Non-significant Reduction In Mortality Research Articles

Abstract GS02-04: Surgical Treatment of Women with Breast Cancer and a BRCA1 Mutation: An International Analysis of the Impact of Bilateral Mastectomy on Survival

Abstract Background: Women with breast cancer and a BRCA1 mutation face a high risk of contralateral breast cancer. For this reason, many women with a unilateral breast cancer opt for bilateral mastectomies. Some will have a contralateral prophylactic mastectomy as a second surgery. However, it is not clear to what extent this operation impacts breast cancer mortality. The objective of the current study was to evaluate the differences in survival by surgical treatment in an international cohort of women with a BRCA1 mutation and unilateral breast cancer. Methods: Eligible participants were identified from a large international cohort of women with breast cancer and a BRCA1 mutation, from 26 collaborating centres. Patients with DCIS and stage IV breast cancer were excluded. Patients with synchronous bilateral cancer were excluded. Demographic data were patient reported and clinical and treatment data were collected from medical records. Women were followed from date of breast cancer diagnosis to either date of last follow-up or date of death. Results: There were 2482 eligible participants from 26 centres from 11 countries. The mean age of breast cancer diagnosis was 43.1 years (range 18-70 years). Among those who had a unilateral mastectomy or lumpectomy, the risk of contralateral breast cancer at 20 years was 27.5%. After experiencing a contralateral cancer the hazard ratio for breast cancer death was 2.14 (95%CI 1.43-3.18), P=0.0002. The fifteen-year breast cancer specific survival in the entire cohort was 82.9%. The survival was 78.7% for those who had a unilateral mastectomy, 86.2% for those who had a lumpectomy, and 88.7% for those who had bilateral mastectomies. 529 of the women who initially underwent a unilateral surgery subsequently had a contralateral or bilateral preventive mastectomy in the follow up period. 529 of the women with unilateral surgery had a contralateral or bilateral preventive mastectomy in the follow up period. After adjusting for age of diagnosis, tumor size, nodal status, chemotherapy (yes/no) and preventive mastectomy (time dependent) the hazard ratio for breast cancer mortality for bilateral surgery versus unilateral surgery was 0.78 (95% CI 0.55-1.13), p = 0.19. Discussion: Women with a BRCA1 mutation and breast cancer who develop a contralateral breast cancer have double the risk of mortality compared to women who do not develop contralateral breast cancer. We observed a small non-significant reduction in mortality for those who had bilateral mastectomies as initial treatment, but the cohort will require longer follow up for definitive results. Women with a BRCA1 mutation should be counselled on the risks of contralateral breast cancer and make surgical decisions with this knowledge. Citation Format: Kelly Metcalfe, Jan Lubinski, Jana Soukupová, Rinat Bernstein-Molho, Mina Lee, Evans Gareth, Arvids Irmejs, Robert Fruscio, Cynthia Villareal Garza, Joanne Ngeow, Jennifer Plichta, Rinat Yerushalmi, Steven Narod. Surgical Treatment of Women with Breast Cancer and a BRCA1 Mutation: An International Analysis of the Impact of Bilateral Mastectomy on Survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-04.

Bosentan for high-risk outpatients with COVID-19 infection: a randomized, double blind, placebo-controlled trial

The endothelium is supposedly activated and damaged in COVID-19 because of endothelin-1 over-secretion. This study evaluates the effect of bosentan as an endothelin receptor blocker on the progression of disease in high-risk outpatients with COVID-19 infection. From 15 December 2021 to 15 May 2022, high-risk outpatients were randomly assigned to receive bosentan, 62.5mg or placebo twice daily from enrollment for 30 days. Both groups received standard medical treatment too. On day 30 of the trial, the patients underwent complete doppler ultrasound of the lower extremities to detect asymptomatic thromboembolic events. The primary outcome in this study was hospitalization or death from any cause within the first 15 days. Secondary outcomes included thromboembolic events, hospital-free days and death from any cause within 30 days after randomization (IRCT.ir, IRCT20211203053263N1). Basal characteristics of the two groups were similar. Primary outcomes occurred in 3 (2.3%) of the 129 patients in the bosentan group versus 15 (11.5%) of the 130 patients in the placebo group [risk difference:-9.2% (95% CI:-15.3 to-3.1), P=0.006]. Median hospital-free days was significantly higher in the bosentan group (P=0.004). A total of three deaths occurred and all were in the control group. Bosentan was associated with a nonsignificant reduction in mortality compared with placebo (P=0.24). Thromboembolic events occurred in one (1%) of 97 patients in the bosentan group versus nine (8.7%) of 104 patients in the placebo group within 30 days after randomization [risk difference:-8.3% (95% CI:-14.4 to-2.2), P=0.008]. Early administration of bosentan may prevent disease progression and thromboembolic events in high-risk outpatients with COVID-19. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Coronary artery bypass grafting using bilateral internal thoracic arteries in patients with diabetes and obesity: A systematic review and meta-analysis

BackgroundPatients with diabetes and obesity are at higher risk of adverse long-term outcomes following coronary artery bypass grafting. The use of bilateral internal thoracic arteries (BITA) can potentially offer survival benefit in higherrisk patientscompared to single internal thoracic artery (SITA), but BITAisnotroutinelyused due tolack of clear evidence of efficacy andconcerns over sternal wound complications. MethodsMedline, Embase and the Cochrane Library were searched forstudies comparing the efficacy and safety of BITA and SITA grafting in patients with diabetes and obesity. Meta-analysis of mortality and sternal wound complications was performed. ResultsWe identified eight observational and ten propensity matched studies, and one RCT, comparing BITA and SITA which included patients with diabetes (n = 19,589); two propensity matched studies and one RCT which included patients with obesity (n = 6,972); mean follow up was 10.5 and 11.3 years respectively. Meta-analysis demonstrated a mortality reduction for BITA compared to SITA in patients with diabetes (risk ratio [RR] 0.79; 95% confidence interval [CI] 0.70–0.90; p = 0.0003). In patients with obesity there was a non-significant reduction in mortality in the BITA group (RR 0.73, 95% CI 0.47–1.12; p = 0.15). There was a significantly higher rate of sternal wound complications following BITA observed in patients with diabetes (RR 1.53, 95% CI 1.23–1.90; p = 0.0001) and obesity (RR 2.24, 95% CI 1.63–3.07; p < 0.00001). ConclusionsBITA is associated with better long-term survival in patients with diabetes. The effects of BITA grafting in patients with obesity are uncertain. BITA is associated with higher rates of sternal wound complications compared to SITA in both patients with diabetes and obesity.

Predictors of Mortality among COVID-19 Patients Admitted to Intensive Care Units: A Single-Center Study in Tehran, Iran.

Iran was one of the first countries to become an epicenter of the coronavirus disease 2019 (COVID-19) epidemic. However, there is a dearth of data on the outcomes of COVID-19 and predictors of death in intensive care units (ICUs) in Iran. We collected extensive data from patients admitted to the ICUs of the one of the tertiary referral hospitals in Tehran, Iran, to investigate the predictors of ICU mortality. The study population included 290 COVID-19 patients who were consecutively admitted to the ICUs of the Sina hospital from May 5, 2021, to December 6, 2021, a period that included the peak of the epidemic of the delta (δ) variant. Demographic data, history of prior chronic diseases, laboratory data (including markers of inflammation), radiologic data, and medication data were collected. Of the 290 patients admitted to the ICUs, 187 (64.5%) died and 103 (35.5%) survived. One hundred forty-one (141, 48.6%) were men, and the median age (10th percentile, 90th percentile) was 60 (41, 80). Using logistic regression models, older age, history of hypertension, high levels of inflammatory markers, low oxygen saturation, substantial lung involvement in computed tomography (CT) scans, and gravity of the disease as indicated by the WHO 8-point ordinal scale were primary predictors of mortality at ICU. The use of remdesivir and imatinib was associated with a statistically non-significant reduction in mortality. The use of tocilizumab had almost no effect on mortality. The findings are consistent with and add to the currently existing international literature. The findings may be used to predict risk of mortality from COVID-19 and provide some guidance on potential treatments.

Impact on the Nutritional Status and Inflammation of Patients with Cancer Hospitalized after the SARS-CoV-2 Lockdown.

Many studies have demonstrated that malnutrition has a negative impact on quality of life and mortality in patients with cancer. During the SARS-CoV-2 lockdown, dietary intake changes were detected in the Spanish population, reflecting an increase in the consumption of fruit, bread, flours, and eggs. The present study analyzed the nutritional status of 728 patients with cancer admitted once the SARS-CoV-2 lockdown finished, comparing it with the previous year as well as with mortality rates. The Malnutrition Universal Screening Tool (MUST) was applied in the first 24 h after admission. Age, gender, days of stay, circulating concentrations of albumin, cholesterol, C-reactive protein (CRP), lymphocytes, prealbumin, and mortality data were analyzed. Patients with cancer admitted between June and December of 2020 exhibited no statistical differences in BMI, age, or gender as compared to patients admitted in 2019. Statistically significant differences in nutritional status (p < 0.05), albumin (p < 0.001), and CRP (p = 0.005) levels regarding lockdown were observed in relation with a small non-significant reduction in mortality. In conclusion, following the SARS-CoV-2 lockdown, an improved nutritional status in cancer patients at admission was observed with a decrease in the percentage of weight loss and CRP levels together with an increase in albumin levels compared to oncological patients admitted the previous year.

Nutrition in acute stroke management: food for thought

Nutrition is crucial in the management of patients with acute stroke. 1 Dziewas R Michou E Trapl-Grundschober M et al. European Stroke Organisation and European Society for Swallowing Disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur Stroke J. 2021; 6: LXXXIX-LXXCXV Crossref PubMed Scopus (0) Google Scholar Clinical features putting patients at risk of malnutrition include dysphagia, impaired consciousness, perception deficits, and cognitive dysfunction. Being malnourished or at risk of malnutrition on admission to hospital after stroke is linked with poor functional outcomes and mortality, and worsening of nutritional status during the acute stage post-stroke is associated with similar adverse outcomes. 2 Dennis M Poor nutritional status on admission predicts poor outcomes after stroke: observational data from the FOOD trial. Stroke. 2003; 34: 1450-1456 Crossref PubMed Scopus (0) Google Scholar Therefore, guidelines dedicated to acute stroke care generally include nutritional management. 1 Dziewas R Michou E Trapl-Grundschober M et al. European Stroke Organisation and European Society for Swallowing Disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur Stroke J. 2021; 6: LXXXIX-LXXCXV Crossref PubMed Scopus (0) Google Scholar , 3 Powers WJ Rabinstein AA Ackerson T et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019; 50: e344-e418 Crossref PubMed Scopus (1816) Google Scholar , 4 Boulanger JM Lindsay MP Gubitz G et al. Canadian stroke best practice recommendations for acute stroke management: prehospital, emergency department, and acute inpatient stroke care, 6th edition, update 2018. Int J Stroke. 2018; 13: 949-984 Crossref PubMed Scopus (154) Google Scholar , 5 Burgos R Bretón I Cereda E et al. ESPEN guideline clinical nutrition in neurology. Clin Nutr. 2018; 37: 354-396 Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar The guideline for the diagnosis and treatment of post-stroke dysphagia from the European Stroke Organization and European Society for Swallowing Disorders, for example, recommends early enteral nutrition via a nasogastric tube if sufficient oral nutrition is not possible. 1 Dziewas R Michou E Trapl-Grundschober M et al. European Stroke Organisation and European Society for Swallowing Disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur Stroke J. 2021; 6: LXXXIX-LXXCXV Crossref PubMed Scopus (0) Google Scholar This recommendation relies mainly on the second substudy of the Feed or Ordinary Diet (FOOD) trial, in which 859 patients with dysphagia after stroke were randomly assigned to either early tube feeding or delayed feeding starting later than 7 days after random assignment. Allocation to early tube feeding was associated with a non-significant reduction in mortality by 5·8% (there were 182 deaths in 429 patients randomly assigned to early tube feeding vs 207 deaths in 430 patients in the delayed feeding group; p=0·09). There were no differences in other outcomes, including severe disability or death (339 of 429 patients in the early-feeding group vs 344 of 430 patients in the delayed feeding group; p=0·7), pneumonia (132 of 429 patients in the early-feeding group vs 133 of 430 patients in the delayed feeding group; p>0·9), and percutaneous endoscopic gastrostomy placement at follow-up (30 of 429 patients in the early-feeding group vs 23 of 430 patients in the delayed feeding group). 6 Dennis M Lewis S Cranswick G Forbes J FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke. Health Technol Assess. 2006; 10: 1-120 Crossref Google Scholar Safety and efficacy of three enteral feeding strategies in patients with severe stroke in China (OPENS): a multicentre, prospective, randomised, open-label, blinded-endpoint trialIn the early phase of severe stroke, modified full enteral nutrition or hypocaloric enteral nutrition did not significantly reduce the risk of a poor outcomes compared with full enteral nutrition over a 90-day period. Hypocaloric enteral nutrition might be associated with increased mortality compared with modified full enteral nutrition. Further studies are needed to investigate whether modified full enteral nutrition might be the optimal strategy. Full-Text PDF

Hormone therapy in the postmenopausal years: considering benefits and risks in clinical practice.

Menopausal symptoms can be very distressing and considerably affect a woman's personal and social life. It is becoming more and more evident that leaving bothersome symptoms untreated in midlife may lead to altered quality of life, reduced work productivity and, possibly, overall impaired health. Hormone therapy (HT) for the relief of menopausal symptoms has been the object of much controversy over the past two decades. At the beginning of the century, a shadow was cast on the use of HT owing to the concern for cardiovascular and cerebrovascular risks, and breast cancer, arising following publication of a large randomized placebo-controlled trial. Findings of a subanalysis of the trial data and extended follow-up studies, along with other more modern clinical trials and observational studies, have provided new evidence on the effects of HT. The goal of the following paper is to appraise the most significant clinical literature on the effects of hormones in postmenopausal women, and to report the benefits and risks of HT for the relief of menopausal symptoms. A Pubmed search of clinical trials was performed using the following terms: estrogens, progestogens, bazedoxifene, tibolone, selective estrogen receptor modulators, tissue-selective estrogen complex, androgens, and menopause. HT is an effective treatment for bothersome menopausal vasomotor symptoms, genitourinary syndrome, and prevention of osteoporotic fractures. Women should be made aware that there is a small increased risk of stroke that tends to persist over the years as well as breast cancer risk with long-term estrogen-progestin use. However, healthy women who begin HT soon after menopause will probably earn more benefit than harm from the treatment. HT can improve bothersome symptoms, all the while conferring offset benefits such as cardiovascular risk reduction, an increase in bone mineral density and a reduction in bone fracture risk. Moreover, a decrease in colorectal cancer risk is obtainable in women treated with estrogen-progestin therapy, and an overall but nonsignificant reduction in mortality has been observed in women treated with conjugated equine estrogens alone or combined with estrogen-progestin therapy. Where possible, transdermal routes of HT administration should be preferred as they have the least impact on coagulation. With combined treatment, natural progesterone should be favored as it is devoid of the antiapoptotic properties of other progestogens on breast cells. When beginning HT, low doses should be used and increased gradually until effective control of symptoms is achieved. Unless contraindications develop, patients may choose to continue HT as long as the benefits outweigh the risks. Regular reassessment of the woman's health status is mandatory. Women with premature menopause who begin HT before 50 years of age seem to have the most significant advantage in terms of longevity. In women with bothersome menopausal symptoms, HT should be considered one of the mainstays of treatment. Clinical practitioners should tailor HT based on patient history, physical characteristics, and current health status so that benefits outweigh the risks.

Pharmacometabolomics identifies candidate predictor metabolites of an L-carnitine treatment mortality benefit in septic shock.

Sepsis‐induced metabolic dysfunction contributes to organ failure and death. L‐carnitine has shown promise for septic shock, but a recent phase II study of patients with vasopressor‐dependent septic shock demonstrated a non‐significant reduction in mortality. We undertook a pharmacometabolomics study of these patients (n = 250) to identify metabolic profiles predictive of a 90‐day mortality benefit from L‐carnitine. The independent predictive value of each pretreatment metabolite concentration, adjusted for L‐carnitine dose, on 90‐day mortality was determined by logistic regression. A grid‐search analysis maximizing the Z‐statistic from a binomial proportion test identified specific metabolite threshold levels that discriminated L‐carnitine responsive patients. Threshold concentrations were further assessed by hazard ratio and Kaplan‐Meier estimate. Accounting for L‐carnitine treatment and dose, 11 1H‐NMR metabolites and 12 acylcarnitines were independent predictors of 90‐day mortality. Based on the grid‐search analysis numerous acylcarnitines and valine were identified as candidate metabolites of drug response. Acetylcarnitine emerged as highly viable for the prediction of an L‐carnitine mortality benefit due to its abundance and biological relevance. Using its most statistically significant threshold concentration, patients with pretreatment acetylcarnitine greater than or equal to 35 µM were less likely to die at 90 days if treated with L‐carnitine (18 g) versus placebo (p = 0.01 by log rank test). Metabolomics also identified independent predictors of 90‐day sepsis mortality. Our proof‐of‐concept approach shows how pharmacometabolomics could be useful for tackling the heterogeneity of sepsis and informing clinical trial design. In addition, metabolomics can help understand mechanisms of sepsis heterogeneity and variable drug response, because sepsis induces alterations in numerous metabolite concentrations.

S0344 Endoscopic Resection of T1b Esophageal Adenocarcinoma Is Comparable to Esophagectomy: A Surveillance, Epidemiology, and End Results Database Study

INTRODUCTION: Current guidelines recommend consideration of endoscopic therapy when treating T1a esophageal adenocarcinoma. However, it remains unclear if endoscopy is appropriate for treating T1b lesions with and without lymph node metastasis. Our study aims to compare survival outcomes following surgical resection and endoscopy in treating T1b esophageal adenocarcinoma. METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results database from 2000 to 2016 of patients with T1b esophageal adenocarcinoma treated with endoscopic resection or esophagectomy. Kaplan Meier estimations and cox proportional hazards models were used to assess survival outcomes. RESULTS: A total of 603 patients with T1b esophageal carcinoma were identified, of whom 87.7% were male. Median age at diagnosis was 67 ± 10.6 years. Overall, males had a higher prevalence of T1b esophageal carcinoma compared to females (87.7% vs. 12.1 per 100,000 per year). Tumors were most common among White patients (95.2%). Most tumors were moderately differentiated (45%), followed by poorly differentiated (33%), well differentiated (10.4%), and undifferentiated (1.0%). Most tumors occurred in the distal third of the esophagus (83.4%) followed by the mid esophagus (8.6%) and the proximal third (1.8%). About 84 (13.9%) underwent endoscopic resection and 367 (60.9%) underwent esophagectomy. One, 3- and 5-year survival for cancer-specific death was associated with survival rates of 91%, 78%, and 74%, respectively, for endoscopic resection. Esophagectomy was associated with 1-, 3 and 5-year survival rates of 91%, 85%, and 73%, respectively. Subgroup analysis showed that in patients with lymph node metastasis (LMN), no significant difference in mortality was observed following surgical and endoscopic resection (Log Rank test = 0.903). Adjusted hazard models indicated that LMN was associated with 2 times higher mortality [HR 2.16, 95% CI 1.250-23.742, P = 0.0.006], and surgical intervention was associated with a non-significant reduction in mortality [HR 0.78, 95% CI 0.414-1.480, P = 0.451]. CONCLUSION: Endoscopic resection was associated with similar cancer-specific survival outcomes compared with esophagectomy in stage T1b esophageal adenocarcinoma, regardless of lymph node metastasis. Endoscopic removal of T1b esophageal adenocarcinoma is an effective strategy for patients including those either refusing esophagectomy or not a candidate for surgical intervention.Figure 1.: Survival following endoscopic resection (ER) and surgical resection (SR).

Using l-Carnitine as a Pharmacologic Probe of the Interpatient and Metabolic Variability of Sepsis.

The objective of this review is to discuss the therapeutic use and differential treatment response to Levo-carnitine (l-carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l-carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. A narrative review was conducted that focused on explaining interpatient variability in l-carnitine treatment response. Relevant biological and patient-level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). Despite promising results in a phase I study, a recent phase II clinical trial of l-carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l-carnitine treatment induces significant interpatient variability in l-carnitine and acylcarnitine concentrations over time. In particular, administration of l-carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l-carnitine. Moreover, provocation of sepsis metabolism with l-carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l-carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l-carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.

P2502Intensity and duration of lifestyle interventions for long term weight loss and association with mortality: a meta-analysis of randomised trials

Abstract Background Lifestyle interventions are widely recommended for weight management, particularly in patients with diabetes and cardiovascular disease. The intensity and duration of interventions needed to achieve sustained weight reduction are uncertain. Objectives To investigate the importance of the frequency and duration of lifestyle interventions for achieving weight loss over ≥ one year, and to evaluate associations between weight loss and all-cause mortality. Method Meta-analysis of randomised trials published in English-language journals from 1980 to June 2018 that assessed lifestyle compared to control interventions on weight loss in ≥100 subjects, and which reported weight change and mortality for ≥ one year. Results 31 randomised trials with a total of 20 816 overweight or obese participants, 70% of whom had cardiometabolic risk factors, were included. The weighted mean difference in body weight between diet and lifestyle intervention and control arms at 1 year was −3.65, 95% confidence interval (CI) −4.66, −2.65 kg, and at 3 years was −2.45, 95% CI: −3.73, −1.17kg. Weight loss at one year was greater in studies with more compared to fewer interventions (&gt;vs ≤28/year (−4.53 [IQR −5.93, −3.12] kg vs −2.38 [−3.98, −0.78] kg, p=0.001). There were 593 deaths (rate ∼0.3%/year), and the odds ratio for mortality for weight loss interventions compared to the controls was 0.86 (95% CI 0.74, 1.01), p=0.09. Table 1. Association with intervention intensity with weight loss achieved and mortality Number of interventions in first year N studies# Number of patients Mean difference p Total deaths Odds ratio p Random effect model (kg) (95% CI) Fixed effect model (95% CI) ≤6 3 510 −0.84 [−1.40, −0.28] &lt;0.0001 5 1.45 [0.22, 9.40] 0.7 7–12 6 2022 −2.04 [−3.24, −0.84] &lt;0.0001 10 1.34 [0.35, 5.16] 0.67 13–24 6* 3490 −2.46 [−5.59, 0.67] &lt;0.0001 23 1.20 [0.49, 2.96] 0.69 ≥25 18 13717 −3.53 [−4.13, −2.92] &lt;0.0001 555 0.84 [0.71, 1.00] 0.05 Total 31 100 −2.98 Total 31 *2 studies reported mortality but not weight loss. Conclusion Lifestyle programs with frequent patient interactions sustained over a year or more achieve modest weight loss. The level of intervention needed for clinically meaningful weight reduction may be unrealistic for most medical practices. There is a modest non-significant reduction in mortality with lifestyle programs, but limited data on whether lifestyle interventions for obesity decrease mortality in persons at higher risk because of cancer, heart failure or ischaemic heart disease. Acknowledgement/Funding None

Implementation of a rapid response team in a large nonprofit Brazilian hospital: improving the quality of emergency care through Plan-Do-Study-Act.

ObjectiveTo describe the implementation of a rapid response team in a large nonprofit hospital, indicating relevant issues for other initiatives in similar contexts, particularly in Latin America.MethodsIn general terms, the intervention consisted of three major components: (1) a tool to detect aggravation of clinical conditions in general wards; (2) the structuring of a rapid response team to attend to all patients at risk; and (3) the monitoring of indicators regarding the intervention. This work employed four half-year Plan-Do-Study-Act cycles to test and adjust the intervention from January 2013 to December 2014.ResultsBetween 2013 and 2014, the rapid response team attended to 2,296 patients. This study showed a nonsignificant reduction in mortality from 8.3% in cycle 1 to 5.0% in cycle 4; however, death rates remained stable in cycles 3 and 4, with frequencies of 5.2% and 5.0%, respectively. Regarding patient flow and continuum of critical care, which is a premise of the rapid response system, there was a reduction in waiting time for intensive care unit beds with a decrease from 45.9% to 19.0% in the frequency of inpatients who could not be admitted immediately after indication (p < 0.001), representing improved patient flow in the hospital. In addition, an increase in the recognition of palliative care patients from 2.8% to 10.3% was noted (p = 0.005).ConclusionImplementing a rapid response team in contexts where there are structural restrictions, such as lack of intensive care unit beds, may be very beneficial, but a strategy of adjustment is needed.

Sex hormone receptor expression and survival in esophageal adenocarcinoma: a prospective cohort study.

IntroductionA striking epidemiological feature of esophageal adenocarcinoma (EAC) is its strong, unexplained male predominance but few studies have evaluated the prevalence of sex hormone receptor expression in EAC.ResultsA low proportion of EAC tumors stained positive for ERα (4%) and AR (3%) while approximately one third stained positive for ERβ (31%). After a mean follow-up of 3 years (max 9 years), no significant associations were seen for ERα, ERβ or AR expression and EAC recurrence or survival. A non-significant reduction in mortality was observed for positive ERβ tumor expression, when restricting to patients with gastro-esophageal junctional (GEJ) cancer (HR 0.58, 95% CI 0.33, 1.03, p = 0.06).Materials and MethodsWe identified all EAC patients who underwent neo-adjuvant chemotherapy prior to surgical resection between 2004–2012 in the Northern Ireland Cancer Centre. Immunohistochemical expression of ERα, ERβ and AR was scored on triplicate cores to generate H-scores. Cox proportional hazards regression was used to evaluate the association between sex hormone receptor expression and overall, cancer-specific and recurrence-free survival.ConclusionWe found little evidence of ERα or AR expression in EAC. A moderate proportion expressed ERβ and there was suggestive evidence that its expression was associated with improved survival in GEJ cancer patients.

Levosimendan in patients with cardiogenic shock complicating myocardial infarction: A meta-analysis

PurposeCardiac shock is the leading cause of death in patients with acute myocardial infarction. The objective of this systematic review and meta-analysis was to evaluate whether levosimendan, compared to any type of control, is associated with improved clinical outcomes in patients with cardiogenic shock complicating myocardial infarction. Materials and methodsThe PubMed, EMBASE, Cochrane Central Register, and China National Knowledge Information databases were searched for pertinent studies published up until 1 May 2016. Randomized and non-randomized clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with cardiogenic shock complicating myocardial infarction, and reporting at least one outcome of interest were included. The primary outcome was mortality, whereas secondary outcomes were length of ICU stay, SOFA score, cardiac index (CI), cardiac power index (CPI), ejection fraction (EF), end-systolic volume (ESV), mean blood pressure (MBP), pulmonary arterial pressure (PAP), mixed venous oxygen saturation (SvO2), pulmonary artery occlusion pressure (PAOP) and glomerular filtration rate (GFR). We pooled risk ratio (RR) and 95% confidence interval (CI) using fixed and random effects models. ResultsThirteen studies comprising a total of 648 patients were included in the analysis. There was a nonsignificant reduction in mortality with levosimendan compared to the controls (RR=0.82 [0.65–1.01], P for effect=0.07, I2=0%). In the levosimendan group PAP and ESV were significantly reduced, while CI, CPI, EF, MBP and SvO2 were significantly increased. No differences in SOFA score, ICU days, PAOP or GFR were noted. ConclusionsLevosimendan can improve hemodynamic parameters and cardiac function when compared with a control group, with no evidence of benefit in terms of survival.

Levosimendan in patients with cardiogenic shock complicating myocardial infarction: A meta-analysis

PurposeCardiac shock is the leading cause of death in patients with acute myocardial infarction. The objective of this systematic review and meta-analysis was to evaluate whether levosimendan, compared to any type of control, is associated with improved clinical outcomes in patients with cardiogenic shock complicating myocardial infarction. Materials and methodsThe PubMed, EMBASE, Cochrane Central Register, and China National Knowledge Information databases were searched for pertinent studies published up until 1 May 2016. Randomized and non-randomized clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with cardiogenic shock complicating myocardial infarction, and reporting at least one outcome of interest were included. The primary outcome was mortality, whereas secondary outcomes were length of ICU stay, SOFA score, cardiac index (CI), cardiac power index (CPI), ejection fraction (EF), end-systolic volume (ESV), mean blood pressure (MBP), pulmonary arterial pressure (PAP), mixed venous oxygen saturation (SvO2), pulmonary artery occlusion pressure (PAOP) and glomerular filtration rate (GFR). We pooled risk ratio (RR) and 95% confidence interval (CI) using fixed and random effects models. ResultsThirteen studies comprising a total of 648 patients were included in the analysis. There was a nonsignificant reduction in mortality with levosimendan compared to the controls (RR=0.82 [0.65–1.01], P for effect=0.07, I2=0%). In the levosimendan group PAP and ESV were significantly reduced, while CI, CPI, EF, MBP and SvO2 were significantly increased. No differences in SOFA score, ICU days, PAOP or GFR were noted. ConclusionsLevosimendan can improve hemodynamic parameters and cardiac function when compared with a control group, with no evidence of benefit in terms of survival.

Impact of Trauma System Structure on Injury Outcomes: A Systematic Review and Meta‐Analysis

The effectiveness of trauma systems in decreasing injury mortality and morbidity has been well demonstrated. However, little is known about which components contribute to their effectiveness. We aimed to systematically review the evidence of the impact of trauma system components on clinically important injury outcomes. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and BIOSIS/Web of Knowledge, gray literature and trauma association Web sites to identify studies evaluating the association between at least one trauma system component and injury outcome. We calculated pooled effect estimates using inverse-variance random-effects models. We evaluated quality of evidence using GRADE criteria. We screened 15,974 records, retaining 41 studies for qualitative synthesis and 19 for meta-analysis. Two recommended trauma system components were associated with reduced odds of mortality: inclusive design (odds ratio [OR]=0.72 [0.65-0.80]) and helicopter transport (OR=0.70 [0.55-0.88]). Pre-Hospital Advanced Trauma Life Support was associated with a significant reduction in hospital days (mean difference [MD]=5.7 [4.4-7.0]) but a nonsignificant reduction in mortality (OR=0.78 [0.44-1.39]). Population density of surgeons was associated with a nonsignificant decrease in mortality (MD=0.58 [-0.22 to 1.39]). Trauma system maturity was associated with a significant reduction in mortality (OR=0.76 [0.68-0.85]). Quality of evidence was low or very low for mortality and healthcare utilization. This review offers low-quality evidence for the effectiveness of an inclusive design and trauma system maturity and very-low-quality evidence for helicopter transport in reducing injury mortality. Further research should evaluate other recommended components of trauma systems and non-fatal outcomes and explore the impact of system component interactions.

Evidence for the Use of Tranexamic Acid in Subarachnoid and Subdural Hemorrhage: A Systematic Review.

AbstractDespite neurosurgical treatment, a subarachnoid hemorrhage (SAH) can cause a debilitating stroke. The case fatality rate ranges from 27 to 44%, and many survivors are left permanently disabled; therefore, the need for improved treatment is obvious. Furthermore, subdural hemorrhages (SDHs) have a cumulative recurrence rate of 14% in the first year and are potentially fatal. The aim of this systematic review is to assess and discuss the evidence for the role of tranexamic acid (TXA) in treatment of SAH and SDH. Systematic literature searches were performed in MEDLINE, Embase, Scopus, and Web of Science (1946–2016). The inclusion criteria were TXA-treated group and control group; SAH or SDH verified by imaging, intraoperatively or at autopsy; human subjects; English; and an objective outcome. The search terms matched 443 records. Eight studies including nontraumatic SAH patients and one study including traumatic intracranial bleeding met the inclusion criteria. Comparing TXA-treated nontraumatic patients with controls, we found an overall odds ratio (OR) for rebleeding of 0.41 (95% confidence interval [CI]: 0.26–0.64), six studies reported the mortality rate with an overall OR of 0.88 (95% CI: 0.68–1.12), four studies reported no statistically significant difference on the Glasgow Outcome Scale, and one study showed a statistically significant increased risk of cerebral ischemia, whereas seven studies found no statistically significant difference. No studies including SDH patients met the inclusion criteria. TXA reduced the overall risk of rebleeding following nontraumatic SAH. A nonsignificant reduction in mortality was demonstrated in nontraumatic SAH without substantial indication of increased risk of ischemic lesions.

Abstract 16: Effect of Long-Term Selenium Supplementation on Mortality: Results From a Multiple-Dose Randomised Controlled Trial

Background: Selenium (Se) is an essential trace element that is incorporated into selenoproteins with a wide range of health effects. The concentration of selenoproteins plateaus at plasma Se concentrations ~125 μg/L, however, and it is unclear whether Se supplementation is beneficial above this plateau. Methods: In a double-blind, randomized, controlled trial of Se supplementation and mortality in Denmark, a population of moderately-low Se status, 491 men and women, 60-74 years of age, were treated with 100, 200, or 300 μg Se/d as Se-enriched yeast or placebo-yeast. From 2008-2009, active treatment was provided for 5 years and post-treatment follow-up for 10 additional years. During 6,871 person-years of follow-up, there were 158 deaths (31 during active treatment and 127 after treatment cessation). Results: The hazard ratio (95% confidence interval [CI]) for all-cause mortality comparing 300 μg Se/d to placebo was 1.62 (0.66 to 3.96) after 5 years of treatment and 1.59 (1.02 to 2.46) over the entire follow-up. Se doses of 100 and 200 μg/d non-significantly decreased mortality during the intervention period but their effects vanished after treatment cessation. The effects on cancer and cardiovascular mortality were similar but less precise than on all-cause mortality. Conclusions: A dose of 300 μg/d of Se (as high-Se yeast) taken for five years in a country with moderately-low Se status increased all-cause mortality 10 years later. Lower doses showed a non-significant reduction in mortality which dissipated after treatment discontinuation. Total Se intake (diet plus supplements) over 300 μg/d should be avoided.

Sorafenib Effectiveness in Advanced Hepatocellular Carcinoma.

Phase III trials show sorafenib improves survival in advanced hepatocellular carcinoma (HCC). Because of narrow trial eligibility, results may not be generalizable to a broader HCC population. We sought to evaluate the effectiveness of initial sorafenib versus no treatment among Medicare beneficiaries with advanced HCC. Patients with advanced HCC diagnosed from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Eligible patients received initial sorafenib or no therapy and were covered by Medicare parts A, B, and D. Sorafenib use and outcomes were described in this population. Using a propensity score (PS)-matched sample, we compared the effectiveness of sorafenib versus no treatment by Cox proportional hazards and binomial regression, using a landmark requiring all patients to survive ≥60 days after diagnosis. Of 1,532 patients, 27% received initial sorafenib. Median duration of sorafenib use was 60 days (interquartile range [IQR], 30-107 days), and median survival from first prescription was 3 months (IQR, 1-8 months). In the PS-matched cohort, median survival was 3 months from the 60-day landmark in sorafenib-treated (n = 223) and 2 months in untreated (n = 223) patients (adjusted hazard ratio, 0.95 [95% confidence interval (CI), 0.78-1.16]). Sorafenib was associated with a nonsignificant reduction in mortality at 3 months (44% versus 51%; adjusted risk ratio, 0.88 [95% CI, 0.72-1.07]), but no reduction thereafter. Survival after sorafenib initiation in newly diagnosed Medicare beneficiaries with HCC is exceptionally short, suggesting trial results are not generalizable to all HCC patients. The downsides of sorafenib use-high drug-related symptom burden and high drug cost-must be considered in light of this minimal benefit. The findings of a median survival of only 3 months in Medicare beneficiaries with HCC prescribed sorafenib as first-line therapy highlight the questionable value of sorafenib in this population. Patients should be cautioned that outside of the narrow confines of randomized trials, their life expectancy may be very short, and any benefit of sorafenib is likely to be quite small. Given that sorafenib causes considerable adverse effects and offers no symptom palliation, supportive care should be discussed as a reasonable alternative to sorafenib, particularly for patients who have a poor performance status or advanced cirrhosis.

Cholesterol trials and mortality.

An overview of clinical trials can reveal a class effect on mortality that is not apparent from individual trials. Most large trials of lipid pharmacotherapy are not powered to detect differences in mortality and instead assess efficacy with composite cardiovascular endpoints. We illustrate the importance of all-cause mortality data by comparing survival in three different sets of the larger controlled lipid trials that underpin meta-analyses. These trials are for fibrates and statins. Fibrate treatment in five of the six main trials was associated with a decrease in survival, one fibrate trial showed a non-significant reduction in mortality that can be explained by a different target population. In secondary prevention, statin treatment increased survival in all five of the main trials, absolute mean increase ranged from 0.43% to 3.33%, the median change was 1.75%, which occurred in the largest trial. In primary prevention, statin treatment increased survival in six of the seven main trials, absolute mean change in survival ranged from -0.09% to 0.89%, median 0.49%. Composite safety endpoints are rare in these trials. The failure to address composite safety endpoints in most lipid trials precludes a balanced summary of risk-benefit when a composite has been used for efficacy. Class effects on survival provide informative summaries of the risk-benefit of lipid pharmacotherapy. We consider that the presentation of key mortality/survival data adds to existing meta-analyses to aid personal treatment decisions.