Margaret Krasne

High-risk geriatric protocol: improving mortality in the elderly.

BACKGROUND Injured geriatric patients pose unique challenges to the trauma team because of their abnormal responses to shock and injury. We have developed the high-risk geriatric protocol (GP) that seeks to identify high-risk geriatric patients. We hypothesized that a high-risk GP would improve outcome in this select group of patients. METHODS Patients from 2000 to 2010 were included. Patients 65 years or older who met high-risk GP based on comorbidities and/or physiologic parameters were compared with those patients who had not received GP before its implementation as well as other non-GP patients. This protocol includes a geriatric consultation, as well as a lactate levels, arterial blood gas levels, and echo test to assess for occult shock. Age, trauma activation, preexisting conditions, Injury Severity Score, Revised Trauma Score, and mortality were reviewed. Univariate and multivariate analyses were conducted to identify factors predictive of mortality. RESULTS A total of 3,902 patients were evaluated. Patients receiving GP were less likely to die (odds ratio, 0.63 [0.39–0.99], p = 0.046). For all patients, there was a dramatic increase in mortality for those patients older than 75 years. CONCLUSION The GP, adjusted for other covariates, significantly reduced mortality in our patient population. Thus, this study confirms the overall effectiveness of our GP, which is hallmarked by prompt identification of those patients with occult shock and a multidisciplinary care of the aged population. LEVEL OF EVIDENCE Therapeutic study, level IV.

Menopause Is a Determinant of Breast Adipose Inflammation

Chronic inflammation is recognized as a risk factor for the development of several malignancies. Local white adipose tissue (WAT) inflammation, defined by the presence of dead or dying adipocytes encircled by macrophages that form crown-like structures (CLS), occurs in the breasts (CLS-B) of most overweight and obese women. Previously, we showed that the presence of CLS-B is associated with elevated tissue levels of proinflammatory mediators and aromatase, the rate-limiting enzyme for estrogen biosynthesis. The associated increased levels of aromatase in the breast provide a plausible mechanistic link between WAT inflammation and estrogen-dependent breast cancers. Thus, breast WAT inflammation could be relevant for explaining the high incidence of estrogen-dependent tumors with aging despite diminished circulating estrogen levels after menopause. To explore this possibility, we determined whether menopause in addition to body mass index (BMI) is associated with breast WAT inflammation among 237 prospectively enrolled women. The presence of CLS-B and its severity (CLS-B/cm2) as indicators of WAT inflammation correlated with menopausal status (P = 0.008 and P < 0.001) and BMI (P < 0.001 for both). In multivariable analyses adjusted for BMI, the postmenopausal state was independently associated with the presence (P = 0.03) and severity of breast WAT inflammation (P = 0.01). Mean adipocyte size increased in association with CLS-B (P < 0.001). Our findings demonstrate that breast WAT inflammation, which is associated with elevated aromatase levels, is increased in association with the postmenopausal state independent of BMI. Breast WAT inflammation, a process that can potentially be targeted, may help to explain the high incidence of estrogen-dependent tumors in postmenopausal women. Cancer Prev Res; 8(5); 349–58. ©2015 AACR.

Has TRISS become an anachronism? A comparison of mortality between the National Trauma Data Bank and Major Trauma Outcome Study databases.

BACKGROUND The Trauma and Injury Severity Score (TRISS) has been the approach to trauma outcome prediction during the past 20 years and has been adopted by many commercial registries. Unfortunately, its survival predictions are based upon coefficients that were derived from a data set collected in the 1980s and updated only once using a data set collected in the early 1990s. We hypothesized that the improvements in trauma care during the past 20 years would lead to improved survival in a large database, thus making the TRISS biased. METHODS The TRISSs from the Pennsylvania statewide trauma registry (Collector, Digital Innovations) for the years 1990 to 2010. Observed-to-expected mortality ratios for each year of the study were calculated by taking the ratio of actual deaths (observed deaths, O) to the summation of the probability of mortality predicted by the TRISS taken over all patients (expected deaths, E). For reference, O/E ratio should approach 1 if the TRISS is well calibrated (i.e., has predictive accuracy). RESULTS There were 408,489 patients with complete data sufficient to calculate the TRISSs. There was a significant trend toward improved outcome (i.e., decreasing O/E ratio; nonparametric test of trend, p < 0.001) over time in both the total population and the blunt trauma subpopulation. In the penetrating trauma population, there was a trend toward improved outcome (decreasing O/E ratio), but it did not quite reach significance (nonparametric test of trend p = 0.073). CONCLUSION There is a steady trend toward improved O/E survival in the Pennsylvania database with each passing year, suggesting that the TRISS is drifting out of calibration. It is likely that improvements in care account for these changes. For the TRISS to remain an accurate outcome prediction model, new coefficients would need to be calculated periodically to keep up with trends in trauma care. This requirement for occasional updating is likely to be a requirement of any trauma prediction model, but because many other deficiencies in the TRISS have been reported, we think that rather than updating the TRISS, it would be more productive to replace the TRISS with a modern statistical model. LEVEL OF EVIDENCE Prognostic study, level II.

Determining venous thromboembolic risk assessment for patients with trauma: the Trauma Embolic Scoring System.

BACKGROUND This study aimed to determine the relative “weight” of risk factors known to be associated with venous thromboembolism (VTE) for patients with trauma based on injuries and comorbidities. METHODS A retrospective review of 16,608 consecutive admissions to a trauma center was performed. Patients were separated into those who developed VTE (n = 141) versus those who did not (16,467). Univariate analysis was performed for each risk factor reported in the trauma literature. Risk factors that were shown to be significant (p < 0.05) by univariate analysis underwent multivariate analysis to develop odds ratios for VTE. The Trauma Embolic Scoring System (TESS) was derived from the multivariate coefficients. The resulting TESS was compared with a data set from the National Trauma Data Bank (2002–2006) to determine its ability to predict VTE. RESULTS The multivariate analysis demonstrated that age, Injury Severity Score, obesity, ventilator use for more than 3 days, and lower-extremity trauma were significant predictors of VTE in our patient population. The TESS was from 0 to 14, with the best prediction for those patients with a score of more than 6 (sensitivity, 81.6%; specificity, 84%). Overall, the model had excellent discrimination in predicting VTE with a receiver operating characteristic curve of 0.89. The VTE rates for TESS in the National Trauma Data Bank data set were similar for all integers except for 3 and 4, in which the VTE rates were significantly higher (3, 0.2% vs. 0.6%; 4, 0.4% vs. 1.0%). CONCLUSION The TESS provides an objective measure of classifying VTE risk for patients with trauma. The TESS could allow informed decision making regarding prophylaxis strategies in patients with trauma. LEVEL OF EVIDENCE Prognostic study, level II.

Periprostatic adipose inflammation is associated with high-grade prostate cancer

Background:Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown.Methods:In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher’s exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics.Results:Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P’s <0.05).Conclusion:Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.

Obesity and menopausal status as determinants of procarcinogenic breast inflammation.

40 Background: Chronic inflammation predisposes to several malignancies. We previously demonstrated an obesity → inflammation → aromatase axis in breast tissue. As obesity is a risk factor for postmenopausal (PoM) but not premenopausal (PreM) breast cancer (BC), we examined whether menopause and body mass index (BMI) independently impact breast white adipose tissue (WAT) inflammation. METHODS WAT was prospectively collected from patients (pts) from 04/10 to 08/13. WAT inflammation, detected by CD68 immunohistochemistry, was defined by the presence of dead or dying adipocytes surrounded by an envelope of macrophages known as crown-like structures of the breast (CLS-B). WAT area was measured with NIH Image J. Adipocyte diameter was measured with Canvas 11 Software. Endpoints were 1) CLS-B (+/-) and 2) CLS-B/cm2. Clinicopathologic associations with CLS-B were analyzed by logistic regression and Fishers exact test. RESULTS WAT (237 mastectomies, 13 abdominal reconstructions) was obtained from 238 pts; median age 48 (range 22 to 90). CLS-B occurrence and number of CLS-B/cm2 were greater in overweight/obese (BMI ≥ 25) and PoM pts compared to lean (BMI < 25) and PreM pts (Table). In multivariable analyses, BMI and PoM state were independently associated with CLS-B presence (p <.01 and p = .04) and greater CLS-B/cm2(p < .01 and p = .01). PoM pts had larger mean adipocyte diameter (105.2 +/- 14.0 μ) than PreM pts (95.7 +/-15.6 μ; p < 0.01). In pts with bilateral breast WAT and abdominal WAT, concordant CLS status (+/-) was found in 49/63 (78%) and 10/13 (77%) pts, respectively. CONCLUSIONS Breast WAT inflammation (both presence and severity), which we have previously linked to increased aromatase activity, is associated with both increased BMI and menopause. These findings can explain the increased risk of estrogen receptor-positive BC with obesity and PoM status and may also provide targets for rational therapies. [Table: see text].

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Obesity, a cause of subclinical inflammation, is a risk factor for the development of postmenopausal breast cancer and is associated with poorer cancer outcomes. Docosahexaenoic acid (DHA), an omega-3 fatty acid, possesses anti-inflammatory properties. We hypothesized that treatment with DHA would reduce the expression of proinflammatory genes and aromatase, the rate-limiting enzyme for estrogen biosynthesis, in benign breast tissue of overweight/obese women. A randomized, placebo-controlled, double-blind phase II study of DHA given for 12 weeks to overweight/obese women with a history of stage I–III breast cancer, DCIS/LCIS, Pagets disease, or proliferative benign breast disease was carried out. In this placebo controlled trial, the primary objective was to determine whether DHA (1,000 mg by mouth twice daily) reduced breast tissue levels of TNFα. Secondary objectives included evaluation of the effect of DHA on breast tissue levels of COX-2, IL1β, aromatase, white adipose tissue inflammation, and gene expression by RNA-seq. Red blood cell fatty acid levels were measured to assess compliance. From July 2013 to November 2015, 64 participants were randomized and treated on trial (32 women per arm). Increased levels of omega-3 fatty acids in red blood cells were detected following treatment with DHA (P < 0.001) but not placebo. Treatment with DHA did not alter levels of TNFα (P = 0.71), or other biomarkers including the transcriptome in breast samples. Treatment with DHA was overall well-tolerated. Although compliance was confirmed, we did not observe changes in the levels of prespecified biomarkers in the breast after treatment with DHA when compared with placebo. Cancer Prev Res; 11(4); 203–14. ©2018 AACR. See related editorial by Fabian and Kimler, p. 187