Search

BACKGROUND: Obstructive sleep apnea (OSA) has been linked to vestibular dysfunction, but no prior studies have investigated the relationship between Persistent Postural-Perceptual Dizziness (PPPD), a common cause of chronic dizziness, and OSA. OBJECTIVE AND METHODS: We determined the frequency of OSA in an uncontrolled group of PPPD patients from a tertiary dizziness clinic based on polysomnogram (PSG). We then assessed the sensitivity and specificity of common OSA questionnaires in this population. RESULTS: Twenty-five patients with PPPD underwent PSG (mean age 47, 60% female, mean BMI 29.5). A majority, or 56%, of patients were diagnosed with OSA, and in most, the OSA was severe. OSA patients were older (56 years versus 40 years, p = 0.0006) and had higher BMI (32 versus 26, p = 0.0078), but there was no clear gender bias (56% versus 64% female, p = 1.00). The mean sensitivity and specificity of the STOP BANG questionnaire for detecting OSA was 86% and 55%, respectively. Sensitivity and specificity of the Berlin Questionnaire was 79% and 45%, respectively. CONCLUSIONS: The prevalence of OSA was much higher in our small PPPD group than in the general population. Screening questionnaires appear to demonstrate good sensitivity to detect PPPD patients at risk of OSA in this small study. Future studies should confirm these findings and determine whether treatment of OSA improves symptoms in PPPD.

Amyotrophic lateral sclerosis (ALS) is one of the most common motoneuronal disease, characterized by motoneuronal loss and progressive paralysis. Despite research efforts, ALS remains a fatal disease, with a survival of 2-5 years after disease onset. Numerous gene mutations have been correlated with both sporadic (sALS) and familiar forms of the disease, but the pathophysiological mechanisms of ALS onset and progression are still largely uncertain. However, a common profile is emerging in ALS pathological features, including misfolded protein accumulation and a cross-talk between neuroinflammatory and degenerative processes. In particular, astrocytes and microglial cells have been proposed as detrimental influencers of perineuronal microenvironment, and this role may be exerted via gap junctions (GJs)- and hemichannels (HCs)-mediated communications. Herein we investigated the role of the main astroglial GJs-forming connexin, Cx43, in human ALS and the effects of focal spinal cord motoneuronal depletion onto the resident glial cells and Cx43 levels. Our data support the hypothesis that motoneuronal depletion may affect glial activity, which in turn results in reactive Cx43 expression, further promoting neuronal suffering and degeneration.

Background Women’s mobile health (mHealth) is a growing phenomenon in the mobile app global market. An increasing number of women worldwide use apps geared to female audiences (female technology). Given the often private and sensitive nature of the data collected by such apps, an ethical assessment from the perspective of data privacy, sharing, and security policies is warranted. Objective The purpose of this scoping review and content analysis was to assess the privacy policies, data sharing, and security policies of women’s mHealth apps on the current international market (the App Store on the Apple operating system [iOS] and Google Play on the Android system). Methods We reviewed the 23 most popular women’s mHealth apps on the market by focusing on publicly available apps on the App Store and Google Play. The 23 downloaded apps were assessed manually by 2 independent reviewers against a variety of user data privacy, data sharing, and security assessment criteria. Results All 23 apps collected personal health-related data. All apps allowed behavioral tracking, and 61% (14/23) of the apps allowed location tracking. Of the 23 apps, only 16 (70%) displayed a privacy policy, 12 (52%) requested consent from users, and 1 (4%) had a pseudoconsent. In addition, 13% (3/23) of the apps collected data before obtaining consent. Most apps (20/23, 87%) shared user data with third parties, and data sharing information could not be obtained for the 13% (3/23) remaining apps. Of the 23 apps, only 13 (57%) provided users with information on data security. Conclusions Many of the most popular women’s mHealth apps on the market have poor data privacy, sharing, and security standards. Although regulations exist, such as the European Union General Data Protection Regulation, current practices do not follow them. The failure of the assessed women’s mHealth apps to meet basic data privacy, sharing, and security standards is not ethically or legally acceptable.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.

The healthy vaginal microbiota is dominated by Lactobacillus spp., which provide an important critical line of defense against pathogens, as well as giving beneficial effects to the host. We characterized L. gasseri 1A‐TV, L. fermentum 18A‐TV, and L. crispatus 35A‐TV, from the vaginal microbiota of healthy premenopausal women, for their potential probiotic activities. The antimicrobial effects of the 3 strains and their combination against clinical urogenital bacteria were evaluated together with the activities of their metabolites produced by cell‐free supernatants (CFSs). Their beneficial properties in terms of ability to interfere with vaginal pathogens (co‐aggregation, adhesion to HeLa cells, biofilm formation) and antimicrobial activity mediated by CFSs were assessed against multidrug urogenital pathogens (S. agalactiae, E. coli, KPC‐producing K. pneumoniae, S. aureus, E. faecium VRE, E. faecalis, P. aeruginosa, P. mirabilis, P. vulgaris, C. albicans, C. glabrata). The Lactobacilli tested exhibited an extraordinary ability to interfere and co‐aggregate with urogenital pathogens, except for Candida spp., as well as to adhere to HeLa cells and to produce biofilm in the Lactobacillus combination. Lactobacillus CFSs and their combination revealed a strong bactericidal effect on the multidrug resistant indicator strains tested, except for E. faecium and E. faecalis. The antimicrobial activity was maintained after heat treatment but decreased after enzymatic treatment. All Lactobacilli showed lactic dehydrogenase activity and production of D‐ and L‐lactic acid isomers on Lactobacillus CFSs, while only 1A‐TV and 35A‐TV released hydrogen peroxide and carried helveticin J and acidocin A bacteriocins. These results suggest that they can be employed as a new vaginal probiotic formulation and bio‐therapeutic preparation against urogenital infections. Further, in vivo studies are needed to evaluate human health benefits in clinical situations., The present study characterized a novel combination of Lactobacillus gasseri 1A‐TV, L. fermentum 18A‐TV, and L. crispatus 35A‐TV as live strains and as non‐live cell‐free supernatants showing antimicrobial activity against the most common multidrug‐resistant urogenital pathogens (Streptococcus agalactiae, Escherichia coli, KPC‐producing Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecium VRE, Enterococcus faecalis, Pseudomonas aeruginosa, P. mirabilis, P. vulgaris, Candida albicans, C. glabrata). Our findings are promising for their use as a new valid vaginal probiotic and bio‐therapeutic formulation against multidrug‐resistant pathogens.

Recent evidence has demonstrated that salivary molecules, as well as bacterial populations, can be perturbed by several pathological conditions, including neuro-psychiatric diseases. This relationship between brain functionality and saliva composition could be exploited to unveil new pathological mechanisms of elusive diseases, such as Autistic Spectrum Disorder (ASD). We performed a combined approach of miRNA expression profiling by NanoString technology, followed by validation experiments in qPCR, and 16S rRNA microbiome analysis on saliva from 53 ASD and 27 neurologically unaffected control (NUC) children. MiR-29a-3p and miR-141-3p were upregulated, while miR-16-5p, let-7b-5p, and miR-451a were downregulated in ASD compared to NUCs. Microbiome analysis on the same subjects revealed that Rothia, Filifactor, Actinobacillus, Weeksellaceae, Ralstonia, Pasteurellaceae, and Aggregatibacter increased their abundance in ASD patients, while Tannerella, Moryella and TM7-3 decreased. Variations of both miRNAs and microbes were statistically associated to different neuropsychological scores related to anomalies in social interaction and communication. Among miRNA/bacteria associations, the most relevant was the negative correlation between salivary miR-141-3p expression and Tannerella abundance. MiRNA and microbiome dysregulations found in the saliva of ASD children are potentially associated with cognitive impairments of the subjects. Furthermore, a potential cross-talking between circulating miRNAs and resident bacteria could occur in saliva of ASD.

Introduction Delay between clinical presentation and treatment of breast cancer (BC) can significantly impact mortality. We aimed at drawing a picture of women with locally advanced breast cancer (LABC) treated at our Breast Unit and at investigating factors associated with treatment delay. Material and methods A retrospective descriptive analysis, using a specific 28-item semi-structured questionnaire, was conducted in 67 patients diagnosed with T4 BC. Results Nearly a third of our patients had at least one known predisposing factor for LABC. 42% of patients did not perform routine medical breast checks, 49% reported indifference as the first feeling and 47% waited at least 3 months before seeking medical attention. The reasons for diagnostic delay were different in the various age groups. Doctor's delay in making the right diagnosis occurred in 60% of younger patients (≤40 years, n = 5), whereas among women aged 41–69years (n = 34) 50% suffered from psychiatric comorbidities. In patients ≥70 years (n = 28) social factors such as isolation, being widowed and living in a retirement home were present in most of the cases. Delay in seeking medical care was also associated with increasing age. Across all age groups, coping factors such as denial and indifference were also associated with an increase in the odds of delayed presentation, as opposed to fear. Conclusions Factors possibly explaining late medical consultation seem to differ according to age. Psychological factors are crucial in patients' delay whereas age and social factors are relevant in doctors' and system's delay.

Purpose: With better access to early diagnosis and appropriate treatment, cervical cancer (CC) burden decreased in several European countries. In Eastern European (EE) countries, which accessed European Union in 2004, CC survival was worse than in the rest of Europe. The present study investigates CC survival differences across five European regions, considering stage at diagnosis (local, regional and metastatic), morphology (mainly squamous versus glandular tumours) and patients’ age. Methods: We analysed 101,714 CC women diagnosed in 2000–2007 and followed-up to December 2008. Age-standardised 5-year relative survival (RS) and the excess risks of cancer death in the 5years after diagnosis were computed. Results: EE women were older and less commonly diagnosed with glandular tumours. Proportions of local stage cancers were similar across Europe, while morphology- and stage-specific RS (especially for non-metastatic disease) were lower in Eastern Europe. Adjusting for age and morphology, excess risk of local stage CC death for EE patients remained higher than that for other European women. Conclusion: Stage, age and morphology alone do not explain worse survival in Eastern Europe: less effective care may play a role, probably partly due to fewer or inadequate resources being allocated to health care in this area, compared to the rest of Europe.

The impact of language interpretation on interactive communication in genetic counseling sessions is not well studied. We sought to determine whether interpretation affects communication in genetic counseling sessions using communication analysis. With a sample of pregnant patients of advanced maternal age, we audiotaped, analyzed, and compared seven Spanish-speaking patients with limited-English proficiency to seven English-speaking patients on length of session, English words spoken, and number of questions asked. An analysis of verbal listening cues, including back-channels and questions asked was performed to evaluate the level of engagement by both provider and patient. Session length did not differ between groups (p > 0.05), however, English-speaking sessions involved significantly more words (mean: 4,798 vs. 2,524) exchanged over the course of the conversation than interpreter-mediated sessions (p

Children with chronic kidney disease (CKD) are at risk for obstructive sleep apnea (OSA) and hypertension. The objectives of this study were to explore associations between OSA severity using the apnea-hypopnea-index(AHI) and obstructive apnea-hypopnea-index(OAHI) on polysomnography (PSG), OSA symptoms, and measures of hypertension in children with CKD. One-night in-laboratory PSGs and 24-h ambulatory blood pressure monitoring (ABPM) were performed on children with CKD stages 2–5 (non-dialysis dependent). Sleep questionnaires, including the modified Epworth Sleepiness Scale (ESS) and the Pediatric Sleep Questionnaire (PSQ), were administered during the sleep study. Nineteen children and adolescents completed a PSG and questionnaires and thirteen completed ABPMs. Mean (standard deviation) age at the time of the sleep study was 14.1 (3.2) years. Eleven (58%) participants had CKD stage two, and eight (42%) had stage 3–4. None of the participants were found to have OSA on PSG. One participant had a positive ESS score (≥ 11) and five participants had positive PSQ scores (≥ eight). Night systolic and diastolic pressures were strongly correlated with the OAHI (r = 0.67 and r = 0.69, respectively, p

Background Cancer registries (CRs) are fundamental for estimating cancer burden, evaluating screening and monitoring health service performance. Stage at diagnosis—an essential information item collected by CRs—has been made available, for the first time, by CRs participating in EUROCARE-5. We analysed the quality of this information and estimated stage-specific survival across Europe for CRs with good data quality. Data and methods Sixty-two CRs sent stage (as TNM, condensed TNM or extent of disease) for 15 cancers diagnosed in 2000–2007. We assessed the quality, partly by comparing stage according to the three systems. We also developed procedures to reconstruct stage (categories: local, regional, metastatic and unknown) using information from all three systems, thus minimising the amount of missing information. Results Moderate-to-excellent stage concordance was found for practically all 24 CRs, for which it was possible to compare at least two staging systems. However, since stage was often incorrectly assigned, and information on the presence/absence of metastases was often lacking, data on only 7/15 cancers from 34/62 CRs (15 countries) were of sufficient quality for further analysis. Cases diagnosed ≥70 years had more advanced (or lacking) stage– and worse stage-specific survival than those Conclusions Many European CRs collect and record reasonably accurate stage information. Others have difficulties. Both the completeness of primary data and the accuracy of stage coding need to be improved in order for CRs to fulfil their expanding roles in cancer control. We propose our stage reconstruction/checking procedures as a means of fully exploiting the stage information provided by EUROCARE CRs. More advanced (or lacking) stage at diagnosis plus poorer stage-specific survival in the elderly are worrying.

Survival for childhood central nervous system (CNS) tumours varies across Europe, partly because of the difficulty of distinguishing malignant from non-malignant disease. This study examines bias in CNS tumours survival analysis to obtain the reliable and comparable survival figures. We analysed survival data for about 15, 000 children (age

Background: Incidence rates of thyroid cancer (TC) increased in several countries during the last 30 years, while mortality rates remained unchanged, raising important questions for treatment and follow-up of TC patients. This study updates population-based estimates of relative survival (RS) after TC diagnosis in Europe by sex, country, age, period and histology.Methods: Data from 87 cancer registries in 29 countries were extracted from the EUROCARE-5 dataset. One-and 5-year RS were estimated using the cohort approach for 86,690 adult TC patients diagnosed in 2000-2007 and followed-up to 12/31/2008. RS trends in 1999-2007 and 10-year RS in 2005-2007 were estimated using the period approach.Results: In Europe 2000-2007, 5-year RS after TC was 88% in women and 81% in men. Survival rates varied by country and were strongly correlated (Pearson rho = 75%) with country-specific incidence rates. Five-year RS decreased with age (in women from > 95% at age 15-54 to 57% at age 75+), from 98% in women and 94% in men with papillary TC to 14% in women and 12% in men with anaplastic TC. Proportion of papillary TC varied by country and increased over time, while survival rates were similar across areas and periods. In 1999-2007, 5-year RS increased by five percentage points for all TCs but only by two for papillary and by four for follicular TC. Ten-year RS in 2005-2007 was 89% in women and 79% in men.Conclusions: The reported increasing TC survival trend and differences by area are mainly explained by the varying histological case-mix of cases. (C) 2017 Elsevier Ltd. All rights reserved.

During the last 20 years, relevant diagnostic procedures and advanced treatments have been progressively introduced in the management of hepatocellular carcinoma (HCC). The aim of the present study was to assess up-to-date survival trends for HCC in southern Switzerland, a region with one of the highest incidence rates in the country.HCCs diagnosed in 1996-2009 were selected by the Ticino Cancer Registry. Cancer-specific survival (CSS) analysis was performed using the Kaplan-Meier method by calendar period: 1996-2000, 2001-2005 and 2006-2009. The log-rank test was used to detect differences in survival curves. Simultaneous assessment of prognostic factors was performed by a multivariate analysis using the Cox proportional-hazards regression model.619 HCCs were analysed. There was a significant increase of patients undergoing transarterial chemoembolisation (TACE), whereas patients undergoing curative or palliative supportive treatments remained unchanged (p0.0001). No shift to earlier stages was detected. Significant differences in CCS were observed by age-group (p0.0001), diagnosis period (p0.0001), diagnosis technique (p = 0.0035), Barcelona-Clinic liver cancer stage (p0.0001), treatment (p0.0001). Multivariate analysis confirmed the independent impact on CSS of factors above mentioned, not including the diagnosis technique. Death risk was higher for patients diagnosed in 1996-2000 (HR: 1.32; 95% CI: 1.03; 1.68) and 2001-2005 (HR: 1.33; 95% CI: 1.05; 1.67) in comparison with 2006-2009 (reference group).The current population-based report describes a major increase in HCC survival. Simultaneously an increased use of TACE has been detected, probable cofactor of the observed survival increase. Possibly additional efforts could be made to decrease the HCC stage at diagnosis through active surveillance of cirrhotic patients to allow an increase in curative treatments. For sure efforts should be made to comply with a standardised staging system for HCC, particularly for comparative population-based issues.

OBJECTIVE: Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. METHODS: The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995-2009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. RESULTS: During 2005-2009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. CONCLUSIONS: The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions.

Basal cell carcinoma (BCC) is the most common of human malignancies, but the mechanism by which metastasis occurs is poorly understood1. Serum exosomes, 30-100 nanometer membrane-bound vesicles containing regulatory microRNAs (miRs), are emerging as a mechanism for cancer metastasis in melanoma2, breast3, prostate4, and lung cancers5, but the role of exosomes in BCC metastasis is not known. In this pilot study, we assessed for differences in exosomal composition in BCC patients with and without metastasis, and whether these differences confer functional changes in vitro. This article is protected by copyright. All rights reserved.

Objective Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15–99years) diagnosed with ovarian cancer during 1995–2009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from 67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated age-standardised 5-year net survival by stage at diagnosis (localised or advanced). Results Survival from type I epithelial ovarian tumours for women diagnosed during 2005–09 ranged from 40 to 70%. Survival from type II epithelial tumours was much lower (20–45%). Survival from germ cell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology.

Purpose Rare cancers represent 22% of all tumors in Europe; however, the quality of the data of rare cancers may not be as good as the quality of data for common cancer. The project surveillance of rare cancers in Europe (RARECARE) had, among others, the objective of assessing rare cancer data quality in population-based cancer registries (CRs). Eight rare cancers were considered: mesothelioma, liver angiosarcoma, sarcomas, tumors of oral cavity, CNS tumors, germ cell tumors, leukemia, and malignant digestive endocrine tumors. Methods We selected data on 18,000 diagnoses and revised, on the basis of the pathologic and clinical reports (but not on pathologic specimens), unspecified morphology and topography codes originally attributed by CR officers and checked the quality of follow-up of long-term survivors of poor prognosis cancers. Results A total of 38 CRs contributed from 13 European countries. The majority of unspecified morphology and topography cases were confirmed as unspecified. The few unspecified cases that, after the review, changed to a more specific diagnosis increased the incidence of the common cancer histotypes. For example, 11% of the oral cavity epithelial cancers were reclassified from unspecified to more specific diagnoses: 8% were reclassified as squamous cell carcinoma (commoner) and only 1% as adenocarcinoma (rarer). The revision confirmed the majority of long-term survivors revealing a relative high proportion of mesothelioma long-term survivors. The majority of appendix carcinoids changed behavior from malignant to borderline lesions. Conclusions Our study suggests that the problem of poorly specified morphology and topography cases is mainly one of difficulty in reaching a precise diagnosis. The awareness of the importance of data quality for rare cancers should increase among registrars, pathologists, and clinicians.

Background/Objective Our objective was to obtain follow-up pulmonary function testing and assessment of clinical respiratory outcomes, at 1-2 years, in preterm infants whose mothers were randomized to a single rescue course of antenatal steroids (AS) versus placebo. Methods Follow-up of a randomized, double-blinded trial. In the original trial pregnant women ≥14 days after initial course of AS were randomized to rescue AS or placebo. Pulmonary function testing and a standardized respiratory questionnaire were obtained at 1-2 years of corrected age. Respiratory compliance (Crs) was measured with the single-breath occlusion and functional residual capacity (FRC) with the nitrogen washout method. Analysis was by intention-to-treat. Results A total of 96 (87%) of available survivors were administered a respiratory questionnaire. Seventy-seven percent of available patients had pulmonary function testing performed. There was no significant difference between groups in incidence of wheezing, asthma, respiratory syncytial virus infection, respiratory readmissions, use of bronchodilators or other medications, or in measurements of pulmonary function. There was also no significant difference in corrected age at study, race, gender, or length at the time of pulmonary function testing. Infants in the rescue group had a comparable mean FRC (249.4 mL vs 246.2 mL; adjusted 95%CI for difference −15.45, 38.20; P = 0.37) versus placebo. There were no differences in tidal volume or Crs. Conclusion A rescue course of AS significantly increases Crs within 72 h of age and decreases oxygen need in newborn infants, without an adverse impact on pulmonary function or clinical respiratory outcomes at 1-2 years of age [NCT00669383].

Many variants of uncertain functional significance in cancer susceptibility genes lie in regulatory regions, and clarifying their association with disease risk poses significant challenges. We studied 17 germline variants (nine of which were novel) in the CDKN2A 5'UTR with independent approaches, which included mono and bicistronic reporter assays, Western blot of endogenous protein, and allelic representation after polysomal profiling to investigate their impact on CDKN2A mRNA translation regulation. Two of the novel variants (c.-27del23, c.-93-91delAGG) were classified as causal mutations (score ≥3), along with the c.-21C>T, c.-34G>T, and c.-56G>T, which had already been studied by a subset of assays. The novel c.-42T>A as well as the previously described c.-67G>C were classified as potential mutations (score 1 or 2). The remaining variants (c.-14C>T, c.-20A>G, c.-25C>T+c.-180G>A, c.-30G>A, c.-40C>T, c.-45G>A, c.-59C>G, c.-87T>A, c.-252A>T) were classified as neutral (score 0). In conclusion, we found evidence that nearly half of the variants found in this region had a negative impact on CDKN2A mRNA translation, supporting the hypothesis that 5'UTR can act as a cellular Internal Ribosome Entry Site (IRES) to modulate p16(INK) (4a) translation.

Importance Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function. Objective To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo. Design, Setting, and Participants Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year. Interventions Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). Main Outcomes and Measures The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed. Results Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H 2 O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) ( P Conclusions and Relevance Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities. Trial Registration clinicaltrials.gov Identifier:NCT00632476

Owing to the difficulty in implementing primary preventive measures for breast cancer, secondary prevention is correspondingly important, aimed at maximising detection of small cancers. Early detection diminishes the likelihood of clinical symptoms, disease progression, recurrence, distant metastasis, and death from breast cancer (Tabar et al, 1999). Trials have concluded that mammography screening in women aged from 50 to 69 can reduce breast cancer mortality by 25–30% (Gotzsche and Nielsen, 2006). Although Swiss French-speaking regions are covered by organised screening, the German- and Italian-speaking regions have no such programme. In the Italian- and French-speaking parts, physician-prescribed mammography is more frequent than in the German-speaking parts (Keller et al, 2001). In the south of Switzerland, the proportion of women aged 50–64 years who had undergone at least one mammography examination increased from 85% in 2002 to 88% in 2007 (Federal Office of Statistics, 2008). The current coexistence of systematic screening programmes and opportunistic screening strategies in Switzerland with its high-quality health-care system provides an opportunity to investigate the merits and drawbacks of the two approaches (Zwahlen et al, 2004). Although both methods seem effective in reducing breast cancer mortality, data on opportunistic screening are limited (de Gelder et al, 2009). The aim of this ecological population-based study was to assess such indicators as incidence rates, percentage of small cancers, stage distribution at diagnosis, axillary lymph node status and corresponding time trends for newly detected breast cancers, and to compare our data with those from populations with programmed screening.

Immunosuppressive treatment has changed the prognosis of Lupus nephritis over time, but improvement in prognosis is difficult to analyze in different historical periods, and should be better demonstrated in comparison with life expectancy of sex-and age-matched people. Long-term patient and renal survival of 90 patients diagnosed with Lupus nephritis at our center from 1968 to 2001 with a follow-up time of 14±8 years was retrospectively evaluated. Patient and kidney survival significantly increased over time. Multivariate analyses show that risks of patient and renal death decreased by 8% at each year of follow-up, and increased by more than 5 time in patients aged > 30 years at diagnosis. As only 14 patients were men, relative survival as compared to that of the sex- and age-matched general population of the Piedmont Region was calculated for the 76 women. Improvement in the survival of the cohort of women was seen at any time of follow-up: in particular, it was sharply lower in the first period (relative survival at 5,10 and 15 years = 0.784, 0.665, and 0.620, respectively) and increased in the second (relative survival at 5,10 and 15 years = 0.939, 0.921, and 0.850, respectively) nearly approaching that expected for the general population, i.e. 0.993, 0.983 and 0.967, respectively. Taken together, our data allow us to draw the conclusion that life expectancy in women with Lupus nephritis has improved over time, paralleling an improved awareness of the disease and a significant increase in steroid pulse therapy as induction/remission phase. Improvement in survival is for the first time demonstrated to cover the gap with life expectancy of the general population for women with Lupus nephritis.

Breast cancer may be classified into distinct molecular subtypes based on gene expression profiling and/or immunophenotypic characteristics. Aim of the study was to investigate prevalence, clinicopathologic features and overall survival (OS) of molecular subtypes, in a large European population-based study.All invasive breast cancers from 2003 to 2007 were selected from the files of Ticino Cancer Registry. Molecular subtypes were defined by immunohistochemical markers. Clinicopathological characteristics and short-term OS were analyzed.Of 1214 invasive breast cancers, 73.2% were luminal A subtype, 13.8% luminal B, 7.4% basal like and 5.6% Her2/neu. Basal like presented largely in premenopausal women and displayed aggressive features, such as large tumor size, poorly differentiated cancers, high Ki-67 proliferation index and the worst 24-month OS. Luminal A included the highest percentage of patients70, the highest proportion of stage I tumors and well/moderately differentiated lesions. Her2/neu was more frequent in postmenopausal women and showed the highest percentage of positive lymph nodes and stage IV cases.This is a comprehensive European population-based study on breast cancer molecular subtypes. We provide strong evidence that the molecular classification is useful for clinical management and superior to World Health Organization classification in terms of short-term prognostic value.

Cetuximab and panitumumab efficacy in metastatic colorectal cancer (mCRC) may be influenced by EGFR gene status and/or deregulation of its downstream signalling proteins detected in primary tumour. However, metastasis might have different molecular patterns with respect to primary tumour, possibly affecting the prediction of EGFR-targeted therapy efficacy. We analysed primary tumour and metastasis in 38 mCRC patients. Twelve cases were cetuximab/panitumumab treated. EGFR gene status and protein expression were investigated through fluorescent in situ hybridisation and immunohistochemistry (IHC), K-Ras/BRAF mutations by sequencing and PTEN expression by IHC. We observed EGFR gene deregulation in 25 out of 36 primary tumours and 29 out of 36 metastases, K-Ras mutations in 16 out of 37 cancers and in 15 out of 37 metastases, BRAF mutations in 2 out of 36 cancers and 2 out of 36 metastases and PTEN loss in 8 out of 38 cancers and 12 out of 38 metastases. For the first time in literature, we show that primary colorectal cancer and paired metastasis may exhibit difference with respect to EGFR pathway deregulation mechanisms possibly implying a different response to cetuximab or panitumumab treatment. The investigation of treated patients confirms this hypothesis. We therefore suggest that the analysis of metastatic lesion should be considered in patient management as well as in designing future clinical trials aimed to investigate the effect of anti-EGFR monoclonal antibodies in the treatment of mCRC.

Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the eff ectiveness of health systems, and to inform global policy on cancer control. Methods Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15–99 years) and 75 000 children (age 0–14 years) diagnosed with cancer during 1995–2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005–09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15–19% in North America, and as low as 7–9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10–20% between 1995–99 and 2005–09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995–99 and 2005–09 have generally been slight. For women diagnosed with ovarian cancer in 2005–09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005–09 was high (54–58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18–23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major defi ciencies in the management of a largely curable disease. Interpretation International comparison of survival trends reveals very wide diff erences that are likely to be attributable to diff erences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems This work was funded by the Canadian Partnership Against Cancer, Cancer Focus Northern Ireland, Cancer Institute New South Wales, Cancer Research UK (C1336/A16148), US Centers for Disease Control and Prevention (CDC; 12FED03123, ACO12036), Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, and the University of Kentucky (3049024672-12-568)

The incidence rate of invasive infections due to Candida species has increased drastically in the last 20 years, causing a 40% mortality rate in hospitalized patients. In order to comprehend the epidemiology of Candida bloodstream infection, the study was carried out.A retrospective study was done based on microbiology laboratory reports from five terciary care hospitals from the city of Cordoba between January 2010 and August 2012.158 patients had candidemia, the average age was 55,8 years, and 54% of patients were in the intensive care unit. Candida albicans (44%), Candida parapsilosis (22%) and Candida tropicalis (12%) were the main fungi isolated. Candida parapsilosis was commonly associated with catether infections.The data from the city of Cordoba showed that C. albicans, C. parapsilosis y C. tropicalis were the more frequent species isolated from blood cultures. This is similar to what is seen in other series published from Argentina and Latinamerica. This study may have implications when it comes to deciding which empiric antifugal agent is best for the treatment of candidemia.La incidencia de infecciones invasivas por Candida ha aumentado en forma dramática en los últimos 20 años, siendo causa importante de mortalidad en torno al 40% en los pacientes hospitalizados. Material y métodos: Se realizó un estudio retrospectivo, basado en reportes de laboratorio de cinco hospitales de tercer nivel de la ciudad de Córdoba entre enero de 2010 y agosto de 2012, con el objetivo de conocer la epidemiología regional. Resultados: 158 pacientes con candidemia, edad promedio de 55.8 años, el 60% internados en unidades de cuidados intensivos. Candida albicans 44%, Candida parapsilosis 22% y Candida tropicalis 12% fueron las principales especies aisladas. Candida parapsilosis estuvo comúnmente asociada a infecciones relacionadas a catéteres. Conclusiones: Esta serie local de la ciudad de Córdoba muestra que C. albicans, C. parapsilosis y C. tropicalis son las especies mas frecuentes coincidente con el perfil de las series publicadas en Argentina y Latinoamérica. Esto puede tener implicancias para decidir que agente antifúngico usar empíricamente para tratar las candidemias.

BACKGROUND: At present, thyroid fine-needle aspiration (FNA) specimens are diagnosed using a tiered classification scheme, with the most popular of these being the 5-tiered and 6-tiered systems. In this study, the authors present their institutional experiences using these 2 different systems and evaluate their efficacy based on the surgical follow-up. METHODS: Thyroid FNA specimens and their corresponding surgical resection specimens were collected between 2007 and 2009. The following diagnostic categories are used in both systems: unsatisfactory/nondiagnostic, benign, follicular neoplasm/suspicious for follicular neoplasm, suspicious for malignancy, and malignant. An additional category termed atypia of undetermined significance/follicular lesion of undetermined significance was used for atypical cases in the 6-tiered system. Statistical analysis was performed by comparing the different diagnostic categories. RESULTS: The case cohort included a total of 7686 thyroid FNA specimens representing 3962 nodules and 3724 nodules, respectively, in the 5-tiered and 6-tiered systems. Negative predictive values for the benign categories (96.9% vs 97.5%; P = 1) and positive predictive values for both the follicular neoplasm categories (26.5% vs 32.1%; P = .2531) and the malignant categories (99.1% vs 99.4%; P = 1) were similar. The most significant differences between the 5-tiered and 6-tiered systems were the percentage of cases classified as benign (83.9% vs 55.4%; P < .0001) and as follicular neoplasms (4.6% vs 23.8%; P < .0001). It is interesting to note that fewer patients were referred for surgery in the 5-tiered system compared with the 6-tiered one (9.1% vs 36.5%; P < .0001). CONCLUSIONS: Use of either the 5-tiered or 6-tiered reporting systems for thyroid FNA specimens can potentially affect the clinical management of patients with thyroid nodules. Cancer (Cancer Cytopathol) 2012. © 2011 American Cancer Society.

We aimed to evaluate low-power laser therapy efficacy on fibrinogen (PF) in the plasma of rats with arthritis induced by urate crystals. In addition, anatomopathological (AP) studies were carried out.Raised blood uric acid may form microscopic crystals in the joint. These crystals set up the inflammation called "acute gouty arthritis."Two mg of uric acid were injected in both joints of the lower limbs of rats over 2 days. A group was treated with He-Ne laser (6 mW) on the injected joints during 3 consecutive days. After 96 h of the first injection, animals were sacrificed to determine fibrinogen by spectrophotometry. Sections from the lower limbs were used for AP studies.A statistically significant increase (p0.001) in plasma fibrinogen levels was observed in the group injected with urates, when compared to both control group and the laser-treated group. The AP observed in the untreated group showed an intense fibroblastic proliferation and chronic inflammation. In the group treated with laser no inflammatory reaction was observed.Laser therapy has an anti-inflammatory effect in arthropathy induced in rats injected with urates, determined by fibrinogen levels and by histological involution.

The objective of this work is to assess the anti-inflammatory capacity of He-Ne laser therapy as determined by the plasmatic levels of inflammatory markers, fibrinogen, and TNFalpha and by histopathological study in rats with arthropathy induced by calcium pyrophosphate crystals.Microcrystalline arthropathies are a group of diseases characterized by the deposit of different crystals in joints.Two milligrams of dicalcium pyrophosphate crystals (DCPP) were injected in both joints of the lower limbs of rats during 2 days. A group was treated with laser of He-Ne (6 mW) on the injected joints during 3 consecutive days. After 96 h of the first injection, animals were sacrificed to determine TNFalpha using the ELISA method and fibrinogen was assessed using spectrophotometry. Sections from the lower limbs were used for histopathology.A statistically significant increase (p0.001) in plasma fibrinogen levels and TNFalpha was noted between the control group and the laser-treated group. The histological transversal section of a posterior limb joint of a rat injected with DCPP showed fibroadipose tissue with diffuse chronic infiltrate. The histopathology of the group of rats injected with DCPP and subsequently treated with He-Ne laser showed no inflammatory response.He-Ne laser treatment in the microcrystalline arthropathy induced in rats by DCPP injection might have an antiinflammatory effect, evaluated by fibrinogen plasma levels and TNF-alpha (inflammatory markers) and by the histopathology regressive process.

The present case series describes four patients with asthma, airway hyper-responsiveness and neutrophilic bronchitis who harboured abnormal cystic fibrosis transmembrance conductance regulator (CFTR) gene mutations. It serves both to alert clinicians to consider CFTR-related disease in both young and elderly patients with persistent neutrophilic bronchitis, and to highlight the potential utility of future genetic testing for CFTR abnormalities in patients with asthma and recurrent bronchitis or pansinusitis, and the role of nebulized hypertonic saline as a therapeutic option in these patients.

Background: Cancer survival is a key measure of the effectiveness of health-care systems. EUROCARE-the largest cooperative study of population-based cancer survival in Europe-has shown persistent differences between countries for cancer survival, although in general, cancer survival is improving. Major changes in cancer diagnosis, treatment, and rehabilitation occurred in the early 2000s. EUROCARE-5 assesses their effect on cancer survival in 29 European countries. Methods: In this retrospective observational study, we analysed data from 107 cancer registries for more than 10 million patients with cancer diagnosed up to 2007 and followed up to 2008. Uniform quality control procedures were applied to all datasets. For patients diagnosed 2000-07, we calculated 5-year relative survival for 46 cancers weighted by age and country. We also calculated country-specific and age-specific survival for ten common cancers, together with survival differences between time periods (for 1999-2001, 2002-04, and 2005-07). Findings: 5-year relative survival generally increased steadily over time for all European regions. The largest increases from 1999-2001 to 2005-07 were for prostate cancer (73·4% [95% CI 72·9-73·9] vs 81·7% [81·3-82·1]), non-Hodgkin lymphoma (53·8% [53·3-54·4] vs 60·4% [60·0-60·9]), and rectal cancer (52·1% [51·6-52·6] vs 57·6% [57·1-58·1]). Survival in eastern Europe was generally low and below the European mean, particularly for cancers with good or intermediate prognosis. Survival was highest for northern, central, and southern Europe. Survival in the UK and Ireland was intermediate for rectal cancer, breast cancer, prostate cancer, skin melanoma, and non-Hodgkin lymphoma, but low for kidney, stomach, ovarian, colon, and lung cancers. Survival for lung cancer in the UK and Ireland was much lower than for other regions for all periods, although results for lung cancer in some regions (central and eastern Europe) might be affected by overestimation. Survival usually decreased with age, although to different degrees depending on region and cancer type. Interpretation: The major advances in cancer management that occurred up to 2007 seem to have resulted in improved survival in Europe. Likely explanations of differences in survival between countries include: differences in stage at diagnosis and accessibility to good care, different diagnostic intensity and screening approaches, and differences in cancer biology. Variations in socioeconomic, lifestyle, and general health between populations might also have a role. Further studies are needed to fully interpret these findings and how to remedy disparities. Funding: Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation, Cariplo Foundation. © 2014 Elsevier Ltd.

Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995-2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000-2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers.

In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of 'riboSNitches' versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3' untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation.

While much is known about genes that promote aging, little is known about genes that protect against or prevent aging, particularly in human skin. The main objective of this study was to perform an unbiased, whole transcriptome search for genes that associate with intrinsic skin youthfulness. To accomplish this, healthy women (n = 122) of European descent, ages 18-89 years with Fitzpatrick skin type I/II were examined for facial skin aging parameters and clinical covariates, including smoking and ultraviolet exposure. Skin youthfulness was defined as the top 10% of individuals whose assessed skin aging features were most discrepant with their chronological ages. Skin biopsies from sun-protected inner arm were subjected to 3'-end sequencing for expression quantification, with results verified by quantitative reverse transcriptase-polymerase chain reaction. Unbiased clustering revealed gene expression signatures characteristic of older women with skin youthfulness (n = 12) compared to older women without skin youthfulness (n = 33), after accounting for gene expression changes associated with chronological age alone. Gene set analysis was performed using Genomica open-access software. This study identified a novel set of candidate skin youthfulness genes demonstrating differences between SY and non-SY group, including pleckstrin homology like domain family A member 1 (PHLDA1) (p = 2.4x10-5), a follicle stem cell marker, and hyaluronan synthase 2-anti-sense 1 (HAS2-AS1) (p = 0.00105), a non-coding RNA that is part of the hyaluronan synthesis pathway. We show that immunologic gene sets are the most significantly altered in skin youthfulness (with the most significant gene set p = 2.4x10-5), suggesting the immune system plays an important role in skin youthfulness, a finding that has not previously been recognized. These results are a valuable resource from which multiple future studies may be undertaken to better understand the mechanisms that promote skin youthfulness in humans.

The aim of the present population-based descriptive study was to evaluate the incidence and mortality trends for melanoma to gain insights on the effectiveness of opportunistic secondary prevention strategies. Data on all invasive cutaneous melanoma cases occurring between 1996 and 2011 were retrieved from the Ticino Cancer Registry, southern Switzerland. The European age-standardized incidence rates were computed by the period of diagnosis, Breslow thickness and histological types. Trends in incidence and mortality rates were measured as the annual per cent change (APC). A total of 1230 patients had a diagnosis of invasive cutaneous melanoma. Cases were categorized as follows: superficial spreading melanoma (55.7%), nodular melanoma (10.0%), lentigo maligna melanoma (5.5%), melanoma not otherwise specified (25.2%) and other types (3.6%). The incidence rate of invasive melanoma rose from 17.4 per 100,000 inhabitants in 1996-2003 to 20.6 in 2004-2011, with an overall APC of +2.1% [95% confidence interval (CI): -0.8%, +5.1%]. An increase in incidence was observed for superficial spreading melanoma (APC = +2.9%; 95% CI: -1.1%, +7.0%) and thin melanomas (i.e. ≤ 1.00 mm) (APC = +3.4%; 95% CI: +0.2%, +6.7%), whereas we detected a descriptive growing incidence of thick melanomas (APC = +2.1%; 95% CI: -1.4%, +5.8%). Mortality trend analysis revealed constant rates throughout the study period (APC = -1.0%; 95% CI: -5.5%, +3.7%). This population-based study confirms that in a country with the highest incidence of cutaneous melanomas, that is, Switzerland, the opportunistic screening strategy does not change the incidence of thick melanomas nor the overall mortality. This study suggests there is still a need for public health efforts in primary and secondary prevention.

Five-tiered and 6-tiered systems for reporting thyroid fine-needle aspiration (FNA) results are used widely throughout the world. In this study, we present a double-blind study of histologically confirmed follicular-patterned neoplasms and evaluate the cytological classification of the same lesions according to both systems. One hundred and forty consecutive surgically resected thyroid follicular-patterned lesions with a diagnostic preoperative FNA were retrieved from our archive. Two cytopathologists, who were blinded to all clinical information, classified each FNA case according to their respective routine diagnostic reporting system (5-tiered or 6-tiered). Interobserver variability was assessed using Cohen's Kappa (K) coefficient. Diagnostic accuracy was determined by measuring sensitivity and specificity. Receiver operator characteristic (ROC) curves were calculated for each cytopathologist. The 140 thyroid FNAs included histologically confirmed nodular hyperplasia, follicular adenomas, follicular carcinomas, and papillary carcinomas, follicular variant (35 cases for each) obtained from 104 females and 36 males with a mean age of 48.8 years and a mean tumor diameter of 27.8 mm. Negative predictive values (PV) for benign cases were 72.2% and 68.8% in the 5-tiered and 6-tiered systems, respectively (P = 0.7009). Positive PV were 100% for malignant cases in both systems. The sensitivity (78.6% vs. 72.9%, P = 0.4305), specificity (55.7% vs. 47.1%, P = 0.3103), and diagnostic accuracy (67.1% vs. 60.0%, P =0.2143) were similar between the systems. ROC curves almost entirely overlapped (P = 0.8937). Both the 5-tiered and 6-tiered systems show similar diagnostic accuracy in follicular-patterned lesions, further supporting the adoption of a common reporting system for thyroid cytopathology.

To compare pulmonary function testing including respiratory compliance (Crs) and time to peak tidal expiratory flow to expiratory time (TPTEF:TE) at term corrected age in healthy infants born at 33-36 weeks of gestation versus healthy infants delivered at term.We performed a prospective cohort study of late preterm infants born at 33-36 weeks without clinical respiratory disease (12 hours of0.21 fraction of inspired oxygen) and studied at term corrected age. The comparison group was term infants matched for race and sex to the preterm infants and studied within 72 hours of delivery. Crs was measured with the single breath occlusion technique. A minimum of 50 flow-volume loops were collected to estimate TPTEF:TE.Late preterm infants (n = 31; mean gestational age 34.1 weeks, birth weight 2150 g) and 31 term infants were studied at term corrected age. The late preterm infants had decreased Crs (1.14 vs 1.32 mL/cm H(2)O/kg; P .02) and decreased TPTEF:TE (0.308 vs 0.423; P .01) when compared with the term infants. Late preterm infants also had an increased respiratory resistance (0.064 vs 0.043 cm H(2)O/mL/s; P .01).Healthy late preterm infants (33-36 weeks of gestation) studied at term corrected age have altered pulmonary function when compared with healthy term infants.

Airway smooth muscle cells produce extracellular matrix proteins, which in turn can promote smooth muscle survival, proliferation and migration. Currently available therapies have little effect on airway smooth muscle matrix production and migration. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to decrease migration and matrix production in various cell lines. In this study, we examined the effect of PPAR ligands on human airway smooth muscle (HASM) matrix production and migration. PPAR expression was examined by RT-PCR and Western blotting. Endogenous PPAR activity was examined by transfecting cells with a PPAR response element-luciferase reporter plasmid. We observed that HASM cells express PPARα, β and γ. A six-fold induction of luciferase activity was observed by stimulating cells with a pan-agonist, indicating endogenous PPAR activity. The PPAR ligands ciglitazone, 15-deoxy-Δ12,14-prostaglandin J(2) and WY-14643 decreased migration towards platelet-derived growth factor receptor. This was not mediated by inhibiting Akt phosphorylation or promoting PTEN activity, but partly through cyclooxygenase-2 induction and prostaglandin E(2) production that increased cyclic AMP levels in the cells. All three ligands also caused an inhibition of collagen and fibronectin secretion by cultured smooth muscle cells. We conclude that PPAR ligands decrease HASM migration and matrix production and are, therefore, potentially useful for modulating airway remodelling.

Preoperative radiotherapy (RT) followed by surgery is widely accepted in the treatment of locally advanced rectal cancer (LARC). This study aimed to estimate at the population-based level the impact of preoperative RT on overall survival (OS) and cancer-specific survival (CSS) in LARCs diagnosed in Southern Switzerland between 1996 and 2007. All patients with LARC were selected from the Ticino Cancer Registry database. Patients were categorized according to the first administered treatment: preoperative radiotherapy (RT) followed by surgery (RT+) versus surgery (RT-). Clinical-pathological characteristics and 5-year OS and CSS were analysed. Among 384 patients with LARC, 54% underwent preoperative RT, occurring more frequently in the mid-distal part of the rectum compared with the RT- group (74.8 vs. 29.8%, respectively). Both 5-year OS and CSS significantly improved in RT+ patients (OS: 68 vs. 54%, respectively; CSS: 71 vs. 63%, respectively). The adjusted hazard ratio for all death was equal to 0.66 (95% confidence interval: 0.46; 0.97); similarly, the hazard ratio for cancer-specific death was 0.63 (95% confidence interval: 0.39; 0.99). These observational population-based results, after controlling for most important diagnostic and clinical prognostic factors, confirm the benefit of preoperative RT of LARC, even if the magnitude seems greater than expected in clinical trials results. Additional studies are needed, particularly with regard to the possible effect of standardized staging procedure and multidisciplinary discussion on patient outcome.

Sarcomas are a heterogeneous group of malignant neoplasms arising from mesenchymal cells which encompass dozens of histological types and can occur in virtually any anatomic site. They form one of the principal groups of rare cancers in Europe as defined in the RARECARE project. We analysed 45,568 incident cases diagnosed during 1995-2002 and registered by 76 population-based cancer registries. Total crude incidence was 5.6 per 100,000 per year with an estimated 27,908 new cases per year in the EU27 countries, of which 84% were soft tissue sarcomas and 14% were bone sarcomas. Gastrointestinal stromal tumours (GIST) were only widely recognised as an entity in the late 1990s and consequently were under-registered. Their true incidence is believed to be about 1.5 per 100,000. Age-standardised incidence of soft tissue sarcomas ranged from 3.3 per 100,000 in Eastern Europe to 4.7 per 100,000 in Northern Europe. About 280,000 persons were estimated to be alive at the beginning of 2003 with a past diagnosis of sarcoma, of which 83% were soft tissue sarcomas and 16% were bone sarcomas. Five-year relative survival for 2000-2002 by the period was 58% for soft tissue sarcomas and 62% for bone sarcomas. The diversity and rarity of sarcomas combined with the quite large number of people affected by them mean that they provide a classic example of the importance of networking in diagnosis, therapy and research for rare cancers.

Purpose: KRAS mutations represent the main cause of resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). We evaluated whether highly sensitive methods for KRAS investigation improve the accuracy of predictions of anti-EGFR MoAbs efficacy. Experimental Design: We retrospectively evaluated objective tumor responses in mCRC patients treated with cetuximab or panitumumab. KRAS codons 12 and 13 were examined by direct sequencing, MALDI-TOF MS, mutant-enriched PCR, and engineered mutant-enriched PCR, which have a sensitivity of 20%, 10%, 0.1%, and 0.1%, respectively. In addition, we analyzed KRAS codon 61, BRAF, and PIK3CA by direct sequencing and PTEN expression by immunohistochemistry. Results: In total, 111 patients were considered. Direct sequencing revealed mutations in codons 12 and 13 of KRAS in 43/111 patients (39%) and BRAF mutations in 9/111 (8%), with almost all of these occurring in nonresponder patients. Using highly sensitive methods, we identified up to 13 additional KRAS mutations compared with direct sequencing, all occurring in nonresponders. By analyzing PIK3CA and PTEN, we found that of these 13 patients, 7 did not show any additional alteration in the PI3K pathway. Conclusions: The application of highly sensitive methods for the detection of KRAS mutations significantly improves the identification of mCRC patients resistant to anti-EGFR MoAbs. Clin Cancer Res; 17(14); 4901–14. ©2011 AACR.

Introduction. Gastrointestinal stromal tumors (GISTs) are characterized at the molecular level by c-kit or PDGFRA oncogene mutations. Although GISTs raised major interest in past decades, population-based studies are still rare. Materials and Methods. All GISTs diagnosed in Southern Switzerland (1999-2005) were identified using Ticino Cancer Registry and analysed for c-kit and PDGFRA mutations. Clinical and molecular features were studied. Results. Annual incidence of GISTs was 1.47 cases/100,000 inhabitants (median age: 64 years; median size: 6.0 cm). Most GISTs arose in the stomach (60.5%). The malignancy risk was very-low/low in 47% of patients. DNA sequences showed a gene alteration in either c-kit or PDGFRA genes in 72.5% of patients. Mutations occurred mostly in c-kit exon 11 (60%). No mutations in c-kit exons 13 or 17 were found. An equal number of alterations in exons 12 and 18, and no mutations in exon 14 were observed in the PDGFRA gene. Discussion. This is the first comprehensive population-based study of GISTs incidence and molecular biology characterization in Central Europe. Our incidence data showed higher age-standardized rates compared to other European countries. The gene mutation spectrum differed when compared to the literature. This is relevant to improve the molecular profile knowledge based on Cancer Registry data.

OBJECTIVES. Our objective was to compare the pulmonary function (respiratory compliance) of infants who were ≤32 weeks' gestation and delivered >7 days after a single course of antenatal steroids versus infants who were delivered 1 to 7 days after a single course of antenatal steroids.METHODS. A prospective cohort study of respiratory system compliance was conducted of infants ≤32 weeks' gestation within 72 hours of life and before surfactant therapy if needed. The study (remote) group was composed of infants who were treated with antenatal steroids >7 days before delivery and the comparison group (ideal group) of matched infants who were treated with antenatal steroids 1 to 7 days before delivery. Respiratory system compliance was measured with the single-breath occlusion technique.RESULTS. Twenty-eight remotely treated infants and 28 ideally treated infants were studied. The remote group had a significantly lower respiratory system compliance per kilogram and total respiratory system compliance when compared with the ideal antenatal steroids group. Within the remote group, infants who received antenatal steroids 8 to 14 days (n = 10) before delivery had a significantly higher respiratory system compliance and a trend to less surfactant need (10% vs 33%) as compared with infants who received antenatal steroids >14 days (n = 18) before delivery.CONCLUSIONS. Infants who were ≤32 weeks' gestation and remotely treated with antenatal steroids (average 21 days) had a significantly lower respiratory compliance compared with matched infants who were ideally treated with antenatal steroids. We speculate that the lower respiratory system compliance may reflect the dissipation of beneficial effects of antenatal steroids on pulmonary function when delivery occurs >7 days after therapy and particularly when therapy is >14 days before delivery.

This article presents the results of laser therapy in crystal (hydroxyapatite, calcium pyrophosphate, and urates) deposition-induced arthritis in rats and the clinical applications in humans.Microcrystalline arthropathies are prevalent among geriatric patients, who are more vulnerable to the side effects of drugs. The effectiveness of laser therapy for pain relief, free of side effects, has been reported in painful conditions.Two milligrams of each of the above-mentioned crystals was injected in both joints of the back limbs in three groups of rats; these groups were then treated with laser irradiation. Three other groups received no treatment after the injections. We determined the plasmatic levels of inflammatory markers (fibrinogen, prostaglandin E2, and TNF(alpha)), tissues (prostaglandin E(2)) and conducted anatomopathological studies. Twenty-five patients with acute gout arthritis were randomized into two groups and treated over 5 days: group A, diclofenac 75 mg orally, twice a day; and group B, laser irradiation once a day. Forty-nine patients with knee chronic pyrophosphate arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Thirty patients with shoulder chronic hydroxyapatite arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day.Fibrinogen, prostaglandin E(2), and TNF(alpha) concentrations in the rats injected with crystals and treated with laser decreased significantly as compared with the groups injected with crystals without treatment. Both laser therapy and diclofenac achieved rapid pain relief in patients with acute gouty arthritis without significant differences in efficacy. Laser therapy was more effective than diclofenac in patients with chronic pyrophosphate arthropathy and in patients with chronic apatite deposition disease.Laser therapy represents an effective treatment in the therapeutic arsenal of microcrystalline arthropathies.