Gary B. Chisholm

Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients

Objective:To determine the effect of blood component ratios in massive transfusion (MT), we hypothesized that increased use of plasma and platelet to red blood cell (RBC) ratios would result in decreased early hemorrhagic death and this benefit would be sustained over the ensuing hospitalization. Summary Background Data:Civilian guidelines for massive transfusion (MT ≥10 units of RBC in 24 hours) have typically recommend a 1:3 ratio of plasma:RBC, whereas optimal platelet:RBC ratios are unknown. Conversely, military data shows that a plasma:RBC ratio approaching 1:1 improves long term outcomes in MT combat casualties. There is little consensus on optimal platelet transfusions in either civilian or military practice. At present, the optimal combinations of plasma, platelet, and RBCs for MT in civilian patients is unclear. Methods:Records of 467 MT trauma patients transported from the scene to 16 level 1 trauma centers between July 2005 and June 2006 were reviewed. One patient who died within 30 minutes of admission was excluded. Based on high and low plasma and platelet to RBC ratios, 4 groups were analyzed. Results:Among 466 MT patients, survival varied by center from 41% to 74%. Mean injury severity score varied by center from 22 to 40; the average of the center means was 33. The plasma:RBC ratio ranged from 0 to 2.89 (mean ± SD: 0.56 ± 0.35) and the platelets:RBC ratio ranged from 0 to 2.5 (0.55 ± 0.50). Plasma and platelet to RBC ratios and injury severity score were predictors of death at 6 hours, 24 hours, and 30 days in multivariate logistic models. Thirty-day survival was increased in patients with high plasma:RBC ratio (≥1:2) relative to those with low plasma:RBC ratio (<1:2) (low: 40.4% vs. high: 59.6%, P < 0.01). Similarly, 30-day survival was increased in patients with high platelet:RBC ratio (≥1:2) relative to those with low platelet:RBC ratio (<1:2) (low: 40.1% vs. high: 59.9%, P < 0.01). The combination of high plasma and high platelet to RBC ratios were associated with decreased truncal hemorrhage, increased 6-hour, 24-hour, and 30-day survival, and increased intensive care unit, ventilator, and hospital-free days (P < 0.05), with no change in multiple organ failure deaths. Statistical modeling indicated that a clinical guideline with mean plasma:RBC ratio equal to 1:1 would encompass 98% of patients within the optimal 1:2 ratio. Conclusions:Current transfusion practices and survival rates of MT patients vary widely among trauma centers. Conventional MT guidelines may underestimate the optimal plasma and platelet to RBC ratios. Survival in civilian MT patients is associated with increased plasma and platelet ratios. Massive transfusion practice guidelines should aim for a 1:1:1 ratio of plasma:platelets:RBCs.

Credentialing a preclinical mouse model of alveolar rhabdomyosarcoma.

The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3:Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3:Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3:Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3:Fkhr signature, including the target gene, SKP2. We further identified 7 druggable kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model.

HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma

The use of biologic markers to predict response to neoadjuvant chemotherapy may permit tailoring regimens to achieve maximal tumor response. Taxanes have demonstrated excellent activity in breast carcinoma; however, tumor‐specific factors that predict clinical response have not been characterized thoroughly.

Near-infrared imaging of injured tissue in living subjects using IR-820.

The unprecedented increase in preclinical studies necessitates high-throughput, inexpensive, and straightforward methods for evaluating diseased tissues. Near-infrared imaging of live subjects is a versatile, cost-effective technology that can be effectively used in a variety of pathologic conditions. We have characterized an inexpensive optoelectronic chemical, IR-820, as an infrared blood pool contrast agent to detect and quantify diseased tissue in live animals. IR-820 has maximal excitation and emission wavelengths of 710 and 820 nm, respectively. IR-820 emission is significantly improved in vivo on serum binding to albumin, and elimination occurs predominantly via the gastrointestinal tract. We demonstrate the utility of this contrast agent for serially imaging of traumatized tissue (muscle), tissue following reperfusion (eg, stroke), and tumors. IR-820 can also be employed to map regional lymph nodes. This novel contrast agent is anticipated to be a useful and an inexpensive tool for screening a wide variety of preclinical models of human diseases.

Obesity and survival in a cohort of predominantly hispanic children with acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL), the most common malignancy in children, constitutes 25% of all pediatric cancer. Childhood cancer patients who are obese at diagnosis represent a particular challenge for the oncologist. Obesity may complicate chemotherapy dose determination, and has been associated with decreased overall and event-free survival in a number of adult cancer patients, and more recently in pediatric patients. The purpose of the present study was to examine whether obesity at diagnosis was associated with decreased overall and event-free survival in a cohort of 322 predominantly Hispanic pediatric patients with B-precursor ALL. Obesity was classified as an age-standardized and sex-standardized body mass index z-score at or above the 95th percentile. Hazard ratios (HRs) for overall and event-free survival were assessed using Cox proportional hazards regression modeling. Obesity at diagnosis was not associated with decreased overall survival (HR=1.40, 95% confidence interval=0.69-2.87) or event-free survival (HR=1.08, 95% confidence interval=0.65-1.82) in the overall cohort or in either of the 2 age-at-diagnosis (2 to 9u2009y; 10 to 18u2009y) subgroups. Our finding of no obesity-related prognostic effect in the overall cohort and in the under 2 to 9-year age-at-diagnosis cohort was consistent with the previous large-scale study of ALL patients; the absence of a prognostic effect in the 10 to 18-year age-at-diagnosis cohort, however, conflicted with previous findings.

Military Return to Duty and Civilian Return to Work Factors Following Burns With Focus on the Hand and Literature Review

Functional recovery and outcome from severe burns is oftentimes judged by the time required for a person to return to work (RTW) in civilian life. The equivalent in military terms is return to active duty. Many factors have been described in the literature as associated with this outcome. Hand function, in particular, is thought to have a great influence on the resumption of preburn activities. The purpose of this investigation was to compare factors associated with civilian RTW with combat injured military personnel. A review of the literature was performed to assimilate the many factors reported as involved with RTW or duty. Additionally, a focus on the influence of hand burns is included. Thirty-four different parameters influencing RTW have been reported inconsistently in the literature. In a military population of combat burns, TBSA burn, length of hospitalization and intensive care and inhalation injury were found as the most significant factors in determining return to duty status. In previous RTW investigations of civilian populations, there exists a scatter of factors reported to influence patient disposition with a mixture of conflicting results. In neither military nor civilian populations was the presence of a hand burn found as a dominant factor. Variety in patient information collected and statistical approaches used to analyze this information were found to influence the results and deter comparisons between patient populations. There is a need for a consensus data set and corresponding statistical approach used to evaluate RTW and duty outcomes after burn injury.

Cancer patients' perceptions regarding the value of the physical examination

Despite its clinical utility, progressive reliance on technology can lead to devaluing the physical examination in patients with advanced cancer. The primary objective of this study was to determine whether these patients have a positive or negative perception of the physical examination. A secondary objective was to determine whether these perceptions are related to interpersonal/relational values (symbolic) or diagnostic/objective values (pragmatic).

A diagnostic model for impending death in cancer patients: Preliminary report

Several highly specific bedside physical signs associated with impending death within 3 days for patients with advanced cancer were recently identified. A diagnostic model for impending death based on these physical signs was developed and assessed.

Caregiver symptom burden assessment using the Edmonton Symptom Assessment System (ESAS): A preliminary report.

227 Background: Regular assessment of caregiver symptom burden during patient visits would allow prompt referral for their care. The ESAS is a multidimensional tool used in patients but not caregivers. The objectives of this study were to determine the feasibility of the ESAS in assessing caregiver symptoms defined as completing 9/12 items, assess caregiver-reported usefulness of its completion, determine the association of symptom scores between patients, caregivers and various clinical and psychosocial factors, and determine concurrent validity with the Zarit Burden Interview-12 (ZBI-12).nnnMETHODSnA prospective study of 90 patient-primary caregiver dyads in an outpatient Supportive Care Center in a cancer center was conducted. The 12 item ESAS-FS was completed by the dyads with other measures of clinical and psychosocial factors [demographics, cancer diagnosis, co-morbidities, caregiving activities, prognostic index and patients performance status].nnnRESULTSnThe ESAS is a feasible tool to assess caregiver symptom burden with 90/90 caregivers [100%] completing at least 9/12 items; 66/90 caregivers [73%] found ESAS useful to report their symptom burden. A significant association was found between ESAS scores of caregivers and patients in depression [p < 0.01], psychosocial items [depression, anxiety, well-being, financial distress, spiritual pain; p < 0.01], and total symptom distress scores [p < 0.01]. Caregiver employment status [p = 0.03] and total caregiver activities [p = 0.04] were significantly associated with total caregiver ESAS scores. There was no significant association between patient and caregiver co-morbidities [p = 0.08], prognostic index [0.07] and performance status [p = 0.26] to total caregiver ESAS scores. Caregivers recommended certain physical symptoms such as pain and nausea may be eliminated. Concurrent validity with ZBI-12 was not achieved [r = 0.53, p = 0.74] suggesting that ESAS measured different caregiver dimensions.nnnCONCLUSIONSnThe ESAS is a feasible tool to measure caregiver symptoms and was found useful by caregivers. Further research is needed to modify the ESAS based on caregivers recommendations and further psychometric studies need to be conducted.

The effects of dexamethasone and placebo on symptom clusters in advanced cancer patients: A preliminary report.

187 Background: Advanced cancer patients frequently experience debilitating symptoms that occur in clusters, but few pharmacological studies have targeted symptom clusters. Our objective was to examine the effects of dexamethasone on symptom clusters.nnnMETHODSnSecondary analysis of a recent RCT of dexamethasone (DEX) vs placebo (PL) on cancer symptoms as assessed by FACIT-F-Fatigue; FAACT-Anorexia-Cachexia; BPI - Pain; HADS- Anxiety-Depression; ESAS: Sleep, Drowsiness, Dyspnea. Symptom clusters were identified based on baseline symptoms [ESAS] using principal component analysis. Cluster scores were computed by adding each scale divided by the maximum value for the scale: Fatigue- Anorexia-Depression = (Fatigue /52 + Anorexia/48+ HADS-Depression/21); Sleep-Anxiety-Drowsiness = (Sleep/10+HADS-Anxiety/21+Drowsiness /10); Pain-Dyspnea = (BPI/10 +Dyspnea /10). Higher number indicates better QOL. Correlations and change in the severity of symptom clusters were analyzed.nnnRESULTSnIn 114 evaluable patients, 3 clusters accounted for 63% of the total variance at baseline: Fatigue-anorexia/cachexia-depression cluster (FAD); sleep-anxiety-drowsiness cluster (SAD) and Pain-Dyspnea cluster (PD). Median (IQR) improvement in the FAD cluster at Day 15 and Day 8 was significantly higher in the DEX than in the PL group [0.22 (-0.04, 0.45) vs. 0.06 (-.30, .20), P = 0.016)] and [0.15 (-0.84, 0.35) vs-0.095 (-0.35, 0.16), p = 0.017] respectively. There was no significant change observed in SAD and PD after DEX. Median (IQR) scores for FAD and PD of the DEX group at baseline, day 8, and day 15 were 1.42(1.1,1.7),1.71(1.3,2.1),1.78(1.4,2.2); [1.1(0.8,1.4); 1.38(.04,1.6); 1.43(1.3,1.7) respectively and significantly correlated over time at Day 8 (r = 0.76; p < 0.001) Day 15 (r = 0.55;p < 0.001) [FAD]; Day 8 (r = 0.36; p < 0.001) Day 15 (r = 0.45; p < 0.001) [PD].nnnCONCLUSIONSnFAD cluster showed improvement with dexamethasone and consistent correlation overtime, as compared to SAD and PD cluster. These findings suggest that fatigue-anorexia/cachexia- and depression share a common a common pathophysiologic basis. Further studies are needed to investigate this cluster and target anti-inflammatory therapies.nnnCLINICAL TRIAL INFORMATIONnNCT00489307.