Jae Won Lee

First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung

PURPOSE Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy. PATIENTS AND METHODS In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs. RESULTS Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died. CONCLUSION Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.

Early Surgery versus Conventional Treatment for Infective Endocarditis

BACKGROUND The timing and indications for surgical intervention to prevent systemic embolism in infective endocarditis remain controversial. We conducted a trial to compare clinical outcomes of early surgery and conventional treatment in patients with infective endocarditis. METHODS We randomly assigned patients with left-sided infective endocarditis, severe valve disease, and large vegetations to early surgery (37 patients) or conventional treatment (39). The primary end point was a composite of in-hospital death and embolic events that occurred within 6 weeks after randomization. RESULTS All the patients assigned to the early-surgery group underwent valve surgery within 48 hours after randomization, whereas 30 patients (77%) in the conventional-treatment group underwent surgery during the initial hospitalization (27 patients) or during follow-up (3). The primary end point occurred in 1 patient (3%) in the early-surgery group as compared with 9 (23%) in the conventional-treatment group (hazard ratio, 0.10; 95% confidence interval [CI], 0.01 to 0.82; P=0.03). There was no significant difference in all-cause mortality at 6 months in the early-surgery and conventional-treatment groups (3% and 5%, respectively; hazard ratio, 0.51; 95% CI, 0.05 to 5.66; P=0.59). The rate of the composite end point of death from any cause, embolic events, or recurrence of infective endocarditis at 6 months was 3% in the early-surgery group and 28% in the conventional-treatment group (hazard ratio, 0.08; 95% CI, 0.01 to 0.65; P=0.02). CONCLUSIONS As compared with conventional treatment, early surgery in patients with infective endocarditis and large vegetations significantly reduced the composite end point of death from any cause and embolic events by effectively decreasing the risk of systemic embolism. (EASE ClinicalTrials.gov number, NCT00750373.).

An extensive comparison of recent classification tools applied to microarray data

Since most classi%cation articles have applied a single technique to a single gene expression dataset, it is crucial to assess the performance of each method through a comprehensive comparative study. We evaluate by extensive comparison study extending Dudoit et al. (J. Amer. Statist. Assoc. 97 (2002) 77) the performance of recently developed classi%cation methods in microarray experiment, and provide the guidelines for %nding the most appropriate classi%cation tools in various situations. We extend their comparison in three directions: more classi%cation methods (21 methods), more datasets (7 datasets) and more gene selection techniques (3 methods). Our comparison study shows several interesting facts and provides the biologists and the biostatisticians some insights into the classi%cation tools in microarray data analysis. This study also shows that the more sophisticated classi%ers give better performances than classical methods such as kNN, DLDA, DQDA and the choice of gene selection method has much e>ect on the performance of the classi%cation methods, and thus the classi%cation methods should be considered together with the gene selection criteria. c 2004 Elsevier B.V. All rights reserved.

Early Surgery Versus Conventional Treatment in Asymptomatic Very Severe Aortic Stenosis

Background— The optimal timing of surgical intervention remains controversial in asymptomatic patients with very severe aortic stenosis. We therefore compared the long-term results of early surgery and a conventional treatment strategy. Methods and Results— From 1996 to 2006, we prospectively included a total of 197 consecutive asymptomatic patients (99 men; age, 63±12 years) with very severe aortic stenosis. Patients were excluded if they had angina, syncope, exertional dyspnea, ejection fraction <0.50, significant mitral valve disease, or age >85 years. Very severe aortic stenosis was defined as a critical stenosis in the aortic valve area ≤0.75 cm2 accompanied by a peak aortic jet velocity ≥4.5 m/s or a mean transaortic pressure gradient ≥50 mm Hg on Doppler echocardiography. The primary end point was defined as the composite of operative mortality and cardiac death during follow-up. Early surgery was performed on 102 patients, and a conventional treatment strategy was used for 95 patients. There were no significant differences between the 2 groups in terms of age, gender, European System for Cardiac Operative Risk Evaluation score, or ejection fraction. During a median follow-up of 1501 days, the operated group had no operative mortalities, no cardiac deaths, and 3 noncardiac deaths; the conventional treatment group had 18 cardiac and 10 noncardiac deaths. The estimated actuarial 6-year cardiac and all-cause mortality rates were 0% and 2±1% in the operated group and 24±5% and 32±6% in the conventional treatment group, respectively (P<0.001), and for 57 propensity score-matched pairs, the risk of all-cause mortality was significantly lower in the operated group than in the conventional treatment group (hazard ratio, 0.135; 95% confidence interval, 0.030 to 0.597; P=0.008). Conclusions— Compared with the conventional treatment strategy, early surgery in patients with very severe aortic stenosis is associated with an improved long-term survival by decreasing cardiac mortality. Early surgery is therefore a therapeutic option to further improve clinical outcomes in asymptomatic patients with very severe aortic stenosis and low operative risk.

Prediction of Recurrence-Free Survival in Postoperative Non–Small Cell Lung Cancer Patients by Using an Integrated Model of Clinical Information and Gene Expression

Purpose: One of the main challenges of lung cancer research is identifying patients at high risk for recurrence after surgical resection. Simple, accurate, and reproducible methods of evaluating individual risks of recurrence are needed. Experimental Design: Based on a combined analysis of time-to-recurrence data, censoring information, and microarray data from a set of 138 patients, we selected statistically significant genes thought to be predictive of disease recurrence. The number of genes was further reduced by eliminating those whose expression levels were not reproducible by real-time quantitative PCR. Within these variables, a recurrence prediction model was constructed using Cox proportional hazard regression and validated via two independent cohorts (n = 56 and n = 59). Results: After performing a log-rank test of the microarray data and successively selecting genes based on real-time quantitative PCR analysis, the most significant 18 genes had P values of <0.05. After subsequent stepwise variable selection based on gene expression information and clinical variables, the recurrence prediction model consisted of six genes (CALB1, MMP7, SLC1A7, GSTA1, CCL19, and IFI44). Two pathologic variables, pStage and cellular differentiation, were developed. Validation by two independent cohorts confirmed that the proposed model is significantly accurate (P = 0.0314 and 0.0305, respectively). The predicted median recurrence-free survival times for each patient correlated well with the actual data. Conclusions: We have developed an accurate, technically simple, and reproducible method for predicting individual recurrence risks. This model would potentially be useful in developing customized strategies for managing lung cancer.

Mitral Valve Repair Versus Revascularization Alone in the Treatment of Ischemic Mitral Regurgitation

Background— For patients with ischemic mitral regurgitation (MR), it is not clear whether adjunctive mitral valve (MV) repair at the time of coronary artery bypass graft surgery (CABG) is beneficial. We sought to test the hypothesis that MV repair with CABG is superior to CABG alone in improving MR without increasing operative or long-term mortality. Methods and Results— A total of 107 consecutive patients with moderate or severe ischemic MR, as determined by preoperative echocardiography, underwent CABG with concomitant MV repair (repair group, n=50) or CABG only (CABG group, n=57). Degree of MR was graded as none, mild, moderate, or severe by the proximal isovelocity surface area method. The groups were similar with respect to age, gender, baseline New York Heart Association class, ejection fraction, and number of bypass grafts. The repair group had a higher percentage of patients with atrial fibrillation or severe MR than the CABG group. The operative mortality was significantly higher for the repair group (12%) than the CABG group (2%), whereas the 5-year actuarial survival rate of the 2 groups was similar (88%±5% versus 87%±6%). On multivariate logistic regression analysis, older age, higher New York Heart Association class, and atrial fibrillation were independent predictors of operative mortality (P<0.05). Among patients with severe MR, ischemic MR was improved in all patients of the repair group and in 67% of patients in the CABG group (P<0.001), whereas improvement rates in patients with moderate MR were similar in the 2 groups (75% versus 67%, P=NS). Conclusions— Although MV repair appears to be more effective at reducing ischemic functional MR, CABG alone may be a preferable treatment option for patients with moderate MR and high operative risk factors such as old age or atrial fibrillation.

Factors associated with development of late significant tricuspid regurgitation after successful left-sided valve surgery

Background: Persistent significant tricuspid regurgitation (TR) after successful left-sided valve surgery is frequently reported. Objectives: To evaluate the incidence, risk factors and clinical impact of development of late significant TR after successful left-sided valve surgery. Methods and results: 638 patients (356 men, mean age 52 (SD 14) years) who had mild (⩽grade 2/4) TR and underwent successful surgery without any procedure for TR were analysed. Development of significant TR was defined as a TR increase by more than one grade and final TR grade ⩾3/4 at follow-up echocardiography. Clinical events were defined as cardiovascular death, repeated open-heart surgery, and congestive heart failure requiring hospital admission. The overall incidence of late significant TR was 7.7% (49/638). Age (hazard ratio (HR), 1.0, 95% CI, 1.0 to 1.1; p = 0.005), female gender (HR, 5.0; 95% CI 2.0 to 12.7; p = 0.001), rheumatic aetiology (HR, 3.8; 95% CI 1.4 to 10.3; p = 0.011), atrial fibrillation (Af) (HR, 2.6; 95% CI 1.1 to 6.4; p = 0.035) and peak pressure gradient of TR at follow-up (HR, 1.1; 95% CI 1.0 to 1.1; p<0.001) were independent factors associated with development of late significant TR. During clinical follow-up of 101 (24) months, patients who developed late significant TR showed a significantly lower 8-year clinical event-free survival rate (76 (6) vs 91 (1)%, p<0.001). Conclusions: Several clinical variables were independent risk factors for development of late significant TR. Early surgical intervention for TR in selected patients with these risk factors may be justified, even though they have only mild TR.

Autologous Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study

Extranodal natural killer (NK)/T cell lymphoma, nasal type, is a recently recognized distinct entity and the most common type of non-B cell extranodal lymphoma in Asia. This retrospective analysis studied the potential survival benefits of hematopoeitic stem cell transplantation (HSCT) compared with a historical control group. A total of 47 patients from 3 previously published series of HSCT were matched according to NK/T cell lymphoma International Prognostic Index (NKIPI) risk groups and disease status at transplantation with 107 patients from a historical control group for analysis. After a median follow-up of 116.5 months, the median survival time was not determined for the HSCT group, but it was 43.5 months for the control group (95% confidence interval [CI] = 6.7 to 80.3 months; P = .127, log-rank test). In patients who were in complete remission (CR) at the time of HSCT or at surveillance after remission, disease-specific survival rates were significantly higher in the HSCT group compared with the control group (disease-specific 5-year survival rate, 87.3% for HSCT vs 67.8% for non-HSCT; P = .027). In contrast, in subgroup analysis on non-CR patients at the time of HSCT or non-HSCT treatment, disease-specific survival rates were not significantly prolonged in the HSCT group compared with the control group (1-year survival rate, 66.7% for HSCT vs 28.6% for non-HSCT; P = .141). The impact of HSCT on the survival of all patients was significantly retained at the multivariate level with a 2.1-fold (95% CI =1.2- to 3.7-fold) reduced risk of death (P = .006). HSCT seems to confer a survival benefit in patients who attained CR on postremission consolidation therapy. These findings suggest that, in particular, patients in CR with high NKIPI risk scores at diagnosis should receive full consideration for HSCT.

Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1β cytokine in Korean patients with gastric cancer

Interleukin‐1B and IL‐1 receptor antagonist gene polymorphisms are associated with an increased risk of gastric cancer (GC) in Caucasian populations. However, recent studies could not find any association between IL‐1B‐511T polymorphism and the risk of GC in Asians. We tested for an association between IL‐1 loci polymorphisms with increased gastric mucosal levels of IL‐1β and an increased risk of developing GC in a Korean population. Polymorphisms of IL‐1A‐889, IL‐1B‐31, IL‐1B‐511 and IL‐1RN were genotyped in 434 controls and 234 patients with GC. Mucosal IL‐1β cytokine was measured using an ELISA. The frequencies of IL‐1A, IL‐1B‐511, IL‐1B‐31 and IL‐1RN were not statistically different between controls and all patients with GC. After subclassification of GC, only patients with intestinal‐type GC showed a higher frequency of IL‐1B‐31T homozygotes (OR = 2.2; 95% CI = 1.1–4.3) compared with controls. Risk was also significantly increased in these patients for IL‐1B‐31T homozygotes compared with patients with diffuse‐type GC (OR = 3.4; 95% CI = 1.5–7.7). As in Caucasian populations, linkage disequilibrium between IL‐1B‐31 and IL‐1B‐511 was nearly complete, but the pattern of haplotype related to the risk of GC (IL‐1B‐31T/IL‐1B‐511C) was opposite (IL‐1B‐511T/IL‐1B‐31C). Mucosal IL‐1β levels in H. pylori‐infected GC patients were higher in patients homozygous for IL‐1B‐31T compared with IL‐1B‐31C/T and IL‐1B‐31C/C. Thus, the combined effects of H. pylori infection and IL‐1B‐31T/IL‐1B‐511C polymorphisms with enhanced mucosal IL‐1β production contributed to the development of intestinal‐type GC in this Korean population.

Bio-inspired, melanin-like nanoparticles as a highly efficient contrast agent for T1-weighted magnetic resonance imaging.

The development of nontoxic and biocompatible imaging agents will create new opportunities for potential applications in clinical MRI diagnosis. Synthetic melanin-like nanoparticles (MelNPs), analogous to natural sepia melanin (a major component of the cuttlefish ink), can be used as contrast agent for MRI. MelNPs complexed with paramagnetic Fe(3+) ions show much higher relaxivity values than existing MRI T1 contrast agents based on gadolinium (Gd) or manganese (Mn); MelNP values at 3T were r1 = 17 and r2 = 18 mM(-1) s(-1) (r2/r1 value of 1.1). With significant enhancement to MRI contrast, this biomimetic approach using MelNPs functionalized with paramagnetic Fe(3+) ions and surface-modified with biocompatible poly(ethylene glycol) units, could provide new insight into how melanin-based bioresponsive and therapeutic imaging probes integrate with their various biological functions.