Mass General Brigham

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology. The Cancer Genome Atlas (TCGA) project reports here its analysis of messenger RNA and microRNA expression, promoter methylation, DNA copy number and exome sequences in 489 high-grade serous ovarian adenocarcinomas. The analyses help establish new tumour subtypes. Among other insights is the finding that while the gene encoding p53 tumour suppressor is mutated in almost all tumours, nine other loci including NF1, BRCA1, BRCA2, RB1 and CDK12 carry recurrent albeit low-prevalence mutations. Homologous recombination is defective in about half of the tumours studied, and Notch and FOXM1 signalling are involved in the pathophysiology.

BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

The attraction of leukocytes to tissues is essential for inflammation and the host response to infection. The process is controlled by chemokines, which are chemotactic cytokines. This review introduces the burgeoning family of cytokines, with special emphasis on their role in the pathophysiology of disease and their potential as targets for therapy.Structure and Function of ChemokinesOver 40 chemokines have been identified to date, most of them in the past few years. The relations among chemokines were not initially appreciated, which led to an idiosyncratic nomenclature consisting of many acronyms. When initially identified, these proteins had no known biologic . . .

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).

Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide and thus represents a viral pandemic, one that is five times as widespread as infection with the human immunodeficiency virus type 1 (HIV-1). The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure. Progression to chronic disease occurs in the majority of HCV-infected persons, and infection with the virus has become the main indication . . .

BACKGROUND: The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS: We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS: The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS: The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed. CONCLUSIONS: Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).

PURPOSE: The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. PATIENTS AND METHODS: Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. RESULTS: Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. CONCLUSION: EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.

Virus-specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. In individuals who control viremia in the absence of antiviral therapy, polyclonal, persistent, and vigorous HIV-1-specific CD4+ T cell proliferative responses were present, resulting in the elaboration of interferon-gamma and antiviral beta chemokines. In persons with chronic infection, HIV-1-specific proliferative responses to p24 were inversely related to viral load. Strong HIV-1-specific proliferative responses were also detected following treatment of acutely infected persons with potent antiviral therapy. The HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.

IMPORTANCE: Targeting oncogenic drivers (genomic alterations critical to cancer development and maintenance) has transformed the care of patients with lung adenocarcinomas. The Lung Cancer Mutation Consortium was formed to perform multiplexed assays testing adenocarcinomas of the lung for drivers in 10 genes to enable clinicians to select targeted treatments and enroll patients into clinical trials. OBJECTIVES: To determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select treatments targeting the identified driver(s) and measure survival. DESIGN, SETTING, AND PARTICIPANTS: From 2009 through 2012, 14 sites in the United States enrolled patients with metastatic lung adenocarcinomas and a performance status of 0 through 2 and tested their tumors for 10 drivers. Information was collected on patients, therapies, and survival. INTERVENTIONS: Tumors were tested for 10 oncogenic drivers, and results were used to select matched targeted therapies. MAIN OUTCOMES AND MEASURES: Determination of the frequency of oncogenic drivers, the proportion of patients treated with genotype-directed therapy, and survival. RESULTS: From 2009 through 2012, tumors from 1007 patients were tested for at least 1 gene and 733 for 10 genes (patients with full genotyping). An oncogenic driver was found in 466 of 733 patients (64%). Among these 733 tumors, 182 tumors (25%) had the KRAS driver; sensitizing EGFR, 122 (17%); ALK rearrangements, 57 (8%); other EGFR, 29 (4%); 2 or more genes, 24 (3%); ERBB2 (formerly HER2), 19 (3%); BRAF, 16 (2%); PIK3CA, 6 (<1%); MET amplification, 5 (<1%); NRAS, 5 (<1%); MEK1, 1 (<1%); AKT1, 0. Results were used to select a targeted therapy or trial in 275 of 1007 patients (28%). The median survival was 3.5 years (interquartile range [IQR], 1.96-7.70) for the 260 patients with an oncogenic driver and genotype-directed therapy compared with 2.4 years (IQR, 0.88-6.20) for the 318 patients with any oncogenic driver(s) who did not receive genotype-directed therapy (propensity score-adjusted hazard ratio, 0.69 [95% CI, 0.53-0.9], P = .006). CONCLUSIONS AND RELEVANCE: Actionable drivers were detected in 64% of lung adenocarcinomas. Multiplexed testing aided physicians in selecting therapies. Although individuals with drivers receiving a matched targeted agent lived longer, randomized trials are required to determine if targeting therapy based on oncogenic drivers improves survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01014286.

CONTEXT: Plasma levels of the inflammatory biomarker C-reactive protein (CRP) predict cardiovascular risk, and retrospective studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may lower CRP in a manner largely independent of low-density lipoprotein cholesterol (LDL-C). However, prospective trial data directly evaluating this anti-inflammatory effect of statins are not available. OBJECTIVE: To test the hypothesis that pravastatin has anti-inflammatory effects as evidenced by CRP reduction. DESIGN, SETTING, AND PARTICIPANTS: Community-based, prospective, randomized, double-blind trial including 1702 men and women with no prior history of cardiovascular disease (primary prevention cohort) and open-label study including 1182 patients with known cardiovascular disease (secondary prevention cohort) who provided at least baseline and 12-week blood samples. The study was conducted in US office-based practices from February to December 2000. INTERVENTIONS: Participants in the double-blind primary prevention trial were randomly assigned to receive 40 mg/d of pravastatin (n = 865) or placebo (n = 837) for 24 weeks. Participants in the secondary prevention cohort received 40 mg/d of open-label pravastatin for 24 weeks. MAIN OUTCOME MEASURE: Change in CRP levels from baseline to 24 weeks. RESULTS: In the primary prevention trial, compared with placebo, pravastatin reduced median CRP levels by 16.9% (P<.001) at 24 weeks, reflecting a decrease of 0.02 mg/dL in the pravastatin group while no change in CRP levels was observed in the placebo group. This effect was seen as early as 12 weeks (median reduction in CRP with pravastatin, 14.7%; P<.001) and was present among all prespecified subgroups according to sex, age, smoking status, body mass index, baseline lipid levels, presence of diabetes, and use of aspirin or hormone replacement therapy. No significant association was observed between baseline CRP and baseline LDL-C levels, end-of-study CRP and end-of-study LDL-C levels, or change in CRP and change in LDL-C levels over time. In linear regression analyses, the only significant predictors of change in CRP on a log scale were randomized pravastatin allocation and baseline CRP levels (P<.001 for both). Similar reductions in CRP levels were observed at 12 weeks (-14.3%) and 24 weeks (-13.1%) in the secondary prevention cohort treated with pravastatin (P<.005 for both). CONCLUSIONS: In this prospective trial, pravastatin reduced CRP levels at both 12 and 24 weeks in a largely LDL-C-independent manner. These data provide evidence that statins may have anti-inflammatory effects in addition to lipid-lowering effects.

BACKGROUND AND OBJECTIVES: We introduce and clinically examine a new concept of skin treatment called fractional photothermolysis (FP), achieved by applying an array of microscopic treatment zones (MTZ) of thermal injury to the skin. STUDY DESIGN/MATERIALS AND METHODS: Two prototype devices emitting at 1.5 microm wavelength provided a pattern of micro-exposures with variable MTZ density. Effects of different MTZ densities were tested on the forearms of 15 subjects. Clinical effects and histology were assessed up to 3 months after exposure. Treatment of photoaged skin on the periorbital area in an additional 30 subjects receiving four treatments over a period of 2-3 weeks was also tested. Tissue shrinkage and clinical effects were assessed up to 3 months after treatment. RESULTS: Pattern densities with spacing of 250 microm or more were well tolerated. Typical MTZ had a diameter of 100 microm and penetrated 300 microm into the skin. Reepithelialization was complete within 1 day. Clinical effects were assessed over a 3-month period. Histology at 3 months revealed enhanced undulating rete ridges and increased mucin deposition within the superficial dermis. Periorbital treatments were well tolerated with minimal erythema and edema. Linear shrinkage of 2.1% was measured 3 months after the last treatment. The wrinkle score improved 18% (P < 0.001) 3 months after the last treatment. CONCLUSIONS: FP is a new concept for skin restoration treatment. Safety and efficacy were demonstrated with a prototype device. Further clinical studies are necessary to refine the optimum parameters and to explore further dermatological applications.

ealth care is growing increasingly complex, and most clinical research focuses on new approaches to diagnosis and treatment. In contrast, relatively little effort has been targeted at the perfection of operational systems, which are partly responsible for the well-documented problems with medical safety. 1 If medicine is to achieve major gains in quality, it must be transformed, and information technology will play a key part, 2 especially with respect to safety.

On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death.

Tthe end of every century it is customary to reflect on the events of the past hundred years and to look toward the future, and in this lecture I should like to do this for cardiovascular disease. This is also an especially opportune time to comment on progress in cardiovascular disease, because both the National Heart, Lung, and Blood Institute and the American Heart Association are celebrating their golden anniversaries within the next 18 months. These two organizations have had the most profound influence on the development of research on cardiovascular disease during the 20th century. A bewildering amount of . . .

SUMMARY: The interpretation of genome-wide association results is confounded by linkage disequilibrium between nearby alleles. We have developed a flexible bioinformatics query tool for single-nucleotide polymorphisms (SNPs) to identify and to annotate nearby SNPs in linkage disequilibrium (proxies) based on HapMap. By offering functionality to generate graphical plots for these data, the SNAP server will facilitate interpretation and comparison of genome-wide association study results, and the design of fine-mapping experiments (by delineating genomic regions harboring associated variants and their proxies). AVAILABILITY: SNAP server is available at http://www.broad.mit.edu/mpg/snap/.

While evidence-based medicine has increasingly broad-based support in health care, it remains difficult to get physicians to actually practice it. Across most domains in medicine, practice has lagged behind knowledge by at least several years. The authors believe that the key tools for closing this gap will be information systems that provide decision support to users at the time they make decisions, which should result in improved quality of care. Furthermore, providers make many errors, and clinical decision support can be useful for finding and preventing such errors. Over the last eight years the authors have implemented and studied the impact of decision support across a broad array of domains and have found a number of common elements important to success. The goal of this report is to discuss these lessons learned in the interest of informing the efforts of others working to make the practice of evidence-based medicine a reality.

BACKGROUND: Iatrogenic injuries related to medications are common, costly, and clinically significant. Computerized physician order entry (CPOE) and clinical decision support systems (CDSSs) may reduce medication error rates. METHODS: We identified trials that evaluated the effects of CPOE and CDSSs on medication safety by electronically searching MEDLINE and the Cochrane Library and by manually searching the bibliographies of retrieved articles. Studies were included for systematic review if the design was a randomized controlled trial, a nonrandomized controlled trial, or an observational study with controls and if the measured outcomes were clinical (eg, adverse drug events) or surrogate (eg, medication errors) markers. Two reviewers extracted all the data. Discussion resolved any disagreements. RESULTS: Five trials assessing CPOE and 7 assessing isolated CDSSs met the criteria. Of the CPOE studies, 2 demonstrated a marked decrease in the serious medication error rate, 1 an improvement in corollary orders, 1 an improvement in 5 prescribing behaviors, and 1 an improvement in nephrotoxic drug dose and frequency. Of the 7 studies evaluating isolated CDSSs, 3 demonstrated statistically significant improvements in antibiotic-associated medication errors or adverse drug events and 1 an improvement in theophylline-associated medication errors. The remaining 3 studies had nonsignificant results. CONCLUSIONS: Use of CPOE and isolated CDSSs can substantially reduce medication error rates, but most studies have not been powered to detect differences in adverse drug events and have evaluated a small number of "homegrown" systems. Research is needed to evaluate commercial systems, to compare the various applications, to identify key components of applications, and to identify factors related to successful implementation of these systems.

Acceleration in discovery of rare genetic variants possibly linked with disease may mean an increased risk of false-positive reports of causality; this Perspective proposes guidelines to distinguish disease-causing sequence variants from the many potentially functional variants in a human genome, and to assess confidence in their pathogenicity, and highlights priority areas for development. The wide-scale availability of high-throughput DNA sequencing technologies means that data on genetic variation in human diseases are accumulating rapidly. In this Perspective, Daniel MacArthur and colleagues sound a note of caution, pointing out that up to a quarter of reported disease-linked mutations have been found to either be common polymorphisms or have lacked sufficient evidence for pathogenicity. The authors discuss the key challenges associated with assessing sequence variants in human disease and propose guidelines for the robust differentiation between disease-causing genetic variants and other variants present in the human genome. They highlight several areas where research and resource development are urgently needed if genomic research findings are to be successfully translated into the clinical diagnostic setting. The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

BACKGROUND: Late stent thrombosis (LST) after Cypher and Taxus drug-eluting stent placement has emerged as a major concern. Although the clinical predictors of LST have been reported, specific morphological and histological correlates of LST remain unknown. METHODS AND RESULTS: From a registry totaling 81 human autopsies of drug-eluting stents, 46 (62 lesions) had a drug-eluting stent implanted >30 days. We identified 28 lesions with thrombus and compared those with 34 of similar duration without thrombosis using computer-guided morphometric and histological analyses. LST was defined as an acute thrombus within a coronary artery stent in place >30 days. Multiple logistic generalized estimating equations modeling demonstrated that endothelialization was the best predictor of thrombosis. The morphometric parameter that best correlated with endothelialization was the ratio of uncovered to total stent struts per section. A univariable logistic generalized estimating equations model of occurrence of thrombus in a stent section versus ratio of uncovered to total stent struts per section demonstrated a marked increase in risk for LST as the number of uncovered struts increased. The odds ratio for thrombus in a stent with a ratio of uncovered to total stent struts per section >30% is 9.0 (95% CI, 3.5 to 22). CONCLUSIONS: The most powerful histological predictor of stent thrombosis was endothelial coverage. The best morphometric predictor of LST was the ratio of uncovered to total stent struts. Heterogeneity of healing is a common finding in drug-eluting stents with evidence of LST and demonstrates the importance of incomplete healing of the stented segment in the pathophysiology of LST.