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Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker. This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.

Objective:To examine longitudinal trajectories of white matter organization in pediatric moderate/severe traumatic brain injury (msTBI) over a 12-month period.Methods:We studied 21 children (16 M/5 F) with msTBI, assessed 2–5 months postinjury and again 13–19 months postinjury, as well as 20 well-matched healthy control children. We assessed corpus callosum function through interhemispheric transfer time (IHTT), measured using event-related potentials, and related this to diffusion-weighted MRI measures of white matter (WM) microstructure. At the first time point, half of the patients with TBI had significantly slower IHTT (TBI-slow-IHTT, n = 11) and half were in the normal range (TBI-normal-IHTT, n = 10).Results:The TBI-normal-IHTT group did not differ significantly from healthy controls, either in WM organization in the chronic phase or in the longitudinal trajectory of WM organization between the 2 evaluations. In contrast, the WM organization of the TBI-slow-IHTT group was significantly lower than in healthy controls across a large portion of the WM. Longitudinal analyses showed that the TBI-slow-IHTT group experienced a progressive decline between the 2 evaluations in WM organization throughout the brain.Conclusions:We present preliminary evidence suggesting a potential biomarker that identifies a subset of patients with impaired callosal organization in the first months postinjury who subsequently experience widespread continuing and progressive degeneration in the first year postinjury.

BACKGROUND A 2015 American Association for the Surgery of Trauma trial reported a 32% mortality for pelvic fracture patients in shock. Angioembolization (AE) is the most common intervention; the Maryland group revealed time to AE averaged 5 hours. The goal of this study was to evaluate the time to intervention and outcomes of an alternative approach for pelvic hemorrhage. We hypothesized that preperitoneal pelvic packing (PPP) results in a shorter time to intervention and lower mortality. METHODS In 2004, we initiated a PPP protocol for pelvic fracture hemorrhage. RESULTS During the 11-year study, 2,293 patients were admitted with pelvic fractures; 128 (6%) patients underwent PPP (mean age, 44 ± 2 years; Injury Severity Score (ISS), 48 ± 1.2). The lowest emergency department systolic blood pressure was 74 mm Hg and highest heart rate was 120. Median time to operation was 44 minutes and 3 additional operations were performed in 109 (85%) patients. Median RBC transfusions before SICU admission compared with the 24 postoperative hours were 8 versus 3 units (p < 0.05). After PPP, 16 (13%) patients underwent AE with a documented arterial blush.Mortality in this high-risk group was 21%. Death was due to brain injury (9), multiple organ failure (4), pulmonary or cardiac failure (6), withdrawal of support (4), adverse physiology (3), and Mucor infection (1). Of those patients with physiologic exhaustion, 2 died in the operating room at 89 and 100 minutes after arrival, whereas 1 died 9 hours after arrival. CONCLUSIONS PPP results in a shorter time to intervention and lower mortality compared with modern series using AE. Examining mortality, only 3 (2%) deaths were attributed to the immediate sequelae of bleeding with physiologic failure. With time to death under 100 minutes in 2 patients, AE is unlikely to have been feasible. PPP should be used for pelvic fracture-related bleeding in the patient who remains unstable despite initial transfusion. LEVEL OF EVIDENCE Therapeutic study, level IV.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2–5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8–18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2–5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory., Highlights • Studied differences in regional volume change longitudinally between TBI and control. • Found decreases in TBI group in white matter, gray matter and subcortical regions • Changes in regional volume were associated with changes in cognitive performance. • Compared subgroups within TBI group based on interhemispheric transfer time (IHTT) • TBI-slow group seems to drive TBI vs. control results, show prolonged degeneration.

Background We implemented expanded screening criteria for blunt cerebrovascular injuries (BCVIs) in an attempt to capture the remaining 20% of patients not historically identified with earlier protocols. We hypothesized that these expanded criteria would capture the additional 20% of BCVI patients not previously identified. Methods Screening criteria for BCVI were expanded in 2011 after identifying new injury patterns. The study population included 4 years prior (2007 to 2010; classic) and following (2011 to 2014; expanded) implementation of expanded criteria. Results BCVIs were identified in 386 patients: 150 during the classic period (2.36% incidence) and 236 in the expanded period (2.99% incidence). In the expanded period, 155 patients were imaged based on classic screening criteria, 62 on expanded criteria (21 complex skull fractures, 20 upper rib fractures, 6 mandible fractures, 2 scalp degloving, 1 great vessel injury, and 12 combination), and 19 for other injuries and symptoms. Conclusions There was a significant increase in the identification of BCVI following the adoption of expanded screening criteria, resulting in a substantial reduction of missed injuries. Expanded criteria should be adopted when screening for BCVI.

Objectives:Following pediatric moderate-to-severe traumatic brain injury (msTBI), few predictors have been identified that can reliably identify which individuals are at risk for long-term cognitive difficulties. This study sought to determine the relative contribution of detailed descriptors of injury severity as well as demographic and psychosocial factors to long-term cognitive outcomes after pediatric msTBI.Methods:Participants included 8- to 19-year-olds, 46 with msTBI and 53 uninjured healthy controls (HC). Assessments were conducted in the post-acute and chronic stages of recovery. Medical record review provided details regarding acute injury severity. Parents also completed a measure of premorbid functioning and behavioral problems. The outcome of interest was four neurocognitive measures sensitive to msTBI combined to create an index of cognitive performance.Results:Results indicated that none of the detailed descriptors of acute injury severity predicted cognitive performance. Only the occurrence of injury, parental education, and premorbid academic competence predicted post-acute cognitive functioning. Long-term cognitive outcomes were best predicted by post-acute cognitive functioning.Discussion:The findings suggest that premorbid factors influence cognitive outcomes nearly as much as the occurrence of a msTBI. Furthermore, of youth with msTBI who initially recover to a level of moderate disability or better, a brief cognitive battery administered within several months after injury can best predict which individuals will experience poor long-term cognitive outcomes and require additional services. (JINS, 2016,22, 1–8)

Traumatic brain injury (TBI) can cause widespread and prolonged brain degeneration. TBI can affect cognitive function and brain integrity for many years after injury, often with lasting effects in children, whose brains are still immature. Although TBI varies in how it affects different individuals, image analysis methods such as tensor-based morphometry (TBM) can reveal common areas of brain atrophy on magnetic resonance imaging (MRI), secondary effects of the initial injury, which will differ between subjects. Here we studied 36 pediatric moderate to severe TBI (msTBI) participants in the post-acute phase (1–6 months post-injury) and 18 msTBI participants who returned for their chronic assessment, along with well-matched controls at both time-points. Participants completed a battery of cognitive tests that we used to create a global cognitive performance score. Using TBM, we created three-dimensional (3D) maps of individual and group differences in regional brain volumes. At both the post-acute and chronic time-points, the greatest group differences were expansion of the lateral ventricles and reduction of the lingual gyrus in the TBI group. We found a number of smaller clusters of volume reduction in the cingulate gyrus, thalamus, and fusiform gyrus, and throughout the frontal, temporal, and parietal cortices. Additionally, we found extensive associations between our cognitive performance measure and regional brain volume. Our results indicate a pattern of atrophy still detectable 1-year post-injury, which may partially underlie the cognitive deficits frequently found in TBI.

Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and reparative processes in patient groups that have divergent functional outcome, with the ultimate goal of developing targeted therapeutic agents.

Background This phase II CALGB trial evaluated the activity and safety of an extended induction schedule of galiximab (G) plus rituximab (R) in untreated follicular lymphoma (FL). Patients and methods Patients with previously untreated FL (grades 1, 2, 3a) received 4 weekly infusions of G + R, followed by an additional dose every 2 months four times. International Workshop Response Criteria were used to evaluate response. Results Sixty-one patients were treated and antibody infusions were well tolerated. The overall response rate (ORR) is 72.1% (95% confidence interval 59.2% to 82.9%): 47.6% complete response (CR)/unconfirmed complete response (CRu) and 24.6% partial response. At a median follow-up time of 4.3 years (range, 0.3–5.3 years) median progression-free survival (PFS) is 2.9 years. Notably, Follicular Lymphoma International Prognostic Index (FLIPI) correlated with ORR, CR rate, and PFS, and the low-risk FLIPI group (n = 12) achieved a 92% ORR, 75% CR/CRu rate, and 75% 3-year PFS. Conclusions An extended induction schedule of G + R in previously untreated FL is well tolerated and appears particularly efficacious in those patients with low-risk FLIPI scores. In addition, this trial served as the initial platform for additional CALGB ‘doublet’ combination regimes of rituximab plus other novel targeted agents.

Purpose Lenalidomide and rituximab (LR) are active agents in follicular lymphoma (FL). Combination regimens have not been previously assessed in randomized studies. Patients and Methods The Cancer and Leukemia Group B (Alliance) 50401 trial is a randomized phase II trial studying rituximab (375 mg/m2 weekly for 4 weeks), lenalidomide (15 mg per day on days 1 to 21, followed by 7 days of rest, in cycle 1 and then 20 mg per day on days 1 to 21, followed by 7 days of rest, in cycles 2 to 12), or LR. The rituximab-alone arm was discontinued as a result of poor accrual. Eligibility included recurrent FL and prior rituximab with time to progression of ≥ 6 months from last dose. Aspirin or heparin was recommended for patients at high thrombosis risk. Results Ninety-one patients (lenalidomide, n = 45; LR, n = 46) received treatment; median age was 63 years (range, 34 to 89 years), and 58% were intermediate or high risk according to the Follicular Lymphoma International Prognostic Index. In the lenalidomide and LR arms, grade 3 to 4 adverse events occurred in 58% and 53% of patients, with 9% and 11% of patients experiencing grade 4 toxicity, respectively; grade 3 to 4 adverse events included neutropenia (16% v 20%, respectively), fatigue (9% v 13%, respectively), and thrombosis (16% [n = 7] v 4% [n = 2], respectively; P = .157). Thirty-six percent of lenalidomide patients and 63% of LR patients completed 12 cycles. Lenalidomide alone was associated with more treatment failures, with 22% of patients discontinuing treatment as a result of adverse events. Dose-intensity exceeded 80% in both arms. Overall response rate was 53% (20% complete response) and 76% (39% complete response) for lenalidomide alone and LR, respectively (P = .029). At the median follow-up of 2.5 years, median time to progression was 1.1 year for lenalidomide alone and 2 years for LR (P = .0023). Conclusion LR is more active than lenalidomide alone in recurrent FL with similar toxicity, warranting further study in B-cell non-Hodgkin lymphoma as a platform for addition of novel agents.

Refinement of criteria for both screening and initiation of empiric therapy in ventilator-associated pneumonia (VAP) will minimize antibiotic overuse. We hypothesized that variables within the commonly used Clinical Pulmonary Infection Score (CPIS) have unfavorable test performance characteristics.Consecutive bronchoalveolar lavage (BAL) cultures obtained from surgical intensive care unit patients were abstracted (2009-2012). Ventilator-associated pneumonia was defined as ≥10(5) cfu/mL. The CPIS both without (CPISclinical) and with (CPISclinical+GS) the result of gram stain (GS) was calculated. Test performance characteristics for the sample, as well as several subgroups, were compared.One thousand thirteen lower respiratory tract cultures from 492 patients were analyzed; 438 (43.2%) of cultures were classified as VAP, and 310 of 492 patients (62.4%) had ≥1 episode of VAP. Both CPISclinical and CPISclinical+GS had poor discrimination for VAP (Receiver-operating characteristic area under the curve=0.55 and 0.66, respectively). Sensitivity of CPISclinical using a threshold of6 was 21%; the lowest threshold for CPISclinical for which the sensitivity was at least 85% was 3. The highest sensitivity among the individual CPIS components was new CXR infiltrate (91.1%). Among the subset of cultures sent during the early VAP window (days intubated 2-5), organisms on GS had a sensitivity of 93.3%. The CPISclinical, CPISclinical+GS, organisms, and neutrophils on GS parameters all became less accurate in both the late VAP window and when screening for recurrent VAP. Every case of VAP had at least one of the following: 1) fever; 2) new CXR infiltrate, or 3) organisms on GS.In this series of BALs, traditional screening tools for VAP missed the majority of microbiological confirmed cases. Screening based on either new CXR infiltrate or fever yielded an acceptably high sensitivity. The only scenario identified in which empiric antibiotics could be withheld safely was the absence of organisms on GS in the early VAP window.

BACKGROUND: Older patients with traumatic brain injury (TBI) may be at high risk of death after hospitalization. The purpose of this study was to characterize long-term mortality of older TBI patients who survived to discharge. We hypothesized that predictors of postdischarge mortality differed from those of inpatient mortality. METHODS: A retrospective cohort study was performed on TBI patients older than 55 years admitted to our Level I trauma center between July 1, 2006, and December 31, 2011. Postdischarge deaths were identified by matching patient data with local vital records up to December 31, 2011, when data collection was terminated (censoring). Patients were categorized by age, comorbidities, history of preinjury anticoagulant/prescription antiplatelet agent therapy, injury severity indices, initial TBI type, prehospital living status, discharge location, and discharge condition. The effect of risk factors on postdischarge mortality was evaluated by Cox proportional hazards modeling. RESULTS: Of 353 patients, 322 (91.2%) survived to discharge. Postdischarge mortality was 19.8% (n = 63) for the study period. Of the postdischarge deaths, 54.0% died within 6 months of discharge, and 68.3% died within 1 year. Median days to death after discharge or censoring were 149 and 410, respectively. Factors associated with death after discharge included age, preinjury anticoagulant use, higher number of Charlson comorbidities, discharge to a long-term care facility, and severe disability. Factors related to injury severity (i.e., Injury Severity Score [ISS], initial Glasgow Coma Scale [GCS] score) and preinjury prescription antiplatelet agent use, previously found to predict inpatient death, did not predict postdischarge mortality. CONCLUSION: Older TBI patients who survive to discharge have a significant risk of death within 1 year. Predictors of postdischarge mortality and inpatient death differ. Death after discharge is largely a function of overall health status. Monitoring health status and continued aggressive management of comorbidities after discharge may be essential in determining long-term outcomes. LEVEL OF EVIDENCE: Epidemiologic/retrospective cohort analysis, level III. Language: en

Her blood pressure is 92/48 mm Hg, and her electrocardiogram shows abnormalities. What is going on?

BACKGROUND: The diagnosis of blunt abdominal trauma can be challenging and resource intensive. Observation with serial clinical assessments plays a major role in the evaluation of these patients, but the time required for intra-abdominal injury to become clinically apparent is unknown. The purpose of this study was to determine the amount of time required for an intra-abdominal injury to become clinically apparent after blunt abdominal trauma via physical examination or commonly followed clinical values. METHODS: A retrospective review of patients who sustained blunt trauma resulting in intra-abdominal injury between June 2010 and June 2012 at a Level 1 academic trauma center was performed. Patient demographics, injuries, and the amount of time from emergency department admission to sign or symptom development and subsequent diagnosis were recorded. All diagnoses were made by computed tomography or at the time of surgery. Patient transfers from other hospitals were excluded. RESULTS: Of 3,574 blunt trauma patients admitted to the hospital, 285 (8%) experienced intra-abdominal injuries. The mean (SD) age was 36 (17) years, the majority were male (194 patients, 68%) and the mean (SD) Injury Severity Score (ISS) was 21 (14). The mean (SD) time from admission to diagnosis via computed tomography or surgery was 74 (55) minutes. Eighty patients (28%) required either surgery (78 patients, 17%) or radiographic embolization (2 patients, 0.7%) for their injury. All patients who required intervention demonstrated a sign or symptom of their intra-abdominal injury within 60 minutes of arrival, although two patients were intervened upon in a delayed fashion. All patients with a blunt intra-abdominal injury manifested a clinical sign or symptom of their intra-abdominal injury, resulting in their diagnosis within 8 hours 25 minutes of arrival to the hospital. CONCLUSION: All diagnosed intra-abdominal injuries from blunt trauma manifested clinical signs or symptoms that could prompt imaging or intervention, leading to their diagnosis within 8 hours 25 minutes of arrival to the hospital. All patients who required an intervention for their injury manifested a sign or symptom of their injury within 60 minutes of arrival. (J Trauma Acute Care Surg. 2014;76:1020Y1023. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Therapeutic study, level IV. Epidemiologic study, level III.

While the incidence of postinjury multiple-organ failure (MOF) has declined during the past decade, temporal trends of its morbidity, mortality, presentation patterns, and health care resources use have been inconsistent. The purpose of this study was to describe the evolving epidemiology of postinjury MOF from 2003 to 2010 in multiple trauma centers sharing standard treatment protocols."Inflammation and Host Response to Injury Collaborative Program" institutions that enrolled more than 20 eligible patients per biennial during the 2003 to 2010 study period were included. The patients were aged 16 years to 90 years, sustained blunt torso trauma with hemorrhagic shock (systolic blood pressure90 mm Hg, base deficit ≥ 6 mEq/L, blood transfusion within the first 12 hours), but without severe head injury (motor Glasgow Coma Scale [GCS] score4). MOF temporal trends (Denver MOF score3) were adjusted for admission risk factors (age, sex, body max index, Injury Severity Score [ISS], systolic blood pressure, and base deficit) using survival analysis.A total of 1,643 patients from four institutions were evaluated. MOF incidence decreased over time (from 17% in 2003-2004 to 9.8% in 2009-2010). MOF-related death rate (33% in 2003-2004 to 36% in 2009-2010), intensive care unit stay, and mechanical ventilation duration did not change over the study period. Adjustment for admission risk factors confirmed the crude trends. MOF patients required much longer ventilation and intensive care unit stay, compared with non-MOF patients. Most of the MOF-related deaths occurred within 2 days of the MOF diagnosis. Lung and cardiac dysfunctions became less frequent (57.6% to 50.8%, 20.9% to 12.5%, respectively), but kidney and liver failure rates did not change (10.1% to 12.5%, 15.2% to 14.1%).Postinjury MOF remains a resource-intensive, morbid, and lethal condition. Lung injury is an enduring challenge and should be a research priority. The lack of outcome improvements suggests that reversing MOF is difficult and prevention is still the best strategy.Epidemiologic study, level III.

To improve long-term outcomes for Burkitt leukaemia/lymphoma (BL) or aggressive lymphomas in adults, we assessed the benefit of adding rituximab and filgrastim support to a dose-dense modified chemotherapy regimen from the Cancer and Leukemia Group B (CALGB) 9251 trial. One hundred and five patients (aged 19-79 years) were enrolled; 27% were >60 years old; 47% had high or high-intermediate risk by International Prognostic Index (IPI) criteria. Common severe toxicities included stomatitis/upper gastrointestinal toxicity (69%), renal insufficiency (10%), neurological events (25%) and pulmonary events (18%). Seven died from treatment-related causes (one central nervous system bleed, four infections, two respiratory failure); five were >60 years old. Results in this adult population are encouraging as complete response (CR) was observed in 83% and 4-year event-free (EFS) and overall survivals (OS) were 74% and 78%, respectively. Results compare favourably to our prior chemotherapy alone study (CALGB 9251) but despite this, high-risk patients still had worse outcomes. In conclusion, short duration, intensive chemo-immunotherapy is feasible and should be considered in adults with BL as it results in high remission rates and durable remissions.

1. B. Jason Brotherton, MD* 2. Irving Steinberg, PharmD* 3. Jeffrey L. Johnson, MD* 1. *LAC + USC Medical Center, Los Angeles, CA. A 4-year-old girl presents with 1 week of fever, vomiting, and increased sleepiness. Her medical history includes cerebral palsy, intellectual disability, and epilepsy treated with carbamazepine (CBZ) for the past 2 years. The last change in CBZ dosing was 2 months ago after a seizure. The girl’s mother reports that she repeated several doses of CBZ after emesis for the past 2 days. Of note, the family travelled to Mexico 3 weeks ago. On physical examination, the girl’s temperature is 102°F (38.8°C); other vital signs are normal for age. She appears fatigued but is easily aroused. When not stimulated during the physical examination, she quickly goes back to sleep. Results of her neurologic evaluation are unchanged from her baseline hypertonia and hyperreflexia. She has scleral icterus. Her abdomen is soft and nontender, with a palpable liver edge 3 cm below the right costal margin. Initial laboratory findings document thrombocytopenia (77×103/μL [77×109/L]), aspartate aminotransferase (AST) 4231 U/L (70.66 μkat/L), alanine aminotransferase (ALT) 2660 U/L (44.42 μkat/L), alkaline phosphatase 375 U/L (6.26 μkat/L), total bilirubin 7.3 mg/dL (124.86 μmol/L), conjugated bilirubin 5.8 mg/dL (99.2 μmol/L), prothrombin time (PT) 23.7 seconds, and international normalized ratio 2.09. Serum CBZ concentration is 25.5 mg/L (therapeutic range, 4–12 mg/L). White blood cell count is 6900/μL (6.9×109/L), with 57% neutrophils, 34.8% lymphocytes, 7.7% monocytes, 0.3% eosinophils, and 0.2% basophils. …

Purpose Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Patients and Methods Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. Results The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. Conclusion CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.

Background Urinary tract infection (UTI) in trauma patients is associated with increased mortality. Whether the urinalysis (UA) is an adequate test for a urinary source of fever in the ICU trauma patient has not been demonstrated. We hypothesized that the UA is a valuable screen for UTI in the febrile, critically ill trauma patient. Study Design All trauma ICU patients in our surgical ICU who had a fever (temperature >38.0°C), urinary catheter, UA, and a urine culture between January 1, 2011 and December 13, 2011 were reviewed. A positive UA was defined as positive leukocyte esterase, positive nitrite, WBC > 10/high power field, or presence of bacteria. A positive urine culture was defined as growth of ≥10 5 colony forming units (cfu) of an organism irrespective of the UA result or ≥10 3 cfu in the setting of a positive UA. A UTI was defined as positive urine culture without an alternative cause of the fever. Results There were 232 UAs from 112 patients that met criteria. The majority (75%) of patients were men; the mean age was 40 (±16) years. Of the 232 UAs, 90 (38.7%) were positive. There were 14 UTIs. The sensitivity, specificity, positive predictive value, and negative predictive value of the UA for UTI were 100%, 65.1%, 15.5%, and 100%, respectively. Conclusions A negative UA reliably excludes a catheter-associated UTI in the febrile, trauma ICU patient with a 100% negative predictive value, and it can rapidly direct the clinician toward more likely sources of fever and reduce unnecessary urine cultures.

BACKGROUND Rhabdomyolysis following trauma has been associated with renal impairment. Nevertheless, the literature is scant in risk assessment of acute kidney injury (AKI) and survival in children experiencing posttraumatic rhabdomyolysis. METHODS After institutional review board approval was obtained, the registry of an urban trauma center was reviewed for pediatric (age < 18 years) trauma admissions with available creatine kinase (CK) values. Variables extracted included demographics and trauma severity indices along with serum creatine, CK, and Blood Urea Nitrogen (BUN) values. AKI was defined per pediatric RIFLE (Risk, Injury, Failure, Loss, End stage) definition. Regression models were deployed to determine the independent risk factors for AKI and CK levels. RESULTS Overall, 521 patients constituted the study sample. AKI occurred in 70 patients (13.4%), with correlation to CK values in excess of 3,000 IU/L (41.4% vs. 4.9%, adjusted p < 0.001). Independent risk factors for AKI proved to be CK level of 3,000 or greater (adjusted odds ratio [AOR], 11.02; 95% confidence interval [CI], 4.56-26.64; p < 0.001), Injury Severity Score (ISS) of 15 or less (AOR, 0.25; 95% CI, 0.10-0.61), Glasgow Coma Scale (GCS) score of 8 or less (AOR, 15.00; 95% CI, 4.98-44.94), abdominal Abbreviated Injury Scale (AIS) score of 3 or less (AOR, 3.14; 95% CI, 1.04-5.36), imaging studies with contrast of 3 or less (AOR, 3.81; 95% CI, 1.37-10.57), blunt mechanism of injury (AOR, 2.76; 95% CI, 1.17-6.49), administration of nephrotoxic agents (AOR, 4.81; 95% CI, 1.23-18.79), and requirement for fluids administration in the emergency department (AOR, 2.36; 95% CI, 1.04-5.36). Mortality in the study sample with CK values of 3,000 or greater versus less than 3,000 IU/L did not reach statistical significance (25.0% vs. 9.3%, adjusted p = 0.787). CONCLUSION AKI in pediatric posttraumatic rhabdomyolysis occurs in 13% of trauma patients. CK values of 3,000 IU/L or greater pose a significant adjusted risk for AKI. Aggressive monitoring of CK values in pediatric trauma patients is warranted. LEVEL OF EVIDENCE Prognostic study, level III.

Purpose The purpose of this study was to determine remission induction frequency when bortezomib was combined with daunorubicin and cytarabine in previously untreated older adults with acute myeloid leukemia (AML) and safety of bortezomib in combination with consolidation chemotherapy consisting of intermediate-dose cytarabine (Int-DAC). Patients and Methods Ninety-five adults (age 60 to 75 years; median, 67 years) with previously untreated AML (including therapy-related and previous myelodysplastic syndrome) received bortezomib 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin 60 mg/m2 on days 1 through 3 and cytarabine 100 mg/m2 by continuous IV infusion on days 1 through 7. Patients who achieved complete remission (CR) received up to two courses of consolidation chemotherapy with cytarabine 2 gm/m2 on days 1 through 5 with bortezomib. Three cohorts with escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m2). Dose-limiting toxicities were assessed during the first cycle of consolidation. The relationship between cell surface expression of CD74 and clinical outcome was assessed. Results Frequency of CR was 65% (62 of 95), and 4% of patients (four of 95) achieved CR with incomplete platelet recovery (CRp). Eleven patients developed grade 3 sensory neuropathy. Bortezomib plus Int-DAC proved tolerable at the highest dose tested. Lower CD74 expression was associated with CR/CRp (P = .04) but not with disease-free or overall survival. Conclusion The addition of bortezomib to standard 3 + 7 daunorubicin and cytarabine induction chemotherapy for AML resulted in an encouraging remission rate. The maximum tested dose of bortezomib administered in combination with Int-DAC for remission consolidation was 1.3 mg/m2 and proved tolerable. Further testing of this regimen is planned.

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R 2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

Relapsed Hodgkin lymphoma remains a clinical challenge, with few non-cytotoxic treatment options. CD80 is a surface antigen that normally functions as a co-stimulatory molecule but is aberrantly and uniformly expressed on Reed–Sternberg cells. Galiximab is a primatized monoclonal antibody against CD80, with a favorable toxicity profile demonstrated in other lymphomas. Cancer and Leukemia Group B (CALGB) 50602 (Alliance) tested single-agent galiximab in a highly refractory group of patients with Hodgkin lymphoma (median 3 prior regimens, 83% failing after prior stem cell transplant) to determine the efficacy. The overall response rate was 10.3% and the median progression-free survival was 1.6 months. Galiximab was well-tolerated, with minimal grade 3 or 4 toxicities. Despite this preclinical rationale, single-agent galiximab had limited activity in heavily pretreated Hodgkin lymphoma.

Analogous to organ injury scales developed for trauma, a scoring system is needed for acute care surgery. The purpose of this study was to develop a disease severity score (DSS) for acute appendicitis, the most common surgical emergency.A panel of acute care surgery experts reviewed the literature and developed a DSS for acute appendicitis as follows: grade 1, inflamed; Grade 2, gangrenous; Grade 3, perforated with localized free fluid; Grade 4, perforated with a regional abscess; and Grade 5, perforated with diffuse peritonitis. We applied the DSS to 1,000 consecutive patients undergoing appendectomy from 1999 to 2009 and examined its association with outcomes (mortality, length of hospital stay, incidence of in-hospital, and postdischarge complications). Of the 1,000 patients, 82 were excluded owing to negative or interval appendectomy or advanced end-stage renal disease.Among 918 eligible patients, the DSS distribution was Grade 1 at 62.4%, Grade 2 at 13.0%, Grade 3 at 18.7%, Grade 4 at 4.4%, and Grade 5 at 1.5%. Statistical analyses indicated a stepwise risk increase in adverse outcomes with higher DSS grades (c statistics ≥ 0.75 for all outcomes). Covariates (age, sex, and type of surgical access) did not add to the predictive power of DSS.Based on this single-institution study, the proposed appendicitis DSS seems to be a useful tool. This DSS can inform future, national efforts, which can build on the knowledge provided by the present investigation. This DSS may be useful for comparing therapeutic modalities, planning resource use, improving programs, and adjusting reimbursementEpidemiologic study, level III.

Summary Background We report the long-term outcome analysis of 12 patients who underwent two-stage abdominal wall reconstruction using combined submuscular tissue expansion and anterior components separation (CS) technique. Methods Outcome measures were (1) the patients were assessed for the presence or absence of recurrence; (2) patient-reported outcomes on physical functioning in relation with the abdominal wall reconstruction were evaluated using the SF 36-item health survey. Results The mean age, average expansion volume, and mean time expansion were 37.5 years, 1250 cc, and 9.5 weeks, respectively. The average soft tissue deficiency size was 15.5 (width) × 19.5 (length) cm 2 . The average fascial defect was 17 (width) × 21.5 (length) cm 2 . No mesh-assisted technique was required. Primary closure was obtained in all. The average follow-up was 39.6 months. Hernia recurrence was noted in one patient (8.3%). All 12 patients completed the SF 36-item health survey. Moreover, 75% of the patients reported 100%, indicating "Not limited in vigorous activities," and 25% indicated "limited a little." All patients reported 100% "not limited at all" in lifting or carrying groceries, climbing several flights of stairs, climbing one flight of stairs, bending, kneeling, stooping, walking more than a mile, walking several blocks, walking one block, bathing, or dressing. Conclusions Parietal laxity obtained with tissue expansion increases the possibility of direct closure of the fascial layer, skin, and subcutaneous tissue components. Combined use of tissue expansion and CS may result in favorable long-term outcomes as evidenced by patient-reported physical functioning data and low rate of hernia recurrence.

© Mary Ann Liebert, Inc. 2016. Traumatic brain injury (TBI) frequently results in diffuse axonal injury and other white matter damage. The corpus callosum (CC) is particularly vulnerable to injury following TBI. Damage to this white matter tract has been associated with impaired neurocognitive functioning in children with TBI. Event-related potentials can identify stimulus-locked neural activity with high temporal resolution. They were used in this study to measure interhemispheric transfer time (IHTT) as an indicator of CC integrity in 44 children with moderate/severe TBI at 3-5 months post-injury, compared with 39 healthy control children. Neurocognitive performance also was examined in these groups. Nearly half of the children with TBI had IHTTs that were outside the range of the healthy control group children. This subgroup of TBI children with slow IHTT also had significantly poorer neurocognitive functioning than healthy controls - even after correction for premorbid intellectual functioning. We discuss alternative models for the relationship between IHTT and neurocognitive functioning following TBI. Slow IHTT may be a biomarker that identifies children at risk for poor cognitive functioning following moderate/severe TBI.

Massive transfusion protocols (MTPs) have become standard of care in the management of bleeding injured patients, yet strategies to guide them vary widely. We conducted a pragmatic, randomized clinical trial (RCT) to test the hypothesis that an MTP goal directed by the viscoelastic assay thrombelastography (TEG) improves survival compared with an MTP guided by conventional coagulation assays (CCA).This RCT enrolled injured patients from an academic level-1 trauma center meeting criteria for MTP activation. Upon MTP activation, patients were randomized to be managed either by an MTP goal directed by TEG or by CCA (ie, international normalized ratio, fibrinogen, platelet count). Primary outcome was 28-day survival.One hundred eleven patients were included in an intent-to-treat analysis (TEG = 56, CCA = 55). Survival in the TEG group was significantly higher than the CCA group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the CCA group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032). CCA patients required similar number of red blood cell units as the TEG patients [CCA: 5.0 (2-11), TEG: 4.5 (2-8)] (P = 0.317), but more plasma units [CCA: 2.0 (0-4), TEG: 0.0 (0-3)] (P = 0.022), and more platelets units [CCA: 0.0 (0-1), TEG: 0.0 (0-0)] (P = 0.041) in the first 2 hours of resuscitation.Utilization of a goal-directed, TEG-guided MTP to resuscitate severely injured patients improves survival compared with an MTP guided by CCA and utilizes less plasma and platelet transfusions during the early phase of resuscitation.

BACKGROUND: Cancer and Leukemia Group B (CALGB) Study 19802, a phase 2 study, evaluated whether dose intensification of daunorubicin and cytarabine could improve disease-free survival (DFS) in adults with acute lymphoblastic leukemia (ALL) and whether high-dose systemic and intrathecal methotrexate could replace cranial radiotherapy for central nervous system (CNS) prophylaxis. METHODS: One hundred sixty-one eligible, previously untreated patients ages 16 to 82 years (median age, 40 years) were enrolled, and 33 (20%) were aged ≥60 years. RESULTS: One hundred twenty-eight patients (80%) achieved complete remission (CR). Dose intensification of daunorubicin and cytarabine was feasible. At a median follow-up of 10.4 years for surviving patients, the 5-year DFS rate was 25% (95% confidence interval, 18%-33%), and the overall survival (OS) rate was 30% (95% confidence interval, 23%-37%). Patients aged

Despite improved resuscitation strategies, acute kidney injury (AKI) remains an important cause of morbidity and high resource use among severely injured patients. Thus, we conducted a comprehensive evaluation of the epidemiology and outcomes of early AKI among severely injured patients as well as its impact on the development of postinjury multiple organ failure (MOF).We queried our 17-year database of high-risk postinjury patients (Injury Severity Score15, age15 years, survival48 hours, and no isolated head injury). MOF and AKI (creatinine1.8 mg/dL) were defined by the Denver MOF score. Patients with documented preexisting renal, hepatic, cardiac, or pulmonary disease (120, 5%) were excluded, leaving 2157 for analysis.Early (day 2) AKI was evident in 2.13% of the patients and associated with a 78% MOF incidence and 27% mortality. Both rates were higher than those associated with early heart, lung, or liver failure.Early AKI is a harbinger of adverse outcome postinjury, outperforming hepatic, cardiac, or pulmonary dysfunction as a predictor of MOF and death. Prevention of early AKI and a better understanding of organ crosstalk may help reduce AKI-associated morbidity, mortality, and obligatory costs of this complication.I, prognostic study.

Background Multiple techniques have been introduced to obtain fascial closure for the open abdomen. Vacuum-assisted closure has reduced but not eliminated the use of either split-thickness skin grafts to cover the exposed bowel or mesh (prosthetic or biological) approximation of the fascia. We hypothesized that a sequential closure technique performed by a systematic protocol would achieve a higher rate of primary fascial closure than other described techniques. Methods Our technique of sequential fascial closure was initiated in 2005. Patients with a postinjury open abdomen undergoing the technique were compared with those patients who did not follow the protocol. In brief, vacuum-assisted closure white sponges cover the bowel; the fascia is placed under moderate tension over the white sponges with no. 1-polydioxanone sutures; the black sponge is placed on top of this with the standard occlusive dressing; patients undergo partial fascial closure and replacement of the sponge sandwich every 2 days until completely closed. Protocol violations were defined as not returning to the operating room every other day and absence of fascial retention sutures. Patients who died before return to the operating room in the first 48 hours were excluded. Results One hundred consecutive patients underwent damage control surgery during the five-year study period and survived to second laparotomy; 49 patients attained fascial closure at the second laparotomy. Fifty-one patients required an open abdomen after the second laparotomy and comprise the study population. The majority were men (80%) with a mean age of 34.7 years ± 2.0 years, mean injury severity score of 37.1 ± 2.4, and mean abdominal trauma index of 26.4 ± 2.1. Average initial base deficit was 15.7 ± 0.6 and 24-hour red cell transfusions were 20.4 ± 2.4 units. Of the 51 patients, 29 followed the protocol and 100% had fascial closure. Of the 22 patients who did not follow the protocol, 12 (55%) attained fascial closure. There were no significant differences in injury severity score, abdominal trauma index, base deficit, or red cell transfusions between the two groups. Conclusions A methodical approach with sequential fascial closure achieves 100% fascial approximation in our experience. This technique reduces the morbidity of the open abdomen and the cost of either complex abdominal reconstruction or biological mesh insertion.

Background A phase II trial of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) from the National Cancer Institute showed promising activity in untreated diffuse large B-cell lymphoma. The Cancer and Leukemia Group B conducted a study to determine if these results could be reproduced in a multi-institutional setting.Design and Methods The study included 69 patients with untreated diffuse large B-cell lymphoma at least 18 years of age and at least stage II. Radiaton therapy was not permitted on study. Median age was 58 years (range 23–83) and 40% had high-intermediate or high International Prognostic Index risk. Immunohistochemical biomarkers for cell of origin and proliferation were performed.Results With a median follow up of 62 months, time to progression and overall survival were 81% and 84%, respectively, and time to progression was 87%, 92% and 54% for low/low-intermediate, high-intermediate and high International Prognostic Index risk groups, respectively, at 5-years and beyond. The time to progression and event-free survival of germinal center B-cell lymphoma were 100% and 94%, respectively, and non-germinal center B-cell GCB diffuse large B-cell lymphoma were 67% and 58%, respectively, at 62 months (germinal center vs. non-germinal center B cell P=0.008). DA-EPOCH-R was tolerated without significant grade 4 non-hematologic toxicities.Conclusions These results provide the first confirmation by a multi-institutional group that DA-EPOCH-R provides high durable remissions in diffuse large B-cell lymphoma and is effective in both germinal center and non-germinal center B-cell subtypes. The trial was registered at ClinicalTrials.Gov (NCT00032019).

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes., Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected “genomic storm.” In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of this genomic reprioritization. The similarities in gene expression patterns between different injuries reveal an apparently fundamental human response to severe inflammatory stress, with genomic signatures that are surprisingly far more common than different. Based on these transcriptional data, we propose a new paradigm for the human immunological response to severe injury.

Cancer and Leukemia Group B conducted a phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low-grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor, and conditioning with cyclophosphamide (1 g/m(2)/day × 3) and fludarabine phosphate (25 mg/m(2)/day × 5). Graft-versus-host prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of 2 prior regimens were accrued. Sixteen patients had follicular non-Hodgkin lymphoma and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia (CLL), and 2 prolymphocytic leukemia (PLL) patients. The 6-month treatment-related mortality (TRM) was 2.4% and 3-year TRM was 9%. Three-year event-free and overall survival were 0.75 and 0.81 for the follicular patients, 0.59 and 0.71 for the CLL/PLL patients, and 0.55 and 0.64 for the other histologies. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 29%, and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced-intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.

To reduce doxorubicin, bleomycin, vinblastine and dacarbazine toxicity, the Cancer and Leukemia Group B conducted a phase 2 trial of doxorubicin, vinblastine, and gemcitabine for newly diagnosed, nonbulky stages I and II Hodgkin lymphoma. Ninety-nine assessable patients received 6 cycles of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and gemcitabine 800 mg/m2 (1000 mg/m2 in first 6) on days 1 and 15 every 28 days. Computed tomography (CT) and positron emission tomography (PET) were performed before and after 2 and 6 cycles. Complete remission (CR)/CR unconfirmed was achieved in 72 of 99 patients (72.7%) and partial remission in 24 of 99 patients (24.2%). The CR rate was 81% when using PET criteria. Two patients have died of Hodgkin lymphoma progression. Median follow-up for nonprogressing patients is 3.3 years. The progression-free survival (PFS) at 3 years was 77% (95% confidence interval, 68%-84%). The relapse rate was less than 10% for patients with favorable prognostic factors. The 2-year PFS for cycle 2 PET-negative and -positive patients was 88% and 54%, respectively (P = .0009), compared with 89% and 27% for cycle 6 PET-negative and -positive patients (P = .0001). Although the CR rate and PFS were lower than anticipated, patients with favorable prognostic features had a low rate of relapse. Cycle 2 PET and cycle 6 PET were predictive of PFS. This clinical trial is registered at www.clinicaltrials.gov as #NCT00086801.

We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic HCT (allo-HCT) using a reduced-intensity conditioning regimen of fludarabine 150 mg/m2 plus intravenous busulfan 6.4 mg/kg. Both matched sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit antithymocyte globulin (ATG) 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9-5.8), treatment-related mortality (TRM) at 6 months and 2 years was 8% and 23%, respectively. Neither TRM nor the rates of acute GVHD (aGVHD) were different in those with sibling or MUD donors. Donor CD3 cell chimerism >90% at day +30 was achieved more often in patients with MUD than with matched sibling donors, 70% versus 23% (P < .0001). Median event-free suvival was higher in patients who achieved early full donor chimerism (14.2 versus 8 months, P = .0395). Allo-HCT using this reduced-intensity conditioning regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve event-free survival.

Preperitoneal pelvic packing/external fixation (PPP/EF) for controlling life-threatening hemorrhage from pelvic fractures is used widely in Europe but has not been adopted in North America. We hypothesized that PPP/EF arrests hemorrhage rapidly, facilitates emergent operative procedures, and ensures efficient use of angioembolization (AE).In 2004 we initiated a PPP/EF guideline for pelvic fracture patients with refractory shock requiring ongoing blood transfusion at our regional trauma center.Among 1,245 patients admitted with pelvic fractures, 75 consecutive patients underwent PPP/EF (age 42 ± 2 years and injury severity score 52 ± 1.5). Emergency department systolic blood pressure was 76 ± 2 mmHg and heart rate 119 ± 2 beats/min. Time to operation was 66 ± 7 minutes, and 65 patients (87%) underwent 3 ± 0.3 additional procedures. Blood transfusion before PPP/EF compared with the first postoperative 24 hours was 10 ± 0.8 units versus 4 ± 0.5 units (p0.05). The fresh frozen plasma-red blood cell ratio was 1:2. After PPP/EF, 10 patients (13%) underwent angioembolization with a documented blush; time to angioembolization was 10.6 ± 2.4 hours (range 1 to 38 hours). Mortality for all pelvic fractures was 8%, with 21% mortality in this high-risk group. There were no deaths due to acute hemorrhage.PPP/EF was effective in controlling hemorrhage from unstable pelvic fractures. None of these high-risk patients died due to pelvic bleeding. Secondary angioembolization was needed in a minority, permitting selective use of this resource-demanding intervention. Additionally, PPP/EF temporizes arterial hemorrhage, providing valuable transfer time for facilities without angiography. With other urgent operative interventions required in85% of patients, combining these procedures with PPP/EF for operative pelvic hemorrhage control appears to optimize patient care.

Background Bedside percutaneous tracheostomy (BPT) is a cost-effective alternative to open tracheostomy. Small series have consistently documented minimal morbidity, but BPT has yet to be embraced as the standard of care. Because this has been our preferred technique in the surgical ICU for more than 20 years, we reviewed our experience to ascertain its safety. We hypothesize that BPT has acceptably minimal morbidity, even in high-risk patients. Study Design Patients undergoing BPT from January 1998 to June 2008 were reviewed. High-risk patients were defined as those with cervical collar or halo, cervical spine injuries, systemic heparinization, positive end-expiratory pressure >10 cm H 2 O or fraction of inspired oxygen > 50%. Results During the study period, 1,000 patients underwent BPT (74% men; mean ± SEM age 46 ± 0.6 years; 70% trauma). BPT was performed 8.9 ± 0.2 days (mean ± SEM) after admission. Patients remained ventilator dependent for an additional 9.7 ± 0.4 days (mean ± SEM). There were 482 (48%) patients undergoing BPT who were considered high-risk: 1 risk category, 273 patients; 2 risk categories, 139 patients; 3 risk categories, 56 patients; 4 risk categories, 12 patients; 5 risk categories, 2 patients. Complications occurred in 14 (1.4%) patients. Early complications included tracheostomy tube misplacement requiring revision (n = 4), bleeding requiring intervention (n = 2), infection (n = 1), and procedure failure requiring cricothyroidotomy (n = 1). Late complications included persistent stoma requiring operative closure (n = 4) and subglottic stenosis (n = 2). There were 6 complications (1.2%) in normal risk and 8 complications (1.7%) in high-risk patients. There were no deaths related to BPT. Conclusions BPT in the surgical intensive care unit is a safe procedure, even in high-risk patients. We believe BPT is the new gold standard for patients requiring tracheostomy for mechanical ventilation.

Anti-B4-blocked ricin (anti-B4-bR) is a potent immunotoxin directed against the CD 19 antigen. Previous phase I and II studies suggested a possible role for anti-B4-bR as consolidation after high-dose chemotherapy and autologous stem cell transplant. Cancer and Leukemia Group B (CALGB) 9254 is a phase III study which randomized 157 patients with B-cell lymphoma in complete remission following autologous transplant to treatment with anti-B4-bR or observation. With a median follow-up time for patients of 5.8 years, the median event-free survival for protocol treatment and observation are 2.1 and 2.9 years, respectively (p = 0.275). The median overall survival for treatment and observation are 6.1 years and not reached, respectively (p = 0.063). Therefore, no differences were found in event-free survival and overall survival between protocol treatment and observation, although there was a trend toward improved survival with observation. These data fail to support a role for anti-B4-bR as consolidative therapy after bone marrow transplant in patients with B-cell lymphoma.

The existence of primary fibrinolysis (PF) and a defined mechanistic link to the "Acute Coagulopathy of Trauma" is controversial. Rapid thrombelastography (r-TEG) offers point of care comprehensive assessment of the coagulation system. We hypothesized that postinjury PF occurs early in severe shock, leading to postinjury coagulopathy, and ultimately hemorrhage-related death.Consecutive patients over 14 months at risk for postinjury coagulopathy were stratified by transfusion requirements into massive (MT)10 units/6 hours (n = 32), moderate (Mod) 5 to 9 units/6 hours (n = 15), and minimal (Min)5 units/6 hours (n = 14). r-TEG was performed by adding tissue factor to uncitrated whole blood. r-TEG estimated percent lysis was categorized as PF when15% estimated percent lysis was detected. Coagulopathy was defined as r-TEG clot strength = G5.3 dynes/cm. Logistic regression was used to define independent predictors of PF.A total of 34% of injured patients requiring MT had PF, which was associated with lower emergency department systolic blood pressure, core temperature, and greater metabolic acidosis (analysis of variance, P0.0001). The risk of death correlated significantly with PF (P = 0.026). PF occurred early (median, 58 minutes; interquartile range, 1.2-95.9 minutes); every 1 unit drop in G increased the risk of PF by 30%, and death by over 10%.Our results confirm the existence of PF in severely injured patients. It occurs early (1 hour), and is associated with MT requirements, coagulopathy, and hemorrhage-related death. These data warrant renewed emphasis on the early diagnosis and treatment of fibrinolysis in this cohort.

BACKGROUND: Life-threatening hemorrhage is a rare event in hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Epidemiologic data are lacking to predict patients at risk for hemorrhage requiring surgical consultation. We sought to identify early clinical predictors of hemorrhagic complications in patients at risk for HELLP syndrome. METHODS: Patients at risk for HELLP syndrome from 1997 to 2007 were identified retrospectively. Variables evaluated in at-risk women were maternal age, gestational history, hepatic transaminase levels, and platelet count. Multiple logistic regression analysis was used to identify independent predictors of poor maternal outcomes, which were defined as hemorrhage requiring transfusion of blood products, need for surgical intervention, hepatic rupture, and death. RESULTS: A total of 109 at-risk women were identified. Adverse outcomes included transfusions (18%), hemorrhage interventions (8%), damage control laparotomy (2.8%), and hepatic rupture (2.8%). Maternal and perinatal mortality were .9% and 3.7%, respectively. Median transfusion requirements for women with hepatic rupture were 56 U of packed red blood cells, 26 U of fresh-frozen plasma, 18 U of platelets, and 6 U of cryoprecipitate. Multiple logistic regression analysis showed previous gestations (P = .002), platelet count (P = .01), and aspartate aminotransferase level increase (P = .04) were independent predictors of life-threatening hemorrhage. Previous gestations increased the risk of adverse outcome 3-fold. CONCLUSIONS: Identifiable risk factors predictive of major hemorrhage are thrombocytopenia (< 100,000 cells/μL), increase of aspartate aminotransferase level greater than 70 IU/L, and previous gestations.

Introduction. Progressive postinjury coagulopathy has become the fundamental rationale for damage control surgery, and the decision to abort operative intervention must occur prior to overt laboratory confirmation of coagulopathy. Current coagulation testing is most commonly performed for monitoring anticoagulation therapy, the results are delayed, and the applicability of these tests in the trauma setting is questionable. Point-of-care (POC) rapid thrombelastography (r-TEG) provides real time analysis of thrombostatic function, which may allow for accurate, goal directed therapy. The test differs from standard thrombelastography (TEG) because the clotting process and subsequent analysis is accelerated by the addition of tissue factor to the whole blood sample, but is limited by the requirement that the analysis be performed within 4 min of blood draw to prevent clot formation. Consequently, citrated specimens have been proposed to obviate this time limitation. We hypothesized that the speed of r-TEG analysis following tissue factor addition to citrated blood might compromise accurate determinations compared with noncitrated whole blood. Additionally, we sought to compare the use of r-TEG with conventional coagulation tests in analysis of postinjury coagulopathy. Methods. We conducted a retrospective study of severely injured patients entered into our trauma database between January and June 2008 who were at risk for postinjury coagulopathy. Patients needed simultaneous conventional coagulation (INR, fibrinogen, platelet count) and r-TEG specimens with either fresh or citrated whole blood for inclusion in the study. κ-Statistics were used to determine the agreement between the tests in predicting hypocoagulability. McNemar's x 2 tests were used to compare theoretical blood product administration between r-TEG and conventional coagulation tests for noncitrated specimens. Therapeutic transfusion triggers were: INR ( >1.5) and r-TEG ACT ( > 125 s) for FFP administration; fibrinogen (

Background Recent guidelines do not support local wound exploration (LWE) or diagnostic peritoneal lavage (DPL) in the evaluation of patients with anterior abdominal stab wounds (AASWs), favoring computed tomography scanning or serial examinations. In patients without immediate indications for laparotomy, we hypothesized that LWE/DPL would identify patients requiring surgery while limiting unnecessary hospital admissions. Methods Patients sustaining penetrating trauma at our level I trauma center over a 3-year period were reviewed. Results During the study period, 139 patients with AASW followed our LWE/DPL algorithm. Fifty-six patients had LWE without fascial penetration: 46 were discharged immediately, 10 required admission. Fifty-eight patients had fascial penetration on LWE but negative DPL: 37 were observed for less than 24 hours, 19 were observed for more than 24 hours, and 2 patients developed peritonitis requiring exploration. Twenty-five patients had positive LWE/DPL: 13 had therapeutic laparotomy, 12 had nontherapeutic laparotomy. Conclusions Only 11% of patients with AASWs without overt indication for laparotomy require surgical care. LWE remains a valid method to exclude intra-abdominal injury and to eliminate hospitalization in more than one third of AASW patients.

High-mobility group box 1 (HMGB1) is a late mediator of the systemic inflammation associated with sepsis. Recently, HMGB1 has been shown in animals to be a mediator of hemorrhage-induced organ dysfunction. However, the time course of plasma HMGB1 elevations after trauma in humans remains to be elucidated. Consequently, we hypothesized that mechanical trauma in humans would result in early significant elevations of plasma HMGB1. Trauma patients at risk for multiple organ failure (ISS > or = 15) were identified for inclusion (n = 23), and postinjury plasma samples were assayed for HMGB1 by enzyme-linked immunosorbent assay. Comparison of postinjury HMGB1 levels with markers for patient outcome (age, injury severity score, units of red blood cell (RBC) transfused per first 24 h, and base deficit) was performed. To investigate whether postinjury transfusion contributes to elevations of circulating HMGB1, levels were determined in both leuko-reduced and non-leuko-reduced packed RBCs. Plasma HMGB1 was elevated more than 30-fold above healthy controls within 1 h of injury (median, 57.76 vs. 1.77 ng/mL; P < 0.003), peaked from 2 to 6 h postinjury (median, 526.18 ng/mL; P < 0.01 vs. control), and remained elevated above control through 136 h. No clear relationship was evident between postinjury HMGB1 levels and markers for patient outcome. High-mobility group box 1 levels increase with duration of RBC storage, although concentrations did not account for postinjury plasma levels. Leuko-reduced attenuated HMGB1 levels in packed RBCs by approximately 55% (P < 0.01). Plasma HMGB1 is significantly increased within 1 h of trauma in humans with marked elevations occurring from 2 to 6 h postinjury. These results suggest that, in contrast to sepsis, HMGB1 release is an early event after traumatic injury in humans. Thus, HMGB1 may be integral to the early inflammatory response to trauma and is a potential target for future therapeutics.

Most multiple organ failure (MOF) scores were developed over a decade ago, but little has been done in terms of validation and to understand the differences between populations identified by each of them. Given the lack of a gold standard, validation must rely on association with objective adverse outcomes. Thus, we propose to (a) validate two widely accepted MOF scores (Denver and Marshall), examining their association with adverse outcomes in a postinjury population; and (b) compare risk factors, characteristics, and outcomes of patients identified by each score. The Denver MOF score grades (from 0-3) four organ dysfunctions (lung, kidney, liver, and heart) and defines MOF as a total score more than 3. The Marshall score grades, in addition, central nervous system and hematologic dysfunction (total of six organs on a 0- to 4-point scale). Using a prospectively collected data set, MOF was scored daily by both scores for 1,389 consecutive trauma patients with Injury Severity Score of more than 15 admitted from 1992 to 2004. Risk factors, clinical outcomes (death, ventilator-free days), and resource utilization outcomes (mechanical ventilation time, length of stay in the intensive care unit) were evaluated. Both scores were associated with areas under the receiver operating characteristic curves of 80 or greater (ideal value = 100), with values for the Denver score being slightly greater (albeit not significantly) regarding prediction of most outcomes. Values of sensitivity and specificity were more than 70% for death and ventilator-free days (with the Denver score showing a consistent trend toward greater specificity), but either sensitivity or specificity was less than 70% for mechanical ventilation time and length of stay in the intensive care unit, suggesting that these scores are appropriately biased toward clinical outcomes as opposed to resource utilization. Both scores performed well, with the Denver MOF score showing greater specificity, which, coupled with its simplicity, makes it an attractive tool for both the research and clinical environments. Basic concepts of each score can probably be combined to produce an improved MOF score.

Human polymerized hemoglobin (PolyHeme) is a universally compatible oxygen carrier developed for use when red blood cells are unavailable and oxygen-carrying replacement is needed to treat life-threatening anemia. This multicenter phase III trial assessed survival of patients resuscitated with a hemoglobin-based oxygen carrier starting at the scene of injury. Patients resuscitated with PolyHeme had outcomes comparable to those receiving the standard of care including rapid access to stored red blood cells. Although there were more adverse events in the PolyHeme group compared with control patients receiving blood, the observed safety profile is acceptable for the intended population. The benefit-to-risk ratio of PolyHeme is favorable when blood is needed but is not available or an option.

Recent military experience suggests that immediate 1:1 fresh frozen plasma (FFP); red blood cells (RBC) for casualties requiring10 units packed red blood cells (RBC) per 24 hours reduces mortality, but no clinical trials exist to address this issue. Consequently, we reviewed our massive transfusion practices during a 5-year period to test the hypothesis that 1:1 FFP:RBC within the first 6 hours reduces life threatening coagulopathy.We queried our level I trauma center's prospective registry from 2001 to 2006 for patients undergoing massive transfusion. Logistic regression was used to evaluate the independent effect of FFP:RBC in 133 patients who received10 units RBC in 6 hours on (1) Coagulopathy (international normalized ratio [INR]1.5 at 6 hours), controlling for our previously described risk factors predictive of coagulopathy, as well as RBC, FFP, and platelet administration (2) Death (controlling for all variables plus age, crystalloids per 24 hours, INR1.5 at 6 hours).Overall mortality was 56%; 50% died from acute blood loss in the operating room. Over 80% of the RBC transfusions were completed in the first 6 hours: (Median RBC: 18 units) Median FFP:RBC survivors, 1:2, nonsurvivors: 1:4. (p0.001) INR1.5 at 6 hours occurred in 30 (23%); 81% died. Regarding mortality, logistic regression showed significant variables (p0.05) included: RBC per 6 hours (OR = 1.248, 95%CI: 1.957-53.255), INR at 6 hours1.5 (OR = 10.208, 95% CI: 1.957-53.255), ED temperature34 degrees C (OR = 15.491, 95% CI 1.376-174.396), and age55 years (OR = 40.531, CI 5.315-309.077). The adjusted OR for FFP:RBC ratio including the quadratic term was found to follow a U-shaped association (quadratic term estimate 0.6737 +/- 0.0345, p = 0.0189).Although our data suggest that 1:1 FFP:RBC reduced coagulopathy, this did not translate into a survival benefit. Our findings indicate that the relationship between coagulopathy and mortality is more complex, and further clinical investigation is necessary before recommending routine 1:1 in the exsanguinating trauma patient.

The proliferation index in mantle cell lymphoma (MCL) has not been validated in the context of aggressive therapy regimens in the rituximab era. We assessed Ki67 and PIM1 (a cell cycle-related gene upregulated in blastoid MCL) expression by immunohistochemistry in a phase II study Cancer and Leukemia Group B 59909 of aggressive chemotherapy and rituximab followed by autologous stem cell transplantation plus rituximab in untreated MCL patients70 years of age. As a continuous variable or using a cutoff of 35%, higher image analysis (IA Ki67, n = 52) was associated with shorter progression free survival (PFS) (Por = 0.030) and event free survival (EFS) (Por = 0.017). PIM1 expression (n = 50) was associated with PFS (P = 0.033) and EFS (P = 0.043). Bivariate Cox models showed IA Ki67 and PIM1 were independent of clinical factors. High Ki67 (35%) is an important independent prognostic marker in aggressively treated MCL in the rituximab era. PIM1 expression predicts poor outcome and, given its potential role as a therapeutic target, deserves further study.

Nucleoside analogue chemotherapy has assumed increasing importance in the therapy of many hematological malignancies. Although fludarabine is a front-line therapy for low-grade lymphomas such as sm...

Background Secondary abdominal compartment syndrome (SACS) is a well-recognized sequelae of massive fluid resuscitation in surgical patients, but has only anecdotally been reported in the medical patient population. The purpose of this study was to compare the clinical scenarios, physiologic indices, and outcomes of patients with SACS due to medical versus trauma etiologies. Methods Patients undergoing decompression for SACS from January 1999 to January 2006 were identified using our computerized operative records. Results During the 7-year study period, 54 patients developed SACS (41 postinjury patients and 13 medical patients). There were no significant differences in demographics, physiologic indices, or fluid resuscitation between the medical and postinjury groups: age (46.6 ± 4.7 vs 40.6 ± 2.3), bladder pressure (33.5 ± 1.1 vs 32.8 ± 1.8), peak airway pressures (45.9 ± 2.4 vs 49.3 ± 2.1), base deficit (14.6 ± 1.4 vs 13.6 ± 1.1), and fluids (18.5 ± 1.8 vs 16.0 ± 1.5 liters). Patients with a medical cause of SACS had a significantly longer time to decompression (21 ± 3.6 versus 6.5 ± 1.9 hours), significantly higher incidence of MOF (62% v 27%), and trend toward greater mortality (54% versus 34%). Conclusions Patients with diverse disease processes may develop SACS. Despite similar age and physiologic indices, the MOF and mortality rates associated with medical SACS are markedly higher. These findings highlight the need for routine monitoring in at-risk patients, prevention of pathologic intra-abdominal hypertension, and a low threshold for decompression.