The mind-skin connection: A narrative review exploring the link between inflammatory skin diseases and psychological stress.

Inflammatory skin diseases are known to negatively impact patient psychology, with individuals experiencing higher rates of stress and subsequent diminished quality of life, as well as mental health issues including anxiety and depression. Moreover, increased psychological stress has been found to exacerbate existing inflammatory skin diseases. The association between inflammatory skin diseases and psychological stress is a timely topic, and a framework to better understand the relationship between the two that integrates available literature is needed. In this narrative review article, we discuss potential neurobiological mechanisms behind psychological stress due to inflammatory skin diseases, focusing mainly on proinflammatory cytokines in the circulating system (the brain-gut-skin communications) and the default mode network in the brain. We also discuss potential descending pathways from the brain that lead to aggravation of inflammatory skin diseases due to psychological stress, including the central and peripheral hypothalamic-pituitary-adrenal axes, peripheral nerves and the skin barrier function.

A multicenter study of transient global amnesia for the better detection of magnetic resonance imaging abnormalities.

BACKGROUND AND PURPOSE: The detection rate of diffusion-weighted (DWI) hyperintense lesions varies widely in patients with transient global amnesia (TGA). The aim was to examine the association of hyperintense lesions on DWI magnetic resonance imaging (MRI) with patient characteristics, precipitating factors, clinical presentation and MRI settings in patients with TGA. METHODS: In this multicenter retrospective observational study, using the standardized diagnosis entry system of electronic health records of four tertiary medical centers in the Kansai district of Japan, TGA patients (n = 261) who underwent brain MRI within 28 days of onset were examined. When the onset time was unavailable, the discovery time was used. RESULTS: Diffusion-weighted hyperintense lesions were observed in 79 patients (30%). There were no significant differences in age, sex, vascular risk factors, precipitating factors or clinical presentation between patients with and without DWI lesions. The detection rate increased linearly 24 h after onset and then reached a plateau of 60%-80% by 84 h. After 84 h, the detection rate decreased rapidly. In a multivariate logistic regression model, MRI examination 24-84 h after onset (odds ratio 7.00, 95% confidence interval 3.50-13.99) and a thin-slice (≤3 mm) DWI sequence (odds ratio 7.59, 95% confidence interval 3.05-18.88) were independent predictors of DWI lesions. CONCLUSIONS: This study suggests that DWI hyperintense lesions in TGA are not associated with patient characteristics and clinical presentation. Brain MRI examination 24-84 h after onset and thin-slice DWI sequences enhance the detection of DWI lesions in TGA patients.

Impact of acute stress on itch sensation and scratching behaviour in patients with atopic dermatitis and healthy controls.

BACKGROUND: Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and scratching behaviour in these patients. OBJECTIVES: We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD. METHODS: The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off-site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes). RESULTS: In patients with AD, stress induced by TSST caused a significant reduction of cowhage-evoked itch but significantly increased off-site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema. CONCLUSIONS: We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress-related exacerbation of itch in patients with AD.

Cancer is an independent predictor of poor outcomes in patients following intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Patients with cancer have been reported to have poorer outcomes following intracerebral hemorrhage (ICH) than those without cancer, but the findings were not consistent between studies. The aim of this study was to test the hypothesis that cancer is associated with poor outcomes following ICH. METHODS: In all, 3137 consecutive patients admitted to the stroke unit of Osaka University Hospital were reviewed. Patients diagnosed with ICH were extracted and divided into two groups according to the presence of cancer. ICH characteristics were compared between the groups. The outcomes were measured using the 30-day and 90-day modified Rankin Scale (mRS). RESULTS: Amongst the 399 ICH patients (37.1% women; median age 66 years), the frequency of cancer was 15.3%. Of these, 70.5% of patients had distant metastatic cancers. Compared to controls, cancer patients were comparable in the Glasgow Coma Scale, hematoma volume and the frequency of infratentorial location and intraventricular hemorrhage extension, but had poorer outcomes following ICH. Ordinal logistic regression analysis revealed that cancer was independently associated with poor outcomes following ICH (odds ratio 5.14; 95% confidence interval 2.63-10.06). Adjustment was made for the covariates age, sex, time from onset to admission, prior use of antithrombotic agents, pre-stroke mRS, Glasgow Coma Scale, hematoma volume, infratentorial location and intraventricular hemorrhage extension. When the analysis was performed using data from individuals with localized cancer, the effect remained significant after assessment with 90-day mRS but not after that with 30-day mRS. CONCLUSIONS: The results suggest that cancer, especially distant metastatic cancer, is an independent predictor of poorer outcomes following ICH.

Relationships between dysphagia and tongue pressure during swallowing in Parkinson's disease patients.

Although dysphagia is a life-threatening problem in patients with Parkinson's disease (PD), the pathophysiology of oropharyngeal dysphagia is yet to be understood. This study investigated the tongue motor function during swallowing in relation to dysphagia and the severity of PD. Thirty patients with PD (14 males and 16 females; average age, 69.4 years), Hoehn and Yahr stage II-IV, in Osaka University Hospital are participated in this study. During swallowing 5 ml of water, tongue pressure on the hard palate was measured using a sensor sheet with 5 measuring points. The maximal tongue pressure at each measuring point during swallowing was compared between patients with PD and healthy controls. Subjective assessment of oropharyngeal dysphagia was performed using Swallowing Disturbance Questionnaire-Japanese. The maximal tongue pressure at each measuring point was significantly lower in patients with PD than in healthy controls (8 males and 12 females; average age, 71.6 years). Furthermore, the maximal tongue pressure was significantly lower in dysphagic PD patients than non-dysphagic PD patients. Loss of tongue pressure production at the anterior part of the hard palate was strongly related to dysphagia in the oral phase as well as in the pharyngeal phase. An abnormal pattern of tongue pressure production was more frequently observed in dysphagic PD patients than in non-dysphagic PD patients. The results suggest that tongue pressure measurement might be useful for early and quantitative detection of tongue motor disability during swallowing in patients with PD.

Randomized clinical trial of 24 versus 72 h antimicrobial prophylaxis in patients undergoing open total gastrectomy for gastric cancer.

BACKGROUND: Open total gastrectomy carries a high risk of surgical-site infection (SSI). This study evaluated the non-inferiority of antimicrobial prophylaxis for 24 compared with 72 h after open total gastrectomy. METHODS: An open-label, randomized, non-inferiority study was conducted at 57 institutions in Japan. Eligible patients were those who underwent open total gastrectomy for gastric cancer. Patients were assigned randomly to continued use of ß-lactamase inhibitor for either 24 or 72 h after surgery. The primary endpoint was the incidence of SSI, with non-inferiority based on a margin of 9 percentage points and a 90 per cent c.i. The secondary endpoint was the incidence of remote infection. RESULTS: A total of 464 patients (24 h prophylaxis, 228; 72 h prophylaxis, 236) were analysed. SSI occurred in 20 patients (8·8 per cent) in the 24-h prophylaxis group and 26 (11·0 per cent) in the 72-h group (absolute difference -2·2 (90 per cent c.i. -6·8 to 2·4) per cent; P < 0·001 for non-inferiority). However, the incidence of remote infection was significantly higher in the 24-h prophylaxis group. CONCLUSION: Antimicrobial prophylaxis for 24 h after total gastrectomy is not inferior to 72 h prophylaxis for prevention of SSI. Shortened antimicrobial prophylaxis might increase the incidence of remote infection. Registration number: UMIN000001062 ( http://www.umin.ac.jp).

FUT2 non-secretor status is associated with Type 1 diabetes susceptibility in Japanese children.

AIM: To examine the contribution of the FUT2 gene and ABO blood type to the development of Type 1 diabetes in Japanese children. METHODS: We analysed FUT2 variants and ABO genotypes in a total of 531 Japanese children diagnosed with Type 1 diabetes and 448 control subjects. The possible association of FUT2 variants and ABO genotypes with the onset of Type 1 diabetes was statistically examined. RESULTS: The se2 genotype (c.385A>T) of the FUT2 gene was found to confer susceptibility to Type 1A diabetes in a recessive effects model [odds ratio for se2/se2, 1.68 (95% CI 1.20-2.35); corrected P value = 0.0075]. CONCLUSIONS: The FUT2 gene contributed to the development of Type 1 diabetes in the present cohort of Japanese children.

DISC1 causes associative memory and neurodevelopmental defects in fruit flies.

Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.

Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: Cancer patients with cryptogenic stroke often have high plasma D-dimer levels and lesions in multiple vascular regions. Hence, if patients with cryptogenic stroke display such characteristics, occult cancer could be predicted. This study aimed to investigate the clinical characteristics of cryptogenic stroke as the first manifestation of occult cancer and to determine whether plasma D-dimer levels and lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. METHODS: Between January 2006 and October 2015, data on 1225 patients with acute ischaemic stroke were extracted from the stroke database of Osaka University Hospital. Among them, 184 patients were classified as having cryptogenic stroke, and 120 patients without a diagnosis of cancer at stroke onset were identified. Clinical variables were analyzed between cryptogenic stroke patients with and without occult cancer. RESULTS: Among 120 cryptogenic stroke patients without a diagnosis of cancer, 12 patients had occult cancer. The body mass index, hemoglobin levels and albumin levels were lower; plasma D-dimer and high-sensitivity C-reactive protein levels were higher; and lesions in multiple vascular regions were more common in patients with than in those without occult cancer. Multiple logistic regression analysis revealed that plasma D-dimer levels (odds ratio, 3.48; 95% confidence interval, 1.68-8.33; P = 0.002) and lesions in multiple vascular regions (odds ratio, 7.40; 95% confidence interval, 1.70-39.45; P = 0.01) independently predicted occult cancer. CONCLUSIONS: High plasma D-dimer levels and lesions in multiple vascular regions can be used to predict occult cancer in patients with cryptogenic stroke.

Variants associated with autoimmune Type 1 diabetes in Japanese children: implications for age-specific effects of cis-regulatory haplotypes at 17q12-q21.

AIMS: The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes. METHODS: We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis. RESULTS: Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10-5 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years. CONCLUSIONS: The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.

Interleukin-6, interleukin-6 receptor gene variant, small-vessel disease and incident dementia.

BACKGROUND AND PURPOSE: Mixed neurogenerative and vascular dementia has emerged as the leading cause of dementia in the elderly. Inflammation is implicated in atherosclerosis, cerebral small-vessel disease (SVD) as well as cognitive impairment. However, longitudinal data on the predictive value of circulating inflammatory markers including gene variants and magnetic resonance imaging (MRI) findings in incident dementia are scarce. It was investigated whether circulating interleukin-6 (IL-6), C-reactive protein (CRP) and gene variants increase dementia risk. METHODS: In a cohort of Japanese participants with vascular risk factors in an observational study from 2001, the association between baseline IL-6, CRP levels, gene variants [interleukin-6 receptor (IL-6R), rs2228145; IL-6, rs2097677; CRP, rs3093059] and incident all-cause dementia was evaluated. Baseline MRI was used to determine SVD (lacuna, white matter hyperintensities) and atrophy (medial-temporal lobe atrophy, bicaudate ratio). Cox proportional hazards analyses were performed for predictors of dementia, adjusting for age, sex, apolipoprotein Eε4, education, cerebrovascular events, vascular risk factors and MRI findings. RESULTS: Of 803 subjects (mean 67.0 ± 8.5 years, males 59%), during a mean of 7.5 ± 3.2 years follow-up, 60 incident dementia patients (Alzheimer's disease 31; vascular dementia 17; mixed-type six; other six) were diagnosed. In multivariable analyses adjusted for age, sex, cerebrovascular events, MRI findings and IL-6R variant (rs2228145), IL-6 levels (relative risk 1.68, P = 0.048) or highest tertile (relative risk 2.38, P = 0.031) for all-cause dementia remained significant. Although subjects with rs2228145 carrier had significantly higher IL-6 levels, a significant association between rs2228145 and dementia was not observed. Conversely, CRP and remaining gene variants were not associated with dementia. CONCLUSIONS: The deleterious effect of higher IL-6 on dementia remains consistent irrespective of conventional risk factors, MRI findings and IL-6R variant.

Serum high-molecular-weight adiponectin level and incident dementia in patients with vascular risk factors.

BACKGROUND AND PURPOSE: The involvement of metabolic factors in the development of dementia has received much attention. However, previous studies have yielded conflicting results regarding how blood adipocytokine level impacts cognitive decline and dementia. This study aimed to clarify whether serum high-molecular-weight (HMW) adiponectin level is related to incident dementia. METHODS: Data were from 466 patients (mean age 67.8 years, male 57%)--who had normal cognitive function and received brain magnetic resonance imaging--from amongst the 1106 patients in the Osaka Follow-up Study for Carotid Atherosclerosis, Part 2, a prospective cohort study of cardiovascular events and dementia amongst patients with vascular risk factors enrolled between 2001 and 2009. Baseline HMW adiponectin levels were measured using frozen serum. Dementia occurrence was examined in June 2013. RESULTS: Serum HMW adiponectin level was 4.33 ± 2.95 µg/ml; the levels were lower in men than in women and negatively correlated with body mass index. During the follow-up period (median 6.9 years), 47 patients had incident dementia including Alzheimer's disease dementia (27), vascular dementia (13), mixed dementia (four), other dementia (three). Risks of dementia in patients with high versus low HMW adiponectin levels were almost identical (P = 0.689). No association was found between adiponectin levels and Alzheimer's disease dementia or vascular dementia in the whole group or amongst men and women separately. CONCLUSIONS: This study demonstrated that serum HMW adiponectin level has little association with future dementia. Determination of metabolic factors involved in dementia requires evaluation of other biomarkers or parameters.

Detection of Copy Number Imbalance in Canine Urothelial Carcinoma With Droplet Digital Polymerase Chain Reaction.

Urothelial carcinoma (UC) is the most common neoplasm of the canine urinary tract. Clinical presentation of UC is shared with several other, more common urinary tract disorders, and this often delays diagnosis of the UC. Definitive diagnosis of UC requires histopathologic examination of a biopsy specimen, but the cost and invasiveness for these diagnostic tests often result in most diagnoses being made on the basis of clinical findings, diagnostic imaging, and cytologic examination of urine sediment. Regardless of the diagnostic process used, most UCs currently are not diagnosed until they are at an advanced clinical stage and so are associated with poor prognosis. Improved methods for earlier and less invasive detection are needed. In a previous study, the authors demonstrated the presence of highly recurrent DNA copy number aberrations (CNAs) in canine UC and hypothesized that detection of these CNAs in tumor cells can be used as a molecular diagnostic for UC. In this study, a multiplexed droplet digital polymerase chain reaction (ddPCR) assay was detected to detect and quantify CNAs of specific regions of canine chromosomes 8, 13, 19, and 36. The assay was effective at differentiating 31 neoplastic and 25 nonneoplastic bladder tissues based on copy number, with 100% sensitivity and specificity in tissue samples. CNAs were also detected by ddPCR in 67% (12 of 18) of urine DNA specimens derived from UC patients. The findings show that ddPCR is a useful molecular technique to detect CNAs and may be used as a noninvasive molecular diagnostic test for canine UC.

Association between carotid stenosis or lacunar infarction and incident dementia in patients with vascular risk factors.

BACKGROUND AND PURPOSE: The association between vascular risk factors and dementia is of interest. Several studies have shown that cerebral small vessel disease (SVD) is associated with dementia. However, the association between cerebral large vessel disease (LVD) and dementia has not been thoroughly examined. METHODS: The Osaka Follow-up Study for Carotid Atherosclerosis, Part 2, was a prospective cohort study of cardiovascular events and dementia in which patients (n = 1106) with vascular risk factors underwent carotid ultrasound. Of these patients, 600 who had normal cognitive function were included and underwent brain magnetic resonance imaging. The presence of lacunar infarction and carotid stenosis served as markers for SVD and LVD, respectively. RESULTS: Amongst 600 patients (mean 68 years, 57% men), 261 (44%) showed lacunar infarction and 94 (16%) showed carotid stenosis. During the follow-up period (median 8.0 years), 57 patients had incident dementia. Patients with carotid stenosis and lacunar infarction were significantly more likely to be diagnosed with dementia (log-rank test, P = 0.037 and P < 0.001, respectively). The association between lacunar infarction and dementia remained significant after adjusting for risk factors including stroke history, apolipoprotein E genotype and years of education (hazard ratio 2.64, 95% confidence interval 1.22-6.09). However, the presence of carotid stenosis was not associated with incident dementia after adjusting for age and sex (P = 0.477). CONCLUSIONS: This study demonstrated that carotid stenosis had little association with dementia, but lacunar infarction had a significant association. The impact of SVD on dementia could be much greater than that of LVD.

Sulcus subarachnoid hemorrhage is a common stroke subtype in patients with implanted left ventricular assist devices.

BACKGROUND AND PURPOSE: Stroke is one of the major complications observed in patients with an implanted left ventricular assist device (LVAD). The purpose of this study was to clarify the types and characteristics of acute stroke in patients after LVAD implantation by using brain computed tomography (CT) findings. METHODS: Between 2005 and 2012, 110 consecutive patients who underwent LVAD implantation were reviewed. The most commonly used device was the pulsatile extracorporeal LVAD. Amongst them, 49 patients suffered from acute stroke at least once with a total of 115 stroke events. The clinical categories, lesion sites, laboratory data and CT findings of each acute stroke event were analyzed. RESULTS: Cerebral infarction (35 patients, 72 events), cerebral hemorrhage (25 patients, 31 events) and subarachnoid hemorrhage (SAH) (23 patients, 33 events) were identified. A mean of 2.3 stroke events occurred per person. Of the 72 infarction events, multiple infarctions were observed in 29 events. Of the cerebral hemorrhage events (n = 31), almost all were subcortical lesions (n = 27) and none were observed in the basal ganglia. Of the 23 patients with SAH events (n = 33), SAH localized within a single sulcus, sulcus SAH, was observed in 25 events. CONCLUSIONS: Computed tomography findings of acute stroke after implantation of an LVAD are characteristically multifocal cortical lesions, regardless of brain infarction and hemorrhage. Unexpectedly, sulcus SAH was a common stroke subtype in patients with implanted LVADs. Sulcus SAH should be carefully examined in patients after LVAD implantation, when they complain of non-specific neurological complaints.

Demonstration of the cell clonality in canine hematopoietic tumors by X-chromosome inactivation pattern analysis.

X-chromosome inactivation pattern (XCIP) analysis has been widely used to assess cell clonality in various types of human neoplasms. In this study, a polymerase chain reaction-based canine XCIP analysis of the androgen receptor (AR) gene was applied for the assessment of cell clonality in canine hematopoietic tumors. This XCIP analysis is based on the polymorphic CAG repeats in the AR gene and the difference of methylation status between active and inactive X chromosomes. We first examined the polymorphisms of 2 CAG tandem repeats in the AR gene in 52 male and 150 female dogs of various breeds. The 2 polymorphic CAG repeats contained 9 to 12 and 10 to 14 CAGs in the first and second CAG repeats, respectively. Of the 150 female dogs, 74 (49.3%) were heterozygous for the first and/or second polymorphic CAG tandem repeats, indicating the utility of XCIP analysis in these dogs. Canine XCIP analysis was then applied to clinical samples from female dogs with canine high-grade lymphoma, chronic myelogenous leukemia, acute myelogenous leukemia, and benign lymph node hyperplasia. Of 10 lymphoma cell samples, 9 (90%) showed skewed XCIPs, indicating their clonal origins, whereas all the nonneoplastic lymph node samples showed balanced XCIPs. Moreover, bone marrow specimen from a dog with acute myelogenous leukemia and peripheral leukocyte specimens from 2 dogs with chronic myelogenous leukemia showed skewed XCIPs. XCIP analysis was successfully employed to demonstrate the cell clonality of canine hematopoietic tumors in this study and will be applicable to evaluate the clonality in various proliferative disorders in dogs.

Recent advance in investigation of gene polymorphisms in Japanese patients with aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD) is a complex clinical syndrome characterised by severe asthmatic attack upon treatment with aspirin and/or non-steroidal anti-inflammatory drugs (NSAIDs). Genetic predisposition has been considered as a crucial determinant and candidate genes have concentrated especially on cysteinyl leukotrienes (LTs)-related genes as the inhibitory action of aspirin and NSAIDs on cyclooxygenase activity may cause overproduction of cysteinyl LTs. However, conflicting results have been reported, in parallel with replication studies in different ethnic groups. Thus, future areas of investigations need to focus on comprehensive approaches towards the discovery of other genetic biomarkers. Unfortunately, few papers have been reported about gene polymorphisms in Japanese patients with AERD. Here, we described on our recent genetic investigations on B2ADR, IL-13, IL-17A, CYP2C19, TBXA2R, CRTH2 and HSP70. This review indicates potential genetic biomarkers contributing to the early diagnosis of AERD, which may include CYP2C19 and HSP70 gene polymorphisms, and future validation studies in independent population are required to provide reassurance about our findings.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.