Citations

Background— Observed rates of restenosis after drug-eluting stenting are low (<10%). Identification of a reliable and powerful angiographic end point will be useful in future trials. Methods and Results— Late loss (postprocedural minimum lumen diameter minus 8-month minimum lumen diameter) was measured in the angiographic cohorts of the SIRIUS (n=703) and E-SIRIUS (n=308) trials. Two techniques, the standard normal approximation and an optimized power transformation, were used to predict binary angiographic restenosis rates and compare them with observed restenosis rates. The mean in-stent late loss observed in the SIRIUS trial was 0.17±0.45 mm (sirolimus) versus 1.00±0.70 mm (control). If a normal distribution was assumed, late loss accurately estimated in-stent binary angiographic restenosis for the control arm (predicted 35.4% versus observed 35.4%) but underestimated it in the sirolimus arm (predicted 0.6% versus observed 3.2%). Power transformation improved the reliability of the estimate in the sirolimus arm (predicted 3.2% [CI 1.0% to 6.7%]) with similar improvements in the E-SIRIUS trial (predicted 4.0% [CI 1.2% to 7.0%] versus observed 3.9%). In the sirolimus-eluting stent arm, in-stent late loss correlated better with target-lesion revascularization than in-segment late loss (c-statistic=0.915 versus 0.665). Conclusions— Because distributions of late loss with a low mean are right-skewed, the use of a transformation improves the accuracy of predicting low binary restenosis rates. Late loss is monotonically correlated with the probability of restenosis and yields a more efficient estimate of the restenosis process in the era of lower binary restenosis rates.

ABSTRACT OBJECTIVE To determine the clinical presentation, imaging characteristics, microscopic and ultrastructural characteristics, and treatment outcomes of patients with clinically silent pituitary corticotroph adenomas. METHODS All silent corticotroph adenomas diagnosed at the Mayo Clinic during the years 1975 through 1997 were selected from the files of the Mayo Tissue Registry. RESULTS We studied 23 cases, occurring in 16 male and 7 female patients (age range, 11–79 yr; mean age, 48 yr), who presented with headaches (50%), visual field defects (61%), extraocular muscle paresis (13%), hypopituitarism (26%), and galactorrhea/amenorrhea (43%/29% of the female patients). No patients exhibited clinical hypercortisolism. All tumors were macroadenomas (2.4 ± 0.8 cm; range, 1.5–4.0 cm) and exhibited suprasellar extension in 87% of the cases and hemorrhage, necrosis, and/or cystic changes in 61%. All tumors stained were variably periodic acid-Schiff-, adrenocorticotropic hormone-, and β-endorphin-positive, particularly Subtype I lesions. Ultrastructural classification was performed in 19 cases. In a comparison of Subtype I and II tumors, differences were observed with respect to sex (male/female, 1.4:1 versus 6:1), preoperative hyperprolactinemia (5 of 16 versus 0 of 6 cases), preoperative hypopituitarism (9 of 16 versus 5 of 7 cases), radiographic or gross invasion (7 of 16 versus 5 of 7 cases), and partial or total postoperative pituitary failure (6 of 16 versus 6 of 6 cases). The overall median postoperative follow-up period was 4.9 years (range, 0.3–16.6 yr); 54% of the patients had persistent or recurrent tumors. CONCLUSION Clinically silent corticotroph adenomas behave in an aggressive manner and are characterized by the following: lack of clinical signs or symptoms of Cushing's syndrome and normal cortisol levels; no or only minor elevations of serum adrenocorticotropic hormone levels; macroadenomas with hemorrhagic infarction; and presentation dominated by mass effect symptoms. The high persistence/recurrence rate underscores the need for long-term follow-up.

Background— Revascularization strategies often hinge on the presence and degree of left anterior descending coronary artery (LAD) stenosis. A decision for bypass surgery is often based on the durability of surgical LAD revascularization compared with percutaneous approaches. By decreasing restenosis, drug-eluting stents may have reduced the “reintervention gap” between surgery and percutaneous intervention, making the percutaneous route preferable. Methods and Results— Of the 1101 patients in the SIRIUS trial, 459 with an LAD stenosis were randomized to percutaneous intervention with either sirolimus-eluting or bare-metal stents. Baseline demographic, clinical, and angiographic data were obtained. Patients had 1-year clinical and 8-month angiographic follow-up. Baseline characteristics were similar in both groups. The majority of lesions were tubular type B lesions (69.7%) with a mean diameter of 2.73 mm and a mean length of 14.0 mm. The binary in-stent restenosis rate was 2% for the sirolimus stent group and 41.6% for the bare-metal arm (relative risk, 0.05; 95% CI, 0.02 to 0.1; P <0.001). One-year major adverse events (defined as cardiac death, Q-wave and non–Q-wave myocardial infarction, or target vessel revascularization) was decreased 59% in the sirolimus-stent group (9.8% versus 24.9%; relative risk, 0.39; 95% CI, 0.26 to 0.61; P <0.001). Subgroup analysis of 135 patients with proximal LAD lesions showed similar benefits. In-stent restenosis was 0 in the proximal LAD sirolimus-eluting group (n=67), compared with 38% in the bare-metal arm (n=68), and major adverse events demonstrated a similar trend, with a 50% decrease compared with control patients (10.4% versus 20.6%, P =NS). Conclusions— Sirolimus-eluting stents significantly decrease revascularization rates in LAD lesions. At 1 year, sirolimus-eluting stent revascularization rates are comparable to historic single vessel bypass surgery revascularization rates.

Purpose Low-dose computed tomography (CT) has been suggested for lung cancer screening. Several observational trials have published their preliminary results, and some investigators suggest that this technique will save lives. There are no mortality statistics, however, and the current study used published data from these trials to estimate the disease-specific mortality in this high-risk population. Patients and Methods Two nonrandomized CT screening trials were selected from the literature for analysis. The number of trial participants, the number of lung cancers diagnosed per year, and stage distribution of the cancers was recorded. Previously published 5-year survival data were used to calculate the number of predicted lung cancer deaths and estimate the overall lung cancer mortality per 1,000 person-years among participants screened. These statistics were then compared to the previous Mayo Lung Project, which used chest radiographs and sputum cytology for screening high-risk individuals. Results This study estimates the lung cancer mortality is 4.1 deaths per 1,000 person-years in the Mayo Clinic CT screening trial, and is 5.5 deaths per 1,000 person-years in the Early Lung Cancer Action Program trial. These data are similar to the lung cancer mortality of 4.4 deaths per 1,000 person-years in the interventional arm, and 3.9 deaths per 1,000 person-years in the usual-care arm of the previous Mayo Lung Project. Conclusion These data suggest that CT screening could produce similar outcomes to prior chest radiographic trials in this high-risk group. Results from randomized trials are required, however, before the true utility of mass screening with CT for lung cancer can be determined.

Mechanical unloading of the heart with a left ventricular assist device (LVAD) significantly decreases mortality in patients with heart failure. Moreover, it provides a human model to define the critical regulatory genes governing myocardial remodeling in response to significant reductions in wall stress. Statistical analysis of a gene expression library of 19 paired human heart samples harvested at the time of LVAD implant and again at explant revealed a set of 22 genes that were downregulated and 85 genes that were upregulated in response to mechanical unloading with a false discovery rate of less than 1%. The analysis revealed a high percentage of genes involved in the regulation of vascular networks including neuropilin-1 (a VEGF receptor), FGF9, Sprouty1, stromal-derived factor 1, and endomucin. Taken together these findings suggest that mechanical unloading alters the regulation of vascular organization and migration in the heart. In addition to vascular signaling networks, GATA-4 binding protein, a critical mediator of myocyte hypertrophy, was significantly downregulated following mechanical unloading. In summary, these findings may have important implications for defining the role of mechanical stretch and load on autocrine/paracrine signals directing vascular organization in the failing human heart and the role of GATA-4 in orchestrating reverse myocardial remodeling. This unbiased gene discovery approach in paired human heart samples has the potential to provide critical clues to the next generation of therapeutic treatments aimed at heart failure.

AbstractImatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFRβ- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFRα (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1–platelet-derived growth factor receptor α (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase–polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.