Citations

Background— Few studies have compared medium-term outcomes for drug-eluting stents (DES) and bare metal stents, and most are relatively small randomized controlled trials. Furthermore, since the introduction of DES, there has been increased use and duration of use of clopidogrel, statins, and other evidence-based therapies. The purpose of the present study was to compare outcomes for patients who underwent stenting in the eras before and after the introduction of DES. Methods and Results— New York state patients undergoing stenting in all nonfederal hospitals in the state were studied. Patients were excluded if they had a previous revascularization. Risk factors that were significant predictors of adverse outcomes were used to adjust adverse outcome rates. The study included 11 436 patients who received stents between October 1, 2002, and March 31, 2003, and 12 926 patients who underwent stenting between October 1, 2003, and March 31, 2004. Death rates, the combined end point of death and myocardial infarction (MI), nonfatal MI requiring readmission, target vessel revascularization, and target lesion revascularization were compared at 2 years. Patients in the DES era had significantly better risk-adjusted outcomes for death/MI (adjusted hazard ratio, 0.90; 95% confidence interval, 0.83 to 0.97), 9.9% versus 10.8%; nonfatal MI requiring readmission (adjusted hazard ratio, 0.86; 95% confidence interval, 0.76 to 0.97); target vessel revascularization (adjusted hazard ratio, 0.60; 95% confidence interval, 0.56 to 0.64), 11.2% versus 17.9%; and target lesion revascularization (hazard ratio, 0.55; 95% confidence interval, 0.51 to 0.59), 8.4% versus 14.7%. Conclusions— Patients in the DES era experienced lower rates of death/MI, nonfatal MI, target vessel revascularization, and target lesion revascularization, but there were no differences in the rates of death. These improvements are likely a result of increased use of clopidogrel, statins, and dual antiplatelet therapy, in addition to the introduction of DES.

Purpose To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer. Patients and Methods In part A, patients received escalating doses to determine the maximum-tolerated dose (MTD). In both parts, blood samples were collected to assess PK and PD parameters. In part B, patients were stratified by cancer type (melanoma v other) and randomly assigned to receive the MTD or 50% MTD. Biopsies were collected to determine inhibition of ERK phosphorylation, Ki-67 expression, and BRAF, KRAS, and NRAS mutations. Results Fifty-seven patients were enrolled. MTD in part A was 200 mg bid, but this dose was discontinued in part B because of toxicity. The 50% MTD (100 mg bid) was well tolerated. Rash was the most frequent and dose-limiting toxicity. Most other adverse events were grade 1 or 2. The PKs were less than dose proportional, with a median half-life of approximately 8 hours and inhibition of ERK phosphorylation in peripheral-blood mononuclear cells at all dose levels. Paired tumor biopsies demonstrated reduced ERK phosphorylation (geometric mean, 79%). Five of 20 patients demonstrated ≥ 50% inhibition of Ki-67 expression, and RAF or RAS mutations were detected in 10 of 26 assessable tumor samples. Nine patients had stable disease (SD) for ≥ 5 months, including two patients with SD for 19 (thyroid cancer) and 22 (uveal melanoma plus renal cancer) 28-day cycles. Conclusion AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing.

Abstract Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% ± 5% vs 88% ± 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Insitute high-risk (NCI HR) patients who were MRD+. The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.

Abstract Rationale The 2002 American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias identified nonspecific interstitial pneumonia (NSIP) as a provisional diagnosis. Concern was expressed that NSIP was a “wastebasket” category, difficult to distinguish from other idiopathic interstitial pneumonias. Objectives The following questions were addressed: (1) Is idiopathic NSIP a distinct entity? 2) If so, what are its clinical, radiologic and pathologic characteristics? (3) What is the role of radiology and pathology in establishing the diagnosis? (4) To make a diagnosis of idiopathic NSIP, what other disorders need to be excluded and how should this be done? Methods Investigators who had previously reported cases of idiopathic NSIP were invited to submit cases for review (n = 305). After initial review, cases with complete clinical, radiologic, and pathologic information (n = 193) were reviewed in a series of workshops. Measurements and Main Results Sixty-seven cases were identified as NSIP. Mean age was 52 years, 67% were women, 69% were never-smokers, and 46% were from Asian countries. The most common symptoms were dyspnea (96%) and cough (87%); 69% had restriction. By high-resolution computed tomography, the lower lung zones were predominantly involved in 92% of cases; 46% had a peripheral distribution; 47% were diffuse. Most showed a reticular pattern (87%) with traction bronchiectasis (82%) and volume loss (77%). Lung biopsies showed uniform thickening of alveolar walls with a spectrum of cellular to fibrosing patterns. Five-year survival was 82.3%. Conclusions Idiopathic NSIP is a distinct clinical entity that occurs mostly in middle-aged women who are never-smokers. The prognosis of NSIP is very good.

Abstract Investment analysts are a growing presence at the Annual Meeting of the American Society of Hematology (ASH), and financial professionals frequently contact ASH members for information and perspective on drugs, devices, and scientific developments. Recent incidents have raised concerns about consulting relationships between physicians and the investment industry; the appropriate role of medical societies in influencing these relationships is unclear. In this essay, I summarize the current situation, discuss potential risks and benefits from interactions between physicians and investment analysts, and outline issues that all individuals involved in investment industry consulting should consider. I also propose changes in ASH policy that may help safeguard public trust as well as preserve the access of clinicians and scientists to clinically relevant data presented at the Annual Meeting.

Abstract Dysfunction in enzymes involved in one-carbon (1-C) metabolism can lead to increased chromosomal strand breaking and abnormal methylation patterns, which are both associated with cancer risk. Availability of 1-C units may modify risk. We investigated the association of single-nucleotide polymorphisms (SNP) in 21 genes in the 1-C transfer pathway among 829 Caucasian cases with primary epithelial ovarian cancer and 941 frequency-matched unaffected controls enrolled at Mayo Clinic (Rochester, MN) and Duke University (Durham, NC) and examined risk modification by multivitamin supplement use. Multivariable-adjusted SNP-specific logistic regression and haplotype analyses were done for 180 SNPs and false positive report probabilities (FPRP) were calculated. Each copy of the minor allele in SHMT1 intron 5 A>G (rs9909104) was associated with epithelial ovarian cancer [odds ratio (OR), 1.2; 95% confidence interval (95% CI), 1.0–1.4; P trend = 0.02; FPRP = 0.16] and a 5-SNP SHMT1 haplotype was associated with decreased risk (P = 0.01; FPRP = 0.09). Three SNPs in DNMT3A were associated with risk among multivitamin supplement users: 3′ untranslated region (UTR) C>G (rs13420827: OR, 0.8; 95% CI, 0.6–1.0; P interaction = 0.006; FPRP = 0.54), intron 6 G>A (rs11887120: OR, 0.8; 95% CI, 0.7–1.0; P interaction = 0.007; FPRP = 0.57), and intron 22 A>T (rs11695471: OR, 1.2; 95% CI, 1.0–1.5; P interaction = 0.01; FPRP = 0.66). These data extend previous findings from other cancers of a role for SHMT1 in ovarian cancer, and provide evidence that SNPs in methylation and DNA synthesis reactions are associated with risk of ovarian cancer. Interventions with modifiable factors such as multivitamin intake may reduce risk. [Cancer Res 2008;68(7):2498–506]

Purpose Early clinical studies with gefitinib showed promising efficacy and mild toxicity in patients with advanced non–small-cell lung cancer (NSCLC). Thus, gefitinib was an ideal agent to evaluate in a maintenance setting in stage III disease. Patients and Methods Untreated patients with stage III NSCLC, a performance score of 0 to 1, and adequate organ function were eligible. All patients received cisplatin 50 mg/m 2 on days 1 and 8 plus etoposide 50 mg/m 2 on days 1 to 5, every 28 days for two cycles with concurrent thoracic radiation (1.8- to 2-Gy fractions per day; total dose, 61 Gy) followed by three cycles of docetaxel 75 mg/m 2 . Patients whose disease did not progress were randomly assigned to gefitinib 250 mg/d or placebo until disease progression, intolerable toxicity, or the end of 5 years. The planned sample size was 672 patients to confer power of 0.89 to detect a 33% increase over the expected median survival time of 21 months (one-sided P = .025, log-rank test). Random assignment was stratified by stage, histology, and measurable versus nonmeasurable disease. Results Enrollment began in July 2001. An unplanned interim analysis conducted in April 2005 rejected the alternative hypothesis of improved survival at the P = .0015 level for 243 randomly assigned patients. The study closed, and preliminary results were reported. Now, with a median follow-up time of 27 months, median survival time was 23 months for gefitinib (n = 118) and 35 months for placebo (n = 125; two-sided P = .013). The toxic death rate was 2% with gefitinib compared with 0% for placebo. Conclusion In this unselected population, gefitinib did not improve survival. Decreased survival was a result of tumor progression and not gefitinib toxicity.

AbstractBackgroundToxic multinodular goiter (Plummer’s disease) has posed challenges to surgeons, endocrinologists, and radiation oncologists since its description in 1913. A literature review with evidenced‐based methodology has not yet been reported.MethodsA systematic review of the English literature from 1950 to 2007 and report of Mayo Clinic experience since 1950 was undertaken to establish evidence‐based recommendations for management.ResultsSurgery and radioactive iodine (RI) are both supported by level IV evidence in the treatment of solitary toxic nodules and toxic multinodular goiter, and treatment is determined by symptoms and co‐morbidities. No evidence suggests a difference in treatment outcome based on pretreatment clinical or subclinical hyperthyroidism. Level IV evidence supports thyroidectomy over RI for large goiters. When compressive symptoms are present, level IV evidence supports thyroidectomy for maximal symptom relief in patients at moderate risk. Occult malignancies are found in 2–3% of thyroidectomy specimens for Plummer’s disease. Despite technical reports of RI dose considerations, there are no prospective studies validating a dose formula. Ethanol ablation of toxic nodules in patients unfit for surgery is supported by level III evidence. Level V data suggest a cost benefit favoring surgery.ConclusionsTreatment of Plummer’s disease with antithyroid medications, ethanol ablation, RI ablation, or surgery must balance the goals of therapy, durability of cure, relief of symptoms, risk of malignancy, and risk of complications. Between 1950 and 2006, 948 (70%) of 1,356 patients with Plummer’s disease have been treated surgically at Mayo Clinic.