OtoRhinoLaryngology News: 12/09/17

Σάββατο 9 Δεκεμβρίου 2017

Prevalence of soft tissue calcifications in the maxillofacial region detected by cone beam CT

Abstract

Objective

To determine the prevalence of soft tissue calcifications in cone beam computed tomography (CBCT) scans with different fields of view (FOV), and to assess its relation with the clinical relevance of the CBCT findings.

Material and Methods

One thousand CBCT scans were grouped according to FOV's size and region scanned (MX-FOV, maxilla; MD-FOV, mandible; and MM-FOV, maxilla/mandible) and evaluated for the presence of soft tissue calcifications. Laterality and length of the elongated styloid processes (ESP) were also assessed.

Results

Eight hundred eighty-two soft tissue calcifications were detected in 626 (62.6%) patients. MM-FOV presented the highest prevalence (76.8%), followed by MD-FOV (60.6%) and MX-FOV (57.2%). ESP and tonsillolith were the most frequent calcifications. Calcifications requiring treatment or not and those in need of follow-up accounted for 6.9%, 92.7% and 0.3% of cases, respectively. There was no association between calcifications and subjects' gender or age (p>0.05). Most cases of ESP occurred bilaterally and were longer in males (p<0.05).

Conclusions

There is a high prevalence of soft tissue calcifications in CBCT, and ESP and tonsilloliths are the most common types in all evaluated FOVs. While most cases do not require treatment, we emphasize the importance of detailed CBCT assessment for its diagnosis.

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The Clinical Use of Neuromuscular Electrical Stimulation for Neuromuscular Rehabilitation: What Are We Overlooking?

Publication date: Available online 9 December 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Nicola A. Maffiuletti, Julien Gondin, Nicolas Place, Jennifer Stevens-Lapsley, Isabelle Vivodtzev, Marco A. Minetto
The clinical success of neuromuscular electrical stimulation (NMES) for neuromuscular rehabilitation is greatly compromised by the poor consideration of different physiological and methodological issues that are not always obvious for the clinicians. Therefore, the aim of this narrative review is to re-examine some of these fundamental aspects of NMES using a tripartite model perspective. First, we contend that NMES does not actually bypass the central nervous system but results in a multitude of neurally-mediated responses that contribute substantially to force generation and may engender neural adaptations. Second, we argue that too much emphasis is generally placed on externally-controllable stimulation parameters, while the major determinant of NMES effectiveness is the intrinsically-determined muscle tension generated by the current (i.e., evoked force). Third, we believe that a more systematic approach to NMES therapy is required in the clinic, and this implies a better identification of the patient-specific impairment and of the potential "responders" to NMES therapy. Based on these considerations, we suggest that the crucial steps for ensuring the clinical effectiveness of a NMES treatment should consist of: (1) identifying the neuromuscular impairment with clinical assessment; (2) implementing algorithm-based NMES therapy while (3) properly dosing the treatment with tension-controlled NMES and eventually amplifying its neural effects.

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Neuronal activity and outcomes from thalamic surgery for spinocerebellar ataxia

Abstract

Objectives

We investigated the effects of deep brain stimulation (DBS) or lesions of the ventral intermediate nucleus (Vim) of the thalamus for spinocerebellar ataxia (SCA) and examined the pathophysiological role of neuronal activity of the Vim underlying ataxia.

Methods

Five patients with SCA with cortical atrophy (ages 60-69 years; 2 sporadic and three familial SCA) and five patients with essential tremor (ET) (ages 57–71 years) were treated with Vim surgery. Intraoperatively, we recorded neuronal activity from single neurons in the Vim thalamus while patients were at rest and compared the physiological properties of those neurons between patients with SCA and those with ET.

Results

Postsurgery mean scores for the Fahn–Tolosa–Marin Tremor Scale were improved from 78 to 44 in SCA patients and from 54 to 21 in ET patients. Stronger stimulation was necessary to optimize outcomes in SCA as compared to ET patients. We analyzed 68 Vim neurons in SCA and 60 Vim neurons in ET. Mean discharge rates, burst characteristics, and oscillatory activity were similar for both patient groups, however, we observed that the ratio of cells responding to passive manipulation was significantly smaller (P = 0.0001) in SCA (22%) than in ET (71%).

Interpretation

Thalamic surgery led to a significant improvement in tremor in SCA patients. One potential mechanism underlying ataxia in SCA may be disruption of cerebellar sensory feedback, which modulates motor commands in the cerebello-thalamo-cortical network.

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Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer

Publication date: January 2018
Source:European Journal of Cancer, Volume 89
Author(s): Takeo Fujii, Naoko Matsuda, Miho Kono, Kenichi Harano, Huiqin Chen, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri, Aysegul A. Sahin, Chetna Wathoo, Aron Y. Joon, Debu Tripathy, Funda Meric-Bernstam, Naoto T. Ueno
BackgroundUnderstanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations.MethodsArchival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model.ResultsA total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both).ConclusionSystemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.

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Complete response of a metastatic porocarcinoma treated with paclitaxel, cetuximab and radiotherapy

Publication date: Available online 9 December 2017
Source:European Journal of Cancer
Author(s): C. Godillot, S. Boulinguez, L. Riffaud, V. Sibaud, C. Chira, E. Tournier, C. Paul, N. Meyer

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Antitumor miR-150-5p and miR-150-3p inhibit cancer cell aggressiveness by targeting SPOCK1 in head and neck squamous cell carcinoma

Publication date: Available online 9 December 2017
Source:Auris Nasus Larynx
Author(s): Keiichi Koshizuka, Toyoyuki Hanazawa, Naoko Kikkawa, Koji Katada, Atsushi Okato, Takayuki Arai, Tetsuya Idichi, Yusaku Osako, Yoshitaka Okamoto, Naohiko Seki
ObjectiveOur recent studies have revealed that both strands of pre-miRNAs, the guide strand and the passenger strand, are involved in cancer pathogenesis. Analyses of miRNA expression signatures by RNA sequencing in head and neck squamous cell carcinoma (HNSCC) showed that both of the strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly downregulated, and that these miRNAs acted as antitumor miRNAs in HNSCC cells. The aim of this study was to identify oncogenic genes in HNSCC cells that were regulated by miR-150-5p and miR-150-3p.MethodsGenome-wide gene expression studies, in silico analyses and dual-luciferase reporter assays were carried out to predict miR-150-5p and miR-150-3p regulation in HNSCC cells. Knockdown assay was applied to investigate the functional significance of the target gene. Overall patient survival as a function of target gene expression was estimated by The Cancer Genome Atlas (TCGA) database.ResultsA total of 19 genes were putative targets of both miR-150-5p and miR-150-3p regulation. Among them, SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was directly regulated by both miRNAs in HNSCC cells. Knockdown studies using si-SPOCK1 showed that expression of SPOCK1 enhanced HNSCC cell aggressiveness. Overexpression of SPOCK1/SPOCK1 was confirmed in HNSCC clinical specimens. Interestingly, analysis of a large number of patients in the TCGA database (n=248) demonstrated that patients with high SPOCK1 expression had significantly shorter survival than did those with low SPOCK1 expression (P=0.0003). Moreover, 15 pathways were identified as SPOCK1-mediated downstream pathways.ConclusionDownregulation of both strands of pre-miR-150 (miR-150-5p and miR-150-3p) and overexpression of SPOCK1 contribute to the aggressive nature of HNSCC. The involvement of passenger strand miRNA in the regulation of HNSCC pathogenesis is a novel concept in RNA research.

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Early-onset childhood atopic dermatitis is related to NLRP2 repression

Publication date: Available online 9 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Loreen Thürmann, Konrad Grützmann, Matthias Klös, Matthias Bieg, Marcus Winter, Tobias Polte, Tobias Bauer, Matthias Schick, Melanie Bewerunge-Hudler, Stefan Roeder, Mario Bauer, Dirk K. Wissenbach, Ulrich Sack, Dieter Weichenhan, Oliver Mücke, Christoph Plass, Michael Borte, Martin von Bergen, Irina Lehmann, Roland Eils, Saskia Trump
Early-onset atopic dermatitis (AD) related repression of the immune regulatory NLRP2 is driven by promoter hypermethylation starting already at time of birth providing an early opportunity to modulate innate immunity to potentially mitigate AD development.

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Homelessness and Emergency Medicine: A Review of the Literature

Abstract

Objectives

We aimed to synthesize the available evidence on the demographics, prevalence, and clinical characteristics, and evidence-based management of homeless persons in the Emergency Department (ED). Where appropriate, we highlight knowledge gaps and suggest directions for future research.

Methods

We conducted a systematic literature search following databases: PubMed, Ovid, and Google Scholar for articles published between January 1, 1990 and December 31, 2016. We supplemented this search by cross-referencing bibliographies of the retrieved publications. Peer-reviewed studies written in English and conducted in the United States (US) that examined homelessness within the ED setting were included. We used a qualitative approach to synthesize the existing literature.

Results

Twenty-eight studies were identified that met the inclusion criteria. Based on our study objectives and the available literature, we grouped articles examining homeless populations in the ED into four broad categories: 1) Prevalence and socio-demographic characteristics of homeless ED visits; 2) ED utilization by homeless adults; 3) Clinical characteristics of homeless ED visits; 4) Medical education and evidence-based management of homeless ED patients.

Conclusion

Homelessness may be under-recognized in the ED setting. Homeless ED patients have distinct care needs and patterns of ED utilization that are unmet by the current disease-oriented and episodic models of emergency medicine. More research is needed to determine the prevalence and characteristics of homelessness in the ED and to develop evidence-based treatment strategies in caring for this vulnerable population.

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KRAS Testing, Tumor Location, and Survival in Patients With Stage IV Colorectal Cancer: SEER 2010-2013

Purpose: KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%–46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS-mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22–1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05–1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study.

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Reviewer Page

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NCCN News

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Prevalence of Physical Problems Detected by the Distress Thermometer and Problem List in Patients With Myeloproliferative Disorders

Background: Patients with myeloproliferative neoplasms (MPNs) can have a severe physical symptom burden over an extended disease trajectory that contributes to decreased quality of life. Few studies, however, have characterized which patients most frequently consider physical symptoms a problem. This study describes the physical symptoms of patients with MPNs and the relationship of these symptoms to patient characteristics. Methods: Patients with MPNs (N=117) completed questionnaires in a dedicated academic medical center MPN clinic. Patients reported demographics (age, race/ethnicity, sex, marital status, employment status), disease characteristics (MPN type, time with MPN), and whether they were bothered by any of 22 variables in the "Physical Problems" list in the Distress Thermometer and Problem List (DT&PL). Results: The median number of physical problems endorsed by patients was 2 (median, 2.26; SD, 3.18), with a range from 0 to 20. Two-fifths endorsed no physical problems, one-fifth endorsed 1 problem, and two-fifths endorsed ≥2 problems, with fatigue (35.5%), sleep (27.1%), pain (21.5%), dry skin/pruritus (18.7%), and memory/concentration (16.8%) being the most commonly reported. Non-Caucasian participants reported more problems with sleep (P=.050), pain (P=.016), and tingling (P=.026). Patients with polycythemia vera (PV) reported more issues with tingling (P=.046) and sexual problems (P=.032). Conclusions: Patients with MPNs are more likely to report physical symptom bother than to report no bother with multiple physical problems on the DT&PL. Patients of minority race/ethnicity and those with PV, however, showed heightened prevalence of physical problems—characteristics which may be used to triage patients for more intensive symptom management.

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It's About Time!

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Controversies Regarding Use of Myeloid Growth Factors in Leukemia

This review focuses on the data supporting the use of myeloid growth factors (MGFs) in patients being treated for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and hairy cell leukemia, for which neutropenia is a common complication of treatment. However, due to the lack of randomized trial data or conflicting results of clinical studies, comprehensive guidelines have been difficult to formulate. Moreover, to date, these diagnoses have not been addressed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MGFs. However, in most cases, the general principles have been included in the applicable NCCN Guidelines for each individual cancer site.

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Behavioral Economics and the Future of Biosimilars

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Champions Rising to the Challenge of Ensuring High-Quality Cancer Care

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Radiosurgery for Brain Metastases: Changing Practice Patterns and Disparities in the United States

Background: Management of brain metastases typically includes radiotherapy (RT) with conventional fractionation and/or stereotactic radiosurgery (SRS). However, optimal indications and practice patterns for SRS remain unclear. We sought to evaluate national practice patterns for patients with metastatic disease receiving brain RT. Methods: We queried the National Cancer Data Base (NCDB) for patients diagnosed with metastatic non–small cell lung cancer, breast cancer, colorectal cancer, or melanoma from 2004 to 2014 who received upfront brain RT. Patients were divided into SRS and non-SRS cohorts. Patient and facility-level SRS predictors were analyzed with chi-square tests and logistic regression, and uptake trends were approximated with linear regression. Survival by diagnosis year was analyzed with the Kaplan-Meier method. Results: Of 75,953 patients, 12,250 (16.1%) received SRS and 63,703 (83.9%) received non-SRS. From 2004 to 2014, the proportion of patients receiving SRS annually increased (from 9.8% to 25.6%; P<.001), and the proportion of facilities using SRS annually increased (from 31.2% to 50.4%; P<.001). On multivariable analysis, nonwhite race, nonprivate insurance, and residence in lower-income or less-educated regions predicted lower SRS use (P<.05 for each). During the study period, SRS use increased disproportionally among patients with private insurance or who resided in higher-income or higher-educated regions. From 2004 to 2013, 1-year actuarial survival improved from 24.1% to 49.6% for patients selected for SRS and from 21.0% to 26.3% for non-SRS patients (P<.001). Conclusions: This NCDB analysis demonstrates steadily increasing—although modest overall—brain SRS use for patients with metastatic disease in the United States and identifies several progressively widening sociodemographic disparities in the adoption of SRS. Further research is needed to determine the reasons for these worsening disparities and their clinical implications on intracranial control, neurocognitive toxicities, quality of life, and survival for patients with brain metastases.

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Pazopanib Sensitivity in a Patient With Breast Cancer and FGFR1 Amplification

Treatment options for patients with hormone receptor–positive (HR+), HER2-negative (HER2–) breast cancer and resistance to endocrine therapy remain limited. An interesting therapeutic target in these patients is fibroblast growth factor receptor 1 (FGFR1). FGFR1 is amplified in approximately 11% of patients with breast cancer, especially those with HR+ disease. This report presents a patient with metastatic HR+ HER2– breast cancer harboring an FGFR1 amplification who was resistant to endocrine therapy but responded to pazopanib, a multi–tyrosine kinase inhibitor with FGFR-inhibiting activity. Upon pazopanib treatment, the patient's brain lesions nearly disappeared, and she experienced therapeutic changes in the lung and an improvement of liver function. This case suggests that pazopanib may be a promising agent for the treatment of patients with breast cancer and FGFR1 amplifications.

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Geographic Variation of Adjuvant Breast Cancer Therapy Initiation in the United States: Lessons From Medicare Part D

Background: Drug utilization under Medicare Part D varies significantly by geographic region. This study examined the extent to which geographic variation in Part D plan characteristics contributes to the variation in choice of initial endocrine therapy agent among women with incident breast cancer. Methods: Two-stage multivariate regression analyses were applied to the 16,541 women identified from Medicare claims as having incident breast cancer in 2006–2007. The first stage determined the effect of state of residence on the probability of having an aromatase inhibitor (AI), as opposed to tamoxifen, as initial endocrine therapy. The second stage provided estimates of the impact of state-specific Part D plan characteristics on variation in choice of initial therapy. Results: There was substantial residual geographic variation in the likelihood of using an AI as initial endocrine therapy, despite controlling for socioeconomic status, breast cancer treatment, and other factors. Regression-adjusted probabilities of starting an AI ranged from 57.3% in Wyoming to 92.6% in the District of Columbia. Results from the second stage revealed that variation in characteristics of Part D plans across states explained approximately one-third (30%) of the state-level variability in endocrine therapy. A higher number of plans with cost-sharing above the mean, greater spread in deductibles, and a greater spread in monthly drug premiums were associated with lower adjusted state probabilities of initiating an AI. In contrast, a higher number of drug plans with monthly premiums above the state mean and higher mean cost-sharing (in dollars) were both positively associated with likelihood of starting on an AI. Conclusions: Study findings suggest that variation in benefit design of Part D plans accounts for an important share of the large and persisting variability in use of AIs—the preferred oral therapy for breast cancer.

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Ensuring Patient Safety and Access in Cancer Care

The inability to obtain the right high-quality cancer care in a timely and safe manner can have devastating results for patients. As cancer care becomes inundated with cutting edge and novel treatments, such as personalized medicine, oral chemotherapy, biosimilars, and immunotherapy, new safety challenges are emerging at increasing speed and complexity. Moreover, shifting federal healthcare policies could have significant implications for the safety and access to high-quality and effective cancer care for millions of patients with cancer. Challenges and opportunities in ensuring patient access to safe, affordable, and high-quality cancer care remain significant within the policy landscape. To address these concerns, NCCN hosted the Ensuring Safety and Access in Cancer Care Policy Summit in June 2017 to discuss pertinent patient safety issues and access implications under the Trump administration, as well as policy and advocacy strategies to address these gaps and build on opportunities moving forward.

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A Patient Risk Model of Chemotherapy-Induced Febrile Neutropenia: Lessons Learned From the ANC Study Group

Neutropenia and its complications, including febrile neutropenia (FN), represent major toxicities associated with cancer chemotherapy, resulting in considerable morbidity, mortality, and costs. The myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) have been shown to reduce the risk of neutropenia complications while enabling safe and effective chemotherapy dose intensity. Concerns about the high costs of these agents along with limited physician adherence to clinical practice guidelines, resulting in both overuse and underuse, has stimulated interest in models for individual patient risk assessment to guide appropriate use of G-CSF. In a model developed and validated by the ANC Study Group, half of patients were classified as high risk and half as low risk based on patient-, disease-, and treatment-related factors. This model has been further validated in an independent patient population. Physician-assessed risk of FN, as well as the decision to use prophylactic CSF, has been shown to correlate poorly with the FN risk estimated by the model. Additional modeling efforts in both adults and children receiving cancer treatment have been reported. Identification of patients at a high individual risk for FN and its consequences may offer the potential for optimal chemotherapy delivery and patient outcomes. Likewise, identification of patients at low risk for neutropenic events may reduce costs when such supportive care is not warranted. This article reviews and summarizes FN modeling studies and the opportunities for personalizing supportive care in patients receiving chemotherapy.

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NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the management of patients with high-risk syndromes associated with an increased risk of colorectal cancer (CRC). The NCCN Panel for Genetic/Familial High-Risk Assessment: Colorectal meets at least annually to assess comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights focus on genes newly associated with CRC risk on multigene panels, the associated evidence, and currently recommended management strategies.

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Disparities in Adjuvant Endocrine Therapy

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Editorial Board

Publication date: January–February 2018
Source:Brain Stimulation, Volume 11, Issue 1

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Publication date: January–February 2018
Source:Brain Stimulation, Volume 11, Issue 1

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Information for Authors

Publication date: January–February 2018
Source:Brain Stimulation, Volume 11, Issue 1

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Masthead

Publication date: January–February 2018
Source:Brain Stimulation, Volume 11, Issue 1

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Network-based brain stimulation selectively impairs spatial retrieval

Publication date: January–February 2018
Source:Brain Stimulation, Volume 11, Issue 1
Author(s): Kamin Kim, Amber Schedlbauer, Matthew Rollo, Suganya Karunakaran, Arne D. Ekstrom, Nitin Tandon
BackgroundDirect brain stimulation via electrodes implanted for intracranial electroencephalography (iEEG) permits the modulation of endogenous electrical signals with significantly greater spatial and temporal specificity than non-invasive approaches. It also allows for the stimulation of deep brain structures important to memory, such as the hippocampus, that are difficult, if not impossible, to target non-invasively. Direct stimulation studies of these deep memory structures, though, have produced mixed results, with some reporting improvement, some impairment, and others, no consistent changes.Objective/hypothesisWe hypothesize that to modulate cognitive function using brain stimulation, it is essential to modulate connected nodes comprising a network, rather than just alter local activity.MethodsiEEG data collected while patients performed a spatiotemporal memory retrieval task were used to map frequency-specific, coherent oscillatory activity between different brain regions associated with successful memory retrieval. We used these to identify two target nodes that exhibited selectively stronger coupling for spatial vs. temporal retrieval. In a subsequent session, electrical stimulation - theta-bursts with a fixed phase-lag (0° or 180°) – was applied to the two target regions while patients performed spatiotemporal retrieval.ResultsStimulation selectively impaired spatial retrieval while not affecting temporal retrieval, and this selective impairment was associated with theta decoupling of the spatial retrieval network.ConclusionThese findings suggest that stimulating tightly connected nodes in a functional network at the appropriate phase-lag may effectively modulate the network function, and while in this case it impaired memory processes, it sets a foundation for further network-based perturbation studies.

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Antitumor miR-150-5p and miR-150-3p inhibit cancer cell aggressiveness by targeting SPOCK1 in head and neck squamous cell carcinoma

Our recent studies have revealed that both strands of pre-miRNAs, the guide strand and the passenger strand, are involved in cancer pathogenesis. Analyses of miRNA expression signatures by RNA sequencing in head and neck squamous cell carcinoma (HNSCC) showed that both of the strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly downregulated, and that these miRNAs acted as antitumor miRNAs in HNSCC cells. The aim of this study was to identify oncogenic genes in HNSCC cells that were regulated by miR-150-5p and miR-150-3p.

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Influence of involuntary cigarette smoke inhalation on osseointegration: a systematic review and meta-analysis of preclinical studies

There are no studies that have systematically reviewed the influence of involuntary cigarette smoke inhalation (ICSI) on the stability of implants. The aim of the present study was to perform a systematic review and meta-analysis of preclinical studies that assessed the influence of involuntary cigarette smoke inhalation ICSI on osseointegration. Indexed databases (PubMed, Google-Scholar, Scopus, EMBASE, and Web of Knowledge) were searched till September 2017. Titles and abstracts of studies identified using the above-described protocol were independently screened by 2 authors.

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Identification of human papillomavirus (HPV) subtype in oral cancer patients through microarray technology

Abstract

Purpose

Human papilloma virus (HPV) is the main source of cervical cancer. Many recent studies have revealed the prevalence and prognosis of HPV associated with oropharyngeal squamous cell carcinoma, but fewer reports have evaluated HPV in oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the prevalence and prognosis of HPV associated with OSCC according to HPV and tumor types.

Materials and methods

We used a DNA chip kit (MY-HPV chip kit ^®, Mygene Co., Korea) to detect high-risk HPV subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58) and low-risk subtypes (6, 11, 34, 40, 42, 43, 44) among 187 patients. The prevalence was determined by Chi-square and Fisher's exact tests, and the prognosis was calculated by the Kaplan–Meier method and the log-rank test.

Results

The overall prevalence of HPV in OSCC was 7.0% for all HPV positives and 4.3% for high-risk HPV positives. The prevalence of HPV was significantly higher in individuals under 65 years old and in those with tumors in the tongue and gum regions. The prognosis did not differ between the HPV-positive and -negative groups. Although the prevalence of HPV-positive cases in OSCC was low (7.0, 4.3%) and the prognosis did not depend on HPV positivity, HPV-associated OSCC should be considered in the evaluation and treatment of oral cancer patients. In addition, separating high- and low-risk groups based on the HPV status of other body parts might not be appropriate.

Discussion

The DNA microarray method can accurately detect known HPV subtypes simultaneously, but has limitations in detecting new subtypes. Vaccines can also be used to prevent HPV-associated OSCC in patients, so further studies on the prognosis and efficacy of vaccines should be undertaken.

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Pattern of care and impact of prognostic factors on the outcome of head and neck extramedullary plasmacytoma: a systematic review and individual patient data analysis of 315 cases

Abstract

Introduction

Head and neck extramedullary plasmacytoma is a rare localized plasma cell neoplasm. We intended to perform this review of the published literature to assess the demographic profile, pattern of care and survival outcomes.

Methods

Two authors independently searched PubMed, Google search and Cochrane library for eligible studies from 1950 till July 1, 2016, published in English language.

Results

Median age of the cohort was 57 years (range 11–85). Site-wise distributions were paranasal sinuses 22.3% (70), nasal cavity 17.5% (55), nasopharynx 10.8% (34). Median size of SEMP was 3 cm (range 0.3–12 cm). Treatment distribution was radiotherapy (RT) in 52% (164), surgery (S) 19% (60), chemotherapy (C) 5% (16), S + RT 23.49% (74),CRT 1.9% (6), S + C 0.6% (2), S + RT + C 0.95% (3).Radiation was used as a modality in 78.4%(247), surgery in 44.1%(139), chemotherapy in 4.8%(15). Median radiation dose used was 45 Gy with range 20–61 Gy. Median overall survival (OS) was 40 months (range 0.5–298). Median local progression-free survival was 36 months (range 0–298). Median myeloma relapse-free survival was 36 months (range 0.5–298). Five- and 10-year OS was 78.33 and 68.61%. Five-year cause-specific survival (CSS) and 10-year CSS was 90.15 and 83.31%. Five-year LPFS was 94.78%, and 10-year LPFS was 88.43%. Five-year myeloma progression-free survival was 84.46%, and 10-year myeloma PFS was 80.44%. The factors associated with risk of local relapse were site of disease (sinonasal), secretory EMP, type of treatment received (surgery + RT > RT alone > surgery on univariate analysis). Risk factors for myeloma relapse were coexisting diseases, site of disease (sinonasal), bony erosion, size of lesion > 5 cm and type of treatment received on univariate analysis.

Conclusion

Our study shows that combined modality S + RT is superior compared to uni-modality in preventing local recurrence. Radiation dose of 45 Gy is optimal. Nodal irradiation has no impact on local recurrence.

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Association between continuous positive airway pressure and serum aminotransferases in patients with obstructive sleep apnea

Abstract

Introduction

Obstructive sleep apnea (OSA) has been suggested to be a potential contributing factor for nonalcoholic fatty liver disease (NAFLD). Studies on the association between continuous positive airway pressure (CPAP) and NAFLD in OSA patients are limited and controversial.

Objectives

The aim of this study was to assess the relationship between OSA and NAFLD and the effect of CPAP therapy on serum aminotransferase levels in OSA patients.

Methods

A total of 160 consecutive patients who underwent standard polysomnography were enrolled. Blood samples were obtained in the morning after sleep for biological profile measurements. Non-invasive ultrasound techniques were used to assess liver steatosis and fibrosis. Within the OSA group, serum aminotransferases were detected before and after CPAP treatment.

Results

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase, and liver steatosis score increased significantly with an increase in OSA severity. Stepwise multiple regression with liver steatosis score, ALT, AST as dependent variable, respectively, apnea–hypopnea index (β = 0.447, p = 0.020; β = 0.266, p = 0.001; β = 0.351, p = 0.020, respectively) significantly predicted the liver steatosis score, ALT, AST after adjustment for confounders. After 3 months of CPAP treatment, there was a significant decrease in both ALT (54.20 ± 24.34 vs. 46.52 ± 24.95, p = 0.000) and AST (31.82 ± 8.91 vs. 29.00 ± 8.34, p = 0.039).

Conclusions

OSA severity was independently associated with liver steatosis and elevation of serum aminotransferases. 3 months of CPAP therapy were associated with a statistically significant improvement on liver injury in OSA patients.

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Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: a multicenter, randomized controlled trial (with video)

To clarify whether dental floss clip traction improves the technical outcomes of endoscopic submucosal dissection (ESD).

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Endoscopic detection rate of sessile serrated lesions in Lynch syndrome patients is comparable to an age- and gender-matched control population: case-control study with expert pathology review

Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) due to microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients to a matched control population.

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Time latencies of Helicobacter pylori eradication after peptic ulcer and risk of recurrent ulcer, ulcer adverse events, and gastric cancer: a population-based cohort study

Helicobacter pylori (H pylori) is associated with peptic ulcer disease and gastric cancer.

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Safety and efficacy of lumen-apposing metal stents with and without simultaneous double-pigtail plastic stents for draining pancreatic

Lumen-apposing metal stents (LAMSs) are used to perform necrosectomy in walled-off necrosis (WON). Although necrosectomy is not required for pancreatic pseudocyst (PP), an increasing number of PPs are also being drained with LAMSs in view of their ease of deployment. The aim of the present study was to evaluate the safety and efficacy of using LAMSs to drain PPs.

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Safety and Efficacy of guselkumab in Japanese patients with moderate-to-severe plaque psoriasis: A Randomised, Placebo-Controlled, Ascending Dose Study

Summary

Background

The Interlukin-23 (IL-23)/Interlukin-17 (IL-17) pathway is central in the pathogenesis of psoriasis. The favourable efficacy and safety of guselkumab, an IL-23 specific monoclonal antibody, has been demonstrated in global Phase 3 studies of plaque psoriasis.

Objectives

To evaluate the safety, efficacy and pharmacokinetics of a single-dose subcutaneous guselkumab in Japanese patients with moderate-to-severe plaque psoriasis.

Methods

Patients with ≥ 10% of total body surface area (BSA) involvement and a Psoriasis Area and Severity Index (PASI) ≥12 were randomised (5:1) to receive guselkumab or placebo in 4 cohorts of this double-blind, placebo-controlled, single ascending dose, single-centre study. Safety, pharmacokinetics, and clinical response were monitored at baseline and specific time points over a 24-wk follow-up period.

Results

Through week 24, 54% (11/20) of guselkumab patients and 50% (2/4) of placebo patients experienced ≥1 adverse event (AE). No deaths, serious AEs, or AEs leading to treatment discontinuation were reported. Maximum clinical response was seen at week 16 with PASI 75 response in 2/5 (10 mg), 4/5 (30 mg and 300 mg), and 3/5 (100 mg) patients and PASI 90 in 0/5 (10 mg), 3/5 (30 mg), 2 /5 (100 mg) and 3/5 (300 mg) patients. Mean C_max and AUC_∞ values increased in a dose-proportional manner with mean terminal t_1/2 of 15.6-17.6 days and median t_max of 4-6 days.

Conclusions

Guselkumab was generally well-tolerated and exhibited sustained high levels of clinical response in Japanese patients with moderate-to-severe psoriasis.

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Which outcomes are reported in cellulitis trials? Results of a review of outcomes included in cellulitis trials and a patient priority setting survey

Summary

Background

There is an emerging need to develop consistent outcomes in clinical trials to allow effective comparison of treatment effects. No systematic review has previously looked at the reporting of outcome measures used in randomised controlled trials (RCTs) on treatment and prevention of cellulitis (erysipelas).

Objectives

The primary aim of this review was to describe the breadth of outcomes reported from RCTs on cellulitis treatment and prevention. The secondary aim was to identify outcome themes from patient and health care professionals' feedback from a cellulitis priority setting partnership (PSP).

Methods

We conducted a review of all outcome measures used in RCTs from two recent Cochrane reviews. Free text responses from a cellulitis priority setting survey were used to understand the perspectives of patients and healthcare professionals.

Results

Outcomes from 42 RCTs on treatment of cellulitis and six RCTs on prevention of cellulitis were reviewed. Only 28 trials stated their primary outcome. For trials assessing treatment of cellulitis, clinical response to treatment was categorised in 25 different ways. Five of these trials used an outcome that was in accordance with FDA guidance and only four trials incorporated either quality of life or patient satisfaction. For trials assessing prevention of cellulitis, recurrence was the key outcome measure. From the cellulitis PSP, prevention of recurrence, clinical features and long-term disease impact were the most important outcome themes for patients.

Conclusions

We have shown that in cellulitis treatment and prevention research, there is significant heterogeneity in clinical outcomes, inadequate focus on patient-reported outcomes, and a disparity between what is currently measured and what patients and healthcare professionals feel is important. We recommend that future cellulitis treatment trials consider the use of longer-term outcomes to capture recurrence and long-term morbidity, as well as short-term resolution of acute infection.

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Auras and the risk of seizures with impaired consciousness following epilepsy surgery: implications for driving

Objective

To calculate the chance of a seizure in the next year (COSY) for seizures with impaired awareness in those experiencing auras only, those with no seizures and those with continuing seizures. Epilepsy surgery is an effective treatment for refractory focal epilepsy. Driving is an important factor affecting quality of life. In the UK, driving is not permitted if focal seizures with no impairment of awareness (auras, simple partial seizures) continue, if there is a prior history of seizures with impaired awareness, as will invariably be the case in those having epilepsy surgery. Current UK driving regulations allow driving if COSY is less than 20%.

Method

We calculated COSY in 819 epilepsy surgery patients with up to 25 years follow-up. Each patient year was graded on the The International League against Epilepsy surgery outcome scale.

Results

Patients who were entirely seizure-free for 1, 2 and 3 years had COSY of 4.9%, 3.5% and 2.4% respectively. Patients with only auras within the last 1, 2 or 3 years had a COSY of 11.3%, 9.2% and 7.8% respectively.

Conclusions

Individuals with auras only after epilepsy surgery had a higher COSY than those who were seizure-free. If a COSY of below 20% is regarded as an acceptable risk, it may be suggested that those with auras only in a given year be allowed to drive. The relative risk of these patients causing accidents is lower than population groups such as those aged <25 or >75 years, who are permitted to drive.

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Pattern of care and impact of prognostic factors on the outcome of head and neck extramedullary plasmacytoma: a systematic review and individual patient data analysis of 315 cases

Abstract

Introduction

Methods

Two authors independently searched PubMed, Google search and Cochrane library for eligible studies from 1950 till July 1, 2016, published in English language.

Results

Conclusion

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Gongylonema pulchrum infection in the human oral cavity – a case report and literature review

Publication date: Available online 8 December 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Xiaodan Liu, Zhensheng Wang, Ying Han, Hongwei Liu, Jianqiu Jin, Peiru Zhou, Sha Su, Zhimin Yan
Gongylonema infection is a zoonotic disease occurring throughout the world and is mainly caused by consumption of contaminated water and raw food. Adult Gongylonema worms can exist as parasites in the human body for up to 10 years and cause symptoms of local irritation in the oral cavity, oesophagus, and pharynx. Herein, we report a rare case in which live Gongylonema pulchrum was detected and extracted from the oral cavity of a woman. The pathogen was confirmed as G. pulchrum on the basis of microscopic examination and morphological analysis. The patient's symptoms resolved immediately after surgical removal of the parasite, and the patient has been advised not to drink water that has not been boiled and to avoid consuming unwashed raw vegetables.

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Quality and readability of internet-based information on halitosis

Publication date: Available online 8 December 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Jung Hwan Jo, Eui Joo Kim, Ji Rak Kim, Moon Jong Kim, Jin Woo Chung, Ji Woon Park
ObjectiveTo evaluate quality and readability of Internet-based information on halitosis.Study DesignAn Internet search through three engines (Google, Yahoo and Bing) was done with the terms ("bad breath", "halitosis", "oral malodor", "foul breath", "mouth malodor", "breath malodor", "fetor ex ore", "fetor oris", "ozostomia", and "stomatodysodia"). The first 50 websites from each engine resulting from each search term were screened. Included websites were evaluated using Health on the Net(HON) criteria, Journal of American Medical Association(JAMA) benchmarks, DISCERN, Ensuring Quality Information for Patients(EQIP), Flesch Reading Ease(FRE) score and Flesch-Kincaid Grade level.ResultsOne hundred and one websites were included. HON, DISCERN, EQIP, and FRE score were 42.9%, 37.6%, 37.4%, and 51.9% of the maximum score, respectively. Fewer than 50% of sites displayed attribution, disclosure, and currency according to JAMA benchmarks. HON score, DISCERN score and EQIP score showed significant correlation with each other and were significantly higher in sites displaying the HON seal.ConclusionThe current quality and readability of informative websites on halitosis are generally low and poorly organized. Clinicians should be able to assess the Internet-based information on halitosis, as well as give accurate advice and guide patients concerning this issue.

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Identification of human papillomavirus (HPV) subtype in oral cancer patients through microarray technology

Abstract

Purpose

Materials and methods

Results

Discussion

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Aging Decreases Chorda-Tympani Nerve Responses to NaCl and Alters Morphology of Fungiform Taste Pores in Rats

Abstract

Sensory processing is susceptible to decline with age. The sense of taste is, however, generally thought to be resistant to aging. We investigated how chorda-tympani nerve responses and fungiform-taste pores are affected by aging in the Sprague-Dawley rat, a model system for salt taste. First, we measured chorda-tympani nerve responses to NH₄Cl and NaCl solutions in young (3–5 months old) and aged (14-15 months old) rats. Aged rats had significantly attenuated chorda-tympani responses to 0.01, 0.03, 0.1, and 0.3M NaCl, whereas responses to NH₄Cl were statistically similar between age groups. Second, we investigated if fungiform papillae, which harbor taste buds innervated by the chorda-tympani nerve, were affected by aging in "young" (4-7 months old) and "aged" ("aged₁" 18 months old and "aged₂" 24-28 months old) rats. Using scanning electron microscopy, we found that aging significantly reduced morphological characteristics associated with intact fungiform-taste pores (hillock, rim, pore presence, and open pore). We conclude that the structure and function of the peripheral-taste system may not be as resistant to aging as previously reported.

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Localizing Speakers in Multiple Rooms by Using Deep Neural Networks

1-s2.0-S0885230817301377-fx1.jpg

Publication date: Available online 7 December 2017
Source:Computer Speech & Language
Author(s): Fabio Vesperini, Paolo Vecchiotti, Emanuele Principi, Stefano Squartini, Francesco Piazza
In the field of human speech capturing systems, a fundamental role is played by the source localization algorithms. In this paper a Speaker Localization algorithm (SLOC) based on Deep Neural Networks (DNN) is evaluated and compared with state-of-the art approaches. The speaker position in the room under analysis is directly determined by the DNN, leading the proposed algorithm to be fully data-driven. Two different neural network architectures are investigated: the Multi Layer Perceptron (MLP) and Convolutional Neural Networks (CNN). GCC-PHAT (Generalized Cross Correlation-PHAse Transform) Patterns, computed from the audio signals captured by the microphone are used as input features for the DNN. In particular, a multi-room case study is dealt with, where the acoustic scene of each room is influenced by sounds emitted in the other rooms. The algorithm is tested by means of the home recorded DIRHA dataset, characterized by multiple wall and ceiling microphone signals for each room. In detail, the focus goes to speaker localization task in two distinct neighbouring rooms. As term of comparison, two algorithms proposed in literature for the addressed applicative context are evaluated, the Crosspower Spectrum Phase Speaker Localization (CSP-SLOC) and the Steered Response Power using the Phase Transform speaker localization (SRP-SLOC). Besides providing an extensive analysis of the proposed method, the article shows how DNN-based algorithm significantly outperforms the state-of-the-art approaches evaluated on the DIRHA dataset, providing an average localization error, expressed in terms of Root Mean Square Error (RMSE), equal to 324 mm and 367 mm respectively for the Simulated and the Real subsets.

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Rank-1 constrained Multichannel Wiener Filter for speech recognition in noisy environments

Publication date: May 2018
Source:Computer Speech & Language, Volume 49
Author(s): Ziteng Wang, Emmanuel Vincent, Romain Serizel, Yonghong Yan
Multichannel linear filters, such as the Multichannel Wiener Filter (MWF) and the Generalized Eigenvalue (GEV) beamformer are popular signal processing techniques which can improve speech recognition performance. In this paper, we present an experimental study on these linear filters in a specific speech recognition task, namely the CHiME-4 challenge, which features real recordings in multiple noisy environments. Specifically, the rank-1 MWF is employed for noise reduction and a new constant residual noise power constraint is derived which enhances the recognition performance. To fulfill the underlying rank-1 assumption, the speech covariance matrix is reconstructed based on eigenvectors or generalized eigenvectors. Then the rank-1 constrained MWF is evaluated with alternative multichannel linear filters under the same framework, which involves a Bidirectional Long Short-Term Memory (BLSTM) network for mask estimation. The proposed filter outperforms alternative ones, leading to a 40% relative Word Error Rate (WER) reduction compared with the baseline Weighted Delay and Sum (WDAS) beamformer on the real test set, and a 15% relative WER reduction compared with the GEV-BAN method. The results also suggest that the speech recognition accuracy correlates more with the Mel-frequency cepstral coefficients (MFCC) feature variance than with the noise reduction or the speech distortion level.

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Neural versus phrase-based MT quality: An in-depth analysis on English–German and English–French

Publication date: May 2018
Source:Computer Speech & Language, Volume 49
Author(s): Luisa Bentivogli, Arianna Bisazza, Mauro Cettolo, Marcello Federico
Within the field of statistical machine translation, the neural approach (NMT) is currently pushing ahead the state of the art performance traditionally achieved by phrase-based approaches (PBMT), and is rapidly becoming the dominant technology in machine translation. Indeed, in the last IWSLT and WMT evaluation campaigns on machine translation, NMT outperformed well established state-of-the-art PBMT systems on many different language pairs. To understand in what respects NMT provides better translation quality than PBMT, we perform a detailed analysis of neural versus phrase-based statistical machine translation outputs, leveraging high quality post-edits performed by professional translators on the IWSLT data. In this analysis, we focus on two language directions with different characteristics: English–German, known to be particularly hard because of morphology and syntactic differences, and English–French, where PBMT systems typically reach outstanding quality and thus represent a strong competitor for NMT. Our analysis provides useful insights on what linguistic phenomena are best modelled by neural models – such as the reordering of verbs and nouns – while pointing out other aspects that remain to be improved – like the correct translation of proper nouns.

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Situated reference resolution using visual saliency and crowdsourcing-based priors for a spoken dialog system within vehicles

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Teruhisa Misu
In this paper, we address issues in situated language understanding in a moving car. More specifically, we propose a reference resolution method to identify user queries about specific target objects in their surroundings. We investigate methods of predicting which target object is likely to be queried given a visual scene and what kind of linguistic cues users naturally provide to describe a given target object in a situated environment. We propose methods to incorporate the visual saliency of the visual scene as a prior. Crowdsourced statistics of how people describe an object are also used as a prior. We have collected situated utterances from drivers using our research system, which was embedded in a real vehicle. We demonstrate that the proposed algorithms improve target identification rate by 15.1% absolute over the baseline method that does not use visual saliency-based prior and depends on public database with a limited number of category information.

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Audio-visual word prominence detection from clean and noisy speech

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Martin Heckmann
In this paper we investigate the audio-visual processing of linguistic prosody, more precisely the detection of word prominence, and examine how the additional visual information can be used to increase the robustness when acoustic background noise is present. We evaluate the detection performance for each modality individually and perform experiments using feature and decision fusion. For the latter we also consider the adaptive fusion with fusion weights adjusted to the current acoustic noise level. Our experiments are based on a corpus with 11 English speakers which contains in addition to the speech signal also videos of the speakers' heads. From the acoustic signal we extract features which are well known to capture word prominence like loudness, fundamental frequency and durational features. The analysis of the visual signal is based on features derived from the speaker's rigid head movements and movements of the speaker's mouth. We capture the rigid head movements by tracking the speaker's nose. Via a two-dimensional Discrete Cosine Transform (DCT) calculated from the mouth region we represent the movements of the speaker's mouth. The results show that the rigid head movements as well as movements inside the mouth region can be used to discriminate prominent from non-prominent words. The audio-only detection yields an Equal Error Rate (EER) averaged over all speakers of 13%. Based only on the visual features we obtain 20% of EER. When we combine the visual and the acoustic features we only see a small improvement compared to the audio-only detection for clean speech. To simulate background noise we added 4 different noise types at varying SNR levels to the acoustic stream. The results indicate that word prominence detection is quite robust against additional background noise. Even at a severe Signal to Noise Ratio (SNR) of −10 dB the EER only rises to 35%. Despite this the audio-visual fusion leads to notable improvements for the detection from noisy speech. We observe relative reductions of the EER of up to 79%.

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Synthetic speech detection using fundamental frequency variation and spectral features

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Monisankha Pal, Dipjyoti Paul, Goutam Saha
Recent works on the vulnerability of automatic speaker verification (ASV) systems confirm that malicious spoofing attacks using synthetic speech can provoke significant increase in false acceptance rate. A reliable detection of synthetic speech is key to develop countermeasure for synthetic speech based spoofing attacks. In this paper, we targeted that by focusing on three major types of artifacts related to magnitude, phase and pitch variation, which are introduced during the generation of synthetic speech. We proposed a new approach to detect synthetic speech using score-level fusion of front-end features namely, constant Q cepstral coefficients (CQCCs), all-pole group delay function (APGDF) and fundamental frequency variation (FFV). CQCC and APGDF were individually used earlier for spoofing detection task and yielded the best performance among magnitude and phase spectrum related features, respectively. The novel FFV feature introduced in this paper to extract pitch variation at frame-level, provides complementary information to CQCC and APGDF. Experimental results show that the proposed approach produces the best stand-alone spoofing detection performance using Gaussian mixture model (GMM) based classifier on ASVspoof 2015 evaluation dataset. An overall equal error rate of 0.05% with a relative performance improvement of 76.19% over the next best-reported results is obtained using the proposed method. In addition to outperforming all existing baseline features for both known and unknown attacks, the proposed feature combination yields superior performance for ASV system (GMM with universal background model/i-vector) integrated with countermeasure framework. Further, the proposed method is found to have relatively better generalization ability when either one or both of copy-synthesized data and limited spoofing data are available a priori in the training pool.

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Predicting speech intelligibility with deep neural networks

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Constantin Spille, Stephan D. Ewert, Birger Kollmeier, Bernd T. Meyer
An accurate objective prediction of human speech intelligibility is of interest for many applications such as the evaluation of signal processing algorithms. To predict the speech recognition threshold (SRT) of normal-hearing listeners, an automatic speech recognition (ASR) system is employed that uses a deep neural network (DNN) to convert the acoustic input into phoneme predictions, which are subsequently decoded into word transcripts. ASR results are obtained with and compared to data presented in Schubotz et al. (2016), which comprises eight different additive maskers that range from speech-shaped stationary noise to a single-talker interferer and responses from eight normal-hearing subjects. The task for listeners and ASR is to identify noisy words from a German matrix sentence test in monaural conditions. Two ASR training schemes typically used in applications are considered: (A) matched training, which uses the same noise type for training and testing and (B) multi-condition training, which covers all eight maskers. For both training schemes, ASR-based predictions outperform established measures such as the extended speech intelligibility index (ESII), the multi-resolution speech envelope power spectrum model (mr-sEPSM) and others. This result is obtained with a speaker-independent model that compares the word labels of the utterance with the ASR transcript, which does not require separate noise and speech signals. The best predictions are obtained for multi-condition training with amplitude modulation features, which implies that the noise type has been seen during training. Predictions and measurements are analyzed by comparing speech recognition thresholds and individual psychometric functions to the DNN-based results.

Graphical abstract

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Application of the pairwise variability index of speech rhythm with particle swarm optimization to the classification of native and non-native accents

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Soumaya Gharsellaoui, Sid Ahmed Selouani, Wladyslaw Cichocki, Yousef Alotaibi, Adel Omar Dahmane
This paper presents a technique that applies the pairwise variability index (PVI), a rhythm metric that quantifies variability in speech rhythm, to the classification of speech varieties. The technique combines the Particle Swarm Optimization (PSO) algorithm with a generalization of several rhythm metrics that are based on the PVI. The performance of this optimization-oriented classification is compared with classification that uses conventional (both PVI-based and interval-based) rhythm metrics. Application is made to the classification of native and non-native Arabic speech using data are from the West Point Arabic Speech Corpus; experiments are based on segmental durations and use Support Vector Machine (SVM) classification. Results show that the optimization-oriented classification provides a better discrimination between native and non-native speech varieties than classification based of the conventional rhythm metrics. When added to different combinations of these conventional metrics, the optimization-oriented procedure consistently improves classification rates.

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Automatic orthographic error tagging and classification for German texts

Publication date: Available online 15 November 2017
Source:Computer Speech & Language
Author(s): Kay Berkling, Rémi Lavalley
This paper evaluates an automatic spelling error tagger and classifier for German texts. After explaining the existing error tags in detail, the accuracy of the tool is validated against a publicly available database containing around 1700 written texts ranging from first grade to eighth grade. The tool is then applied to a longitudinal study consisting of weekly children's texts from second and third grades. It can be shown which error categories contribute most significantly to children's error profiles. Additionally, it can be shown whether or not children make progress on improving in the categories under study.

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Assessment of pitch-adaptive front-end signal processing for children’s speech recognition

Publication date: March 2018
Source:Computer Speech & Language, Volume 48
Author(s): Rohit Sinha, S. Shahnawazuddin
On account of large acoustic mismatch, automatic speech recognition (ASR) systems trained using adults' speech data yield poor recognition performance when evaluated on children's speech data. Despite the use of common speaker normalization techniques like feature-space maximum likelihood regression (fMLLR) and vocal tract length normalization (VTLN), a significant gap remains between the recognition rates for matched and mismatched testing. Our earlier works have already highlighted the sensitivity of salient front-end features including the popular Mel-frequency cepstral coefficient (MFCC) to gross pitch variation across adult and child speakers. Motivated by that, in this work, we explore pitch-adaptive front-end signal processing in deriving the MFCC features to reduce the sensitivity to pitch variation. For this purpose, first an existing vocoder approach known as STRAIGHT spectral analysis is employed for obtaining the smoothed spectrum devoid of pitch harmonics. Secondly, a much simpler spectrum smoothing approach exploiting pitch adaptive-liferting is also presented. The proposed approach is noted to be less sensitive to errors in the pitch estimation than the STRAIGHT-based approach. Both these approaches result in significant improvements for children's mismatch ASR. The effectiveness of the proposed adaptive-liftering-based approach is also demonstrated in the context of acoustic modeling paradigms based on the subspace Gaussian mixture model (SGMM) and the deep neural network (DNN). Further, it has been shown that the effectiveness of existing speaker normalization techniques remain intact even with the use of proposed pitch-adaptive MFCCs, thus leading to additional gains.

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Speaker and Language Recognition and Characterization: Introduction to the CSL Special Issue

Publication date: Available online 8 December 2017
Source:Computer Speech & Language
Author(s): Eduardo Lleida, Luis Javier Rodriguez-Fuentes
Speaker and language recognition and characterization is an exciting area of research that has gained importance in the field of speech science and technology. This special issue features, among other contributions, some of the most remarkable ideas presented and discussed at Odyssey 2016: the Speaker and Language Recognition Workshop, held in Bilbao, Spain, in June 2016. This introduction provides an overview of the selected papers in the context of current challenges.

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Conversational telephone speech recognition for Lithuanian

Publication date: Available online 6 December 2017
Source:Computer Speech & Language
Author(s): Rasa Lileikytė, Lori Lamel, Jean-Luc Gauvain, Arseniy Gorin
The research presented in the paper addresses conversational telephone speech recognition and keyword spotting for the Lithuanian language. Lithuanian can be considered a low e-resourced language as little transcribed audio data, and more generally, only limited linguistic resources are available electronically. Part of this research explores the impact of reducing the amount of linguistic knowledge and manual supervision when developing the transcription system. Since designing a pronunciation dictionary requires language-specific expertise, the need for manual supervision was assessed by comparing phonemic and graphemic units for acoustic modeling. Although the Lithuanian language is generally described in the linguistic literature with 56 phonemes, under low-resourced conditions some phonemes may not be sufficiently observed to be modeled. Therefore different phoneme inventories were explored to assess the effects of explicitly modeling diphthongs, affricates and soft consonants. The impact of using Web data for language modeling and additional untranscribed audio data for semi-supervised training was also measured. Out-of-vocabulary (OOV) keywords are a well-known challenge for keyword search. While word-based keyword search is quite effective for in-vocabulary words, OOV keywords are largely undetected. Morpheme-based subword units are compared with character n-gram-based for their capacity to detect OOV keywords. Experimental results are reported for two training conditions defined in the IARPA Babel program: the full language pack and the very limited language pack, for which, respectively, 40 h and 3 h of transcribed training data are available. For both conditions, grapheme-based and phoneme-based models are shown to obtain comparable transcription and keyword spotting results. The use of Web texts for language modeling are shown to significantly improve both speech recognition and keyword spotting performance. Combining full-word and subword units leads to the best keyword spotting results.

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Learning static spectral weightings for speech intelligibility enhancement in noise

Publication date: Available online 8 November 2017
Source:Computer Speech & Language
Author(s): Yan Tang, Martin Cooke
Near-end speech enhancement works by modifying speech prior to presentation in a noisy environment, typically operating under a constraint of limited or no increase in speech level. One issue is the extent to which near-end enhancement techniques require detailed estimates of the masking environment to function effectively. The current study investigated speech modification strategies based on reallocating energy statically across the spectrum using masker-specific spectral weightings. Weighting patterns were learned offline by maximising a glimpse-based objective intelligibility metric. Keyword scores in sentences in the presence of stationary and fluctuating maskers increased, in some cases by very substantial amounts, following the application of masker- and SNR-specific spectral weighting. A second experiment using generic masker-independent spectral weightings that boosted all frequencies above 1 kHz also led to significant gains in most conditions. These findings indicate that energy-neutral spectral weighting is a highly-effective near-end speech enhancement approach that places minimal demands on detailed masker estimation.

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American Journal of Cancer Research; +19 new citations

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

American Journal of Cancer Research

These pubmed results were generated on 2017/12/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Bilateral sequential peripheral vestibulopathy.

http:--highwire.stanford.edu-icons-exter

Bilateral sequential peripheral vestibulopathy.

Neurology. 2016 04 12;86(15):1454-6

Authors: Young AS, Taylor RL, McGarvie LA, Halmagyi GM, Welgampola MS

PMID: 26968514 [PubMed - indexed for MEDLINE]

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Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Cancer Biol Ther. 2017 Dec 08;:1-4

Authors: Schmidt KT, Madan RA, Figg WD

PMID: 29219670 [PubMed - as supplied by publisher]

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Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer.

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer.

Cancer Biol Ther. 2017 Dec 08;:1-8

Authors: Yang L, Liu Z, Tan J, Dong H, Zhang X

Abstract
Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections. Quantitative analysis was carried out by a scoring system by InForm software. It revealed that TGF-β signaling was hyper active. The levels of TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD1/5/9 and p-SMAD2/3 were significantly increased in cancer tissues when compared their levels in normal tissues. Furthermore, the levels of eight proteins in stroma were significantly lower than the levels that in cancer tissues. Clinical pathological relevant analysis exhibited that TGF-β signaling inclined to suppress the progression of tumor. SMAD1/5/9, TGFBRII, SMAD2/3 were confirmed as significant predictors for overall survival. In conclusion, we established a method based on multispectral imaging to extensively explore the clinical relevant of TGF-β signaling proteins. These results provided an opportunity to consider the novel application for proteins involving TGF-β signaling that used as diagnostic or prognostic biomarkers to conduct tumor therapy.

PMID: 29219668 [PubMed - as supplied by publisher]

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The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib.

The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib.

Cancer Biol Ther. 2017 Dec 08;:1-6

Authors: Booth L, Roberts JL, Poklepovic A, Kirkwood J, Sander C, Avogadri-Connors F, Cutler RE, Lalani AS, Dent P

Abstract
The FDA approved irreversible inhibitor of ERBB1/2/4, neratinib, was recently shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET and mutant K-RAS via autophagic degradation. In the present studies, in a dose-dependent fashion, neratinib reduced the expression levels of mutant K-RAS or of mutant N-RAS, which was augmented in an additive to greater than additive fashion by the HDAC inhibitors sodium valproate and AR42. Neratinib could reduce PDGFRα levels in GBM cells, that was enhanced by sodium valproate. Knock down of Beclin1 or of ATG5 prevented neratinib and neratinib combined with sodium valproate / AR42 from reducing the expression of mutant N-RAS in established PDX and fresh PDX models of ovarian cancer and melanoma, respectively. Neratinib and the drug combinations caused the co-localization of mutant RAS proteins and ERBB2 with Beclin1 and cathepsin B. The drug combination activated the AMP-dependent protein kinase that was causal in enhancing HMG Co A reductase phosphorylation. Collectively, our data reinforce the concept that the irreversible ERBB1/2/4 inhibitor neratinib has the potential for use in the treatment of tumors expressing mutant RAS proteins.

PMID: 29219657 [PubMed - as supplied by publisher]

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Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics.

Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics.

Cancer Biol Ther. 2017 Dec 08;:1-10

Authors: Patel H, Nilendu P, Jahagirdar D, Pal JK, Sharma NK

Abstract
The microenvironment in which cancer resides plays an important role in regulating cancer survival, progression, malignancy and drug resistance. Tumor microenvironment (TME) consists of heterogeneous number and types of cellular and non-cellular components that vary in relation to tumor phenotype and genotype. In recent, non-cellular secreted components of microenvironmental heterogeneity have been suggested to contain various growth factors, cytokines, RNA, DNA, metabolites, structural matrix and matricellular proteins. These non-cellular components have been indicated to orchestrate numerous ways to support cancer survival and progression by providing metabolites, energy, growth signals, evading immune surveillance, drug resistance environment, metastatic and angiogenesis cues. Thus, switching action from pro-cancer to anti-cancer activities of these secreted components of TME has been considered as a new avenue in cancer therapeutics and drug resistance. In this report, we summarize the recent pre-clinical and clinical evidences to emphasize the importance of non-cellular components of TME in achieving precision therapeutics and biomarker study.

PMID: 29219656 [PubMed - as supplied by publisher]

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Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Expanding the use of abiraterone in prostate cancer: Is earlier always better?

Cancer Biol Ther. 2017 Dec 08;:1-4

Authors: Schmidt KT, Madan RA, Figg WD

PMID: 29219670 [PubMed - as supplied by publisher]

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BmVyGB

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer.

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer.

Cancer Biol Ther. 2017 Dec 08;:1-8

Authors: Yang L, Liu Z, Tan J, Dong H, Zhang X

PMID: 29219668 [PubMed - as supplied by publisher]

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2AQhmJZ

The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib.

The levels of mutant K-RAS and mutant N-RAS are rapidly reduced in a Beclin1 / ATG5 -dependent fashion by the irreversible ERBB1/2/4 inhibitor neratinib.

Cancer Biol Ther. 2017 Dec 08;:1-6

Authors: Booth L, Roberts JL, Poklepovic A, Kirkwood J, Sander C, Avogadri-Connors F, Cutler RE, Lalani AS, Dent P

PMID: 29219657 [PubMed - as supplied by publisher]

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C12gPW

Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics.

Modulating secreted components of tumor microenvironment: A masterstroke in tumor therapeutics.

Cancer Biol Ther. 2017 Dec 08;:1-10

Authors: Patel H, Nilendu P, Jahagirdar D, Pal JK, Sharma NK

PMID: 29219656 [PubMed - as supplied by publisher]

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The development of the human hyoid-larynx complex revisited.

The development of the human hyoid-larynx complex revisited.

Laryngoscope. 2017 Dec 08;:

Authors: de Bakker BS, de Bakker HM, Soerdjbalie-Maikoe V, Dikkers FG

Abstract
OBJECTIVES/HYPOTHESIS: The hyoid-larynx complex is highly prone to anatomical variation. The etiology of anatomical variants such as Eagle's syndrome and the aberrant hyoid apparatus can be explained from embryonic development. Modern textbooks state that the hyoid bone body develops from the second and third pharyngeal arch cartilages, and that thyroid cartilage derives from the fourth and sixth arch cartilages. This description, however, is incompatible with various anatomical variants, and it is unclear whether it was based on observations in human embryos or on comparative embryology.
STUDY DESIGN: 14 human embryos from the Carnegie collection between Carnegie stage 17 and 23 (42-60 days) were selected based on their histological quality.
METHODS: Histological sections of the selected embryos were examined. Three-dimensional models were prepared in an interactive format. These anatomical models provide crucial spatial information and facilitate interpretation.
RESULTS: We observed a less-complicated development of the hyoid-larynx complex than is currently described in textbooks. The body of the hyoid bone originates from a single growth center, without overt contributions from second and third pharyngeal arch cartilages. The fourth and sixth arch cartilages were not detected in human embryos; the thyroid and cricoid cartilages develop as mesenchymal condensations in the neck region.
CONCLUSIONS: Despite new research techniques, theories about hyoid-larynx complex development from the beginning of the 20th century have not been refuted properly and can still be found in modern literature. Based on observations in human embryos, we propose a new and relatively simple description of the development of the hyoid-larynx complex to facilitate better understanding of the etiology of anatomical variants.
LEVEL OF EVIDENCE: NA Laryngoscope, 2017.

PMID: 29219191 [PubMed - as supplied by publisher]

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Toxicity trial of canine posterior cricoarytenoid intramuscular vincristine injections.

Toxicity trial of canine posterior cricoarytenoid intramuscular vincristine injections.

Laryngoscope. 2017 Dec 08;:

Authors: Paniello RC, Bhatt NK, Chernock R

Abstract
OBJECTIVES/HYPOTHESIS: In animal studies, intramuscular vincristine injections have been shown to block reinnervation of the denervated target muscle. This application could be used selectively to influence recovery patterns following injury of recurrent laryngeal nerves (RLNs). However, vincristine is currently Food and Drug Administration approved only for intravenous use. A formal toxicity trial of intramuscular injections was performed.
STUDY DESIGN: Animal study.
METHODS: Sixteen female canines underwent direct laryngoscopy with injection of moderate- (0.4 mg, n = 8) or high-dose (0.6 mg, n = 8) vincristine into the posterior cricoarytenoid (PCA) muscles. Plasma samples were collected at various time points postinjection and vincristine levels determined. At 24 hours (n = 7) or 14 days (n = 9) postinjection, animals were anesthetized and videolaryngoscopy documented vocal fold mobility and mucosal appearance. Adductor function was measured during stimulation of the RLN. Larynges were processed for histology.
RESULTS: Fifteen minutes after injection, plasma vincristine levels averaged 10.2% ± 6.7% of the intravenous maximum, suggesting about 90% of the vincristine remained within the PCA muscle. Plasma levels were usually below detectable limits within 24 hours. At the end points, all animals had grossly normal-appearing mucosa and full range of motion. Laryngeal adductor strength was normal in all cases. Histology showed moderate to severe acute inflammation in the submucosa only in the high-dose group at 24 hours. There was no necrosis of muscle or mucosa.
CONCLUSIONS: Intramuscular vincristine injections into the canine PCA muscles resulted in no significant local toxicity, even at the maximum dose. It would be reasonable to evaluate this treatment strategy in a phase I human trial.
LEVEL OF EVIDENCE: NA Laryngoscope, 2017.

PMID: 29219188 [PubMed - as supplied by publisher]

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Improved adductor function after canine recurrent laryngeal nerve injury and repair using muscle progenitor cells.

Improved adductor function after canine recurrent laryngeal nerve injury and repair using muscle progenitor cells.

Laryngoscope. 2017 Dec 08;:

Authors: Paniello RC, Brookes S, Bhatt NK, Bijangi-Vishehsaraei K, Zhang H, Halum S

Abstract
OBJECTIVE: Muscle progenitor cells (MPCs) can be isolated from muscle samples and grown to a critical mass in culture. They have been shown to survive and integrate when implanted into rat laryngeal muscles. In this study, the ability of MPC implants to enhance adductor function of reinnervated thyroarytenoid muscles was tested in a canine model.
STUDY DESIGN: Animal study.
METHODS: Sternocleidomastoid muscle samples were harvested from three canines. Muscle progenitor cells were isolated and cultured to 107 cells over 4 to 5 weeks, then implanted into right thyroarytenoid muscles after ipsilateral recurrent laryngeal nerve transection and repair. The left sides underwent the same nerve injury, but no cells were implanted. Laryngeal adductor force was measured pretreatment and again 6 months later, and the muscles were harvested for histology.
RESULTS: Muscle progenitor cells were successfully cultured from all dogs. Laryngeal adductor force measurements averaged 60% of their baseline pretreatment values in nonimplanted controls, 98% after implantation with MPCs, and 128% after implantation with motor endplate-enhanced MPCs. Histology confirmed that the implanted MPCs survived, became integrated into thyroarytenoid muscle fibers, and were in close contact with nerve endings, suggesting functional innervation.
CONCLUSION: Muscle progenitor cells were shown to significantly enhance adductor function in this pilot canine study. Patient-specific MPC implantation could potentially be used to improve laryngeal function in patients with vocal fold paresis/paralysis, atrophy, and other conditions. Further experiments are planned.
LEVEL OF EVIDENCE: NA. Laryngoscope, 2017.

PMID: 29219186 [PubMed - as supplied by publisher]

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Mucous Membrane Pemphigoid with Ocular Involvement: The Clinical Phenotype and Its Relationship to Direct Immunofluorescence Findings.

Mucous Membrane Pemphigoid with Ocular Involvement: The Clinical Phenotype and Its Relationship to Direct Immunofluorescence Findings.

Ophthalmology. 2017 Dec 04;:

Authors: Ong HS, Setterfield JF, Minassian DC, Dart JK, Mucous Membrane Pemphigoid Study Group 2009–2014

Abstract
PURPOSE: This study explored the validity of the First International Consensus on Mucous Membrane Pemphigoid (MMP) guidance, which recommends that clinically indistinguishable patients, who have direct immunofluorescence (DIF)-negative biopsies, be excluded from a diagnosis of MMP. Misdiagnosis, or delayed diagnosis, of MMP with ocular involvement leads to the inappropriate use of topical therapy, the standard of care for causes of cicatrising conjunctivitis other than MMP, rather than systemic immunomodulatory therapy, resulting in irreversible clinical deterioration in patients with MMP.
DESIGN: Prospective, cross-sectional study.
PARTICIPANTS: Patients meeting the clinical criteria of ocular MMP, including those with positive and negative DIF findings.
METHODS: A case report form was used to collect the demographic details, the clinical history, and the results of a detailed clinical assessment by ophthalmologists, otolaryngologists, dermatologists, and oral medicine specialists. All anatomic sites potentially affected by MMP were examined apart from the esophagus (and larynx in a subset). The DIF results were recorded.
MAIN OUTCOME MEASURES: Differences between DIF-positive and -negative patients in demography, sites of involvement, and disease severity as determined by the degree of conjunctival scarring (using Tauber staging), central corneal disease (vascularization, scarring, ulceration, and conjunctivalization), history of conjunctival or lid surgery, and requirement for systemic immunotherapy at the time of screening.
RESULTS: A total of 73 patients with ocular MMP were recruited, of whom 20 of 73 (27.4%) had ocular-only disease. There was no significant demographic or clinical difference between patients with positive and negative DIF results. This finding included differences in disease severity for which the only significant difference was that of more severe central corneal disease in DIF-negative patients. Asymptomatic disease at different sites was frequent.
CONCLUSIONS: These findings do not support the classification of DIF-negative patients, meeting the clinical criteria for ocular MMP, as having a different disease. This category of patients should be accepted as having DIF-negative MMP, for clinical management purposes, with patients having inflamed eyes being treated with systemic immunomodulatory therapy. The frequent finding of asymptomatic ocular, oral, and nasopharyngeal MMP is clinically significant and implies that these sites should be routinely screened in asymptomatic patients.

PMID: 29217149 [PubMed - as supplied by publisher]

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Αρχειοθήκη ιστολογίου

Σάββατο 9 Δεκεμβρίου 2017

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