Promoter methylation of the Wnt/beta-catenin signaling antagonist Dkk-3 is associated with poor survival in gastric cancer.

BACKGROUND: Abnormal activation of the Wnt/beta-catenin signaling pathway is common and critical in the pathogenesis of digestive cancers. In this study, the authors investigated the promoter methylation of the dickkopf homolog 3 gene Dkk-3 in these cancers and its prognostic significance in gastric cancer. METHODS: Dkk-3 methylation was assessed in 173 patients with gastric cancers (including 104 patients who were followed for up to 4090 days) and in 128 patients with colorectal cancer. Cell growth was evaluated by using a colony-formation assay. For survival analyses, the authors used Kaplan-Meier plots, the log-rank test, and Cox proportional regression. RESULTS: Dkk-3 was silenced or down-regulated in 12 of 17 gastric cancer cell lines (70.6%) and in 3 of 9 colon cancer cell lines (33.3%). The loss of gene expression was associated with promoter methylation, which could be restored by demethylating agents. Ectopic expression of Dkk-3 suppressed colony formation. Moreover, methylation of Dkk-3 was detected in 117 of 173 primary gastric tumors (67.6%) and in 67 of 128 colorectal tumors (52.3%). The clinical significance and the prognostic value of Dkk-3 methylation also were examined in 104 gastric cancers and in 84 colorectal cancers. Multivariate analysis indicated that Dkk-3 methylation was associated significantly and independently with poor disease survival (relative risk, 2.534; 95% confidence interval, 1.54-4.17; P=.002) in gastric cancer, but not in colorectal cancer. Kaplan-Meier survival curves revealed that patients who had Dkk-3 methylated gastric cancers had a significantly shorter survival (median, 0.76 years) compared with patients who did not have Dkk-3 methylation (median, 2.68 years; P<.0001; log-rank test). CONCLUSIONS: Epigenetic silencing of the Dkk-3 gene by promoter methylation was a common event in gastric cancer and was associated with a poor outcome in such patients.

Gender and age differences in medications dispensed from a national chain drugstore.

OBJECTIVES: Our objective was to compare sex and age differences in the medications dispensed in pharmacies from a large national drugstore chain. METHODS: Using a list for the 200 most commonly prescribed medicines, we assessed prescriptions dispensed by a large national chain drug store over 1 year (2002-2003). The analysis used U.S. census data adjusted for the population by sex and age and weighted by the number of pharmacies per state. Results are reported as an odds ratio (OR) of prescriptions dispensed to females and males. RESULTS: Under age 18, 24 drug classes were dispensed more commonly to females (OR > 1) and 18 drug classes more commonly to males (OR < 1). In the 18-24 age group, 48 of 53 drug classes were dispensed more frequently to females. Across other adult groups, females were dispensed more medications than males for 156 of 180 medications. There was greater dispensing to females of antibiotics (OR = 1.74, 95% confidence interval [CI] 1.74-1.74), analgesics (OR = 1.70, 95% CI 1.70-1.70), antihistamines and sympathomimetics (OR = 1.46, 95% CI 1.45-1.46), benzodiazapines (OR = 2.08, 95% CI 2.07-2.08), antidepressants (OR = 2.40, 95% CI 2.39-2.40), diuretics (OR = 1.9328, 95% CI 1.93-1.94), and thyroid drugs (OR = 4.80, 95% CI 4.78-4.82). However, males had higher dispensing of antianginal drugs (OR = 0.84, 95% CI 0.83-0.85), anticoagulants (OR = 0.89, 95% CI 0.88-0.90), glycosides (OR = 0.80, 95% CI 0.79-0.81), and antihypertensives (OR = 0.91, 95% CI 0.91-0.91). More females were dispensed propoxyphene with acetaminophen (OR = 2.23, 95% CI 2.23-2.24), which has been associated with adverse outcomes (hospitalizations, emergency department visits, and deaths). CONCLUSIONS: Females, especially during the reproductive years, are dispensed more medications than males.

Retrospective claims database analysis to determine relationship between renin-angiotensin system agents, rehospitalization, and health care costs in patients with heart failure or myocardial infarction.

BACKGROUND: Heart failure (HF) and myocardial infarction (MI) cause considerable morbidity and mortality, but the outcomes and health care costs related to adherence to treatment guidelines for HF and MI are not fully understood. OBJECTIVES: The aims of this study were as follows: (1) to determine the proportion of patients discharged from the hospital with a primary diagnosis of HF or MI who subsequently received prescriptions for American Heart Association/American College of Cardiology-recommended angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), also referred to as renin-angiotensin system agents; (2) to investigate the relationship between adherence to and persistence with ACEIs/ARBs and risk of rehospitalization; and (3) to assess the relationship between adherence to and persistence with ACEIs or ARBs, cardiovascular-related health care costs, and total health care costs. METHODS: Using the prescription and medical service records of a large national pharmacy-benefit database, we conducted a retrospective analysis of patients discharged from the hospital with a primary diagnosis of HF or MI between July 1, 2003, and June 30, 2006. Medication adherence, persistence, rehospitalization risk, and health care costs during 1-year follow-up were measured. Logistic regression models were used to estimate the likelihood of rehospitalization for different levels of adherence and persistence. Generalized linear models were used to investigate the impact of adherence and persistence on total health care costs and cardiovascular-related health care costs. RESULTS: A total of 799 HF and 696 MI patients were included in the analysis; 57.20% of HF patients and 59.20% of MI patients were prescribed an ACEI or an ARB after discharge from the hospital. The mean (SD) age was 65.7 (13.7) years in the HF group and 60.6 (10.7) years in the MI group. In both groups, men accounted for a greater proportion of the patients than women. In the HF group, adherence and persistence were associated with a lower likelihood of rehospitalization compared with nonadherence and nonpersistence (P < 0.042 and P < 0.005, respectively). In the MI group, there was no significant difference in rehospitalization risk between those who were adherent and those who were not. However, among these patients, persistence was associated with a lower risk of rehospitalization than nonpersistence (P < 0.036). Adherence and persistence were associated with lower health care costs (HF: P < 0.001 for all comparisons; MI: P < 0.019 for adherence and total cost, P = NS for persistence and total cost, P < 0.012 for adherence and cardiovascular cost, P < 0.031 for persistence and cardiovascular cost). CONCLUSION: Adherence to and persistence with ACEIs or ARBs may reduce the risk of rehospitalization in patients with HF or MI, thereby potentially reducing health care costs.

The Medicare Part D doughnut hole: effect on pharmacy utilization.

The Medicare Prescription Drug Improvement and Modernization Act of 2003 offers prescription drug coverage through the Medicare part D program. However, the standard benefit does include a gap in coverage, commonly known as the "doughnut hole". This study, which included 90,615 subjects, aimed to evaluate the effect of the prescription drug coverage gap on drug utilization and expenditures. Beneficiaries in the study group were older (76.34 vs. 73.04 yr, P < .0001) and sicker (5.39 vs. 3.66 disease conditions, P < .0001) than those in the control group. They also incurred substantially higher out-of-pocket expenses ($2534 vs. $598, P < .0001) than the individuals in the control group. From the preperiod to the postperiod, the study group's average days of therapy decreased by 15.85% (from 1104 to 929, P < .0001), and total costs fell 28.02% (from $2441 to $1757, P < .0001). The average out-of-pocket costs increased by 88.94% (from $877 to $1657, P < .0001); in the control group, however, the average days of therapy increased by 1.77% (from 680 to 692), and total costs rose by 2.19% (from $1322 to $1351). Out-of-pocket costs decreased by 5.54% ($307 to $290). Using difference-indifference models, the Medicare part D prescription drug coverage gap was estimated to have reduced medication utilization by 187.49 days of therapy (P < .0001) while raising out-of-pocket costs by $796.49 (P < .0001) and increasing the generic utilization rate by 7.33% (P < .0001). Regular Medicare part D beneficiaries reduced medication utilization after they reached the coverage gap, which raises concerns those beneficiaries may face an increased risk of adverse health events.

Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization.

OBJECTIVE: Cyclo-oxygenase-2 (COX-2) inhibitors rofecoxib and valdecoxib were withdrawn from the market because of their association with cardiovascular problems. There is a lack of information on the impact of the COX-2 inhibitors withdrawal on the prescribing and utilization of related drugs. The main objective of this study was to evaluate to what extent prescriptions of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and gastroprotective drugs changed after the removal of the two COX-2 inhibitors. RESEARCH DESIGN AND METHODS: A segmented regression of interrupted time series approach was used to analyze prescription data from July 1, 2003 through December 31, 2005 from a pharmacy claims database maintained by a large pharmacy benefit manager (PBM). Patients continuously eligible for the pharmacy benefit but not enrolled in COX-2 or proton pump inhibitor (PPI) Step Care programs during the study period were included. The number of prescriptions per thousand patients per month for targeted drugs were analyzed and compared. RESULTS: A total of 175 193 patients were included in the analysis. After the withdrawal of the COX-2 inhibitor, the average monthly non-selective NSAID and PPI prescriptions per thousand patients increased from 13.96 to 19.63 (a change of 40.62%, p < 0.0001) and from 38.67 to 43.33 (a change of 12.05%, p < 0.0001) respectively, whereas COX-2 prescriptions decreased by 54.51% (from 23.61 to 10.74, p < 0.0001). Among non-selective NSAIDs, the five drugs with highest percentage increase were meloxicam (167.12%, from 1.46 to 3.90, p < 0.0001), etodolac (72.06%, from 0.68 to 1.17, p < 0.0001), piroxicam (58.33%, from 0.36 to 0.57, p < 0.0001), nabumetone (52.38%, from 1.26 to 1.92, p < 0.0001), and diclofenac (37.89%, from 1.61 to 2.22, p < 0.0001). LIMITATIONS: This study was restricted to patients with employer-sponsored drug coverage which might not be representative of the national population. Since over-the-counter (OTC) PPI, non-selective NSAID and H2RA were not captured in our claims data, we were unable to examine whether and to what extent the utilization of these drugs has changed. Additionally, the direct impact of these changes on population based outcomes is unknown. CONCLUSIONS: After the withdrawal of COX-2 inhibitors rofecoxib and valdecoxib, there were significant increases in non-selective NSAID and PPI prescriptions but not H2RA and misoprostol. Given the safety concerns with the NSAIDs, further studies are warranted regarding the clinical outcomes associated with the increased use of non-selective NSAIDs with or without gastroprotective agents.

The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas.

Aberrant activation of the wingless-type- (Wnt)-signaling pathway is common in many cancers including nasopharyngeal (NPC) and esophageal squamous cell (ESCC) carcinomas, both prevalent in Southern China and Southeast Asia. However, the molecular mechanism leading to this abnormality is still obscure. Wnt inhibitory factor-1 (WIF1) is a secreted antagonist of the Wnt pathway, and is recently shown to be inactivated by epigenetic mechanism in some tumors. Here, we examined whether WIF1 is also inactivated epigenetically in NPC and ESCC. With semiquantitative reverse transcription-PCR and methylation-specific PCR, we detected WIF1 downregulation or silencing in 6/6 of NPC and 12/19 of ESCC cell lines, which is well correlated with its methylation status. Methylation was further confirmed by high-resolution bisulfite genomic sequencing. Methylation was also frequently observed in a large collection of primary tumors of NPC (85%, 55/65) and ESCC (27%, 25/92), with WIF1 expressed and unmethylated in normal NPC and esophageal cell lines and normal tissues. Treatment of 5-aza-2'-deoxycytidine demethylated WIF1 and induced its expression in NPC and ESCC cell lines, highlighting a direct role of epigenetic inactivation. Ectopic expression of WIF1 in NPC and ESCC tumor cells resulted in significant inhibition of tumor cell colony formation, similar to TP53, and also significant downregulation of beta-catenin protein level in NPC cells. Thus, WIF1 functions as a tumor suppressor for both NPC and ESCC through suppressing the Wnt-signaling pathway, but is frequently silenced by epigenetic mechanism in a tumor-specific way. Our study indicates that epigenetic inactivation of WIF1 contributes to the aberrant activation of Wnt pathway and is involved in the pathogenesis of both tumors. WIF1 methylation could also serve as a specific biomarker for these tumors.

Application of variables control charts to risk-adjusted time-ordered healthcare data.

In a previous article (M. K. Hart, Qual Manag Health Care. 2003;12(1):5-19), the authors presented risk-adjusted control charts applicable for attributes data. The present article discusses a similar class of control charts applicable for variables data that are often skewed. The key feature of these charts is their application of risk-adjusted data in addition to actual performance data. The resulting charts should decrease the occurrence of both type I and type II errors as compared to the unadjusted control charts. This article presents several control charts that vary in the data transformation and combination approaches. Data depicting hospital length of stay following coronary artery bypass graft procedures were used to illustrate the use of transformed and risk-adjusted control charts.

Application of attribute control charts to risk-adjusted data for monitoring and improving health care performance.

This article proposes a new class of control charts that may be used for monitoring and improving the quality of care. Unlike conventional control charts that rely on observed performance data, these charts use risk-adjusted data in addition to the observed data. The resulting time-ordered charts are capable of reducing time-to-time variation that may stem from uncontrollable changes in patient mix over time. Depending on how observed and risk-adjusted data are combined, proposed charts are categorized under the framework of either additive or multiplicative models. Risk-adjusted rates are obtained using multivariate logistic regression models. It was found that the risk-adjusted control charts could be effective in reducing biases that arise from variation in patient mix. These charts can potentially achieve higher sensitivity and specificity compared with ordinary control charts.

Using comparison charts to assess performance measurement data.

BACKGROUND: In 1997 the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) announced the ORYX initiative, which integrates outcomes and other performance measurement data into the accreditation process. JCAHO uses control and comparison charts to identify performance trends and patterns that are provided to JCAHO surveyors in advance of a health care organization's (HCO's) survey. During the survey, the HCO is asked to explain its rationale for its selection of performance measures, how the ORYX data have been analyzed and used to improve performance, and the outcomes of these activities. CONSTRUCTING COMPARISON CHARTS: A comparison chart, a graphical summary of the comparison analysis, consists of actual (or observed) rates, expected rates, and expected ranges (upper and lower limits) for a given time frame. The expected range describes the degree of certainty that a given point is different from the average score (population). THE USE OF COMPARISON CHARTS: Comparison charts are primarily useful for telling an HCO whether one of its selected performance measures may be evidencing one of the three types of measurement outcomes: exemplary performance, average performance, or substandard performance (indicating an opportunity for improvement). The comparison charts compare an HCO's outcomes to those of its comparison group or to its risk-adjusted data. The charts provide guidance to an HCO about whether it should continue to monitor a process so as to maintain its current level of performance or whether it should try to improve its current performance.