Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer.

BACKGROUND: At the primary data cut-off, the ALUR study demonstrated significantly improved progression-free survival (PFS) and central nervous system (CNS) objective response rate (ORR) with alectinib versus chemotherapy in pretreated, advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer. We report final efficacy and safety data, and exploratory molecular profiling. PATIENTS AND METHODS: Patients who received prior platinum-doublet chemotherapy and crizotinib were randomized 2 : 1 to receive alectinib 600 mg twice daily (n = 79) or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, every 3 weeks; n = 40) until progressive disease, death or withdrawal. The primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, CNS ORR and safety. Plasma samples were collected at baseline, then every 6 weeks until progressive disease; molecular factors detected by next-generation sequencing were correlated with outcomes. RESULTS: Investigator-assessed PFS was significantly longer with alectinib than chemotherapy (median 10.9 versus 1.4 months; hazard ratio 0.20, 95% confidence interval 0.12-0.33; P < 0.001). ORR was 50.6% with alectinib versus 2.5% with chemotherapy (P < 0.001). In patients with measurable CNS metastases at baseline, CNS ORR was 66.7% with alectinib versus 0% with chemotherapy (P < 0.001). No new safety signals were seen. ALK rearrangement was identified in 69.5% (n = 41/59) of baseline plasma samples. Confirmed partial responses were observed with alectinib in 6/11 patients with a secondary ALK mutation and 4/6 patients with a non-EML4-ALK (where EML4 is echinoderm microtubule-associated protein-like 4) fusion. Detection of mutant TP53 in baseline plasma resulted in numerically shorter PFS with alectinib (hazard ratio 1.88, 95% confidence interval 0.9-3.93). CONCLUSIONS: Final efficacy data from ALUR confirmed the superior PFS, ORR and CNS ORR of alectinib versus chemotherapy in pretreated, advanced ALK-positive non-small-cell lung cancer. Alectinib prolonged PFS versus chemotherapy in patients with wild-type or mutant TP53; however, alectinib activity was considerably decreased in patients with mutant TP53.

Clinical effectiveness of efinaconazole 10% solution for treatment of onychomycosis with longitudinal spikes.

Onychomycosis with longitudinal spikes in the nail plate has been reported to be refractory to oral drugs as with dermatophytoma. We evaluated the efficacy of 10% efinaconazole solution in the treatment of onychomycosis with longitudinal spikes. Of the 223 subjects who were enrolled in a previous study, a post-hoc analysis of 82 subjects with longitudinal spikes was performed in this study. The opacity ratio of longitudinal spikes was decreased over time from 8.1 to 0.9 at the final assessment. In addition, the longitudinal spike disappearance rate increased early after the application to 81.7% at the final assessment. Therefore, 10% efinaconazole solution can be a first-line drug for longitudinal spikes, which have been regarded as refractory to oral drugs.

Association of Frailty with Healthcare Costs Using Claims Data in Korean Older Adults Aged 66.

OBJECTIVE: To explore the association of frailty and its eight components with claims-based healthcare costs among South Korean older adults aged 66 from 2009 to 2012. DESIGN: A cross-sectional design. SETTING: Data were obtained from administrative claims, Regular Biennial General and Cancer Screening Examinations, and the 66-year Lifetime Transitional Period Health Examination. PARTICIPANTS: South Korean older adults aged 66 (N = 818,337). MEASUREMENTS: Frailty was measured using eight components (i.e., hospital admission, self-assessed health status, polypharmacy, weight loss, depressed mood, incontinence, visual and auditory problems, and performance on the Timed Up and Go test). Healthcare costs included those associated with inpatient and outpatient care and pharmaceuticals. Multiple Tobit regression was used to assess the association between frailty and healthcare costs before and after propensity score matching. RESULTS: The mean annual total healthcare cost was $1,403.24 in robust participants, $2,364.78 in pre-frail participants, and $3,655.13 in frail participants. Among participants after propensity score matching, total healthcare costs were higher by $959.58 in the pre-frail (P < 0.001) and by $2,249.70 in the frail group (P < 0.001) compared to the robust group. The presence of each of the eight frailty components was significantly associated with higher total healthcare costs. CONCLUSION: By comparing the variables of interest using claims data, our study showed that frailty and each of its eight symptoms was associated with increased healthcare costs. This provides evidence of the need for identifying and managing frailty to reduce healthcare costs among South Korean older adults.

Effects of anti-osteoporosis medications on radiological and clinical results after acute osteoporotic spinal fractures: a retrospective analysis of prospectively designed study.

Effects of anti-osteoporosis medications such as anti-resorptive and anabolic agents on healing of osteoporotic spinal fracture were retrospectively investigated. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented good pain relief. These findings suggest that proper selection of medication could improve initial management of acute osteoporotic spinal fractures (OSFs). INTRODUCTION: Although anti-osteoporosis medications have beneficial effects on prevention of osteoporotic spinal fractures (OSFs), few studies have compared effects of medications on fracture healing following OSFs. Therefore, the purpose of this study was to elucidate the effects of different anti-osteoporosis medications on radiological and clinical outcomes after acute OSFs. METHODS: A total of 132 patients diagnosed with acute OSFs were enrolled and allocated into three groups [group I (n = 39, no anti-osteoporosis medication), group II (n = 66, bisphosphonate), and group III (n = 27, parathyroid hormone (PTH)]. Radiological parameters including magnetic resonance (MR) classification, occurrence of intravertebral cleft (IVC), and clinical outcomes such as numerical rating scale (NRS) and Oswestry disability index were assessed. Risk analyses for IVC and progressive collapse were done along the related factors and medication type. RESULTS: IVC sign was observed in 30 patients. The rate of IVC sign was lower in group III (7.4%) than that in group I (20.5%) or group II (30.3%), although the difference was not statistically significant. Moreover, the degree of NRS improvement was better in group III than that in group I or group II (5.7 vs. 3.1 vs. 3.5, p < 0.001). On multiple regression analysis, mid-portion type fracture in MR classification was a significant risk factor for progressive OSFs. The use of PTH showed significant lower incidences of occurrence of IVC (odds ratio (OR) = 0.160) and increase in height loss (OR = 0.325). CONCLUSIONS: Different anti-osteoporosis medications presented different clinical and radiological results after acute OSFs. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented better clinical outcomes. Proper selection of medication might improve initial management of acute OSFs.

Efficacy of long-term treatment with efinaconazole 10% solution in patients with onychomycosis, including severe cases: A multicenter, single-arm study.

We evaluated the efficacy of efinaconazole 10% topical solution in long-term use, for up to 72 weeks, for onychomycosis, including severe cases. Among 605 participants, 219 patients diagnosed as having onychomycosis were evaluated for the efficacy of efinaconazole. The treatment success rate (<10% clinical involvement of the target toenail) at the final assessment time point was 56.6%, the complete cure rate was 31.1% and the mycological cure rate was 61.6%, all of which increased over time, demonstrating that continuous application contributed to the improvement of cure rate. Even in severe cases, reduction of the affected nail area was observed, showing the potential efficacy of the treatment. Responses to a quality of life questionnaire among patients with onychomycosis, OnyCOE-t, suggested that efinaconazole treatment improved the patients' quality of life. The incidence of adverse drug reaction in the patients eligible for the assessment was 6.3%, and this developed only in the administration site in all cases. No systemic adverse event was observed. In addition, no increase in the incidence of adverse drug reaction due to long-term use was found. Efinaconazole therapy was proved to exhibit excellent balance between efficacy and safety, and thus may serve as a useful treatment option for onychomycosis.

Estimation of thermal comfort felt by human exposed to extreme heat wave in a complex urban area using a WRF-MENEX model.

Thermal comfort could indicate human thermal sensation when exposed to a local meteorological condition. Because humans can suffer illness when exposed to heat or even die, it is essential to assess human comfort levels to increased temperature and to provide this information to the public. This study aims to estimate thermal comfort using the human heat balance model combined with a numerical meteorological model in Seoul mega city during the heat wave periods experienced during 2016. The gridded thermal comfort index of physiological subjective temperature (PST) was calculated based on the Man-Environment Heat Exchange (MENEX) model, which used as inputs the meteorological parameters, clothing insulations, and metabolic rates. High-resolution meteorological parameters were obtained by coupling Weather Research and Forecasting (WRF) model with Building Effect Parameterization (BEP) + Building Energy Model (BEM) using detailed urban classification. The modeling results showed that the PST distribution has a clearly heterogeneous spatial distribution during the heat wave period. The high PST values were largely found in the residential area during the day, due to the high temperature and low wind speed associated with high-density buildings, and the daily maximum PST reached a very hot level (44.1-54.0 °C). Our study suggested that the human heat balance model combined with the numerical meteorological model could be used to provide more reliable information about thermal comfort to groups that may be vulnerable to the effects of heat waves in complex urban environments.

Anticarcinogenic activity of blue fluorescent hexagonal boron nitride quantum dots: as an effective enhancer for DNA cleavage activity of anticancer drug doxorubicin.

Blue fluorescent hexagonal boron nitride quantum dots (h-BNQDs) of ∼10 nm size as an effective enhancer for DNA cleavage activity of anticancer drug doxorubicin (DOX) were synthesized using simple one-step hydrothermal disintegration of exfoliated hexagonal boron nitride at very low temperature âˆ¼ 120 °C. Boron nitride quantum dots (BNQDs) at a concentration of 25 µg/ml enhanced DNA cleavage activity of DOX up to 70% as checked by converting supercoiled fragment into nicked circular PBR322 DNA. The interaction of BNQDs with DOX is proportional to the concentration of BNQDs, with binding constant K b ∼0.07338 µg/ml. In addition, ab initio theoretical results indicate that DOX is absorbed on BNQDs at the N-terminated edge with binding energy -1.075 eV and prevented the normal replication mechanisms in DNA. BNQDs have been shown to kill the breast cancer cell MCF-7 extensively as compared with the normal human keratinocyte cell HaCaT. The cytotoxicity of BNQDs may be correlated with reduced reactive oxygen species level and increased apoptosis in MCF-7 cells, which may be liable to enhance the anticancerous activity of DOX. The results provide a base to develop BNQD-DOX as a more effective anticancer drug.

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study.

Background: This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods: ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). Results: Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9-12.2] with alectinib and 1.4 months (95% CI: 1.3-1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08-0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17-0.59); median PFS was 7.1 months (95% CI: 6.3-10.8) with alectinib and 1.6 months (95% CI: 1.3-4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks). Conclusion: Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registration: ClinicalTrials.gov NCT02604342; Roche study MO29750.

Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABA(A) receptor.

Enhancement of tonic inhibition mediated by extrasynaptic α5-subunit containing GABAA receptors (GABAARs) has been proposed as the mechanism by which a variety of anesthetics, including the general anesthetic etomidate, impair learning and memory. Since α5 subunits preferentially partner with ß3 subunits, we tested the hypothesis that etomidate acts through ß3-subunit containing GABAARs to enhance tonic inhibition, block LTP, and impair memory. We measured the effects of etomidate in wild type mice and in mice carrying a point mutation in the GABAAR ß3-subunit (ß3-N265M) that renders these receptors insensitive to etomidate. Etomidate enhanced tonic inhibition in CA1 pyramidal cells of the hippocampus in wild type but not in mutant mice, demonstrating that tonic inhibition is mediated by ß3-subunit containing GABAARs. However, despite its inability to enhance tonic inhibition, etomidate did block LTP in brain slices from mutant mice as well as in those from wild type mice. Etomidate also impaired fear conditioning to context, with no differences between genotypes. In studies of recombinant receptors expressed in HEK293 cells, α5ß1γ2L GABAARs were insensitive to amnestic concentrations of etomidate (1 µM and below), whereas α5ß2γ2L and α5ß3γ2L GABAARs were enhanced. We conclude that etomidate enhances tonic inhibition in pyramidal cells through its action on α5ß3-containing GABAA receptors, but blocks LTP and impairs learning by other means - most likely by modulating α5ß2-containing GABAA receptors. The critical anesthetic targets underlying amnesia might include other forms of inhibition imposed on pyramidal neurons (e.g. slow phasic inhibition), or inhibitory processes on non-pyramidal cells (e.g. interneurons).

Semi-quantitative HPV viral load in patients with ASC-US cytology: viral load correlates strongly with the presence of CIN but only weakly with its severity.

OBJECTIVES: This study was performed to evaluate the prognostic significance of human papillomavirus (HPV) viral load, expressed in relative light units (RLUs), in patients with atypical squamous cells of undetermined significance (ASC-US) cytology. METHODS: A total of 349 ASC-US cases with HPV infection, detected using Hybrid Capture 2, were diagnosed histologically. A colposcopically directed punch biopsy was performed on acetowhite areas. Endocervical curettage biopsy and random cervical punch biopsy in four quadrants were performed in unsatisfactory colposcopy cases. In negative colposcopy cases, random cervical punch biopsy in four quadrants was performed. RESULTS: Case with no cervical intraepithelial neoplasia (CIN), CIN1 and CIN2+ (CIN2/CIN3) accounted for 162, 135 and 52 cases, respectively. The mean age showed no difference among the three groups (P = 0.510). There was a significant correlation between RLU values and the presence of CIN (P < 0.001), but less so with its severity: the median RLU values for negative, CIN1 and CIN2+ cases were 42.68, 146.45 and 156.43, respectively, with widely overlapping confidence intervals. The cut-off values of RLU to detect CIN1+ and CIN2+ were 6.73 and 45.64, respectively. CONCLUSIONS: The HPV viral load in ASC-US cases showed a significant correlation with the presence of CIN and less so with its severity, and showed large overlap of viral loads between grades of CIN. In ASC-US cases, RLU was not an accurate predictor of immediate high-grade CIN.

Measuring the burden of disease due to climate change and developing a forecast model in South Korea.

OBJECTIVES: Climate change influences human health in various ways, and quantitative assessments of the effect of climate change on health at national level are becoming essential for environmental health management. STUDY DESIGN: This study quantified the burden of disease attributable to climate change in Korea using disability-adjusted life years (DALY), and projected how this would change over time. METHODS: Diseases related to climate change in Korea were selected, and meteorological data for each risk factor of climate change were collected. Mortality was calculated, and a database of incidence and prevalence was established. After measuring the burden of each disease, the total burden of disease related to climate change was assessed by multiplying population-attributable fractions. Finally, an estimation model for the burden of disease was built based on Korean climate data. RESULTS: The total burden of disease related to climate change in Korea was 6.85 DALY/1000 population in 2008. Cerebrovascular diseases induced by heat waves accounted for 72.1% of the total burden of disease (hypertensive disease 1.82 DALY/1000 population, ischaemic heart disease 1.56 DALY/1000 population, cerebrovascular disease 1.56 DALY/1000 population). According to the estimation model, the total burden of disease will be 11.48 DALY/1000 population in 2100, which is twice the total burden of disease in 2008. CONCLUSIONS: This study quantified the burden of disease caused by climate change in Korea, and provides valuable information for determining the priorities of environmental health policy in East Asian countries with similar climates.

Insulin-derived amyloidosis and poor glycemic control: a case series.

OBJECTIVES: Insulin-derived amyloidosis is a rare skin-related complication of insulin therapy. The purpose of this study was to show the effects of insulin-derived amyloidosis on blood glucose levels, insulin dose requirements, and insulin absorption. METHODS: Seven patients were found to have insulin-derived amyloidosis at the Tokyo Medical University Ibaraki Medical Center. The clinical characteristics and insulin therapy of the 7 patients were investigated. Insulin absorption was studied by comparing the serum insulin levels after insulin injections into insulin-derived amyloidosis sites versus injections into normal sites in 4 patients. RESULTS: When the insulin-derived amyloidosis was discovered, the mean hemoglobin A1c level was 9.3%, and the mean daily insulin dose was 57 units. After changing the injection sites to avoid the insulin-derived amyloidosis, the blood glucose concentrations improved, and the mean daily insulin dose could be reduced to 27 units (P = .035; 53% reduction). The insulin absorption at insulin-derived amyloidosis sites was 34% of that at normal sites (P = .030). CONCLUSIONS: Insulin-derived amyloidosis caused poor glycemic control and increased insulin dose requirements because of impairments in insulin absorption.

Combinations of eight key mutations in the X/preC region and genomic activity of hepatitis B virus are associated with hepatocellular carcinoma.

Accumulation of eight key mutations located in the X/preC regions of the hepatitis B virus (HBV) genome (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A and G1899A) is a risk marker for the development of hepatocellular carcinoma (HCC). In this study, we analysed the 8 key mutations in 442 serum samples collected from 310 non-HCC and 132 HCC patients to identify the combinations linked to HCC. After the patients were stratified according to the age groups and mutation combinations, clinical parameters were compared between the HCC and the non-HCC groups. Analyses were focused on patient ≥40 years of age infected by HBV genotype C with A1762T and G1764A mutations in the basal core promoter region (BCP double mutation). In patients with ≥6 mutations, the combination of [G1613A + C1653T + A1846T + G1896A] mutations was closely linked to HCC, whereas no specific single or double mutation combination was associated with HCC. In patients with ≤5 mutations, HBeAg and HBV DNA serum titres were lower in the HCC group than those in the non-HCC group. Unlike the number of mutations, no specific combination correlated with advanced clinical stage in HCC. Of the BCP double mutation-based HBV mutant types, combinations of ≥6 mutations that include G1613A + C1653T + A1846T + G1896A, and combinations of ≤5 mutations with reduced HBeAg production, may be more specific indicators of HCC risk than only the number of mutations or any specific combination(s).

The rate of decline of glomerular filtration rate is a predictor of long-term graft outcome after kidney transplantation.

BACKGROUND: To improve the long-term outcome of kidney transplantation (KT), it is important to identify and take active steps to reduce the number or severity of novel risk factors. We investigated whether changes in estimated glomerular filtration rate over the first year after KT (ΔeGFR12-3) was associated with long-term renal allograft function and survival. METHODS: Four hundred twenty-eight allograft recipients transplanted between 1990 and 2001 underwent ΔeGFR12-3 calculation using the equation: ΔeGFR12-3 = ([eGFR at 12 months post-KT - eGFR at 3 months post-KT]/[eGFR at 3 months post-KT]) × 100%. Recipients were divided into 3 groups according to their ΔeGFR12-3: group I (n = 150), ΔeGFR12-3 ≥ 10%; group II (n = 151), 10 > ΔeGFR12-3 ≥ -10%; and group III (n = 127), ΔeGFR12-3 < -10%. Multiple linear regression analysis was used to adjust for confounding variables that may affect long-term renal allograft function, and Kaplan-Meier analysis, to compare allograft survival. RESULTS: At a mean follow-up of 120 ± 58 months, we observed 112 renal allograft losses. The ΔeGFR over 10 years post-KT (ΔeGFR120-3) was significantly associated with the serum uric acid levels at 3 months post-transplantation and ΔeGFR12-3. Group III showed poor renal allograft survival; group I, 194 ± 8 months; group II, 197 ± 7 month and; group III, 163 ± 4 months; (log-rank test, P < .05). A Cox proportional hazard model revealed ΔeGFR12-3 to be independently associated with future renal allograft loss (hazard ratio, 0.981; 95% confidence interval, 0.974-0.992). CONCLUSION: Our results suggested that ΔeGFR12-3 may be an independent predictor of kidney allograft survival. Routine application of eGFR is strongly recommended to identify patients at risk for chronic allograft dysfunction.

Character comparison of abdomen-derived and eyelid-derived mesenchymal stem cells.

OBJECTIVES: While most human adipose tissues, such as those located in the abdomen, hip and thigh, are of mesodermal origin, adipose tissues located in the face are of ectodermal origin. The present study has compared stem cell-related features of abdomen-derived adult stem cells (A-ASCs) with those of eyelid-derived adult stem cells (E-ASCs). MATERIALS AND METHODS: Adipose tissue-derived cells were maintained in DMEM supplemented with 10% FBS. Before passage 6, cells were analysed using FACS, immunocytochemistry and quantitative real time PCR (qRT-PCR). To examine multi-differentiational potential, early passage ASCs were cultivated in each of a commercial Stempro(®) Differentiation kit. RESULTS: Unlike fibroblast-like morphology of A-ASCs, E-ASCs had bipolar morphology. Both types of cell exhibited similar surface antigens, and neuronal cell-related genes and proteins. However, there were differences in mRNA expression levels of CD90 and CD146; neuron-specific enolase (NSE) and nuclear receptor-related protein 1 (Nurr1) were different between the two cell types. There was no difference in multi-differentiational potential between 3 E-ASCs lines, however, E-ASCs had higher expression levels of chondrocyte-related genes compared to A-ASCs. These cells underwent senescence and maintained normal karyotypes. CONCLUSIONS: Although isolated from similar adipose tissues, both types of cells displayed many contrasting characteristics. Understanding defining phenotypes of such cells is useful for making suitable choices in differing clinical indications.

Syntaxin4 interacting protein (Synip) binds phosphatidylinositol (3,4,5) triphosphate.

The insulin responsive Glut4 transport vesicles contain the v-SNARE protein Vamp2 that associate with the plasma membrane t-SNARE protein Syntaxin 4 to drive insulin-stimulated Glut4 translocation in skeletal muscle and adipocytes. The syntaxin 4 interacting protein (Synip) binds to syntaxin 4 in the basal state and dissociates in the insulin-stimulated state allowing for the subsequent binding of Vamp2 containing Glut4 vesicles and fusion with the plasma membrane. In this study, we have found that Synip binds phosphatidylinositol 3,4,5-triphosphate (PIP3), but not phosphatidylinositol 3 phosphate (PIP) or phosphatidylinositol 3,4-biphosphate (PIP2) through the Synip WW domain as deletion of this domain (Synip ΔWW) failed to bind PIP3. Over-expressed Synip ΔWW in 3T3L1 adipocytes reduced the basal levels of Glut4 at the plasma membrane with no effect on the binding to syntaxin 4 in vitro. Subcellular fractionation demonstrated that the amount of Synip ΔWW at the PM was decreased in response to insulin in 3T3L1 adipocytes whereas the amount of Synip WT increased. These data suggest that in the presence of insulin, the dissociated Synip remains anchored to the plasma membrane by binding to PIP3.