Παρασκευή, 23 Ιουνίου 2017

Model-based spike sorting with a mixture of drifting t-distributions

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Publication date: Available online 23 June 2017
Source:Journal of Neuroscience Methods
Author(s): Kevin Q. Shan, Evgueniy V. Lubenov, Athanassios G. Siapas
BackgroundChronic extracellular recordings are a powerful tool for systems neuroscience, but spike sorting remains a challenge. A common approach is to fit a generative model, such as a mixture of Gaussians, to the observed spike data. Even if non-parametric methods are used for spike sorting, such generative models provide a quantitative measure of unit isolation quality, which is crucial for subsequent interpretation of the sorted spike trains.New methodWe present a spike sorting strategy that models the data as a mixture of drifting t-distributions. This model captures two important features of chronic extracellular recordings—cluster drift over time and heavy tails in the distribution of spikes—and offers improved robustness to outliers.ResultsWe evaluate this model on several thousand hours of chronic tetrode recordings and show that it fits the empirical data substantially better than a mixture of Gaussians. We also provide a software implementation that can re-fit long datasets in a few seconds, enabling interactive clustering of chronic recordings.Comparison with existing methodsWe identify three common failure modes of spike sorting methods that assume stationarity and evaluate their impact given the empirically-observed cluster drift in chronic recordings. Using hybrid ground truth datasets, we also demonstrate that our model-based estimate of misclassification error is more accurate than previous unit isolation metrics.ConclusionsThe mixture of drifting t-distributions model enables efficient spike sorting of long datasets and provides an accurate measure of unit isolation quality over a wide range of conditions.



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Overcoming obstacles in the design of cancer anorexia/weight loss trials

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Publication date: Available online 24 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jennifer G. Le-Rademacher, Jeffrey Crawford, William J. Evans, Aminah Jatoi
Most advanced cancer patients suffer loss of appetite (anorexia) and loss of weight. Despite the fact that cancer anorexia and weight loss are associated with a poor prognosis and detract from quality of life, no interventions have been demonstrated to palliate this syndrome in its entirety, particularly in patients with treatment-refractory malignancies. Recently, two registration trials − one with anamorelin and another with enobosarm − failed to reach their primary endpoints, thus raising questions. Were both these agents ineffective? Alternatively, did study design issues compromise the ability of these trials to identify effective agents? Thus, this review is timely insofar it serves as an introduction to study design, offers guidance on how to test promising agents for cancer anorexia/weight loss, and provides advice for overcoming trial design obstacles.



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UNRAVELLING THE COMPLEXITY OF SIGNALLING NETWORKS IN CANCER: A REVIEW OF THE INCREASING ROLE FOR COMPUTATIONAL MODELLING

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Publication date: Available online 23 June 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): John Garland
Cancer induction is a highly complex process involving hundreds of different inducers but whose eventual outcome is the same. Clearly, it is essential to understand how signalling pathways and networks generated by these inducers interact to regulate cell behaviour and create the cancer phenotype. While enormous strides have been made in identifying key networking profiles, the amount of data generated far exceeds our ability to understand how it all “fits together”. The number of potential interactions is astronomically large and requires novel approaches and extreme computation methods to dissect them out. However, such methodologies have high intrinsic mathematical and conceptual content which is difficult to follow. This review explains how computation modelling is progressively finding solutions and also revealing unexpected and unpredictable nano-scale molecular behaviours extremely relevant to how signalling and networking are coherently integrated. It is divided into linked sections illustrated by numerous figures from the literature describing different approaches and offering visual portrayals of networking and major conceptual advances in the field. First, the problem of signalling complexity and data collection is illustrated for only a small selection of known oncogenes. Next, new concepts from biophysics, molecular behaviours, kinetics, organisation at the nano level and predictive models are presented. These areas include: visual representations of networking, Energy Landscapes and energy transfer/dissemination (entropy); diffusion, percolation; molecular crowding; protein allostery; quinary structure and fractal distributions; energy management, metabolism and re-examination of the Warburg effect. The importance of unravelling complex network interactions is then illustrated for some widely-used drugs in cancer therapy whose interactions are very extensive. Finally, use of computational modelling to develop micro- and nano- functional models (“bottom-up” research) is highlighted. The review concludes that computational modelling is an essential part of cancer research and is vital to understanding network formation and molecular behaviours that are associated with it. Its role is increasingly essential because it is unravelling the huge complexity of cancer induction otherwise unattainable by any other approach.



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Pure intraductal carcinoma of the parotid gland: Cytologic findings on FNA sample. Report of one case

One case of intraductal carcinoma of the parotid gland in a 67-year-old male patient is here introduced. The patient, who had a one-year history of a parotid mass, had undergone ultrasound and MRI examination that disclosed a 13x4x3 mm well delimited nodular mass of the accessory lobe of his left parotid gland. Ultrasound-guided Fine Needle Aspiration (FNA) had been performed by the clinician. The obtained smears showed widespread cellular necrosis in which cellular clusters with moderate and focally severe atypias displayed papillary and cribriform architecture and were admixed with sheets of epithelial cells with less striking nuclear atypias, squamous, or apocrine metaplasia. Histopathological examination disclosed a pure intraductal carcinoma of the parotid gland with classical morphology, which was radically excised. The differential cytological diagnosis of pure intraductal carcinoma of salivary glands may be difficult and comprises mucoepidermoid carcinoma as well as “in situ” carcinomas developping in the context of sclerosing polycystic adenosis, mammary analogue secretory carcinoma (MASC) of the salivary glands and cystic variants of salivary adenocarcinoma NOS (formerly called cystadenocarcinomas).



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Ovarian Cancer Knowledge in Women and Providers Following Education with Inside Knowledge Campaign Materials

Abstract

Because no effective methods for preventing or screening for ovarian cancer exist, symptom recognition is integral to its early detection. The Centers for Disease Control and Prevention’s Inside Knowledge: Get the Facts about Gynecologic Cancer campaign was developed to raise awareness and educate women and providers about risk factors, symptoms, recommended screening, and prevention strategies for the five main gynecologic cancers, including ovarian cancer. Inside Knowledge campaign materials were utilized by CDC’s National Comprehensive Cancer Control Program grantees to educate women and providers about gynecologic cancer from 2014 to 2015. Grantees recruited participants and held educational sessions using Inside Knowledge materials. Questionnaires were given before and after the sessions to assess changes in awareness, confidence, and behavioral intentions around gynecologic cancer information and analyzed in 2016. This analysis focused on an assessment of changes related to ovarian cancer information. Participants’ knowledge increased after educational sessions. Among women, there were increases in correctly identifying that the Papanicolaou (Pap) test does not screen for ovarian cancer (89.2%) and that genetic testing is available (77.9%). There was a lower increase in knowledge that HPV is not a cause of ovarian cancer (56.4%). Providers and women reported significant increases in their confidence in their ability to talk to each other about gynecologic cancer post-session. Ovarian cancer awareness, confidence, and related behaviors increased in participants exposed to Inside Knowledge materials. Using these materials to increase knowledge could lead to more empowered patients, better provider-patient communications, and improved care for gynecologic cancers, including ovarian cancer.



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National Survey Among Radiation Oncology Residents Related to Their Needs in Geriatric Oncology

Abstract

Currently, there is no formal curriculum addressing geriatric oncology within Canadian radiation oncology (RO) residency programs. Knowledge related to geriatric medicine may help radiation oncologists modify RT based on frailty status and geriatric considerations. Understanding specific learning needs allow program coordinators to align the current curriculum with residents’ geriatric oncology learning needs. The purpose of this study is to determine the geriatric oncology educational needs of the Canadian RO residents and to inform Canadian RO residency training. A cross-sectional survey, with Likert, multiple choice, and open-ended questions, was pretested and distributed electronically by program directors to Canadian RO residents over 6 weeks. Responses were analyzed with descriptive statistics and common themes. One-hundred and thirty-five Canadian RO residents were contacted and 63 responded (47%). Half (49%) lacked confidence managing the elderly with multiple comorbidities, polypharmacy, functional and cognitive impairment, and challenging social circumstances;73% agreed additional training would be helpful. Forty-four percent lacked confidence regarding psychogeriatric referrals, fall prevention, palliative and hospice care, and community resources preventing re-hospitalization; 63% agreed additional training would be helpful. Seventy-six percent believed discussion groups, continuing education, geriatric oncology electives, and journal clubs would provide learning opportunities. Seventy-one percent agreed integrating geriatric assessment into RO curricula would improve care. Seventy-nine percent believed geriatric oncology principles have not been adequately integrated into radiation oncology curricula. There are significant gaps specific to geriatric assessment and management of older cancer patients in the current Canadian RO curricula. Most residents agreed that it is important to integrate geriatric oncology training to improve and personalize the care of older cancer patients.



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A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors

Purpose: The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on and off target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.<br /><br />Experimental Design: <p>We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended Phase II dose (RP2D). During the dose-selection and dose-escalation stages (Parts 1 and 2), patients with phosphatase and tensin homolog (PTEN)-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily [QD]) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (Part 3) were implemented to further assess tumor responses at the RP2D.</p> <br />Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg QD was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including 2 other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg QD oral induced sufficient exposure and target inhibition with a manageable safety profile.<br /><br />Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771.



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Mutational Heterogeneity in APC and KRAS Arises at the Crypt level and Leads to Polyclonality in Early Colorectal Tumorigenesis

Purpose:  The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer (CRC) are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model. <p>Experimental design: High-depth next-generation sequencing and SNP arrays were performed in whole lesion extracts of 37 FAP colorectal adenomas. Also, ultra-sensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n=59) and crypts (n=591) from 18 adenomas and 7 carcinomas and adjacent normal tissues.</p> <p>Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultra-sensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Non-random heterogeneity among crypts was also observed.</p> Conclusions: The striking degree of non-random intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis.



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Combined BTK and PI3K{delta} inhibition with acalabrutinib and ACP-319 improves survival and tumor control in CLL mouse model

Purpose: Targeting the B-cell receptor (BCR) pathway with inhibitors of BTK and PI3K-delta is highly effective for the treatment of chronic lymphocytic leukemia (CLL). However, deep remissions are uncommon and drug resistance with single-agent therapy can occur. In vitro studies support the effectiveness of combing PI3K-delta and BTK inhibitors. <p>Experimental design: As CLL proliferation and survival depends on the microenvironment, we used murine models to assess the efficacy of the BTK inhibitor acalabrutinib combined with the PI3K-delta inhibitor ACP-319 in vivo. We compared single-agent with combination therapy in TCL1-192 cell-injected mice, a model of aggressive CLL.</p> <p>Results: We found significantly larger reductions in tumor burden in the peripheral blood and spleen of combination-treated mice. While single-agent therapy improved survival compared with control mice by a few days, combination therapy extended survival by over two weeks compared to either single agent. The combination reduced tumor proliferation, NF-KB signaling and expression of BCL-xL and MCL-1 more potently than single-agent therapy.</p> <p>Conclusion: The combination of acalabrutinib and ACP-319 was superior to single-agent treatment in a murine CLL model, warranting further investigation of this combination in clinical studies.



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T cell receptors for clinical therapy: in vitro assessment of toxicity risk

Adoptive therapy with T cell receptor (TCR)-engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T cell reactivity. Here, we propose a sequence of in vitro assays to improve selection of TCRs, and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against Cancer Germline Antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif towards its cognate peptide, and TCR's cross-reactivity towards non-cognate peptides.



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Relay transport of aerosols to Beijing-Tianjin-Hebei region by multi-scale atmospheric circulations

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Publication date: September 2017
Source:Atmospheric Environment, Volume 165
Author(s): Yucong Miao, Jianping Guo, Shuhua Liu, Huan Liu, Gen Zhang, Yan Yan, Jing He
The Beijing-Tianjin-Hebei (BTH) region experiences heavy aerosol pollution, which is found to have close relationships with the synoptic- and local-scale atmospheric circulations. However, how and to what extent these multi-scale circulations interplay to modulate aerosol transport have not been fully understood. To this end, this study comprehensively investigated the impacts of these circulations on aerosol transport in BTH by focusing on an episode occurred on 1 June 2013 through combining both observations and three-dimensional simulations. It was found that during this episode, the Bohai Sea acted as a transfer station, and the high-pressure system over the Yellow Sea and sea-breeze in BTH took turns to affect the transport of aerosols. In the morning, influenced by the high-pressure system, lots of aerosols emitted from Shandong and Jiangsu provinces were first transported to the Bohai Sea. After then, these aerosols were brought to the BTH region in the afternoon through the inland penetration of sea-breeze, significantly exacerbating the air quality in BTH. The inland penetration of sea-breeze could be identified by the sharp changes in ground-based observed temperature, humidity, and wind when the sea-breeze front (SBF) passed by. Combining observations with model outputs, the SBF was found to be able to advance inland more than ∼150 km till reaching Beijing. This study has important implications for better understanding the aerosol transport in BTH, and improving the forecast of such aerosol pollution.



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Mass size distribution of particle-bound water

Publication date: September 2017
Source:Atmospheric Environment, Volume 165
Author(s): S. Canepari, G. Simonetti, C. Perrino
The thermal-ramp Karl-Fisher method (tr-KF) for the determination of PM-bound water has been applied to size-segregated PM samples collected in areas subjected to different environmental conditions (protracted atmospheric stability, desert dust intrusion, urban atmosphere). This method, based on the use of a thermal ramp for the desorption of water from PM samples and the subsequent analysis by the coulometric KF technique, had been previously shown to differentiate water contributes retained with different strength and associated to different chemical components in the atmospheric aerosol.The application of the method to size-segregated samples has revealed that water showed a typical mass size distribution in each one of the three environmental situations that were taken into consideration. A very similar size distribution was shown by the chemical PM components that prevailed during each event: ammonium nitrate in the case of atmospheric stability, crustal species in the case of desert dust, road-dust components in the case of urban sites.The shape of the tr-KF curve varied according to the size of the collected particles. Considering the size ranges that better characterize the event (fine fraction for atmospheric stability, coarse fraction for dust intrusion, bi-modal distribution for urban dust), this shape is coherent with the typical tr-KF shape shown by water bound to the chemical species that predominate in the same PM size range (ammonium nitrate, crustal species, secondary/combustion species - road dust components).

Graphical abstract

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The impact of household cooking and heating with solid fuels on ambient PM2.5 in peri-urban Beijing

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Publication date: September 2017
Source:Atmospheric Environment, Volume 165
Author(s): Jiawen Liao, Anna Zimmerman Jin, Zoë A. Chafe, Ajay Pillarisetti, Tao Yu, Ming Shan, Xudong Yang, Haixi Li, Guangqing Liu, Kirk R. Smith
Household cooking and space heating with biomass and coal have adverse impacts on both indoor and outdoor air quality and are associated with a significant health burden. Though household heating with biomass and coal is common in northern China, the contribution of space heating to ambient air pollution is not well studied. We investigated the impact of space heating on ambient air pollution in a village 40 km southwest of central Beijing during the winter heating season, from January to March 2013. Ambient PM2.5 concentrations and meteorological conditions were measured continuously at rooftop sites in the village during two winter months in 2013. The use of coal- and biomass-burning cookstoves and space heating devices was measured over time with Stove Use Monitors (SUMs) in 33 households and was coupled with fuel consumption data from household surveys to estimate hourly household PM2.5 emissions from cooking and space heating over the same period. We developed a multivariate linear regression model to assess the relationship between household PM2.5 emissions and the hourly average ambient PM2.5 concentration, and a time series autoregressive integrated moving average (ARIMA) regression model to account for autocorrelation. During the heating season, the average hourly ambient PM2.5 concentration was 139 ± 107 μg/m3 (mean ± SD) with strong autocorrelation in hourly concentration. The average primary PM2.5 emission per hour from village household space heating was 0.736 ± 0.138 kg/hour. The linear multivariate regression model indicated that during the heating season – after adjusting for meteorological effects – 39% (95% CI: 26%, 54%) of hourly averaged ambient PM2.5 was associated with household space heating emissions from the previous hour. Our study suggests that a comprehensive pollution control strategy for northern China, including Beijing, should address uncontrolled emissions from household solid fuel combustion in surrounding areas, particularly during the winter heating season.



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Impact of LULCC on the emission of BVOCs during the 21st century

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Publication date: September 2017
Source:Atmospheric Environment, Volume 165
Author(s): Sebastian Szogs, Almut Arneth, Peter Anthoni, Jonathan C. Doelman, Florian Humpenöder, Alexander Popp, Thomas A.M. Pugh, Elke Stehfest
Land-use and land-cover change (LULCC) is one of the key drivers of anthropogenic climate change. In addition to greenhouse gases such as CO2 or CH4, LULCC affects also the emission of other carbon trace gases such as biogenic volatile organic compounds (BVOCs). We investigate the impact of changing LULCC on the emission of isoprene and monoterpenes during the 21st century using seven different land-use projections, applying the dynamic vegetation modelling framework LPJ-GUESS. Climate change, and atmospheric CO2-concentration are based on the RCP2.6 scenario. The different LULCC-scenarios explore the impact of different land-based climate change mitigation strategies (such as afforestation and avoided deforestation, or bioenergy). We show that the increase of land area under crops or grassland would lead to a significant decrease of BVOC emissions, with a strong negative correlation between the fraction of managed global land area and the emission of isoprene and monoterpenes. But the choice of crops is important, especially for the bioenergy scenarios in which increasing fractional cover leads to decreasing BVOC emissions in our simulations; use of woody bioenergy crops can reverse this decrease. The strong impact of LULCC on the global and regional emission of BVOCs implies the need to include the impact of these changes in projections of atmospheric composition and air quality.



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Sedentary work and the risks of colon and rectal cancer by anatomical sub-site in the Canadian census health and environment cohort (CanCHEC)

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Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Manisha Pahwa, M. Anne Harris, Jill MacLeod, Michael Tjepkema, Paul A. Peters, Paul A. Demers
BackgroundSedentary behaviour is a potential risk factor for colorectal cancer. We examined the association between sedentary work, based on body position, and colorectal cancer risk in Canadians.MethodsA working body position category (a. sitting; b. standing and walking; c. sitting, standing, and walking; d. other) was assigned to occupations reported by 1991 Canadian Census respondents based on national occupational counselling guidelines. Adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated for cancers of the colon (overall, proximal, and distal) and rectum in men and women newly diagnosed from 1992 to 2010.ResultsCompared to “sitting” jobs, men in occupations with “other” (non-sitting, −standing, or −walking) body positions had a weakly significant reduced colon cancer risk (HR=0.93, 95% CI: 0.89, 0.98) primarily attributed to protection at the distal site (HR=0.90, 95% CI: 0.84, 0.97). Men in “standing and walking” and “sitting, standing, and walking” jobs did not have significantly reduced colon cancer risks. No effects were observed for rectal cancer in men or colon and rectal cancer in women.ConclusionThe two significant findings of this analysis should be followed-up in further investigations with additional information on potential confounders. Null findings for rectal cancer were consistent with other studies.



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Predominant obstructive or central sleep-apnea in patients with atrial fibrillation: influence of characterizing apneas versus apneas and hypopneas

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Publication date: Available online 23 June 2017
Source:Sleep Medicine
Author(s): Johanna Strotmann, Henrik Fox, Thomas Bitter, Florian Schindhelm, Klaus-J. Gutleben, Dieter Horstkotte, Olaf Oldenburg
Objective/backgroundSleep-disordered breathing (SDB) is common in patients with atrial fibrillation (Afib). Although a high proportion of respiratory events are hypopneas, previous studies have only used apneas to differentiate obstructive (OSA) from central (CSA) sleep apnea. This study investigated the impact of using apneas and hypopneas versus apneas only to define the predominant type of SDB in Afib patients with preserved ejection fraction.Patients/methodsThis retrospective analysis was based on high-quality cardiorespiratory polygraphy (PG) recordings (07/2007 to 03/2016) that were re-analyzed using 2012 American Academy of Sleep Medicine criteria, with differentiation of apneas and hypopneas as obstructive or central. Classification of predominant (>50% of events) OSA and CSA was defined based on apneas only (OSAAI and CSAAI) or apneas and hypopneas (OSAAHI and CSAAHI). SDB was defined as an apnea-hypopnea index ≥5/h.ResultsA total of 211 patients were included (146 male, age 68.7±8.5y). Hypopneas accounted for >50% of all respiratory events. Based on apneas only, 46% of patients had predominant OSA and 44% had predominant CSA. Based on apneas and hypopneas, the proportion of patients with OSA was higher (56%) and that with CSA was lower (36%). In the subgroup of patients with moderate to severe SDB (AHI ≥15/h), the proportion with predominant CSA was 55.2% based on apneas only versus 42.1% with apneas and hypopneas.ConclusionsIn hospitalized patients with Afib and SDB, use of apneas and hypopneas versus apneas alone had an important influence on the proportion of patients classified as having predominant OSA or CSA.



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Ovarian Cancer Knowledge in Women and Providers Following Education with Inside Knowledge Campaign Materials

Abstract

Because no effective methods for preventing or screening for ovarian cancer exist, symptom recognition is integral to its early detection. The Centers for Disease Control and Prevention’s Inside Knowledge: Get the Facts about Gynecologic Cancer campaign was developed to raise awareness and educate women and providers about risk factors, symptoms, recommended screening, and prevention strategies for the five main gynecologic cancers, including ovarian cancer. Inside Knowledge campaign materials were utilized by CDC’s National Comprehensive Cancer Control Program grantees to educate women and providers about gynecologic cancer from 2014 to 2015. Grantees recruited participants and held educational sessions using Inside Knowledge materials. Questionnaires were given before and after the sessions to assess changes in awareness, confidence, and behavioral intentions around gynecologic cancer information and analyzed in 2016. This analysis focused on an assessment of changes related to ovarian cancer information. Participants’ knowledge increased after educational sessions. Among women, there were increases in correctly identifying that the Papanicolaou (Pap) test does not screen for ovarian cancer (89.2%) and that genetic testing is available (77.9%). There was a lower increase in knowledge that HPV is not a cause of ovarian cancer (56.4%). Providers and women reported significant increases in their confidence in their ability to talk to each other about gynecologic cancer post-session. Ovarian cancer awareness, confidence, and related behaviors increased in participants exposed to Inside Knowledge materials. Using these materials to increase knowledge could lead to more empowered patients, better provider-patient communications, and improved care for gynecologic cancers, including ovarian cancer.



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National Survey Among Radiation Oncology Residents Related to Their Needs in Geriatric Oncology

Abstract

Currently, there is no formal curriculum addressing geriatric oncology within Canadian radiation oncology (RO) residency programs. Knowledge related to geriatric medicine may help radiation oncologists modify RT based on frailty status and geriatric considerations. Understanding specific learning needs allow program coordinators to align the current curriculum with residents’ geriatric oncology learning needs. The purpose of this study is to determine the geriatric oncology educational needs of the Canadian RO residents and to inform Canadian RO residency training. A cross-sectional survey, with Likert, multiple choice, and open-ended questions, was pretested and distributed electronically by program directors to Canadian RO residents over 6 weeks. Responses were analyzed with descriptive statistics and common themes. One-hundred and thirty-five Canadian RO residents were contacted and 63 responded (47%). Half (49%) lacked confidence managing the elderly with multiple comorbidities, polypharmacy, functional and cognitive impairment, and challenging social circumstances;73% agreed additional training would be helpful. Forty-four percent lacked confidence regarding psychogeriatric referrals, fall prevention, palliative and hospice care, and community resources preventing re-hospitalization; 63% agreed additional training would be helpful. Seventy-six percent believed discussion groups, continuing education, geriatric oncology electives, and journal clubs would provide learning opportunities. Seventy-one percent agreed integrating geriatric assessment into RO curricula would improve care. Seventy-nine percent believed geriatric oncology principles have not been adequately integrated into radiation oncology curricula. There are significant gaps specific to geriatric assessment and management of older cancer patients in the current Canadian RO curricula. Most residents agreed that it is important to integrate geriatric oncology training to improve and personalize the care of older cancer patients.



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Massive Middle Cerebral Artery Infarction After Surgically Assisted Rapid Palatal Expansion: A Case Report

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): Kenneth Kufta, Luis Perez Melean, M. Sean Grady, Neeraj Panchal
Dentofacial deformities have a marked impact on a patient's quality of life. Fortunately, these deformities often can be corrected through orthodontic and surgical treatment. In adults, transverse maxillary discrepancies are often corrected by performing a surgically assisted rapid palatal expansion (SARPE) procedure. This procedure is accompanied by many of the same complications involved in performing a Le Fort I osteotomy. Although major complications from maxillary surgery are uncommon, severe hemorrhage and cerebrovascular accidents are real risks accompanied by serious sequelae. The purpose of this case report is to describe a case in which a patient developed a massive middle cerebral artery infarct after a SARPE procedure. The authors discuss the possible etiology and pathogenesis of the complication. They also aim to remind surgeons of this rare complication to ensure prompt recognition and management to prevent delays in care.



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Editorial Board Page

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7





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Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility

Abstract

The zona pellucida (ZP) is an extracellular matrix universally surrounding mammalian eggs, which is essential for oogenesis, fertilization, and pre-implantation embryo development. Here, we identified two novel heritable mutations of ZP2 and ZP3, both occurring in an infertile female patient with ZP-abnormal eggs. Mouse models with the same mutations were generated by CRISPR/Cas9 gene editing system, and oocytes obtained from female mice with either single heterozygous mutation showed approximately half of the normal ZP thickness compared to wild-type oocytes. Importantly, oocytes with both heterozygous mutations showed a much thinner or even missing ZP that could not avoid polyspermy fertilization, following the patient's pedigree. Further analysis confirmed that precursor proteins produced from either mutated ZP2 or ZP3 could not anchor to oocyte membranes. From these, we conclude that ZP mutations have dosage effects which can cause female infertility in humans. Finally, this patient was treated by intracytoplasmic sperm injection (ICSI) with an improved culture system and successfully delivered a healthy baby.



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Antibiotic Prophylaxis in Blepharoplasty: Review of the Current Literature

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): Elie M. Ferneini, Steven Halepas, Steven I. Aronin
The purpose of this study was to provide an evidence-based overview of antibiotic prophylaxis in blepharoplasty. We performed a literature search that evaluated the risk of infection associated with blepharoplasty, as well as the risks and benefits of antibiotic prophylaxis. The overall infection rate associated with eyelid surgery is extremely low. However, the use of antibiotic prophylaxis has increased over the past 25 years in esthetic facial procedures. There is no standard of care for or against antibiotic prophylaxis, and routine practices vary widely. This leads to the question of whether reducing the risk of surgical-site infection to near zero outweighs the real danger of antibiotic-related complications, including the escalating emergence of antibiotic-resistant bacteria. No direct consensus can be drawn from the current literature; thus, at this time, there is no current standard of care for oral and maxillofacial surgeons to adhere to in terms of when and if antibiotic prophylaxis is needed when performing blepharoplasty.



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Table of Contents

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7





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Alternative Distraction Osteogenesis Technique After Implant Placement for Alveolar Ridge Augmentation of the Maxilla

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): Renato Luiz Maia Nogueira, Rafael Lima Verde Osterne, Ricardo Teixeira Abreu, Phelype Maia Araújo
An alternative technique to reconstruct atrophic alveolar vertical bone after implant placement is presented. The technique consists of distraction osteogenesis or direct surgical repositioning of an implant-and-bone block segment after segmental osteotomies that can be used in esthetic or unesthetic cases. Initially, casts indicating the implant position are obtained and the future ideal prosthetic position is determined to guide the model surgery. After the model surgery, a new provisional prosthesis is fabricated, and an occlusal splint, which is used as a surgical guide and a device for distraction osteogenesis, is custom fabricated. Then, the surgery is performed. For mobilization of the implant-and-bone block segment, 2 vertical osteotomies are performed and then joined by a horizontal osteotomy. The implant-and-bone block segment is moved to the planned position. If a small movement is planned, then the implant-and-bone segment is stabilized; for larger movements, the implant-and-bone segment can be gradually moved to the final position by distraction osteogenesis. This technique has good predictability of the final position of the implant-and-bone segment and relatively fast esthetic rehabilitation. It can be considered for dental implants in regions of vertical bone atrophy.



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AAOMS Author Disclosure forms

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7





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The Dynamic Landscape of Health Care Insurance—Implications for Our Specialty

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): James R. Hupp




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Masthead

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7





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Primary Lacrimal Sac Melanoma With Metastatic Cervical Disease: A Review of the Literature and Case Report

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): Shiva S. Subramaniam, Rajiv Anand, Timothy K. Mellor, Peter A. Brennan
Primary melanoma arising from the nasolacrimal sac is a rare form of mucosal melanoma, with only 30 cases previously reported in the literature and none reporting cervical metastatic disease. Given the extremely rare nature of this disease, specific guidelines for staging and intervention are impractical and do not exist. As such, case presentations have formed the basis for management. This report describes the only case to the authors' knowledge of primary nasolacrimal sac mucosal melanoma with cervical metastatic disease at the time of diagnosis, which was detected only with positron emission tomographic computer tomography, and briefly reviews the existing published cases to help assist in the development of a general algorithm for patient care.



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Loss of PTEN Expression Is Associated With High MicroRNA 24 Level and Poor Prognosis in Patients With Tongue Squamous Cell Carcinoma

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Publication date: July 2017
Source:Journal of Oral and Maxillofacial Surgery, Volume 75, Issue 7
Author(s): Jingzhu Zhao, Jiadong Chi, Ming Gao, Jingtai Zhi, Yigong Li, Xiangqian Zheng
PurposeThe aim of this study was to detect the relationship between phosphatase and tensin homolog deletion on chromosome 10 (PTEN) and microRNA 24 (miR-24) and correlate PTEN expression with important clinical parameters of patients with tongue squamous cell carcinoma (TSCC).Materials and MethodsIn this retrospective case series, all TSCC patients treated at Tianjin Medical University Cancer Institute and Hospital between March 2005 and October 2011 were retrospectively reviewed. Demographic information and clinical data (histologic type, clinical stage, tumor differentiation, and so on) were collected. The miR-24 level was detected by quantitative reverse transcription–polymerase chain reaction. The PTEN level was analyzed by immunohistochemistry and quantitative reverse transcription–polymerase chain reaction. Data analyses were performed by Spearman correlation analysis, Pearson χ2 test, and paired t test. Kaplan-Meier curves, log-rank analyses, and a Cox proportional hazards model were used to evaluate the prognostic value of PTEN.ResultsA total of 90 patients (aged 59.4 ± 9.5 years, 53 men and 37 women) were identified. Loss of PTEN expression was detected in 28 of 90 tumors (31.1%). The PTEN messenger RNA level was negatively correlated with the miR-24 level (r = −0.569, P < .01). PTEN expression also was negatively correlated with the miR-24 level (r = −0.621, P < .01). Furthermore, PTEN expression was significantly lower in cancer tissues than in adjacent normal tissues, and its expression was negatively correlated with clinical stage (P < .01) and positively correlated with differentiation (P < .05) in TSCC patients. In addition, the Kaplan-Meier curve indicated that loss of PTEN expression resulted in poor survival of TSCC patients (P < .01). Multivariate analysis indicated that PTEN expression level and clinical stage may be independent prognostic factors for TSCC patients.ConclusionsThis study suggested that PTEN expression was negatively correlated with the miR-24 level in TSCC. The loss of PTEN expression may serve as a predictor of unfavorable prognosis for TSCC patients.



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Is neuroglial antigen 2 a potential contributor to cilengitide response in glioblastoma?

Hatice Sevim Nalkiran, Kerrie Leanne McDonald

Journal of Cancer Research and Therapeutics 2017 13(2):329-336

Background: Determining the expression levels of neuroglial antigen 2 (NG2) in glioma cell lines and to evaluate the potential contribution of NG2 to cilengitide response were aimed. Materials and Methods: Endogenous expression level of NG2 was determined using quantitative reverse transcription polymerase chain reaction and immunoblotting. Cilengitide responses of the cells were monitored to determine half maximal inhibitory concentration values. Whether the suppression of NG2 expression alters the response of A172 cells to cilengitide was examined. Results: The effect of cilengitide on inducing apoptosis of the cells was determined by TUNEL staining. High mRNA and protein expression of NG2 was detected in A172 and U-87MG cells, while T98G, M059K and M059J cells demonstrated low levels of NG2. A172, U-87MG and positive control MG-63 were relatively sensitive to cilengitide compared to T98G, M059K and M059J. MG-63, A172 and U-87MG were unexpectedly found to be more susceptible to cilengitide. In addition, NG2 knock-down showed no significant difference in cell death between small interfering RNA (siRNA)-transfected and cilengitide-treated groups. The results showed that cilengitide caused detachment and subsequently initiated apoptosis. Glioma cell lines express variable levels of NG2 and differ in their responses to cilengitide. Although increased numbers of apoptotic cells were found in untransfected cells compared to siRNA-transfected cells upon exposed to cilengitide, the difference was not documented to be significant between two groups. Conclusion: It may be proposed that the combination therapy of NG2 suppression and cilengitide treatment showed no considerable effect on glioblastoma compared to cilengitide therapy alone. Response to therapy may be further improved by targeting other factors act in concert in this signaling pathway.

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Modeling of lung cancer risk due to radon exhalation of granite stone in dwelling houses

Akbar Abbasi

Journal of Cancer Research and Therapeutics 2017 13(2):208-212

Aims: Due to increasing occurrences of lung cancer, radon exhalation rates, radon concentrations, and lung cancer risks in several types of commonly used granite stone, samples used for flooring in buildings, have been investigated. Subjects and Methods: We measured the radon exhalation rates due to granite stones by means of an AlphaGUARD Model PQ2000 in a cube container with changeable floor by various granite stones. The lung cancer risk and percentage of lung cancer deaths (LCRn) due to those conditions were calculated using Darby's model. Results: The radon exhalation rates ranged from 1.59 ± 0.41 to 9.43 ± 0.74 Bq/m 2/h. The radon concentrations in the standard room with poor and normal ventilation were calculated 20.10–71.09 Bq/m 3 and 16.12–47.01 Bq/m 3, respectively. Conclusions: The estimated numbers of lung cancer deaths attributable to indoor radon due to granite stones in 2013 were 145 (3.33%) and 103 (2.37%) for poor and normal ventilation systems, respectively. According to our estimations, the values of 3.33% and 2.37% of lung cancer deaths in 2013 are attributed to radon exhalation of granite stones with poor and normal ventilation systems, respectively.

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Validation of microsatellite instability histology scores with Bethesda guidelines in hereditary nonpolyposis colorectal cancer

Mustafa Kaya, Fatih Basak, Abdullah Sisik, Mustafa Hasbahceci, Gurhan Bas, Orhan Alimoglu, Cumhur Selçuk Topal, Gozde Kir

Journal of Cancer Research and Therapeutics 2017 13(2):356-361

Aims: Hereditary nonpolyposis colorectal cancer (HNPCC) is a subgroup of colorectal cancer (CRC) which should be differentiated because of the high risk for additional cancers and risk evaluation for other family members, especially for CRC. It is not practical to perform genetic testing for all CRC patients; therefore, various prediction modalities, for example, Bethesda guideline (BG) were studied in the literature. We aimed to assess the association of microsatellite instability (MSI), histology scores, and BG for predicting HNPCC risk. Subjects and Methods: Data were collected from CRC patients between 2009 and 2012. A total of 127 patients were retrospectively reviewed for BG status and the MSI scores, MsPath, and PathScore. Statistical Analysis Used: Definitive statistical methods (mean, standard deviation, median, frequency, and percentage) were used to evaluate the study data. Comparison used Student's t-test, Continuity (Yates) correction, Fisher-Freeman-Halton test, Pearson correlation, and receiver operating characteristics curve analysis. Results: Patients who were detected as Bethesda-positive had significantly higher MsPath and PathScore scores (P = 0.001 and P = 0.007, respectively). According to the cut-off value of 2.8 and 2.9 for MsPath and PathScore, respectively, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 90%, 43%, 22.8%, 95.8%, and 50.4% for MsPath, and 55%, 83.2%, 37.9%, 90.8%, and 78.7% for PathScore, respectively. Conclusions: The MSI scoring systems, MsPath, and PathScore, are reliable systems and effectively correlated with BG for predicting patients who need advanced analysis techniques because of the risk of HNPCC.

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The pitfalls in cytology diagnosis of poorly differentiated neuroendocrine carcinoma of lung and their treatment response

Debarshi Saha, Ankit Kumar, Sourjya Banerjee, M Nirupama, HB Sridevi, Priya Garg, Flora D Lobo

Journal of Cancer Research and Therapeutics 2017 13(2):213-217

Context: Lung is the most common site of small cell carcinoma (SCLC) – a poorly differentiated neuroendocrine carcinoma (PDNEC). SCLC comprises 15–20% of the invasive cancers of the lung. Aim: This study was conducted to appraise the accuracy and pitfalls of the diagnosis of PDNEC on cytology along with treatment responses if available. Settings and Design: Retrospective study for 2 years yielded 21 cases on cytology. Subjects and Methods: Slides of fine-needle aspiration of lymph nodes, the tumor, bronchial brush, and bronchoalveolar lavage specimens were used. The histological correlation was obtained as were treatment responses. Results: Eighteen SCLCs were confirmed on review. Of these, 13 initial reports were concordant and five, discordant. The rest three cases which initially reported as SCLC were found to be negative (2) and combined SCLC (1). One SCLC with concordant initial and reviewed diagnoses failed to confirm on histopathology. The patients, all heavy smokers, were predominantly males in the seventh to eighth decade age group. The sensitivity and specificity of reviewed diagnoses were better than that of the original. The difference between histopathology and cytology diagnoses (reviewed and original) was statistically insignificant. All patients were categorized as “extensive stage” by positron emission tomography-computerized tomography, and five were treated with etoposide and cisplatin with/without radiotherapy. Conclusion: Age group (61–70) and gender (males) distribution were statistically significant. Intermediate variants of SCLC may be misdiagnosed as adenocarcinoma. Similarly, combined SCLC may be missed on cytology if the observer does not sustain a high index of suspicion. Unequivocal cytology diagnosis opposed to negative histopathology report demands repeat biopsy.

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Clear cell odontogenic carcinoma: A rare case report with emphasis on differential diagnosis

Uma Vasant Datar, Mamata Sharad Kamat, Sampada Shriram Kanitkar, Sanjay Satappa Byakodi

Journal of Cancer Research and Therapeutics 2017 13(2):374-377

Clear cell odontogenic carcinoma (CCOC) is a rare odontogenic malignancy with a female predilection, typically presenting as swelling in anterior region of mandible. CCOC was classified as a malignant neoplasm of odontogenic origin by the WHO in 2005 as it exhibits an aggressive growth pattern, local recurrence, and tendency of distant metastasis. Histologically, CCOC is characterized by sheets and islands of vacuolated/clear cells. Since clear cells are present in few odontogenic tumors, salivary gland neoplasms, and metastatic tumors to the jaws; presence of clear cells in a lesion of head and neck area poses a diagnostic challenge. Knowledge about the clinical course, histopathologic pattern, and immunoprofile of CCOC aids in differentiating it from other clear cell tumors. Herein, we present a case of CCOC in anterior mandibular region of 60-year-old female patient with an emphasis on its differential diagnosis from other clear cell lesions of the jaws.

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Changes in pharyngeal constrictor volumes during head and neck radiation therapy: Implications for dose delivery

Akila Kumarasiri, Chang Liu, Mona Kamal, Correen Fraser, Stephen Brown, Indrin J Chetty, Jinkoo Kim, Farzan Siddiqui

Journal of Cancer Research and Therapeutics 2017 13(2):218-223

Objective: The objective of this study was to evaluate the anatomical changes and associated dosimetric consequences to pharyngeal constrictor muscles (PCMs) that occur during head and neck (H and N) radiotherapy (RT). Materials and Methods: A cohort of 13 oropharyngeal cancer patients with daily cone beam computed tomography (CBCT) was retrospectively studied. On every 5th CBCT image, PCM was manually delineated by a radiation oncologist. The anterior-posterior PCM thickness was measured at the midline level of C3 vertebral body. Delivered dose to PCM was estimated by calculating dose on daily images and performing dose accumulation on corresponding planning CT images using a parameter-optimized B-spline-based deformable image registration algorithm. The mean and maximum delivered dose (Dmean, Dmax) to PCM were determined and compared with the corresponding planned quantities. Results: The average (±standard deviation) volume increase (ΔV) and thickness increase (Δt) over the course of 35 total fractions were 54 ± 33% (11.9 ± 7.6 cc) and 63 ± 39% (2.9 ± 1.9 mm), respectively. The resultant cumulative mean dose increase from planned dose to PCM (ΔDmean) was 1.4 ± 1.3% (0.9 ± 0.8 Gy), while the maximum dose increase (ΔDmax) was 0.0 ± 1.6% (0.0 ± 1.1 Gy). Patients who underwent adaptive replanning (n = 6) showed a smaller mean dose increase than those without (n = 7); 0.5 ± 0.2% (0.3 ± 0.1 Gy) versus 2.2 ± 1.4% (1.4 ± 0.9 Gy). There were statistically significant (P = 0.001) strong correlations between ΔDmean and Δt (Pearson coefficient r = 0.78), as well as between ΔDmean and ΔV (r = 0.52). Conclusion: The patients underwent considerable anatomical changes to PCM during H and N RT. However, the resultant increase in dose to PCM was minor to moderate. PCM thickness measured at C3 level is a good predictor for the mean dose increase to PCM.

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Adult rhabdomyosarcoma: Multimodality management and results

Abhijeet Ashok Salunke, Jaymin Shah, Nayan Gupta, Jyotindra Pandit

Journal of Cancer Research and Therapeutics 2017 13(2):384-386



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NF1+/- hematopoietic cells accelerate malignant peripheral nerve sheath tumor development without altering chemotherapy response

Haploinsufficiency in the tumor suppressor NF1 contributes to the pathobiology of type 1 neurofibromatosis, but a related role has not been established in malignant peripheral nerve sheath tumors (MPNST) where NF1 mutations also occur. Patients with NF1-associated MPNST appear to have worse outcomes than patients with sporadic MPNST, but the mechanism underlying this correlation is not understood. To define the impact of stromal genetics on the biology of this malignancy, we developed unique mouse models that reflect the genetics of patient-associated MPNST. Specifically, we used adenovirus-cre injections to generate MPNST in Nf1 Flox/Flox ; Ink4a/Arf Flox/Flox and Nf1 Flox/- ; Ink4a/Arf Flox/Flox paired littermate mice to model tumors from NF1-wildtype and NF1-associated patients, respectively. In these models, Nf1 haploinsufficiency in hematopoietic cells accelerated tumor onset and increased levels of tumor-infiltrating immune cells comprised of CD11b+ cells, monocytes and mast cells. We observed that mast cells were also enriched in human NF1-associated MPNST. In a co-clinical trial to examine how the tumor microenvironment influences the response to multi-agent chemotherapy, we found that stromal Nf1 status had no effect. Taken together, our results clarify the role of the NF1-haploinsufficient tumor microenvironment in MPNST.

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MCAM mediates chemoresistance in small cell lung cancer via the PI3K/AKT/SOX2 signaling pathway

Despite favorable responses to initial therapy, small cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Due to limited accessibility of patient tissues for research purposes, SCLC-patient derived xenografts (PDX) have provided the best opportunity to address this limitation. Here we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines and in chemoresistant PDX compared to matched treatment-naïve tumors. MCAM depletion in chemoresistant cells reduced cell proliferation and reduced the IC50 inhibitory concentration of chemotherapeutic drugs in vitro. This MCAM-mediated sensitization to chemotherapy occurred via SOX2-dependent upregulation of mitochondrial 37S ribosomal protein 1/ATP binding cassette subfamily C member 1 (MRP1/ABCC1) and the PI3/AKT pathway. Metabolomic profiling revealed that MCAM modulated lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. Our results suggest that MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC.

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EIF1AX and NRAS mutations co-occur and cooperate in low-grade serous ovarian carcinomas

Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF and NRAS. RAS pathway mutations were mutually exclusive, however we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Co-expression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first example of co-occurring, growth-promoting mutational events in ovarian cancer.

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Functionally null RAD51D missense mutation associates strongly with ovarian carcinoma

RAD51D is a key player in DNA repair by homologous recombination (HR) and RAD51D truncating mutation carriers have an increased risk for ovarian cancer (OC). However, the contribution of non-truncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a high risk for ovarian high-grade serous carcinoma (HGSC) (3.8% cases vs 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas or colorectal adenocarcinomas. Functionally, we show for the first time that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP-inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in OC patients carrying deleterious missense RAD51D mutations.

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Withholding vs. Continuing ACEIs or ARBs Before Surgery

ACE inhibitors and angiotensin II receptor blockers are commonly withheld before surgery due to concern over intraoperative hypotension and its impact on outcomes, but are these concerns valid?
Anesthesiology

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Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel–Lindau ( VHL ), Succinate Dehydrogenase ( SDHX ) and Transmembrane Protein 127 ( TMEM127 )

Abstract

Alterations of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX), and TMEM127 have been associated with the development of pheochromocytomas (PCs) and paragangliomas (PGLs) and are also associated with the development of renal neoplasms. This study involved 2 primary renal PGL and 12 cases of PC/PGL with associated renal neoplasia with a mean follow up of 74 months. Germline VHL and SDHX mutation status was obtained from the medical record. Immunohistochemistry for SDHB and mutation analysis for TMEM127 was performed, in addition to analysis of The Cancer Genome Atlas datasets for SDHX and TMEM127 mutated renal cell carcinomas (RCCs). The spectrum of renal neoplasia included clear cell and tubulocystic and papillary RCC, as well as a case of multiple papillary adenomas. Three patients had metastatic PC/PGL and three patients had VHL syndrome. Previously unreported TMEM127 alterations were identified in two patients, both without evidence of VHL syndrome or SDH-deficiency, and were classified as variants of uncertain significance. Primary renal PGL and neoplasia was associated with about 2% of 710 cases of PC/PGL. These were diagnosed concurrently or on average 27 months prior to the PC/PGL, and most were low-grade, low-stage clear cell RCCs. Up to half of patients with PC/PGL and renal neoplasia had VHL syndrome, SDH deficiency, or alterations in TMEM127. One (of three) case of metastatic PC/PGL had SDHB mutation and loss of SDHB by immunohistochemistry. The other two cases had retained SDHB expression.



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CRISPR/Cas9-based Pten knock-out and Sleeping Beauty Transposon-mediated Nras knock-in induces hepatocellular carcinoma and hepatic lipid accumulation in mice

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Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

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Zinc oxide nanoparticles antagonize the effect of Cetuximab on head and neck squamous cell carcinoma in vitro

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Depletion of signal recognition particle 72kDa increases radiosensitivity

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Functional analysis of rare variants in mismatch repair proteins augments results from computation-based predictive methods

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Diagnosis, staging, and risk stratification in prostate cancer: Utilizing diagnostic tools to avoid unnecessary therapies and side effects

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Hearing loss in enlarged vestibular aqueduct and incomplete partition type II

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Publication date: Available online 23 June 2017
Source:American Journal of Otolaryngology
Author(s): Emily Ahadizadeh, Mustafa Ascha, Nauman Manzoor, Amit Gupta, Maroun Semaan, Cliff Megerian, Todd Otteson
PurposeThe purpose of this work is to identify the role of incomplete partition type II on hearing loss among patients with enlarged vestibular aqueduct (EVA).BackgroundEVA is a common congenital inner ear malformation among children with hearing loss, where vestibular aqueduct morphology in this population has been shown to correlate to hearing loss. However, the impact of incomplete partition between cochlear turns on hearing loss has not been, despite meaningful implications for EVA pathophysiology.MethodsA retrospective review of radiology reports for patients who had computed tomography (CT) scans with diagnoses of hearing loss at a tertiary medical center between January 2000 and June 2016 were screened for EVA. CT scans of the internal auditory canal (IAC) for those patients with EVA were examined for evidence of incomplete partition type II (IP-II), measurements of midpoint width and operculum width a second time, and patients meeting Cincinnati criteria for EVA selected for analysis. Statistical analysis including chi-square, Wilcoxon rank-sum, and t-tests were used to identify differences in outcomes and clinical predictors, as appropriate for the distribution of the data. Linear mixed models of hearing test results for all available tests were constructed, both univariable and adjusting for vestibular aqueduct morphometric features, with ear-specific intercepts and slopes over time.ResultsThere were no statistically significant differences in any hearing test results or vestibular aqueduct midpoint and operculum widths. Linear mixed models, both univariable and those adjusting for midpoint and operculum widths, did not indicate a statistically significant effect of incomplete partition type II on hearing test results.ConclusionsHearing loss due to enlarged vestibular aqueduct does not appear to be affected by the presence of incomplete partition type II. Our results suggest that the pathophysiological processes underlying hearing loss in enlarged vestibular aqueduct may not be a result of cochlear malformation, and instead are more likely to involve vestibular aqueduct or cellular and molecular-level mechanisms of hearing loss.



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The landmark for removal of sialoliths using sialendoscopy alone in parotid gland sialolithiasis

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Publication date: Available online 23 June 2017
Source:Auris Nasus Larynx
Author(s): Norio Kondo, Toshio Yoshihara, Yukie Yamamura, Kaoru Kusama, Eri Sakitani, Yukako Seo, Mayako Tachikawa, Keiko Kujirai, Erika Ono, Yasuyo Maeda, Tomohito Nojima, Akiko Tamiya, Emiri Sato, Manabu Nonaka
ObjectiveTo assess the general guidelines for removal of sialoliths in parotid gland sialolithiasis using sialendoscopy alone.MethodsWe analyzed 34 sialoliths treated using sialendoscopy in 26 patients with parotid gland sialolithiasis. We divided the Stensen’s duct and parotid gland into for parts using computed tomography findings: (A) front of the masseter, (B) anterior and lateral to the center (anterolateral) of the masseter, (C) posterior and lateral to the center (posterolateral) of the masseter, (D) behind of the masseter. The location and size of each sialolith was assessed.ResultsThe removal rates of sialoliths in the different locations by sialendoscopy alone were as follows: front of the masseter, 68.8%; anterolateral of the masseter, 60.0%; posterolateral of the masseter, 0%; and behind of the masseter, 33.3%. The removal rate using sialendoscopy alone was significantly higher in the sections anterior to the center of the masseter than in those posterior to the center of the masseter (66.7% [14/21] vs. 20.0% [2/10]; P=0.019). The size of the sialolith was not correlated to the removal rate by sialendoscopy alone.ConclusionSialoliths of the parotid gland located in positions anterior to the center of the masseter are significantly easier to remove by sialendoscopy alone. The center of the masseter is a general landmark for removal of sialoliths from the parotid gland using sialendoscopy alone. The size of the sialolith is not correlated with removal, except rare huge sialoliths.



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Gamma radiation increases the risk of radiation-related root dental caries

The association between radiation exposure and dental caries has been widely discussed. Several factors contribute to dentition breakdown and radiation-related caries (RRC) development but this condition has previously been associated to be an indirect effect due to radiation-induced salivary gland damage [1,2]. It is well known that radiotherapy of head-and-neck induces damage to the salivary glands, which means that patients with chronic hyposalivation are at high-risk for RRC development and progression [3].

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Formation of an international intergroup to coordinate clinical trials in head and neck cancers: HNCIG

Clinical trials in head and neck cancer (HNC) face multiple challenges including low global incidence, excessive patient comorbidity rate, high treatment-related toxicity and more recently a changing tumor biology landscape. As clinical trials evolve to address new knowledge about HNC biology, the overall pool of eligible patients for each trial becomes smaller, leading to more accrual challenges. These challenges have led to the formation of the Head and Neck Cancer Intergroup (HNCIG) comprised of large HNC international and national cooperative groups and sites with the goal of facilitating the conduct of high quality clinical trials in a timely manner to improve outcomes in HNC.

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Primary Renal Paragangliomas and Renal Neoplasia Associated with Pheochromocytoma/Paraganglioma: Analysis of von Hippel–Lindau ( VHL ), Succinate Dehydrogenase ( SDHX ) and Transmembrane Protein 127 ( TMEM127 )

Abstract

Alterations of von Hippel-Lindau (VHL), succinate dehydrogenase (SDHX), and TMEM127 have been associated with the development of pheochromocytomas (PCs) and paragangliomas (PGLs) and are also associated with the development of renal neoplasms. This study involved 2 primary renal PGL and 12 cases of PC/PGL with associated renal neoplasia with a mean follow up of 74 months. Germline VHL and SDHX mutation status was obtained from the medical record. Immunohistochemistry for SDHB and mutation analysis for TMEM127 was performed, in addition to analysis of The Cancer Genome Atlas datasets for SDHX and TMEM127 mutated renal cell carcinomas (RCCs). The spectrum of renal neoplasia included clear cell and tubulocystic and papillary RCC, as well as a case of multiple papillary adenomas. Three patients had metastatic PC/PGL and three patients had VHL syndrome. Previously unreported TMEM127 alterations were identified in two patients, both without evidence of VHL syndrome or SDH-deficiency, and were classified as variants of uncertain significance. Primary renal PGL and neoplasia was associated with about 2% of 710 cases of PC/PGL. These were diagnosed concurrently or on average 27 months prior to the PC/PGL, and most were low-grade, low-stage clear cell RCCs. Up to half of patients with PC/PGL and renal neoplasia had VHL syndrome, SDH deficiency, or alterations in TMEM127. One (of three) case of metastatic PC/PGL had SDHB mutation and loss of SDHB by immunohistochemistry. The other two cases had retained SDHB expression.



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The outcomes of endoscopic management in young children with subglottic stenosis

Publication date: August 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 99
Author(s): Chao Chen, Wei-hua Ni, Tan-le Tian, Zheng-min Xu
Subglottic stenosis (SGS) is a common cause of obstructed airway in children, and the treatment of pediatric SGS, especially congenital SGS, remains a challenge for the otolaryngologist.ObjectiveTo analyze the outcomes of endoscopic management in young children with SGS.MethodsWe performed a retrospective review of treatment with endoscopic balloon dilation (EBD) or EBD combined with endoscopic anterior cricoid split (EACS) for young SGS children, from December 2008 to December 2015. The ages of patients ranged from 2 days to 12 years, median age was 5 months. The grade of them ranged from II to IV.ResultsFor acute acquired SGS, 19 cases received EBD alone and the other 3 cases received EBD and EACS, the success rate was about 95.5%; For chronic acquired SGS, EBD and EACS was performed in 6 patients with a success rate of 66.7%; For congenital SGS, EBD and EACS was performed in 28 patients with a success rate of 85.7%. Overall, the success rate of endoscopic management in 56 young children was about 87.5%. Besides, No procedure-related complications were observed in any patients.ConclusionsEndoscopic surgical technique offers a safe and effective approach for treatment of young children with SGS, especially in congenital SGS.



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A case of improved hearing with cochlear implantation in Gaucher disease type 1

Gaucher disease is a lysosomal storage disorder that is caused by congenital defective function of the enzyme glucocerebrosidase. Glucocerebroside that is not hydrolyzed by glucocerebrosidase mainly accumulates in the reticular tissue. We describe a Japanese boy with Gaucher disease type 1 who developed bilateral profound sensorineural hearing loss within approximately 4years. We performed cochlear implantation initially on his right ear and again on his left ear 5 months later. The cochlear implants were successfully utilized with a speech discrimination score of 95% on a Japanese sentence recognition test.

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Neck metastasis in patients with T1-2 supraglottic cancer

Unlike glottic cancer, supraglottic cancer often presents with neck metastases. This different might be attributable to the location of the primary lesion. This study aimed to clarify the relationships between the sublocation of T1-2 supraglottic cancer, human papillomavirus (HPV) infection, neck metastasis, and prognosis of supraglottic cancer.

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Texas Nurse Charged With Death of Second Baby

Decades after prosecutors convicted Genene Jones of killing a single infant, a Texas grand jury has indicted the former nurse on a second new charge of murder. Prosecutors hope to prevent Jones’ release from prison, which is scheduled for next year.
ProPublica

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Surgery May Help in Diabetic Neuropathy With Squeezed Leg Nerves

Nerve-decompression surgery in diabetic peripheral neuropathy is considered "unproven" and is not reimbursed, but when these stronger data are published, this may change.
Medscape Medical News

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Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation

Acute myeloid leukemia (AML) is a heterogeneous disease that remains challenging to treat because of patient factors (age and coexisting diseases) and intrinsic biologic factors. Cytogenetic and mutational data are used to divide patients into subgroups defined according to prognostic factors and…

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Health-related quality of life, fear of recurrence, and emotional distress in patients treated for thyroid cancer

Diagnosis of differentiated thyroid carcinoma (papillary or follicular) and its treatment may be associated with a poor health-related quality of life (HRQoL), and with fear of recurrence (FoR), and distress. To our knowledge, this is the first time a single FoR screening question (written to complement a HRQoL questionnaire), has been reported with HRQoL and levels of distress in patients treated for the disease. In April 2014 we did a cross-sectional survey of patients who had presented to the Merseyside and Cheshire thyroid cancer network between April 2009 and November 2013.

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Use of a three-dimensional custom-made porous titanium prosthesis for mandibular body reconstruction

The progress made in recent years in the field of head and neck bone reconstruction is directly related to technological advancements made in computer-aided design and manufacturing (CAD/CAM) and three-dimensional printing in particular. Today these technologies are mainly used in mandibular reconstruction to manufacture aids for harvesting and shaping bone flaps. However problems remain when addressing patients with a contraindication to microsurgery who need extensive bone reconstruction. For these patients who cannot benefit from vascularized bone grafts, surgeons have to find alternative solutions aimed at maintaining best function and aesthetics.

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A comparative study of MED-EL FMT attachment to the long process of the incus in intact middle ears and its attachment to disarticulated stapes head

S03785955.gif

Publication date: Available online 23 June 2017
Source:Hearing Research
Author(s): Tao Chen, Liu-Jie Ren, Dong-Ming Yin, Jia Li, Lin Yang, Pei-Dong Dai, Tian-Yu Zhang
The Vibrant Soundbridge© (VSB) active middle-ear implant provides an effective treatment for mild-to-severe sensorineural hearing loss in the case of normal middle ear anatomy and mixed hearing loss in middle ear malformation. The VSB floating mass transducer (FMT), with proper couplers, can be installed on various structures of the ossicular chain, e.g., the short and long process of the incus, the stapes head, and the stapes footplate. A long process (LP) coupler is most commonly used for FMT attachment to the long process of the incus with intact ossicular chain, while CliP and Bell couplers are two standardized and reliable methods for FMT attachment to the stapes head with missing incus and malleus. However, the difference and relationship of the vibration properties among these three FMT couplers remain unclear.In the present study, the stapes footplate velocity responses of the LP, CliP, and Bell couplers have been investigated in eight fresh temporal bones (TBs) to evaluate the vibration properties of these three couplers. Normal and reconstructed middle ear transfer functions (METFs) were determined from laser Doppler vibrometer (LDV) measurements. A mastoidectomy and a posterior tympanotomy were performed to expose the ossicular chain. The METFs of the normal middle ear and middle ear with LP-FMT-coupler were compared under acoustic stimulation, thus the mass effect of the FMT with LP coupler was evaluated. Additional comparisons were made between the stapes footplate vibrations of the LP-FMT-coupler (with the intact ossicular chain at the long process of the incus), CliP-FMT-coupler and Bell-FMT-coupler on the stapes head (after incus and malleus removed) under active electromechanical stimulation. After the installation of CliP-FMT-coupler and Bell-FMT-coupler to the middle ear, the average velocity amplitude of the stapes footplate, comparing to the LP-FMT-coupler, was about 15 dB higher between 1 and 6 kHz, and 10 dB lower at about 0.5 kHz. Quantitatively, there was no significant difference between the CliP-FMT-coupler and Bell-FMT-coupler.According to our study, installation of CliP-FMT-coupler or Bell-FMT-coupler on the stapes head provides considerable improvement of the middle ear mechanical and functional responses, comparing with the LP-FMT-coupler in the temporal bone experiments. Moreover, the installation of the Bell-FMT-coupler to the stapes head produces essentially the same footplate velocity responses in comparison to the CliP-FMT-coupler.



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Reproduction of the atopic march in an adult after allogeneic bone marrow transplantation from an atopic sibling

Allogeneic bone marrow transplantation (BMT) or hematopoietic stem cell transplantation is an established treatment for several hematologic disorders, such as severe aplastic anemia, leukemia, or severe combined immunodeficiency, among others. Transfer of specific IgE (sIgE)–mediated hypersensitivity after allogeneic BMT to a previously nonallergic recipient has been described.1,2 A prospective study found a long-term allergen sIgE-mediated hypersensitivity transferred during BMT.3 Another study found the appearance of a new allergen sIgE after BMT from atopic donors, suggesting that the atopic condition was transferred from the donor to the recipient.

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Formation of an international intergroup to coordinate clinical trials in head and neck cancers: HNCIG

Clinical trials in head and neck cancer (HNC) face multiple challenges including low global incidence, excessive patient comorbidity rate, high treatment-related toxicity and more recently a changing tumor biology landscape. As clinical trials evolve to address new knowledge about HNC biology, the overall pool of eligible patients for each trial becomes smaller, leading to more accrual challenges. These challenges have led to the formation of the Head and Neck Cancer Intergroup (HNCIG) comprised of large HNC international and national cooperative groups and sites with the goal of facilitating the conduct of high quality clinical trials in a timely manner to improve outcomes in HNC.

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Gamma radiation increases the risk of radiation-related root dental caries

The association between radiation exposure and dental caries has been widely discussed. Several factors contribute to dentition breakdown and radiation-related caries (RRC) development but this condition has previously been associated to be an indirect effect due to radiation-induced salivary gland damage [1,2]. It is well known that radiotherapy of head-and-neck induces damage to the salivary glands, which means that patients with chronic hyposalivation are at high-risk for RRC development and progression [3].

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A comparative study of MED-EL FMT attachment to the long process of the incus in intact middle ears and its attachment to disarticulated stapes head

Publication date: Available online 23 June 2017
Source:Hearing Research
Author(s): Tao Chen, Liu-Jie Ren, Dong-Ming Yin, Jia Li, Lin Yang, Pei-Dong Dai, Tian-Yu Zhang
The Vibrant Soundbridge© (VSB) active middle-ear implant provides an effective treatment for mild-to-severe sensorineural hearing loss in the case of normal middle ear anatomy and mixed hearing loss in middle ear malformation. The VSB floating mass transducer (FMT), with proper couplers, can be installed on various structures of the ossicular chain, e.g., the short and long process of the incus, the stapes head, and the stapes footplate. A long process (LP) coupler is most commonly used for FMT attachment to the long process of the incus with intact ossicular chain, while CliP and Bell couplers are two standardized and reliable methods for FMT attachment to the stapes head with missing incus and malleus. However, the difference and relationship of the vibration properties among these three FMT couplers remain unclear.In the present study, the stapes footplate velocity responses of the LP, CliP, and Bell couplers have been investigated in eight fresh temporal bones (TBs) to evaluate the vibration properties of these three couplers. Normal and reconstructed middle ear transfer functions (METFs) were determined from laser Doppler vibrometer (LDV) measurements. A mastoidectomy and a posterior tympanotomy were performed to expose the ossicular chain. The METFs of the normal middle ear and middle ear with LP-FMT-coupler were compared under acoustic stimulation, thus the mass effect of the FMT with LP coupler was evaluated. Additional comparisons were made between the stapes footplate vibrations of the LP-FMT-coupler (with the intact ossicular chain at the long process of the incus), CliP-FMT-coupler and Bell-FMT-coupler on the stapes head (after incus and malleus removed) under active electromechanical stimulation. After the installation of CliP-FMT-coupler and Bell-FMT-coupler to the middle ear, the average velocity amplitude of the stapes footplate, comparing to the LP-FMT-coupler, was about 15 dB higher between 1 and 6 kHz, and 10 dB lower at about 0.5 kHz. Quantitatively, there was no significant difference between the CliP-FMT-coupler and Bell-FMT-coupler.According to our study, installation of CliP-FMT-coupler or Bell-FMT-coupler on the stapes head provides considerable improvement of the middle ear mechanical and functional responses, comparing with the LP-FMT-coupler in the temporal bone experiments. Moreover, the installation of the Bell-FMT-coupler to the stapes head produces essentially the same footplate velocity responses in comparison to the CliP-FMT-coupler.



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Effects of Straw Phonation Through Tubes of Varied Lengths on Sustained Vowels in Normal-Voiced Participants

To examine the immediate effects of straw phonation exercises in normal subjects while altering the effective length of the vocal tract.

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Phonak Celebrates its 70 Years of History in Hearing Technology

Phonak_Alpina.jpgPhonak (http://ift.tt/1TpqSBL) is hosting an Open Door Day to celebrate its 70-year history on June 24, 2017, which is expected to draw over 8,000 people to the company's headquarters in Staefa, Switzerland. The event, which runs from 10 a.m. to 5 p.m. this Saturday, will feature a self-guided tour of the building, including of the labs and Research & Development, as well as a separate tour of the production facility. One of the highlights of the day will be a visual presentation of Phonak's innovations from 1947 to the present entitled Phonak's "Walk of Fame." Phonak has also created a microsite for those who can't make it in person to join in the celebration remotely. Visitors of the site can thank someone special by using the Phonak card creator, which allows them to upload their photos, choose from predefined card designs, customize a message, and send their cards to their recipients. The website also features a history page that details the company's milestones since its inception in the '40s. 

Published: 6/23/2017 9:35:00 AM


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Positional and ultrastructural changes in peripheral pulp capillaries correlate with the active phase of dentin deposition and mineralization in rat molars

Publication date: Available online 23 June 2017
Source:Journal of Oral Biosciences
Author(s): Yuta Seino, Yoshiro Takano, Hayato Ohshima
ObjectivesThe mechanisms regulating positional and ultrastructural changes in peripheral pulp capillaries during dentinogenesis have yet to be fully elucidated. This study aimed to clarify the relationship between the spatiotemporal localization and ultrastructure of peripheral capillaries and the dentin deposition and mineralization rate.MethodsMaxillary first molars of 5- to 100-day-old Wistar rats were collected and prepared for transmission electron microscopy. The animals who had received multiple injections of lead disodium ethylenediaminetetraacetic acid were analyzed for dentin deposition rate. Non-demineralized maxillae were examined with an electron probe micro analyzer.ResultsThe dentin deposition rate at the coronal position where dentinogenesis began on day 5 reached a peak during days 10–30, gradually decreased, and ceased on day 60. The mineral content of enamel was low on day 10 (the secretory stage of amelogenesis), drastically increased on day 15 (the maturation stage of amelogenesis), and reached a maximum and persisted until day 30. The dentin underneath the maturing enamel exhibited a synchronous increase in mineral content. The distance between the mineralization front and peripheral capillaries remained almost constant, suggesting that the positional changes of capillaries into the odontoblast layer were not due to migration of capillaries but could be attributed to an increase in the height of the odontoblast layer. Endothelial fenestrations became prominent in the most active phase of dentin deposition and mineralization.ConclusionsThese results indicate that the positional and ultrastructural changes in peripheral capillaries correlate with the active phase of dentin deposition and mineralization.



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Long-term follow-up of a child with Klinefelter syndrome and achondroplasia from infancy to 16 years

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Joint association of screen time and physical activity with anthropometric measures in Iranian children and adolescents: the weight disorders survey of the CASPIAN-IV study

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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High prevalence of organ specific autoantibodies in Indian type 1 diabetic patients

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Comparison of Tanner staging of HIV-infected and uninfected girls at the University of Nigeria Teaching Hospital, Ituku/Ozalla, Enugu, Nigeria

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Clinical, biochemical and genetic features with nonclassical 21-hydroxylase deficiency and final height

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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How Often Is Hearing Loss Considered?

As audiologists, we know firsthand the impact that hearing loss has on communication. Before we begin speaking, we look at our patients and provide an unobstructed view of our face. As soon as patients walk into our office, we adjust the volume, pitch, and tempo of our speech to ensure that they can hear and understand us. We hope that other health-care providers, including physicians, are also attuned to their patients’ hearing needs particularly when helping older adults where a prevalence of hearing loss is high.



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Fosphenytoin-induced purple glove syndrome: A case report

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Publication date: September 2017
Source:Clinical Neurology and Neurosurgery, Volume 160
Author(s): Joseph W. Newman, Joseph R. Blunck, Ronald K. Fields, John E. Croom
BackgroundPurple glove syndrome (PGS) is a poorly understood severe adverse drug reaction that is typically associated with intravenous phenytoin administration. Although fosphenytoin is thought to circumvent this risk of PGS, we reveal a rare case of PGS in a patient treated with fosphenytoin therapy.Case summaryA 71-year-old male with history of epilepsy was admitted for seizures and traumatic brain injury and intravenous fosphenytoin and levetiracetam were initiated. The patient continued to have seizure activity on continuous electroencephalography for which fosphenytoin dosing was increased with subsequent seizure control. Serum phenytoin levels became elevated with a total level reaching as high as 25.8ug/mL. Three days into fosphenytoin therapy he developed PGS in both hands. Causation was assessed with the Naranjo adverse drug reaction algorithm that suggested fosphenytoin was probably the cause of PGS. Ten days after discontinuing the fosphenytoin and administering a 7-day course of methylprednisolone, the purple glove syndrome completely resolved.ConclusionEarly recognition and emergent management of PGS are key for optimal recovery. Although fosphenytoin has a significantly reduced risk of associated PGS compared to phenyotin, increased awareness for fosphenytoin-induce PGS can accelerate intervention and minimize morbidity of this rare yet detrimental adverse reaction.



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PTH monitoring after total parathyroidectomy with forearm auto-transplantation: potential for spuriously high levels from grafted forearm

We have identified a cause of falsely elevated parathyroid hormone (PTH) levels after total parathyroidectomy with forearm auto-transplantation (TPT-ATx). Our cases highlight the need to draw PTH samples remot...

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Facial soft tissue response to maxillo-mandibular advancement in obstructive sleep apnea syndrome patients

Facial profile soft tissue changes after orthognathic surgery are crucial for surgery success. This retrospective study evaluated soft tissue changes after maxillo-mandibular Advancement and counter clockwise ...

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Different patterns in the risk of newly developed fatty liver and lipid changes with tamoxifen versus aromatase inhibitors in postmenopausal women with early breast cancer: A propensity score–matched cohort study

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Publication date: September 2017
Source:European Journal of Cancer, Volume 82
Author(s): Namki Hong, Han Gyul Yoon, Da Hea Seo, Seho Park, Seung Il Kim, Joo Hyuk Sohn, Yumie Rhee
BackgroundManagement of metabolic complications of long-term adjuvant endocrine therapy in early breast cancer remained an unmet need. We aimed to compare the effects of tamoxifen (TMX) and aromatase inhibitors (AIs) on the risk of fatty liver in conjunction with longitudinal changes in the serum lipid parameters.MethodsAmong 1203 subjects who were taking adjuvant TMX or AI (anastrozole or letrozole) without fatty liver at baseline, those taking TMX or AI were 1:1 matched on the propensity score. The primary outcome was newly developed fatty liver detected on annual liver ultrasonography.ResultsAmong 328 matched subjects (mean age 53.5 years, body mass index 22.9 kg/m2), 62 cases of fatty liver in the TMX group and 41 cases in the AI group were detected in a total of 987.4 person-years. The incidence rate of fatty liver was higher in the TMX group than in the AI group (128.7 versus 81.1 per 1000 person-years, P = 0.021), particularly within the first 2 years of therapy. TMX was associated with an increased 5-year risk of newly developed fatty liver (adjusted hazard ratio 1.61, P = 0.030) compared with AI independent of obesity and cholesterol level. Subjects who developed fatty liver had higher triglycerides (TGs) and lower high-density lipoprotein cholesterol (HDL-C) level at baseline than those without, which was sustained during follow-up despite the serum cholesterol–lowering effect of TMX.ConclusionsTMX independently increased the 5-year risk of newly developed fatty liver compared with AI in postmenopausal women with early breast cancer. Our findings suggest the need for considering the risk of fatty liver as a different adverse event profile between AI and TMX, particularly in patients with obesity, high TGs and low HDL-C.



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Significance of extranodal tumour deposits in colorectal cancer: A systematic review and meta-analysis

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Publication date: September 2017
Source:European Journal of Cancer, Volume 82
Author(s): Amy C. Lord, Nigel D'Souza, Philip H. Pucher, Brendan J. Moran, A. Muti Abulafi, Andrew Wotherspoon, Shahnawaz Rasheed, Gina Brown
AimsThe presence and significance of extranodal tumour deposits (ENTDs) in colorectal cancer (CRC) continue to cause controversy in terms of origin, classification and prognostic significance. This review aims to assess current evidence on the origin of ENTDs in CRC and their effect on overall and disease-free survival.MethodsA systematic review and meta-analysis were carried out in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines. End-points included prevalence of ENTDs, relationship with extramural venous invasion (EMVI), overall survival (OS) and disease-free survival (DFS). Pooled hazard ratios (HRs) and odds ratios (ORs) were calculated using Stata software.ResultsTwenty-six studies comprising 19,980 patients were included. The prevalence of ENTDs ranged from 10.2% to 44.2% (median 21.3%). There was a significantly increased odds of having ENTD if EMVI was present with a pooled OR of 2.51 (95% CI 2.27–2.77) p ≤ 0.001. The pooled HR for adverse OS in patients with ENTD was 1.63 (95% CI 1.44–1.61), p ≤ 0.001. For adverse DFS the pooled HR was 1.77 (95% CI 1.37–2.11), p ≤ 0.001.ConclusionThis meta-analysis confirms the negative impact of ENTDs on OS and DFS despite variations in classification and prevalence. ENTDs are significantly associated with EMVI. The prognostic implications of ENTDs are not sufficiently recognised in current staging systems. TNM 8 has failed to address this and has not made use of the available evidence to determine the correct position of ENTDs according to their prognostic effect. The prognostic hierarchy should be N0, N1, N2 with N1c being the most severe. Additionally the exclusion of lesions of vascular, lymphatic and perineural origin by TNM 8 has no evidence base.



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