Citations

Background— The clinical significance of incomplete coronary revascularization (ICR) after percutaneous coronary intervention in patients with acute coronary syndromes is unknown. Methods and Results— We performed quantitative angiography of the entire coronary tree in 2954 patients with acute coronary syndromes in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. ICR was variably defined if any lesion with diameter stenosis (DS) cutoffs ranging from ≥30% to ≥70% with reference vessel diameter ≥2.0 mm remained after percutaneous coronary intervention. The primary outcome was 1-year composite rate of major adverse cardiac events (death, myocardial infarction, or ischemia-driven unplanned revascularization). With the use of DS cutoffs ≥30%, ≥40%, ≥50%, ≥60%, and ≥70%, the prevalence of ICR after percutaneous coronary intervention was 75%, 55%, 37%, 25%, and 17%, respectively. The 1-year major adverse cardiac event rate was increased among patients with ICR using all of the DS cutoffs. ICR (≥50% DS) was associated with higher 1-year rates of myocardial infarction (12.0% versus 8.2%; hazard ratio, 1.50; 95% confidence interval, 1.18–1.89; P =0.0007) and ischemia-driven unplanned revascularization (15.7% versus 10.2%; hazard ratio, 1.58; 95% confidence interval, 1.28–1.96; P <0.0001), with a trend toward increased mortality (3.1% versus 2.2%; hazard ratio, 1.43; 95% confidence interval, 0.90–2.27; P =0.13). By multivariable analysis, ICR (≥50% DS) was an independent predictor of 1-year major adverse cardiac events (hazard ratio, 1.36; 95% confidence interval, 1.12–1.64; P =0.002). The impact of ICR on major adverse cardiac events was similar regardless of chronic total occlusion presence, but it was more pronounced with a greater number of nonrevascularized lesions. Conclusions— Depending on the threshold of percent DS, ICR was present in 17% to 75% of patients with acute coronary syndromes after percutaneous coronary intervention. Regardless of the threshold, ICR was strongly associated with 1-year myocardial infarction, ischemia-driven unplanned revascularization, and major adverse cardiac events. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00093158.

SummaryPreviously, we reported increased risk of heavy‐chain (HC) monoclonal gammopathy of undetermined significance (MGUS) among first‐degree (1°) relatives of multiple myeloma (MM) or HC‐MGUS probands. This study investigated whether there was comparable risk for light‐chain (LC) MGUS among 911 relatives of the same HC‐MGUS/MM probands versus a reference population of 21 463. Seventeen 1° relatives had LC‐MGUS (adjusted prevalence = 1·7%, 95% CI = 0·9–2·6%). There was increased risk of LC‐MGUS in relatives of MM probands (RR = 3·4, 95% CI = 2·0–5·5). We saw no increased risk in relatives of HC‐MGUS probands. We conclude that the prevalence of LC‐MGUS is significantly higher among 1° relatives of MM probands compared to the reference population.

Abstract Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma (MM), is one of the most common premalignant conditions in the general population. The cause of MGUS is largely unknown. Recent studies show that there is an increased prevalence of MGUS in blood relatives of persons with lymphoproliferative and plasma cell proliferative disorders, suggesting presence of shared underlying genetic influences. In the past few years, additional studies have examined risk factors and biologic characteristics that may contribute to the increased prevalence of MGUS among relatives of probands with MGUS, MM, and other blood malignancies. This article reviews the known epidemiology and risk factors for familial MGUS and myeloma, the risk of lymphoproliferative disorders and other malignancies among blood-relatives of patients with MGUS and MM, and discusses future directions for research.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Abstract Routine incorporation of FISH into multiple myeloma (MM) diagnostic testing has led to a better appreciation of the heterogeneity of genetic abnormalities associated with this disease. We studied a group of 484 patients with newly diagnosed symptomatic MM to better understand the prevalence of the various abnormalities and the prognostic significance of the overlapping abnormalities. A translocation involving the IgH locus and 1 of the 5 recurrent partner chromosomes was seen in 161 (33%) patients, and 275 (57%) had trisomy of at least 1 odd-numbered chromosome. High-risk FISH, defined as the presence of t(4;14), t(14;16), t(14;20), or loss of P53, was seen in 115 (24%) patients; the median overall survival for this group was 3.9 years, compared with “not reached” for standard-risk patients (P < .001). Among the patients with high-risk FISH, 49 patients who also had at least 1 trisomy had a median overall survival that was not reached, compared with 3 years for high-risk patients without a concurrent trisomy (P = .01). Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers.

PRSS3/mesotrypsin is an atypical isoform of trypsin, the up-regulation of which has been implicated in promoting tumour progression. Mesotrypsin inhibitors could potentially provide valuable research tools and novel therapeutics, but small-molecule trypsin inhibitors have low affinity and little selectivity, whereas protein trypsin inhibitors bind poorly and are rapidly degraded by mesotrypsin. In the present study, we use mutagenesis of a mesotrypsin substrate, APPI (amyloid precursor protein Kunitz protease inhibitor domain), and of a poor mesotrypsin inhibitor, BPTI (bovine pancreatic trypsin inhibitor), to dissect mesotrypsin specificity at the key P2′ position. We find that bulky and charged residues strongly disfavour binding, whereas acidic residues facilitate catalysis. Crystal structures of mesotrypsin complexes with BPTI variants provide structural insights into mesotrypsin specificity and inhibition. Through optimization of the P1 and P2′ residues of BPTI, we generate a stable high-affinity mesotrypsin inhibitor with an equilibrium binding constant Ki of 5.9 nM, a &gt;2000-fold improvement in affinity over native BPTI. Using this engineered inhibitor, we demonstrate the efficacy of pharmacological inhibition of mesotrypsin in assays of breast cancer cell malignant growth and pancreatic cancer cell invasion. Although further improvements in inhibitor selectivity will be important before clinical potential can be realized, the results of the present study support the feasibility of engineering protein protease inhibitors of mesotrypsin and highlight their therapeutic potential.

We reviewed surrogate calls (i.e. those made on behalf of the patient) to a national triage call centre to determine whether there were differences between calls made by surrogates and self calls. During a three-year period there were 14,646 calls (14% of the total) made by a surrogate on behalf of the patient. Surrogate calls, as a percentage of total calls, increased with the age of the patient from 12% in the 18–34 year age group to 43% in the 80 and over age group ( P < 0.0001). The symptoms of vomiting or nausea and dizziness or light-headedness were significantly more likely to be reported by surrogate callers than self callers. Surrogates reported a higher original intention of taking patients to the hospital emergency department (ED) compared with self callers across all adult age groups (OR 1.64; 95% CI 1.57 to 1.71). A higher proportion (38%) of surrogate calls ended with the nurse recommending an ED visit compared with only 26% of self calls (OR 1.72; 95% CI 1.66 to 1.79). Calls about men accounted for 54% of surrogate calls but only 26% of self calls (OR 3.3; 95% CI 3.2 to 3.4), suggesting that surrogate calls may be a way of increasing medical access for men.