Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice

Steroid use in acute liver failure

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (\u3e40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH \u3c 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. CONCLUSION: Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores

Silicate Treatment to Inhibit Corrosion of Hot, Potable Water Systems, Phase I

Research has been conducted to determine the variables involved in the use of the sodium silicate treatment technique and in the design of a system which utilizes or controls these variables for the efficient control of corrosion of steel, galvanized steel, and copper piping exposed to hot, potable water. Test loops were designed and constructed at nine selected sites to investigate the influence that temperature flow velocity, water chemistry, and silicate formulation and dosage have on the effectiveness of sodium silicate as a corrosion inhibitor for steel, galvanized steel, and copper piping exposed to heat (140°F and 180°F) in aggressive, potable water of four different compositions. Recommendations are made to conduct further research to determine ( 1) silicate treatment variables involved in treating low alkalinity and low hardness water; {2) the practicality of employing silicate treatment of hard water; (3) the effectiveness of zinc salts as a supplement to silicate; and (4) the corrosion resistance of ASTM A-268 Grade 409 stainless steel.AIR FORCE WEAPONS LABORATORY - Air Force Systems Command - Kirtland Air Force Base, New MericoOpe

The association of sport and exercise activities with cardiovascular disease risk: The Atherosclerosis risk in Communities (ARIC) study

Background: This study assessed the independent associations between participation in self-reported sport and exercise activities and incident cardiovascular disease (CVD). Methods: Data were from 13,204 participants in the Atherosclerosis Risk in Communities Study cohort (1987–2015). Baseline sport and exercise activities were assessed via the modified Baecke questionnaire. Incident CVD included coronary heart disease, heart failure, or stroke. Multivariable-adjusted Cox proportional hazard models assessed the association of participation in specific sport and exercise activities at enrollment with risk of CVD. Results: During a median follow-up time of 25.2 years, 30% of the analytic sample (n = 3966) was diagnosed with incident CVD. In fully adjusted models, participation in racquet sports (hazard ratio [HR] 0.75; 95% confidence interval [CI], 0.61–0.93), aerobics (HR 0.75; 95% CI, 0.63–0.88), running (HR 0.68; 95% CI, 0.54–0.85), and walking (HR 0.89; 95% CI, 0.83–0.95) was significantly associated with a lower risk of CVD. There were no significant associations for bicycling, softball/baseball, gymnastics, swimming, basketball, calisthenics exercises, golfing with cart, golfing with walking, bowling, or weight training. Conclusions: Participation in specific sport and exercises may substantially reduce the risk for CVD

Association Between Results of a Gene Expression Signature Assay and Recurrence-Free Interval in Patients With Stage II Colon Cancer in Cancer and Leukemia Group B 9581 (Alliance)

PURPOSE: Conventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581. PATIENTS AND METHODS: C9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables. RESULTS: Fifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk. CONCLUSION: ColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L

Clinical Best Practice Advice for Hepatology and Liver Transplant Providers During the COVID‐19 Pandemic: AASLD Expert Panel Consensus Statement

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156235/2/hep31281.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156235/1/hep31281_am.pd

Improved Classification of Alzheimer's Disease Data via Removal of Nuisance Variability

Diagnosis of Alzheimer's disease is based on the results of neuropsychological tests and available supporting biomarkers such as the results of imaging studies. The results of the tests and the values of biomarkers are dependent on the nuisance features, such as age and gender. In order to improve diagnostic power, the effects of the nuisance features have to be removed from the data. In this paper, four types of interactions between classification features and nuisance features were identified. Three methods were tested to remove these interactions from the classification data. In stratified analysis, a homogeneous subgroup was generated from a training set. Data correction method utilized linear regression model to remove the effects of nuisance features from data. The third method was a combination of these two methods. The methods were tested using all the baseline data from the Alzheimer's Disease Neuroimaging Initiative database in two classification studies: classifying control subjects from Alzheimer's disease patients and discriminating stable and progressive mild cognitive impairment subjects. The results show that both stratified analysis and data correction are able to statistically significantly improve the classification accuracy of several neuropsychological tests and imaging biomarkers. The improvements were especially large for the classification of stable and progressive mild cognitive impairment subjects, where the best improvements observed were 6% units. The data correction method gave better results for imaging biomarkers, whereas stratified analysis worked well with the neuropsychological tests. In conclusion, the study shows that the excess variability caused by nuisance features should be removed from the data to improve the classification accuracy, and therefore, the reliability of diagnosis making