Safety and efficacy of first-line dacomitinib in Japanese patients with advanced non-small cell lung cancer.

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first-line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28-d cycles, in patients with EGFR-activating mutation-positive (EGFR-positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non-small cell lung cancer (NSCLC). The primary endpoint was progression-free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307-0.961]; 2-sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0-31.3] mo, 9.3 [95% CI, 7.4-14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first-line dacomitinib in Japanese patients with EGFR-positive advanced NSCLC.

Serum osteoprotegerin concentration is associated with carotid atherosclerotic plaque in patients with rheumatoid arthritis.

OBJECTIVE: Osteoprotegerin (OPG), a regulator of bone resorption, is involved in the pathogenesis of rheumatoid arthritis (RA) and atherosclerosis. OPG is elevated in patients with coronary artery disease, and high OPG levels are associated with cardiac disease severity and mortality in the general population. The purpose of this study was to investigate the relationship of serum OPG levels, traditional coronary risk factors, and RA-related factors to carotid atherosclerosis in RA patients. METHODS: Ninety-one RA patients were studied (85 % women, age 60 ± 10 years). Serum OPG levels were measured by an enzyme-linked immunosorbent assay. The prevalence of carotid plaque was assessed by ultrasonographic imaging in all patients. The relationship between various clinical characteristics, OPG, and carotid plaque was examined. RESULTS: Serum OPG levels were significantly higher in patients with carotid plaque than in those without plaque (median level 1,397 vs. 887 pg/mL, respectively; P = 0.006). There were no significant differences between RA patients with and without carotid plaque with respect to sex, duration of RA, blood pressure, body mass index, smoking, low-density lipoprotein cholesterol, Disease Activity Score-28, van der Heijde-modified Sharp score, and prednisolone dose. After adjusting for age, sex, and C-reactive protein, elevated levels of OPG were still associated with a higher prevalence of carotid plaque in patients with RA (P = 0.038). CONCLUSION: RA patients suffer from accelerated atherosclerosis and also have increased levels of OPG. The serum OPG level is independently associated with carotid plaque.

Diagnostic performance of quantitative fecal immunochemical test and multivariate prediction model for colorectal neoplasms in asymptomatic individuals.

OBJECTIVE: Quantitative fecal immunochemical test (QTFIT) has the advantage of being able to describe test characteristics on a scaled rather than binary system. The aims of this study were to decide the optimal cut-off points of QTFIT and to make a multivariate prediction model for colorectal neoplasms in asymptomatic adults. MATERIALS AND METHODS: We retrospectively analyzed 1085 consecutive asymptomatic individuals who completed both full colonoscopy and QTFIT at a general health checkup clinic. Advanced adenomatous polyps (AP) were defined as APs of at least 1 cm in diameter; adenomas with villous component or high-grade dysplasia; and significant neoplasia (SN) including both advanced AP and colorectal cancer. RESULTS: The ideal cut-off value of QTFIT was chosen based on a value that maximized the sum of both sensitivity and specificity, and clinical utility. For AP, 25 ng/ml was chosen as the optimal cut-off value and provided a sensitivity of 31% [95% confidence interval (CI): 27-36] and specificity of 79% (95% CI: 76-82). For SN, the ideal QTFIT cut-off value was 25 ng/ml, providing a sensitivity of 51% (95% CI: 39-62) and specificity of 77% (95% CI: 74-80). For colorectal cancer, the optimal cut-off point was 50 ng/ml, offering a sensitivity of 75% (95% CI: 41-93) and specificity of 86% (95% CI: 85-86). The multivariate prediction model was represented by nomogram and was validated by bootstrap method. CONCLUSION: The diagnostic performance of QTFIT for CRC is promising, although its sensitivity for AP and SN is unsatisfactory. BMI, in addition to age and sex improves the accuracy of SN screening by QTFIT.

Methodological development of a clonogenic assay to determine endothelial progenitor cell potential.

The precise and conceptual insight of circulating endothelial progenitor cell (EPC) kinetics is hampered by the absence of an assay system capable of evaluating the EPC differentiation cascade. An assay system for EPC colony formation was developed to delineate circulating EPC differentiation. EPC colony-forming assay using semisolid medium and single or bulk CD133(+) cells from umbilical cord blood exhibited the formation of two types of attaching cell colonies made of small or large cells featuring endothelial lineage potential and properties, termed small EPC colony-forming units and large EPC colony-forming units, respectively. In vitro and in vivo assays of each EPC colony-forming unit cell revealed a differentiation hierarchy from small EPC to large EPC colonies, indicating a primitive EPC stage with highly proliferative activity and a definitive EPC stage with vasculogenic properties, respectively. Experimental comparison with a conventional EPC culture assay system disclosed EPC colony-forming unit cells differentiate into noncolony-forming early EPC. The fate analysis of single CD133(+) cells into the endothelial and hematopoietic lineage was achieved by combining this assay system with a hematopoietic progenitor assay and demonstrated the development of colony-forming EPC and hematopoietic progenitor cells from a single hematopoietic stem cell. EPC colony-forming assay permits the determination of circulating EPC kinetics from single or bulk cells, based on the evaluation of hierarchical EPC colony formation. This assay further enables a proper exploration of possible links between the origin of EPC and hematopoietic stem cells, representing a novel and powerful tool to investigate the molecular signaling pathways involved in EPC biology.

Maternal body mass index and gestational weight gain and their association with perinatal outcomes in Viet Nam.

OBJECTIVE: To examine the association between gestational weight gain and maternal body mass index (BMI) among Vietnamese women and the risk of delivering an infant too small or too large for gestational age. METHODS: A prospective health-facility-based study of 2989 pregnant Vietnamese women was conducted in the city of Nha Trang in 2007-2008. Cubic logistic regression was used to investigate the association of interest. Infants were classified into weight-for-gestational-age categories according to weight centiles for the Asian population. Gestational age was based on the date of last menstrual period and adjusted by the results of first-trimester ultrasound. FINDINGS: BMI was low (< 18.5), normal (18.5-22.9) and high (≥ 23.0) in 26.1%, 65.4% and 8.5% of the women, respectively. In each of these BMI categories, the percentage of women who delivered infants too small for gestational age was 18.1, 10.0 and 9.4, respectively, and the mean gestational weight gain was 12.5 kg (standard deviation, SD: ± 3.6), 12.2 kg (SD: ± 3.8) and 11.5 kg (SD: ± 4.7), respectively. Among women with low BMI, the risk of delivering an infant too small for gestational age ranged from approximately 40% if the gestational weight gain was < 5 kg to 20% if it was 5-10 kg. CONCLUSION: Having a low BMI, commonly found in Viet Nam, puts women at risk of delivering an infant too small for gestational age, especially when total maternal gestational weight gain is < 10 kg.

Risk factor profiles of stroke, myocardial infarction, and atrial fibrillation: a Japanese Multicenter Cooperative Registry.

OBJECTIVE: We sought to clarify risk factor profiles and current treatment of Japanese patients with stroke, myocardial infarction (MI), and nonvalvular atrial fibrillation (NVAF) using the database of the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE). METHODS: J-TRACE is a nationwide multicenter cooperative cohort of Japanese patients with MI, stroke, and NVAF. Baseline characteristics of 8087 Japanese patients (5804 male, average age 68.7 years) with history of stroke (n=3554), MI (n=2291), or NVAF (n=2242) were analyzed. RESULTS: History of stroke (14.7%) was more frequent than history of MI (2.6%) in patients with stroke, whereas history of stroke (6.6%) was less frequent than history of MI (7.6%) in patients with MI. In patients with NVAF, history of stroke (14.3%) was far more frequent than history of MI (3.4%). Hypertension was more frequent in stroke (74.4%) than MI (62.0%) or NVAF (57.7%), whereas hypercholesterolemia, diabetes mellitus, and cigarette smoking were more prevalent in patients with MI (56.1%, 35.1%, and 33.3%, respectively) than in those with stroke (35.7%, 22.4%, and 19.7%, respectively) or NVAF (26.9%, 17.2%, and 16.1%, respectively). Alcohol consumption (34.9%) and obesity (body mass index>25) (32.8%) were most common in patients with NVAF. In all patients, nonmedication rates were higher in patients with hypercholesterolemia (29.8%) or diabetes (36.9%) than in those with hypertension (9.5%). Warfarin was used in 58.9% of patients with low-risk and 75.4% with high-risk NVAF. CONCLUSION: Risk factor profiles and their modification were not similar among patients in Japan with MI, stroke, and NVAF, although they share a high risk of thrombotic events.

Influence of maternal bifidobacteria on the establishment of bifidobacteria colonizing the gut in infants.

The aim of this study was to examine the influence of maternal intestinal and vaginal bifidobacteria on the establishment of bifidobacteria colonizing the gut in infants. Fecal samples from 110 healthy pregnant mothers within 1 mo before delivery and their babies at 1 mo of age and 100 vaginal swabs from the mother within 7 d before delivery were collected at a maternity hospital in Fukuoka city, Japan. The fecal and vaginal samples were assayed by PCR to detect Bifidobacterium species and by real-time PCR assays to estimate the bifidobacterial number. The detection of Bifidobacterium breve in the mothers' feces was significantly associated with increases in both the bifidobacterial counts and number of Bifidobacterium species in the babies' feces. In addition, a cesarean section was significantly associated with both a decrease in the counts and diversity of bifidobacteria in the babies' feces. The number of Bifidobacterium species detected in the vaginal swabs of mothers were not associated with either the bifidobacterial counts or the diversity of bifidobacteria in the babies' feces. The most important determinants of intestinal bifidobacteria in infants were the colonization of B. breve in the mothers' gut and vaginal delivery.

Beneficial effects of medical advice provided to elderly persons under the anti-aging health check-up system at Tokai University Tokyo Hospital.

OBJECTIVE: Tokai University Tokyo Hospital implemented its holistic anti-aging health check-up system in June 2006. This system is characterized by more than 70 check items and the provision of individual post-diagnostic advice of far greater detail than an ordinary health check-up. We analyzed aging-related changes in subjects who had completed their second check-up in order to determine the difference before and after coaching type of medical advice. SUBJECTS AND METHODS: Twenty-five recipients of the anti-aging health check-up at Tokai University Tokyo Hospital between June 2006 and April 2008 were included (15 males 10 females, mean age 65.1 ± 9.6 years, average check-up interval 12.5 ± 1.6 months). Based on the results of the first check-up, written advice on issues including diet, exercise, rest (sleep), smoking, alcohol intake, and supplements was provided by nutritionists, supplement advisers, and trainers specializing in Sports Medical Science in Tokai University. Besides this, doctors specializing in anti-aging medicine provided comprehensive coaching. Changes in BMI, abdominal girth at navel level, pressure wave velocity (PWV) and serum levels of total cholesterol (TC), HDL cholesterol (HDL-C), adiponectin (Adi) and free testosterone (in males) were expressed as % basal change and compared in the first and second check-ups. RESULTS: A year after the coaching, Adi and HDL-C both increased significantly while PWV tended to decrease. However, BMI and abdominal girth were unchanged. DHEA-S showed a rising trend while free testosterone also increased significantly. CONCLUSIONS: These results indicate that the coaching type of medical advice provided in the anti-aging health check-up potentially mitigates aging-related detrimental changes, bringing some benefits to elderly persons.

Purification of glucosyltransferase from cell-lysate of Streptococcus mutans by counter-current chromatography using aqueous polymer two-phase system.

Counter-current chromatography (CCC) using a cross-axis coil planet centrifuge (X-axis CPC) was applied to the purification of glucosyltransferase (GTF) from a cell-lysate of cariogenic bacteria. The purification was performed using an aqueous polymer two-phase system composed of 4.4% (w/w) polyethylene glycol (PEG) 8000-6% (w/w) dextran T500 containing 10mM phosphate buffer at pH 9.2 by eluting the upper phase (UP) at 1.0ml/min. The bacterial GTF in the cell-lysate of Streptococcus mutans was selectively retained in the dextran-rich lower stationary phase. The column contents were diluted and subjected to hydroxyapatite (HA) chromatography to remove the polymers from the GTF. Fractions eluted with 500mM potassium phosphate buffer were analyzed by GTF enzymatic activity as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The GTF purity in the final product was increased about 87 times as that in the cell-lysate with a good recovery rate of about 79% through this purification process.