Masataka Taguri

Peripheral Endothelial Function and Cardiovascular Events in High-Risk Patients

Background Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high‐risk patients. Methods and Results We undertook a two‐center prospective study in 528 stable patients at high‐risk for cardiovascular events from the years 2006–2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow‐up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure‐induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person‐years of follow‐up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B‐type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C‐statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031). Conclusions Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high‐risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc. Clinical Trial Registration URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Postprogression survival for first-line chemotherapy of patients with advanced non-small-cell lung cancer.

BACKGROUNDnGiven the growing number of drugs available for non-small-cell lung cancer (NSCLC), an effect of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. We examined the relation between postprogression survival (PPS) and OS in phase III trials of first-line chemotherapy for advanced NSCLC.nnnPATIENTS AND METHODSnA literature search identified 69 trials that were published during the past decade. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment.nnnRESULTSnThe average PPS was longer in recent trials than in older trials (6.5 versus 4.4 months, P < 0.0001). For all trials, PPS was strongly associated with OS (r = 0.82), whereas PFS was moderately associated with OS (r = 0.43). The correlation between OS and PPS in recent trials was stronger than that in older trials (r = 0.89 and 0.66).nnnCONCLUSIONSnOur findings indicate that, especially for recent trials, PPS is highly associated with OS in first-line chemotherapy for advanced NSCLC, whereas PFS is only moderately associated with OS.

Extensive Reconstruction of the Left Anterior Descending Coronary Artery With an Internal Thoracic Artery Graft

BACKGROUNDnRevascularization of the diffusely diseased coronary artery is a big challenge for both cardiologists and cardiac surgeons. Long reconstruction of the diffusely diseased vessel may be a useful surgical option. The aim of this study is to assess clinical and angiographic outcomes of extensive reconstruction (≥4 cm) of the left anterior descending coronary artery (LAD) using an internal thoracic artery (ITA) graft with or without endarterectomy.nnnMETHODSnWe retrospectively reviewed 213 patients who underwent extensive reconstruction of the LAD using an ITA graft between September 2004 and July 2009. The diffusely diseased LAD was extensively incised, additional endarterectomy was performed if necessary, and then the LAD was reconstructed with an ITA graft in a long on-lay fashion. Early and 1-year postoperative angiography was performed in 188 patients (88.3%) and 152 patients (71.4%), respectively.nnnRESULTSnThe mean length of the reconstructed LAD was 5.4 ± 1.2 cm. Endarterectomy was performed in 46.0% of the patients. The operative mortality was 1.4%. Low cardiac output and perioperative myocardial infarction were observed in 3.3 and 5.2% of the patients, respectively. Freedom from death and other cardiac or cerebrovascular events was 91.5 ± 2.2% at 3 years. The early and 1-year patency rates of the ITA to LAD grafting were 95.7% and 93.4%, respectively.nnnCONCLUSIONSnExtensive reconstruction of the diffusely diseased LAD using an ITA graft could be performed safely. Early and 1-year angiographic outcome were excellent. This surgical revascularization is an useful option for revascularization of the diffuse coronary artery disease.

Single-incision laparoscopic surgery using colon-lifting technique for colorectal cancer: a matched case–control comparison with standard multiport laparoscopic surgery in terms of short-term results and access instrument cost

BackgroundSingle-incision laparoscopic surgery (SILS) has been used for colorectal cancer as a minimally invasive procedure. However, there are still difficulties concerning effective triangulation and countertraction. The study’s purpose was to clarify the usefulness of the colon-lifting technique (CLT) in SILS for colorectal cancer.MethodsSILS was performed for cancer (cT2N0 or less) of the right-sided colon (near the ileocecum), sigmoid, or rectosigmoid. The SILS™ Port was used for transumbilical access. A suture string was inserted through the abdominal wall and passed through the mesocolon. The colon was retracted anteriorly and fixed to the abdominal wall. The main mesenteric vessels were placed under tension. Lymph node dissection was performed by medial approach. Short-term surgical outcomes and access port costs were compared between SILS (using CLT) and the standard multiport technique (MPT). The two groups were case-matched by propensity scoring. Analyzed variables included preoperative Dukes stage and tumor location.ResultsFrom June 2009 to April 2011, 27 patients underwent SILS, and from April 2005 to April 2011, 85 patients underwent MPT. Propensity scoring generated 23 matched patients per group for SILS versus MPT comparisons. There were no significant differences in operating time, blood loss, early complications, postoperative analgesic frequency, or length of hospital stay. One MPT patient was converted to open surgery (4.5%); no SILS patients were converted. There were no significant differences in the length of distal cut margin and the number of harvested lymph nodes, except incision length (SILS vs. MPT: 33 vs. 55xa0mm, Pxa0<xa00.001). Significant differences favored SILS in access instrument cost (SILS vs. MPT: 62,761 vs. 77,130 Japanese yen, Pxa0<xa00.001).ConclusionsSILS performed using CLT was safe and effective in providing radical treatment of cT2N0 cancer in the right-sided colon, sigmoid, or rectosigmoid. SILS was advantageous with respect to cosmesis and lower cost of access instruments.

SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women

Purpose The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer. Experimental Design We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.–617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients’ overall survival. Results Patients harboring wild-type (WT) homozygous (c.–617C/C), SNP heterozygous (c.–617C/A), and SNP homozygous (c.–617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.–617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.–617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank pu200a=u200a0.021). Conclusion SNP homozygous (c.–617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

Impact of IL28B Genetic Variation on HCV-Induced Liver Fibrosis, Inflammation, and Steatosis: A Meta-Analysis

Background & Aims IL28B polymorphisms were shown to be strongly associated with the response to interferon therapy in chronic hepatitis C (CHC) and spontaneous viral clearance. However, little is known about how these polymorphisms affect the natural course of the disease. Thus, we conducted the present meta-analysis to assess the impact of IL28B polymorphisms on disease progression. Methods A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library. Integrated odds ratios (OR) were calculated with a fixed-effects or random-effects model based on heterogeneity analyses. Results We identified 28 studies that included 10,024 patients. The pooled results indicated that the rs12979860 genotype CC was significantly associated (vs. genotype CT/TT; OR, 1.122; 95%CI, 1.003–1.254; Pu200a=u200a0.044), and that the rs8099917 genotype TT tended to be (vs. genotype TG/GG; OR, 1.126; 95%CI, 0.988–1.284; Pu200a=u200a0.076) associated, with an increased possibility of severe fibrosis. Both rs12979860 CC (vs. CT/TT; OR, 1.288; 95%CI, 1.050–1.581; Pu200a=u200a0.015) and rs8099917 TT (vs. TG/GG; OR, 1.324; 95%CI, 1.110–1.579; Pu200a=u200a0.002) were significantly associated with a higher possibility of severe inflammation activity. Rs8099917 TT was also significantly associated with a lower possibility of severe steatosis (vs. TG/GG; OR, 0.580; 95%CI, 0.351–0.959; Pu200a=u200a0.034), whereas rs12979860 CC was not associated with hepatic steatosis (vs. CT/TT; OR, 1.062; 95%CI, 0.415–2.717; Pu200a=u200a0.901). Conclusions IL28B polymorphisms appeared to modify the natural course of disease in patients with CHC. Disease progression seems to be promoted in patients with the rs12979860 CC and rs8099917 TT genotypes.

Postprogression Survival in Patients With Advanced Non–Small-Cell Lung Cancer Who Receive Second-Line or Third-Line Chemotherapy

BACKGROUNDnThe increased availability of active agents has improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). We previously showed that postprogression survival (PPS) is highly associated with OS in the first-line setting, but little is known about PPS in the salvage setting. In this study, we analyzed PPS in phase III trials in the second-line or third-line setting.nnnPATIENTS AND METHODSnA literature search identified 18 trials for previously treated patients with advanced NSCLC. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the association between OS and either PFS or PPS. Correlation analysis to examine whether a treatment benefit for PFS carried over to OS was performed by calculation of incremental gains in OS and PFS at the trial level.nnnRESULTSnThe average median PPS was longer than the average median PFS (5.4 and 2.6 months, respectively). The induction rate for subsequent chemotherapy after second-line or third-line treatment was related to the duration of PPS in linear regression analysis (r(2) = 0.4813). Median OS was highly associated with median PPS but not with PFS (r = 0.94 and 0.51, respectively), and only a weak association between the treatment benefits for PFS and OS was detected (r = 0.29).nnnCONCLUSIONSnTreatment benefit for OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Whether PFS or OS is the more appropriate endpoint for trials in the salvage setting should be considered.

Clostridium difficile infection in patients with ulcerative colitis: investigations of risk factors and efficacy of antibiotics for steroid refractory patients.

BACKGROUND AND OBJECTIVEnThe incidence of Clostridium difficile infection (CDI) has increased throughout the world and patients with ulcerative colitis (UC) are at a high risk for CDI. Potentially, CDI can exacerbate UC. Therefore, knowledge on the prevalence of CDI should contribute to better management of UC patients.nnnMETHODSnThe presence of toxin A antigen was defined as CDI, and the outcome of the test in patients with active UC during 2006-2009 was reviewed for identifying patients with CDI. Demographic data (disease profile, clinical response to medications and the need for colectomy) in UC patients with CDI were compared with the data from CDI free UC patients.nnnRESULTSnFifty-five of 137 patients (40.1%) were CDI positive. Univariate and multivariate analyses revealed that CDI was not associated with any demographic factor. Intensive antibiotic therapy spared five of 17 (29.4%) steroid refractory patients with CDI from steroids. CDI was not a predictor of colectomy although this could be an outcome of efficient eradication strategy.nnnCONCLUSIONnCDI was not associated with any demographic factor or colectomy rate. However, CDI eradication therapy allowed some refractory patients to withdraw from steroids. Patients with active UC benefit from regular CDI test and eradication treatment for CDI.

Novel Lens culinaris agglutinin-reactive fraction of α-fetoprotein: a biomarker of hepatocellular carcinoma recurrence in patients with low α-fetoprotein concentrations

BackgroundLens culinaris agglutinin-reactive fraction of α-fetoprotein (AFP-L3) is a specific marker used to detect hepatocellular carcinoma (HCC). However, its clinical utility is not sufficient in patients with low total AFP concentrations because of limitations in instrument sensitivity. Recent advances have led to the introduction of a highly sensitive AFP-L3% assay (sensitive AFP-L3%), provided by a novel on-chip, liquid-phase binding assay. This cross-sectional study was conducted to evaluate the clinical significance of the sensitive AFP-L3% in determining HCC recurrence in patients with low total AFP concentrations.MethodsA total of 370 consecutive patients with HCC were screened within 1–3xa0months of locoregional treatment, and 215 of the 370 patients showed serum AFP <20xa0ng/ml. Total AFP, sensitive AFP-L3%, and des-gamma-carboxy prothrombin (DCP) were measured in those 215 patients and HCC recurrence was evaluated by radiological findings. Optimal cutoff values of the markers for detecting HCC recurrence were obtained on the basis of receiver operating characteristic (ROC) curve.ResultsThe area under the ROC curve of the total AFP, sensitive AFP-L3%, and DCP in HCC patients with serum AFP <20xa0ng/ml were 0.638, 0.724, and 0.779, respectively. The diagnostic accuracies of the total AFP, sensitive AFP-L3%, and DCP were 60.9% (cutoff value 5xa0ng/ml), 67.7% (cutoff value 7%), and 64.6% (cutoff value 40xa0ng/ml), respectively.ConclusionsThe new sensitive AFP-L3% assay provides great utility in determining HCC recurrence in patients with low AFP concentrations. Further studies focusing on the combinatorial use of the markers (total AFP, sensitive AFP-L3%, and DCP) are required.

A comparison of multimodality treatment: two and four courses of neoadjuvant chemotherapy using S-1/CDDP or S-1/CDDP/docetaxel followed by surgery and S-1 adjuvant chemotherapy for macroscopically resectable serosa-positive gastric cancer: a randomized phase II trial (COMPASS-D trial).

This randomized Phase II trial will compare the outcome of neoadjuvant chemotherapy using two and four courses of S-1 plus cisplatin or S-1 plus cisplatin plus docetaxel by a two-by-two factorial design for patients with macroscopically resectable serosa-positive gastric cancer. After neoadjuvant chemotherapy, patients will receive D2 gastrectomy followed by S-1 chemotherapy for 1 year postoperatively. The primary endpoint is the 3-year overall survival. The sample size is 120 for the two hypotheses: the superiority of four courses compared with two courses and the superiority of S-1 plus cisplatin plus docetaxel compared with S-1 plus cisplatin. This trial will be able to define the more suitable number of cycles and better regimen of neoadjuvant chemotherapy for gastric cancer.