Citations

BACKGROUNDFluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) tests are commonly used to assess human epidermal growth factor 2 (HER2) status of tumors in patients with breast cancer. This analysis evaluates the likely cost‐effectiveness of expanded retesting to assess HER2 tumor status in women with early stage breast cancer.METHODSWe developed a decision‐analytic model to estimate the incremental cost‐effectiveness ratio (ICER) of expanded reflex testing from a US payer perspective. Expanded reflex testing is defined as retesting tumor specimens from patients whose tumors are IHC0, IHC1+, or FISH‐negative on their first test. In the base case, we assumed that 80% of patient tumors are initially IHC‐tested and 20% are FISH‐tested. Testing outcomes for IHC and FISH with and without retesting were based on published meta‐analyses. The cost of tests and treatment and the long‐term health outcomes were obtained from the literature.RESULTSIn the base case, we estimated that 2.27% of women who received expanded reflex testing would be HER2‐positive and receive trastuzumab treatment: the projected ICER was $36,721 per life year or $39,745 per quality‐adjusted life year (QALY). This varied between $47,100 per QALY and $35,500 per QALY if we assumed that 1%‐8% of patients retested were then HER2+, respectively. The results of deterministic and probabilistic sensitivity analysis were robust. This strategy would result in 4700 (2000‐17,000) patients being eligible to receive trastuzumab treatment annually.CONCLUSIONSRetesting patients who are IHC0, IHC1+, or FISH‐negative is projected to be a cost‐effective clinical strategy. Cancer 2013;119:3113–3122. © 2013 American Cancer Society.

OBJECTIVEThe Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN).RESEARCH DESIGN AND METHODSDPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates.RESULTSResults are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01).CONCLUSIONSAmong patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.

ObjectiveTo identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA).MethodsWe carried out a genome‐wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls.ResultsGenome‐wide significant associations were identified in 32 single‐nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA–DPB1 and HLA–DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10−50 and 2.18 × 10−39, respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA–DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome‐wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10−8).ConclusionWe identified the SEMA6A and HLA–DP loci as significant contributors to risk for GPA, with the HLA–DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.

Genetic College Many genomic elements in humans are associated with behavior, including educational attainment. In a genome-wide association study including more than 100,000 samples, Rietveld et al. (p. 1467 , published online 30 May; see the Perspective by Flint and Munafò ) looked for genes related to educational attainment in Caucasians. Small genetic effects at three loci appeared to impact educational attainment.

Background The etiologies of ischemic stroke remain undetermined in 15% to 40% of patients. Apart from atrial fibrillation, other arrhythmias are less well‐characterized as risk factors. Premature cardiac contractions are known to confer long‐term cardiovascular risks, like myocardial infarction. Ischemic stroke as cardiovascular risk outcome remains a topic of interest. We examined the prospective relationships in the Atherosclerosis Risk in Communities ( ARIC ) study, to determine whether premature atrial ( PAC ) or ventricular ( PVC ) contractions are associated with increased risk for incident ischemic stroke. Methods and Results We analyzed 14 493 baseline stroke‐free middle‐aged individuals in the ARIC public‐use data. The presence of PAC or PVC at baseline was assessed from 2‐minute electrocardiogram. A physician‐panel confirmed and classified all stroke cases. Average follow‐up time was 13 years. Proportional hazards models assessed associations between premature contractions and incident stroke. PAC s and PVC s were identified in 717 (4.9%) and 793 (5.5%) participants, respectively. In all, 509(3.5%) participants developed ischemic stroke. The hazard ratio ( HR ) (95% confidence interval [ CI ]) associated with PVC was 1.77 (1.30, 2.41), attenuated to 1.25 (0.91, 1.71) after adjusting for baseline stroke risk factors. The interaction between PVC and baseline hypertension was marginally significant ( P =0.08). Among normotensives, having PVC s was associated with nearly 2‐fold increase in the rate of incident ischemic stroke ( HR 1.69; 95% CI 1.02, 2.78), adjusting for stroke risk factors. The adjusted risk of ischemic stroke associated with PAC s was 1.30 (95% CI 0.92, 1.83). Conclusions Presence of PVC s may indicate an increased risk of ischemic stroke, especially in normotensives. This risk approximates risk of stroke from being black, male, or obese in normotensives from this cohort.

This white paper, prepared by a working group of the Catholic Medical Association, provides a commentary on a new type of end-of-life document called a POLST form (Physician Orders for Life-Sustaining Treatment) as well as on its model (or “paradigm”) for implementation across the United States. After an introductory section reviewing the origin, goals, and standard defenses of the POLST paradigm and form, the paper offers a critical analysis of POLST, including an analysis of the risks that POLST poses to sound clinical and ethical decision-making. The paper ends with several recommendations to help Catholic healthcare professionals and institutions better address the challenges of end-of-life care with alternatives to POLST.