) men and 34 (20%) women. Overall mortality (all in-hospital) was 32% (head-related = 22%). Of the 117 survivors, follow-up was obtained in all but 6 (95%). Good outcome was achieved in 96 patients (56% overall, 82% of survivors). Those with good outcome were younger (26 years vs. 43 years, p = 0.0028) and experienced a greater change in predecompression to postdecompression ICP (ICP reduced by 23 mm Hg vs. 10 mm Hg, p < 0.0001). Not surprisingly, unchanged ICP (predecompression to postdecompression) was associated with poor outcome (p = 0.0031). There was no difference in immediate predecompression ICP between survivors versus nonsurvivors. However, immediate predecompression Glasgow Coma Score was significantly higher in survivors compared with nonsurvivors (7 vs. 5, p < 0.0001). CONCLUSIONS DC resulted in good functional outcome in >50% of patients with severe TBI. The greatest benefit was observed in younger patients with a demonstrable reduction in ICP after decompression. The prospect of improved functional outcome offered by this procedure in the treatment of severe TBI warrants prospective investigation.

Improved Survival After Hemostatic Resuscitation: Does the Emperor Have No Clothes?

BACKGROUND In light of recent data, controversy surrounds the apparent 30-day survival benefit of patients achieving a fresh frozen plasma (FFP) to packed red blood cell (PRBC) ratio of at least 1:2 in the face of massive transfusions (MT) (≥10 units of PRBC within 24 hours of admission). We hypothesized that initial studies suffer from survival bias because they do not consider early deaths secondary to uncontrolled exsanguinating hemorrhage. To help resolve this controversy, we evaluated the temporal relationship between blood product administration and mortality in civilian trauma patients receiving MT. METHODS Patients requiring MT over a 22-month period were identified from the resuscitation registry of a Level I trauma center. Shock severity at admission and timing of shock-trauma admission, blood product administration, and death were determined. Patients were divided into high- and low-ratio groups (≥1:2 and<1:2 FFP:PRBC, respectively) and compared. Kaplan-Meier analysis and log-rank test was used to examine 24-hour survival. RESULTS One hundred three patients (63% blunt) were identified (66 high-ratio and 37 low-ratio). Those patients who achieved a high-ratio in 24 hours had improved survival. However, severity of shock was less in the high-group (base excess: -8.0 vs. -11.2, p=0.028; lactate: 6.3 vs. 8.4, p=0.03). Seventy-five patients received MT within 6 hours. Of these, 29 received a high-ratio in 6 hours. Again, severity of shock was less in the high-ratio group (base excess: -7.6 vs. -12.7, p=0.008; lactate: 6.7 vs. 9.4, p=0.02). For these patients, 6-hour mortality was less in the high-group (10% vs. 48%, p<0.002). After accounting for early deaths, groups were similar from 6 hours to 24 hours. CONCLUSIONS Improved survival was observed in patients receiving a higher plasma ratio over the first 24 hours. However, temporal analysis of mortality using shorter time periods revealed those who achieve early high-ratio are in less shock and less likely to die early from uncontrolled hemorrhage compared with those who never achieve a high-ratio. Thus, the proposed survival advantage of a high-ratio may be because of selection of those not likely to die in the first place; that is, patients die with a low-ratio not because of a low-ratio.

Diagnosing ruptured appendicitis preoperatively in pediatric patients.

BACKGROUND Over the past decade, pediatric patients with ruptured appendicitis (RA) have been successfully treated with IV antibiotics and an interval appendectomy. Because the treatment of acute appendicitis (AA) and RA in children is now diverging, distinguishing between these two conditions preoperatively is critical. STUDY DESIGN A prospective cohort study was conducted. Clinical data were collected, and the attending surgeons preoperative diagnosis was recorded. Accuracy of the pediatric surgeons diagnosis was determined. Univariable and multivariable logistic regression were then used to determine independent clinical predictors of RA. Using the relative beta coefficients of these predictors, a scoring system was constructed to aid in the diagnosis of RA. RESULTS Two hundred forty-seven patients were evaluated: 98 AA (40%), 53 RA (21%), and 97 not appendicitis (39%). Median age was 10 years old. The overall accuracy of the pediatric surgeons preoperative diagnosis was 92%. Sensitivity and specificity for the diagnosis of RA were 96% and 83%, respectively. Multivariable regression analysis identified generalized tenderness on examination, duration of symptoms longer than 48 hours, WBC>19,400 cells/microL, abscess, and fecalith on CT scan as independent predictors for RA. A novel scoring system was developed with these variables, and, when applied to the study population, the specificity for the diagnosis of RA improved to 98%. CONCLUSIONS Pediatric surgeons differentiate AA from RA and not appendicitis preoperatively with high accuracy and sensitivity, but the specificity for diagnosing ruptured appendicitis is lower. The scoring system improved the specificity of the preoperative diagnosis. The validity and utility of this scoring system should be examined in future studies in larger patient populations.

Management of congenital diaphragmatic hernia: A systematic review from the APSA outcomes and evidence based practice committee

OBJECTIVE Variable management practices complicate the identification of optimal strategies for infants with congenital diaphragmatic hernia (CDH). This review critically appraises the available evidence to provide recommendations. METHODS Six questions regarding CDH management were generated. English language articles published between 1980 and 2014 were compiled after searching Medline, Cochrane, Embase and Web of Science. Given the paucity of literature on the subject, all studies irrespective of their rank in the levels of evidence hierarchy were included. RESULTS Gentle ventilation with permissive hypercapnia provides the best outcomes. Initial high frequency ventilation may be considered but its overall efficacy is unproven. Routine inhaled nitric oxide (iNO) or other medical adjuncts for acute, severe pulmonary hypertension demonstrate no benefit. Evidence does not support routine administration of pre- or postnatal glucocorticoids. Mode of extracorporeal membrane oxygenation (ECMO) has little bearing on outcomes. While the overall timing of repair does not impact outcomes, early repair on ECMO has benefits. Open repair leads to significantly fewer recurrences. Polytetrafluoroethylene (PTFE) is the most durable patch repair material. CONCLUSIONS Limited high-level evidence prevents the development of robust management guidelines for CDH. Prospective, multi-institutional studies are needed to identify best practices and optimize outcomes.

Hospital cost analysis of a prospective, randomized trial of early vs interval appendectomy for perforated appendicitis in children

BACKGROUND The methods of surgical care for children with perforated appendicitis are controversial. Some surgeons prefer early appendectomy; others prefer initial nonoperative management followed by interval appendectomy. Determining which of these two therapies is most cost-effective was the goal of this study. STUDY DESIGN We conducted a prospective, randomized trial in children with a preoperative diagnosis of perforated appendicitis. Patients were randomized to early or interval appendectomy. Overall hospital costs were extracted from the hospitals internal cost accounting system and the two treatment groups were compared using an intention-to-treat analysis. Nonparametric data were reported as median ± standard deviation (or range) and compared using a Wilcoxon rank sum test. RESULTS One hundred thirty-one patients were randomized to either early (n = 64) or interval (n = 67) appendectomy. Hospital charges and costs were significantly lower in patients randomized to early appendectomy. Total median hospital costs were

Bevacizumab Suppresses Neuroblastoma Progression in the Setting of Minimal Disease

17,450 (range

IFN-β sensitizes neuroblastoma to the antitumor activity of temozolomide by modulating O6-methylguanine DNA methyltransferase expression

7,020 to

Impact of Airbags on a Level I Trauma Center: Injury Patterns, Infectious Morbidity, and Hospital Costs

55,993) for patients treated with early appendectomy vs