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PDF file - 46K, Patient Level Data. This table tabulates chemotherapy cycles received, response and DLT per patient.

Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy.Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies.Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies.Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.

PDF file - 39K, Probability of DLT. This table estimates the probability of dose-limiting toxicity by dose level

BACKGROUND We present data on a cohort of patients diagnosed with sepsis over a 10-year period comparing outcomes in solid organ transplant (SOT) and non-solid organ transplant (non-SOT) recipients. METHODS This is a retrospective single-center study of patients with diagnosis of sepsis from 1/1/06 to 6/30/16. Cases and controls were matched by year of sepsis diagnosis with propensity score matching. Conditional logistic regression and repeated measurement models were performed for binary outcomes. Trends over time for in-hospital mortality were determined using the Cochran-Armitage test. A gamma-distributed model was performed on the continuous variables. RESULTS Overall, there were 18 632 admission encounters with a discharge diagnosis of sepsis in 14 780 unique patients. Of those admissions, 1689 were SOT recipients. After 1:1 matching by year, there were three thousand three hundred and forty patients (1670 cases; 1670 controls) diagnosed with sepsis. There was a decreasing trend for in-hospital mortality for sepsis over time in SOT patients and non-SOT patients (P

Although various interventions targeted at reducing hospital readmissions have been identified in the literature, little is known about actual operationalization of such evidence-based interventions. This study conducted a systematic review and a survey of key informants in 2 leading hospitals, Houston Methodist (HM) and MD Anderson Cancer Center (MDACC), to compare and contrast the most cited evidence-based interventions in the current literature with interventions reported by those hospitals. The authors found that both hospitals followed evidence-based practices reported as successful in the literature. Both hospitals have implemented interventions for inpatient settings, and the timing of interventions was very similar. Major implementation differences observed for post-discharge interventions focused on collaboration. It also was found that HM was more likely than MDACC to use medication reconciliation in outpatient ( P = .018) and discharge planning for community/home patients ( P = .032). Results will provide hospital professionals with insights for implementing the most effective interventions to reduce readmissions.

PURPOSE: It is easier for us to judge facial deformity when the patient’s head is in anatomic position. The purposes of this study were to determine: 1) if a group of expert observers agree more than a group of non-experts on what is the correct anatomical position of the head, 2) whether there is more variation in the alignment of an asymmetrical face compared with a symmetrical one, and 3) whether the alignments of experts are more repeatable than those of non-experts. SUBJECTS AND METHODS: Thirty-one orthodontists (experts) and 31 dental students (nonexperts) were recruited in this mixed-model study. They were shown randomly oriented three-dimensional head photographs of a symmetrical adult and an asymmetrical adolescent. In a viewing software, the observers oriented the images into anatomical position. They repeated the orientations 4 weeks later. The data was analyzed using a Generalized Linear Model and Bland-Altman plots. The primary predictor variables were experience and symmetry status. The outcome variable was anatomical position of the head. The other variables of interest included time, and orientational direction. RESULTS: There was a statistically significant difference between the measurements completed by experts and non-experts [F(1,60)=14.83, P

Objective: Currently, there are no objective metrics included in the intensive care unit (ICU) discharge decision making process. In this study, we evaluate Rothman Index(RI) data for a possible metric as part of a quality improvement project. Our objectives were to determine whether RI could predict adverse events occurring within 72 hours of ICU discharge decision, the optimal clinical cutoff value for this metric, and to determine whether there is a relation between the RI warning alert 24 hours prior to discharge and adverse events postdischarge. Design: Retrospective observational study. Setting: Single center tertiary hospital. Patients: Adult medical ICU patients discharged from the ICU between January 20, 2015 and March 14, 2015. Interventions: None. Measurements and Main Results: A total of 194 patients were studied with mean age of 62.74 (18.37) years. Data collection included RI at the time of decision-making for ICU discharge and the presence of any warning signals in the previous 24 hours. A 72-hour follow-up chart review recorded any adverse events, including readmission to a higher level of care, discontinuation of discharge due to clinical status change, emergency department visit if discharged home, rapid response activation, or cardiopulmonary arrest postdischarge. Adverse events after ICU discharge were observed in 31 (16%) patients with 9 events being ICU readmission (4.6%). Based on an age-adjusted multivariate model, a higher RI was associated with lower odds of an adverse event (odds ratio [OR] = 0.969, P = .006, confidence interval [CI]: 0.9487-0.9911). An RI value ≥ 50 was associated with 72% lower odds of an adverse event (OR = 0.2887, 95% CI = 0.1278-0.6517 and P = .003) compared to RI < 50. This RI cutoff value was associated with the largest decrease in odds of events. As expected, patients with a very high-risk warning alert had a higher proportion of adverse events compared to patients who did not. (31.75% vs 12.65%, P = < .02). Conclusions: Patients who have an RI < 50 or a very high-risk warning alert have a higher risk of adverse events postdischarge from the ICU. Rothman Index may be a useful metric for ICU discharge decision-making.

Introduction An adequate dose of marrow derived total nucleated cells (TNCs) is essential for engraftment in recipients undergoing allogeneic hematopoietic stem cell (HSC) transplant. Marrow collection centers anticipate the harvest volume required to meet a minimum collection goal of 2 × 108 TNCs/kg based on published aggregates of donor marrow TNC concentrations (currently set at 18.3 × 109/L). However, marrow TNCs are highly variable among marrow donors. We hypothesized that baseline donor characteristics such as age, BMI, and ethnicity, could be used to more accurately predict TNCs. Objectives We commissioned an IRB-approved retrospective single center study to ascertain which donor characteristics could independently predict marrow TNCs during a harvest as well as the impact on successful recipient engraftment. Methods Univariate linear regression was conducted to estimate the crude association between each factor and TNC (487 donors). The following variables were considered as possible predictors: donor BMI, age, ethnicity, gender, and total harvest volume. Variables that had a p value Results Univariate analysis revealed no difference in TNCs between genders (p = 0.697). BMI was significantly positively correlated with TNCs (t = 4.17; p Conclusion Our findings demonstrate that multiple donor characteristics can predict marrow TNCs. The impact of ethnicity on marrow TNC counts, but not on engraftment rates, suggests that the true HSC concentrations might be higher in these donors despite the lower TNCs. As donor pools diversify and use of haploidentical donors increases, our observations indicate that expected TNC counts during marrow harvests will vary based on baseline donor characteristics.

Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.

Background: While innovation drives advancement, it is not immune to failure. Previously, we reported a corrosion-related revision rate of 28% (23 of 81 total hip arthroplasties) among patients who received the Rejuvenate modular-neck stem implant with short-term follow-up. Because we observed a dramatic interval failure rate after our initial report, we undertook this study. Methods: We prospectively followed a cohort of patients who had undergone implantation of the Rejuvenate modular-neck stem, as previously reported. At a minimum of 3 years of follow-up (range, 3.0 to 5.5 years), 73 hips in 63 patients (90% of the original group) were available for analysis. The mean serum cobalt and chromium ion levels were obtained preoperatively and postoperatively. Elevated serum cobalt ion levels (>4 μg/L), pain, or abnormal magnetic resonance imaging (MRI) findings were indications for revision surgery. Patient factors and serum metal ion levels were correlated to revision surgery. Additionally, post-revision serum cobalt and chromium ion level trends were assessed. Results: An 86% clinical failure rate (63 of the 73 hips) was observed at a mean follow-up of 4.2 ± 0.6 years (range, 3.0 to 5.5 years); 57 (78%) of the hips underwent revision at a mean of 3.2 ± 1.0 years (range, 1.0 to 5.5 years), and 6 (8%) of the hips were scheduled for revision. Patients who underwent revision surgery were younger and had greater serum metal ion levels and greater pain compared with patients who did not undergo revision. An elevated serum cobalt ion level was the most important independent factor associated with revision surgery. Cobalt ion levels decreased sharply after revision; however, some patients demonstrated persistent elevation with more gradual decline. Conclusions: Emphasizing the reporting of positive results may leave orthopaedic surgeons reticent to publicize negative results; however, the high failure rate of this implant design within 5 years prompted this report. We believe that patients and orthopaedic surgeons should be made aware of this implant’s clinical problems and patients should be followed closely. Expedient revision is necessary when failure is identified, to minimize potentially severe tissue damage and metal toxicity. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Introduction: Fever worsens outcomes in patients with ischemic and hemorrhagic stroke. Fever can be infectious or non-infectious (central) in etiology. Previous literature suggests 32% of patients with ICH and 31% of ischemic stroke patients have noninfectious fever. Hypothesis: Central fever is rare in stroke patients undergoing a rigorous evaluation for infection. Methods: We retrospectively reviewed the electronic medical records of 419 patients with ICH (n=199), ischemic stroke (n=107) and subdural hemorrhage (SDH, n=113) from January 2011 to February 2014. We collected data on the following diagnostic measures: fever (temperature ≥ 100.4°F), Leukocytosis (white blood cell ≥ 11X109 cells/L), positive blood culture, positive urinalysis, positive chest X-ray, and use of non-prophylactic antibiotics. We identified patients who had evidence of fever without any other positives out of the above mentioned measures. These patients were identified as having noninfectious or central origin of their fever. Results: Of the 419 patients studied, 45 (22.6% of ICH), 27(25.2% of ischemic stroke) and 29(25.7% of SDH) patients with ICH, ischemic stroke and SDH respectively had fever at least once during the first 72 hours of their hospital stay. Of these patients with early fever, 8(4.02%), 3(2.8%) and 0 patients, respectively, had noninfectious fever. Out of 419 patients studied, 101(24.1%) patients had fever and 11(2.6%) of those were noninfectious in origin. Also, significantly higher number of patients with ICH had noninfectious fever as compared to patients with ischemic stroke (P=0.042). Additional analysis of the ICH population revealed that IVH was directly correlated with early fever incidence (p Conclusion: Even though fever was commonly observed in about 25% of stroke patients, central fever was rare, occurring in fewer than 3%. Among stroke patients, those with intraventricular hemorrhage were most likely to have central origin of fever. Our data suggest that overall, infections etiologies of fever outnumber central fever approximately 10 to 1.

Patients with HIV-associated dyslipidemic lipodystrophy (HADL) have characteristic lipid kinetic defects: accelerated lipolysis, blunted fat oxidation and increased hepatic fatty acid reesterification. HADL patients with lipoatrophy also have leptin deficiency. Small or non-randomized studies have suggested that leptin replacement improves glucose metabolism in HADL, with very limited data regarding its effects on the lipid kinetic abnormalities. We performed a randomized, double-blind, placebo-controlled, dose-escalating (0.02 mg/kg/d for two months; 0.04 mg/kg/d for a further two months) study of the effects of metreleptin on lipid kinetics in 17 adults with HADL, hypertriglyceridemia and hypoleptinemia. Rates of lipolysis, intra-adipocyte and intrahepatic reesterification and fatty acid oxidation were measured using infusions of (13)C(1)-palmitate and (2)H(5)-glycerol, and indirect calorimetry. Fasting lipid profiles and glucose and insulin responses to oral glucose challenge were also measured. Metreleptin treatment induced significant, dose-dependent increases in fasting plasma leptin levels. There was no significant change in total lipolysis, net lipolysis, adipocyte or hepatic re-esterification or fatty acid oxidation, or in fasting triglyceride or HDL-C concentrations, with metreleptin treatment. Metreleptin decreased fasting non-HDL-C levels (P

Coronary heart disease (CHD) is the leading cause of death in the United States.This study compares differences in risk factors for CHD in diabetic vs. nondiabetic Strong Heart Study participants.This was an observational study.The study was conducted at three centers in Arizona, Oklahoma, and North and South Dakota.Data were obtained from 3563 of 4549 American Indians free of cardiovascular disease at baseline.CHD events were ascertained during follow-up.CHD events were classified using standardized criteria.In diabetic and nondiabetic participants, 545 and 216 CHD events, respectively, were ascertained during follow-up (21,194 and 22,990 person-years); age- and sex-adjusted incidence rates of CHD were higher for the diabetic group (27.5 vs. 12.1 per 1,000 person-years). Risk factors for incident CHD common to both groups included older age, male sex, prehypertension or hypertension, and elevated low-density lipoprotein cholesterol. Risk factors specific to the diabetic group were lower high-density lipoprotein cholesterol, current smoking, macroalbuminuria, lower estimated glomerular filtration rate, use of diabetes medication, and longer duration of diabetes. Higher body mass index was a risk factor only for the nondiabetic group. The association of male sex and CHD was greater in those without diabetes than in those with diabetes.In addition to higher incidence rates of CHD events in persons with diabetes compared with those without, the two groups differed in CHD risk factors. These differences must be recognized in estimating CHD risk and managing risk factors.

Red cell distribution width (RDW), a measure of the variability in size of circulating erythrocytes, is an independent predictor of mortality in patients with cardiovascular disease. We hypothesized that RDW is a prognostic marker of death, myocardial infarction and unplanned revascularization in a broad population undergoing percutaneous coronary intervention (PCI). We investigated the prognostic value of RDW derived from a complete blood count drawn ≤24 h of PCI in 1,689 patients at four centers who underwent PCI between 2004 and 2007 in the evaluation of drug eluting stents and ischemic events registry. Patients who underwent blood transfusions were excluded. Multivariable analyses of death, MI, unplanned revascularization, and the combined occurrence of these events at 1 year were performed using methods from survival analysis. The analysis was adjusted for creatinine ≥1.5 mg/dL, hemoglobin, congestive heart failure, coronary artery bypass grafting history, male sex, BMI, atherosclerosis of ≥2 coronary vessels, and hypertension. In univariate analysis of RDW stratified by quartiles, membership in the highest quartile was a predictor of mortality as compared to the lowest quartile (HR 5.07, CI 2.07–12.40, p

We identified 90 germline single nucleotide polymorphisms (SNPs) that were informative for discriminative analysis of 9 major cancers among genotyped Framingham Heart Study participants. Support vector machines resulted in the greatest classification performance, which was in the range of 70–100%. The germline SNPs identified are based on DNA from peripheral blood lymphocytes obtained during non-invasive blood draws, and unlike SNPs in tumor DNA, may not be functionally related to tumor characteristics. Further validation studies are required in order to understand the role of the seeding, genetic selection, and lifetime cumulative effects of these germline SNPs in cancer development.

Study objective Coronary artery calcium scoring (CACS) is a simple and readily available test for identifying coronary artery disease. Our objective is to evaluate whether a CACS of zero will identify chest pain patients who can be safely discharged home, without need for further cardiac testing. Methods This was a prospective observational cohort study conducted at an urban tertiary care hospital of stable patients presenting to the emergency department (ED) with chest pain of uncertain cardiac cause. Patients with a normal initial troponin level, nonischemic ECG, and no history of coronary artery disease had stress myocardial perfusion imaging (SPECT) and CACS within 24 hours of ED admission. Cardiac events were defined as an acute coronary syndrome during the index hospitalization or in follow-up. CACS results were assessed in relation to SPECT findings and cardiac events. Results The 1,031 patients enrolled (mean [SD] age 54 [13] years) had a median CACS of 0 (61% with CACS of 0). The frequency of an abnormal SPECT ranged from 0.8% (CACS of 0) to17% (CACS>400). Cardiac events occurred in 32 patients (3.1%) during the index hospitalization (N=28) or after hospital discharge (N=4) (mean 7.4 [3.3] months). Only 2 events occurred in 625 patients with a CACS of 0 (0.3%; 95% confidence interval 0.04% to 1.1%). Thus, 2 of 32 patients with a cardiac event had a CACS of 0 (6%; 95% confidence interval 0.8% to 21%). Both of these patients developed increased troponin levels during their index visit but had normal serial ECG and SPECT study results and no cardiac events at 6-month follow-up. Conclusion A majority of patients (61% in our sample) evaluated for chest pain of uncertain cardiac cause have a CACS of 0, which predicts both a normal SPECT result and an excellent short-term outcome. Our results suggest that patients with a CACS of 0 can be discharged home, without further cardiac testing.