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Παρασκευή, 2 Φεβρουαρίου 2018

Prognostic significance of pretreatment total lymphocyte count and neutrophil-to-lymphocyte ratio in extensive-stage small-cell lung cancer

We evaluated pretreatment total lymphocyte count (TLC, marker of immunosuppression), neutrophil-to-lymphocyte ratio (NLR, marker of inflammation), and overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC).

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Radiotherapy for prostate cancer – Does daily image guidance with tighter margins improve patient reported outcomes compared to weekly orthogonal verified irradiation? Results from a randomized controlled trial

In radical RT for prostate cancer, daily CBCT IGRT with reduced PTV margins demonstrated no advantage with respect to patient reported side effects at end of RT as compared to weekly orthogonal offline portal imaging with standard PTV margins.

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Impact of pemetrexed on intracranial disease control and radiation necrosis in patients with brain metastases from non-small cell lung cancer receiving stereotactic radiation

Pemetrexed is a folate antimetabolite used in the management of advanced adenocarcinoma of the lung. We sought to assess the impact of pemetrexed on intracranial disease control and radiation-related toxicity among patients with adenocarcinoma of the lung who received stereotactic radiation for brain metastases.

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A qualitative signature for predicting pathological response to neoadjuvant chemoradiation in locally advanced rectal cancers

The standard therapy for locally advanced rectal cancers (LARCs) is neoadjuvant chemoradiation (nCRT) followed by surgical resection. Pathological response to nCRT varies among patients, and it remains a challenge to predict pathological response to nCRT in LARCs.

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Evaluation of clinical and endoscopic toxicity after external beam radiotherapy and endorectal brachytherapy in elderly patients with rectal cancer treated in the HERBERT study

The HERBERT study evaluated a high-dose-rate endorectal brachytherapy boost (HDREBT) after EBRT in medically inoperable/elderly patients with rectal cancer. The response-rates are promising but not without risk of toxicity. The current analysis provides a comprehensive overview of patient reported, physician reported and endoscopically observed toxicity.

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Radionuclide transport in the “sediments – water – plants” system of the water bodies at the Semipalatinsk test site

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Publication date: Available online 1 February 2018
Source:Journal of Environmental Radioactivity
Author(s): A.K. Aidarkhanova, S.N. Lukashenko, N.V. Larionova, V.V. Polevik
This paper provides research data on levels and character of radionuclide contamination distribution in the «sediments– water – plants » system of objects of the Semipalatinsk test site (STS). As the research objects there were chosen water bodies of man-made origin which located at the territory of "Experimental Field", "Balapan", "Telkem" and "Sary-Uzen" testing sites. For research the sampling of bottom sediments, water, lakeside and water plants was taken. Collected samples were used to determine concentration of anthropogenic radionuclides 90Sr, 239+240Pu, 241Am, 137Cs. The distribution coefficient (Kd) was calculated as the ratio of the content of radionuclides in the sediments to the content in water, and the concentration ratio (FV) was calculated as the ratio of radionuclide content in plants to the content in sediments or soil.



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Acidified seawater increases accumulation of cobalt but not cesium in manila clam Ruditapes philippinarum

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Publication date: Available online 1 February 2018
Source:Journal of Environmental Radioactivity
Author(s): Narin Sezer, Hasan Oğuz Kocaoğlan, Önder Kılıç, Thomas Lacoue-Labarthe, Murat Belivermiş
The pH of seawater around the world is expected to continue its decline in the near future in response to ocean acidification that is driven by heightened atmospheric CO2 emissions. Concomitantly, economically-important molluscs that live in coastal waters including estuaries and embayments, may be exposed to a wide assortment of contaminants, including trace metals and radionuclides. Seawater acidification may alter both the chemical speciation of select elements as well as the physiology of organisms, and may thus pose at risk to many shellfish species, including the manila clam Ruditapes philippinarum. The bioconcentration efficiency of two common radionuclides associated with the nuclear fuel cycle, 134Cs and 57Co, were investigated by exposing live clams to dissolved 134Cs and 57Co at control (pH = 8.1) and two lowered pH (pH = 7.8 and 7.5) levels using controlled aquaria. The uptake and depuration kinetics of the two radionuclides in the whole-body clam were followed for 21 and 35 days, respectively. At steady-state equilibrium, the concentration factor (CFss) for 57Co increased as the pH decreased (i.e. 130 ± 5, 194 ± 6, and 258 ± 10 at pH levels 8.1, 7.8 and 7.5, respectively), whereas the 134Cs uptake was not influenced by a change in pH conditions. During depuration, the lowest depuration rate constant of 57Co by the manila clam was observed at the intermediate pH of 7.8. An increase in the accumulation of 57Co at the intermediate pH value was thought to be caused mainly by the aragonitic shell of the clam, as well as the low salinity and alkalinity of seawater used in the experiment. Considering that accumulation consists of uptake and depuration, among the three pH conditions moderately acidified seawater enhanced most the accumulation of 57Co. Accumulation of 134Cs was not strongly influenced by a reduced pH condition, as represented by an analogous uptake constant rate and CFss in each treatment. Such results suggest that future seawater pH values that are projected to be lower in the next decades, may pose a risk for calcium-bearing organisms such as shellfish.



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Ramie (Boehmeria nivea)'s uranium bioconcentration and tolerance attributes

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Publication date: Available online 1 February 2018
Source:Journal of Environmental Radioactivity
Author(s): Wei-hong Wang, Xue-gang Luo, Lai Liu, Yan Zhang, Hao-zhou Zhao
The authors sampled and analyzed 15 species of dominant wild plants in Huanan uranium tailings pond in China, whose tailings' uranium contents were 3.21–120.52 μg/g. Among the 15 species of wild plants, ramie (Boehmeria nivea) had the strongest uranium bioconcentration and transfer capacities. In order to study the uranium bioconcentration and tolerance attributes of ramie in detail, and provide a reference for the screening remediation plants to phytoremedy on a large scale in uranium tailings pond, a ramie cultivar Xiangzhu No. 7 pot experiment was carried out. We found that both wild ramie and Xiangzhu No. 7 could bioconcentrate uranium, but there were two differences. One was wild ramie's shoots bioconcentrated uranium up to 20 μg/g (which can be regarded as the critical content value of the shoot of uranium hyperaccumulator) even the soil uranium content was as low as 5.874 μg/g while Xiangzhu No. 7's shoots could reach 20 μg/g only when the uranium treatment concentrations were 275 μg/g or more; the other was that all the transfer factors of 3 wild samples were >1, and the transfer factors of 27 out of 28 pot experiment samples were <1. Probably wild ramie was a uranium hyperaccumulator. Xiangzhu No. 7 satisfied the needs of uranium hyperaccumulator on accumulation capability, tolerance capability, bioconcentration factor, but not transfer capability, so Xiangzhu No. 7 was not a uranium hyperaccumulator.We analyzed the possible reasons why there were differences in the uranium bioconcentration and transfer attributes between wild ramie and Xiangzhu No. 7., and proposed the direction for further research.In our opinion, both the plants which bioconcentrate contaminants in the shoots and roots can act as phytoextractors. Although Xiangzhu No. 7's biomass and accumulation of uranium were concentrated on the roots, the roots were small in volume and easy to harvest. And Xiangzhu No. 7's cultivating skills and protection measures had been developed very well. Xiangzhu No. 7's whole bioconcentration factors and the roots' bioconcentration factors, which were 1.200–1.834 and 1.460–2.341, respectively, increased with the increases of uranium contents of pot soil when the soil's uranium contents are 25–175 μg/g, so it can act as a potential phytoextractor when Huanan uranium tailings pond is phytoremediated.



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The incidence of occult metastasis and the status of elective neck dissection in salivary adenoid cystic carcinoma – a single center study.

Publication date: Available online 2 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Robert Cordesmeyer, Philipp Kauffmann, Rainer Laskawi, Anna Rau, Felix Bremmer
Background and PurposeAdenoid cystic carcinoma (ACC) is characterized by high rate of local recurrence and late distant metastasis. The status of an elective neck dissection (END) is controversial discussed in the literature.MethodsIn this study we analyzed the surgical treatment and follow up examinations of 59 patients with adenoid cystic carcinomas of a salivary gland treated in a single center between 1980 and 2016 retrospectively.ResultsThe incidence of occult nodal metastases among all patients who underwent elective neck dissection was 20.6%. The overall survival and the disease free survival of patients who underwent END vs. patients without END showed no significant differences. Even in case of positive lymph nodes metastasis there was no significant benefit in the survival or the local recurrence control.ConclusionThe incidence of occult neck metastases in patients with ACC was 20.6%. There was no significant enhanced survival shown in the group of patients who underwent an END.



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Expression of cyclin d1 correlates with p27KIP1 and regulates the degree of oral dysplasia and squamous cell carcinoma differentiation.

Publication date: Available online 1 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Guangzhao Guan, Mahmoud M. Bakr, Norman Firth, Robert M. Love
Objectives.The aim of this study was to show an association or link between cyclin D1 and P27KIP1 protein expression and dysplastic changes or progression.Study design.Oral mucosal biopsies with a diagnosis of non-neoplastic tissue (Gingivitis) (n=10), mild to moderate oral epithelial dysplasia (n=12) and oral squamous cell carcinoma (n=11) were evaluated by using immunohistochemistry. Scanning software was used to determine cyclin D1 and p27KIP1 intensity of expression, location and pattern.Results.A significant increase in expression of cyclin D1 and a decrease in expression of p27KIP1 proteins were observed in oral epithelial dysplasia and less differentiated OSCC. There was a more diffuse distribution of cyclin D1 protein expression extending from the basal cell layer into the prickle cell layers in epithelial dysplasia, and extending within all epithelial layers in OSCC. Cases of oral epithelial dysplasia showed moderate infrequent expression of p27KIP1. There were no p27KIP1 positive cells in OSCC. The percentage of cells with both nuclear and cytoplasmic cyclin D1 staining was higher in oral squamous cell carcinoma specimens than control groups and oral epithelial dysplasia.Conclusions.The expression of both cyclin D1 and p27KIP1 correlate with the grade of oral epithelial dysplasia and degree of OSCC differentiation. The results obtained will be verified through a basic follow up of the cases to determine the prognosis/progression of oral dysplasia.



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Expression Of Cell Cycle Proteins According To HPV Status In Oral Squamous Cell Carcinoma Affecting Young Patients: A Pilot Study

Publication date: Available online 2 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Marisol Miranda Galvis, Juscelino Freitas Jardim, Estela Kaminagakura, Alan Roger Santos-Silva, Felipe Paiva Fonseca, Oslei Paes Almeida, Marcio Ajudarte Lopes, Clóvis Lópes Pinto, Luiz Paulo Kowalski
ObjectiveTobacco and alcohol consumption are considered the main risk factors for oral squamous cell carcinoma (OSCC); however, the role of these factors in patients younger than 40 years is controversial, so it has been suggested that genomic instability and high-risk human papillomavirus (HR-HPV) infection may be contributing factors to oral carcinogenesis at a young age. Therefore, the aim of this study was to evaluate the immunoexpression of cell cycle proteins according HPV status in OSCC affecting young patients.MethodsA tissue microarray construction based on 34 OSCC samples from young patients (<40 years old) was subjected to immunohistochemical reactions for Ki-67, Cyclin D1, C-ErbB2, p21, Myc, EGFR, p53 and p16 antibodies.ResultsThe clinicopathological features and the immunoexpression of all tested proteins were similar in both groups. HPV-related OSSC tended to have better cancer-specific survival (39% vs 60% 5-year CSS), and overall survival (OS) (29.2% vs 60% 5-year OS). However, it were not statistically significant.ConclusionNo significant difference exists in the expression of cell cycle proteins studied between HR-HPV DNA-positive and negative OSCC affecting young patients.



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Does the andrews facial analysis predict esthetic sagittal maxillary position?

Publication date: Available online 1 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Cory M. Resnick, Kimberly M. Daniels, Maryann Vlahos
ObjectiveCephalometric analyses have limited utility in planning maxillary sagittal position for orthognathic surgery. In Six Elements of Orofacial Harmony, Andrews quantified maxillary position relative to forehead projection and angulation, and proposed an ideal relationship. The purpose of this study was to investigate the ability of this technique to predict esthetic sagittal maxillary position.Study DesignSurvey study including a male and female with straight facial profiles, normal maxillary incisor angulations, and Angle Class I. Maxillary position was modified on lateral photographs to create 5 images for each subject with Incisor-GALL distances of -4, -2, 0, +2, +4mm. A series of healthcare professionals and lay people were asked to rate each photo in order of attractiveness.Results100 complete responses were received. Incisor-GALL distances of +4mm (41%) and +2mm (40%) were most commonly considered "most esthetic" for the female volunteer (p<0.001). For the male volunteer, there were two peak "most esthetic" responses: Incisor-GALL distances of 0mm (37%) and -4mm (32%) (p<0.001).ConclusionRespondents considered maxillary incisor position 2-4mm anterior to GALL most attractive in a female, and 0-4mm posterior to GALL most esthetic in a male. Using these modified target distances, this analysis may be useful for orthognathic surgery planning.



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Current practice in provision of alcohol assessment and support for patients following alcohol related facial fractures

Publication date: Available online 1 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Kai Lee, Michael Qiu, Jiandong Sun
Objectives: Algorithm of maxillofacial trauma management is well defined, however provision of alcohol assessment for patients post trauma is not widely practised. This study aims to investigate the rate of alcohol assessment achieved within facial trauma demographic and circumstances where this intervention was implemented. Methods: This study retrospectively examined the Victorian admitted episodes data-set (VAED) from 2004-2013. Results: Of a total of 54,730 presentations with facial fractures to all Victorian Hospitals, 0.9% in non-alcohol involved group and 4.3% in alcohol involved group received alcohol assessment during their inpatient stay (p<0.001). Among patients with alcohol involvement, the likelihood of assessment was significantly different between length of stay, age, trauma mechanism and gender. Positive blood alcohol test did not relate to probability of assessment. Those with acute alcohol intoxication was less likely to be assessed (p<0.001), while those with harmful alcohol use, alcohol dependence or alcohol withdrawal state were much more likely to be assessed (p<0.001). Conclusions: this study found no consistent practice of alcohol support to patients following alcohol-related facial fractures. Post trauma alcohol support may optimise perioperative management of patients, education of alcohol harm and reduce future trauma risk. Development and refinement of such practice is an area for further research.



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The management of head and neck cancer in elderly patients.

Publication date: Available online 1 February 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Mauro Magnano, Fabio Bertone, Marco Andreis, Paolo Boffano, Giacomo Machetta
ObjectiveA progressive increase of the number of elderly patients with head-andneck cancer has been observed in the last years. The aim of this study was to assess our experience in the management of elderly patients with head and neck cancer in comparison with younger patients.Study designA retrospective review was conducted for all patients admitted and treated for newly diagnosed head and neck cancer between January 2008 and December 2012. The clinical characteristics, management approaches, and outcome data were recorded.ResultsA total of 316 head and neck cancer patients (232 males, 84 females) were enrolled: 203 (64%) were in the young group, whereas 113 patients (36%) were in the elderly group. Comorbidities (p < 0.000005) and stage IV tumors (p < 0.0005) were more frequently observed in the elderly group. Treatment options were uniformly distributed within the two groups; only radiotherapy alone was more frequently administered in elderly patients (p < 0.0005).ConclusionsChronologic age should not be a reason to deny appropriate treatments that could prevent death in elderly patients. A careful pre-treatment assessment should always be performed.



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Multidetector computed tomography imaging characteristics of asymptomatic palatine tonsilloliths: a retrospective study on 3886 examinations

Publication date: Available online 31 January 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Mi-Jin Kim, Jo-Eun Kim, Kyung-Hoe Huh, Won-Jin Yi, Min-Suk Heo, Sam-Sun Lee, Soon-Chul Choi
ObjectiveThis study aims to estimate the prevalence of palatine tonsilloliths and analyze their multidetector computed tomography (CT) imaging features.Study DesignThe CT images of 3886 subjects (1654 men, 2232 women; mean age of 35.8 years) were reviewed. The distribution, dimension, morphology, and location of each tonsillolith was assessed. The correlation between subject demographics and the characteristics (prevalence, number, size) of tonsilloliths was determined.ResultsThe prevalence of palatine tonsilloliths was 30.3%, the prevalence and size showed significant difference between men and women. The prevalence of tonsilloliths significantly increased with age (p<0.001). The mean number of tonsilloliths per subject was 2.7, and 64.7% of subjects had 1–2 tonsilloliths. Ovoid-shaped tonsilloliths were the most frequent (approximately 80%). The centers of the tonsillar crypts contained the majority of the tonsilloliths, 50.3% of which had sizes of 1-2 mm.ConclusionThe results, based on a larger sample size compared to previous studies, can be applied as guidelines for the diagnosis of tonsilloliths on CT images.



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PSMA PET/CT visualises prostate cancer recurrence early, impacts radiation therapy

A nuclear medicine scan may locate prostate cancer recurrence after radical prostatectomy early after disease recurrence and could help guide salvage radiotherapy, according to new research from the University of California Los Angeles (UCLA). The study,...

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New focus on where heart disease and breast cancer treatment meet

A new scientific statement issued today by the American Heart Association underscores the commonalities between cardiovascular disease and breast cancer among women, and it calls for more focus on research and specialised treatment where the diseases...

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Why basal cell tumours return when drug treatment stops

What happens when the most common and least threatening type of cancer gets complicated? A new study pinpoints a mechanism that controls how basal cell cancers respond to treatment and offers new ideas for controlling this disease when it gets...

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Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene

Human Molecular Genetics 2018; 27(4): 625–637. doi: 10.1093/hmg/ddx430

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Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease

Human Molecular Genetics 2018; 27(4): 649–666. doi: 10.1093/hmg/ddx432

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CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency

Abstract
Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p.R15L and p.G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p.P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p.R15L and p.G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p.R15L, but not of CHCHD10 p.G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p.G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p.P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.

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Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics

Abstract
Genome-wide association studies of birth weight have focused on fetal genetics, whereas relatively little is known about the role of maternal genetic variation. We aimed to identify maternal genetic variants associated with birth weight that could highlight potentially relevant maternal determinants of fetal growth. We meta-analysed data on up to 8.7 million SNPs in up to 86 577 women of European descent from the Early Growth Genetics (EGG) Consortium and the UK Biobank. We used structural equation modelling (SEM) and analyses of mother–child pairs to quantify the separate maternal and fetal genetic effects. Maternal SNPs at 10 loci (MTNR1B, HMGA2, SH2B3, KCNAB1, L3MBTL3, GCK, EBF1, TCF7L2, ACTL9, CYP3A7) were associated with offspring birth weight at P <5 × 10−8. In SEM analyses, at least 7 of the 10 associations were consistent with effects of the maternal genotype acting via the intrauterine environment, rather than via effects of shared alleles with the fetus. Variants, or correlated proxies, at many of the loci had been previously associated with adult traits, including fasting glucose (MTNR1B, GCK and TCF7L2) and sex hormone levels (CYP3A7), and one (EBF1) with gestational duration. The identified associations indicate that genetic effects on maternal glucose, cytochrome P450 activity and gestational duration, and potentially on maternal blood pressure and immune function, are relevant for fetal growth. Further characterization of these associations in mechanistic and causal analyses will enhance understanding of the potentially modifiable maternal determinants of fetal growth, with the goal of reducing the morbidity and mortality associated with low and high birth weights.

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A recurrent de novo missense mutation in UBTF causes developmental neuroregression

Abstract
UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf−/− is early embryonic lethal in mice, Ubtf+/− mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.

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Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene

Abstract
Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32–12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

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Myostatin inhibition using mRK35 produces skeletal muscle growth and tubular aggregate formation in wild type and TgACTA1D286G nemaline myopathy mice

Abstract
Nemaline myopathy (NM) is a heterogeneous congenital skeletal muscle disease with cytoplasmic rod-like structures (nemaline bodies) in muscle tissue. While weakness in NM is related to contractile abnormalities, myofiber smallness is an additional abnormality in NM that may be treatable. We evaluated the effects of mRK35 (a myostatin inhibitor developed by Pfizer) treatment in the TgACTA1D286G mouse model of NM. mRK35 induced skeletal muscle growth that led to significant increases in animal bodyweight, forelimb grip strength and muscle fiber force, although it should be noted that animal weight and forelimb grip strength in untreated TgACTA1D286G mice was not different from controls. Treatment was also associated with an increase in the number of tubular aggregates found in skeletal muscle. These findings suggest that myostatin inhibition may be useful in promoting muscle growth and strength in Acta1-mutant muscle, while also further establishing the relationship between low levels of myostatin and tubular aggregate formation.

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Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model

Abstract
In humans, a copy of the DUX4 retrogene is located in each unit of the D4Z4 macrosatellite repeat that normally comprises 8–100 units. The D4Z4 repeat has heterochromatic features and does not express DUX4 in somatic cells. Individuals with facioscapulohumeral muscular dystrophy (FSHD) have a partial failure of somatic DUX4 repression resulting in the presence of DUX4 protein in sporadic muscle nuclei. Somatic DUX4 derepression is caused by contraction of the D4Z4 repeat to 1–10 units (FSHD1) or by heterozygous mutations in genes responsible for maintaining the D4Z4 chromatin structure in a repressive state (FSHD2). One of the FSHD2 genes is the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. SMCHD1 mutations have also been identified in FSHD1; patients carrying a contracted D4Z4 repeat and a SMCHD1 mutation are more severely affected than relatives with only a contracted repeat or a SMCHD1 mutation. To evaluate the modifier role of SMCHD1, we crossbred mice carrying a contracted D4Z4 repeat (D4Z4–2.5 mice) with mice that are haploinsufficient for Smchd1 (Smchd1MommeD1 mice). D4Z4–2.5/Smchd1MommeD1 mice presented with a significantly reduced body weight and developed skin lesions. The same skin lesions, albeit in a milder form, were also observed in D4Z4–2.5 mice, suggesting that reduced Smchd1 levels aggravate disease in the D4Z4–2.5 mouse model. Our study emphasizes the evolutionary conservation of the SMCHD1-dependent epigenetic regulation of the D4Z4 repeat array and further suggests that the D4Z4–2.5/Smchd1MommeD1 mouse model may be used to unravel the function of DUX4 in non-muscle tissues like the skin.

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Systematic genetic interaction studies identify histone demethylase Utx as potential target for ameliorating Huntington’s disease

Abstract
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins. We carried out systematic genetic interaction studies testing lysine and arginine methylases and demethylases in a Drosophila melanogaster HD model. We found that modulating methylation enzymes that typically affect histone positions H3K4, H3K36 or H3K79 had varying effects on HD pathology while modulating ones that typically affect constitutive heterochromatin marks at H3K9 and H4K20 generally had limited impact on HD pathology. In contrast, modulating enzymes acting on the facultative heterochromatin mark at H3K27 had specific effects on HD pathology, with reduction of the demethylase Utx rescuing HTT-induced pathology while reducing Polycomb Repressive Complex2 core methylase components led to more aggressive pathology. Further exploration of the mechanism underlying the methylation-specific interactions suggest that these lysine and arginine methylases and demethylases are likely exerting their influence through non-histone targets. These results highlight a novel therapeutic approach for HD in the form of Utx inhibition.

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Cereblon suppresses the formation of pathogenic protein aggregates in a p62-dependent manner

Abstract
Formation of protein aggregates is the hallmark of neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and frontotemporal dementia. Many ubiquitin-associated proteins are recruited to protein aggregates, such as sequestosome 1/p62 (p62), parkin, and cereblon (CRBN). However, the roles of these proteins in the regulation of the formation of protein aggregates are not well understood. Here, using cell and animal models, we discover that CRBN directly interacts with p62 and inhibits the formation of protein aggregates induced by mutant huntingtin (Htt-polyQ) and TAR DNA-binding protein 43 (TDP43C) in a p62-dependent manner. Furthermore, we find the suppression of the formation of protein aggregates by CRBN is caused by the decrease of the binding affinity of p62 to ubiquitinated proteins but not by the change of p62 protein level. Our study reveals a novel role of CRBN and the underlying molecular mechanism in the regulation of misfolded proteins in neurodegenerative diseases, which may provide new insights for finding pharmacological targets for these diseases.

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Selective vulnerability in neuronal populations in nmd/SMARD1 mice

Abstract
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease causing distal limb muscle atrophy that progresses proximally and is accompanied by diaphragmatic paralysis. Neuromuscular junction (NMJ) alterations have been reported in muscles of SMARD1 model mice, known as nmd mice, with varying degrees of severity, suggesting that different muscles are specifically and selectively resistant or susceptible to denervation. To evaluate the extent of NMJ pathology in a broad range of muscles, a panel of axial and appendicular muscles were isolated and immunostained from nmd mice. These analyses revealed that selective distal appendage muscles were highly vulnerable to denervation. Susceptibility to pathology was not limited to NMJ alterations, but included defects in myelination within those neurons innervating susceptible muscles. Interestingly, end plate fragmentation was present within all muscles independent of the extent of NMJ alterations, suggesting that end plate fragmentation is an early hallmark of SMARD1 pathogenesis. Expressing the full-length IGHMBP2 cDNA using an adeno-associated virus (AAV9) significantly decreased all aspects of muscle and nerve disease pathology. These results shed new light onto the pathogenesis of SMARD1 by identifying specific motor units that are resistant and susceptible to neurodegeneration in an important model of SMARD1.

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Inhibition of antigen presentation during AAV gene therapy using virus peptides

Abstract
The clinical trial using adeno-associated virus (AAV) vector delivery of mini-dystrophin in patients with Duchenne Muscular Dystrophy (DMD) demonstrated a cytotoxic lymphocyte (CTL) response targeting the transgene product. These mini-dystrophin-specific T-cells have the potential to clear all transduced muscle, presenting the general gene therapy concern of overcoming the CTL response to foreign proteins that provide therapeutic benefit. In this study, we exploited a natural immunosuppression strategy employed by some viruses that results in CTL evasion only in transduced cells. After transfection of the plasmids encoding viral peptides and ovalbumin, which includes the immune-domain epitope SIINFEKL, several viral small peptides (ICP47 and US6) inhibited the SIINFEKL peptide presentation. A single AAV vector genome that consisted of either transgene AAT fused with SIINFEKL epitope and, separately, ICP47 expressed from different promoters or a single fusion protein with ICP47 linked by a furin cleavage peptide (AATOVA-ICP47) decreased antigen presentation. Compared with AAV/AATOVA in which decreased AAT expression was observed at late time points, persistent transgene expression was obtained after systemic administration of AAV/AATOVA-ICP47 vectors in mice. We extended this strategy to DMD gene therapy. After administration of AAV vector encoding human mini-dystrophin fusion protein with ICP47 into mdx mice, a lower mini-dystrophin-specific CTL response was induced. Importantly, the ICP47 fusion to mini-dystrophin inhibited CTLs mediated cytotoxicity. Although demonstrated herein using AAT and mini-dystrophin transgenes in an AAV context, the collective results have implications for all gene therapy applications resulting in foreign peptides by immune suppression in only genetically modified cells.

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Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa

Abstract
Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is associated with different groups of genes, including those encoding proteins involved in centriole and cilium biogenesis. Exome sequencing revealed a homozygous nonsense mutation [c.304_305delGA (p. D102*)] in POC5, encoding the Proteome Of Centriole 5 protein, in a patient with RP, short stature, microcephaly and recurrent glomerulonephritis. The POC5 gene is ubiquitously expressed, and immunohistochemistry revealed a distinct POC5 localization at the photoreceptor connecting cilium. Morpholino-oligonucleotide-induced knockdown of poc5 translation in zebrafish resulted in decreased length of photoreceptor outer segments and a decreased visual motor response, a measurement of retinal function. These phenotypes could be rescued by wild-type human POC5 mRNA. These findings demonstrate that Poc5 is important for normal retinal development and function. Altogether, this study presents POC5 as a novel gene involved autosomal recessively inherited RP, and strengthens the hypothesis that mutations in centriolar proteins are important cause of retinal dystrophies.

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Validation and uncertainty analysis of a pre-treatment 2D dose prediction model

Independent verification of complex treatment delivery with megavolt photon beam radiotherapy (RT) has been effectively used to detect and prevent errors. This work presents the validation and uncertainty analysis of a model that predicts 2D portal dose images (PDIs) without a patient or phantom in the beam. The prediction model is based on an exponential point dose model with separable primary and secondary photon fluence components. The model includes a scatter kernel, off-axis ratio map, transmission values and penumbra kernels for beam-delimiting components. These parameters were derived through a model fitting procedure supplied with point dose and dose profile measurements of radiation fields. The model was validated against a treatment planning system (TPS; Eclipse) and radiochromic film measurements for complex clinical scenarios, including volumetric modulated arc therapy (VMAT). Confidence limits on fitted model parameters were calculated based on simulated meas...

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Validation of a Monte Carlo code system for grid evaluation with interference effect on Rayleigh scattering

Anti-scatter grids are commonly used in x-ray imaging systems to reduce scatter radiation reaching the image receptor. Anti-scatter grid performance and validation can be simulated through use of Monte Carlo (MC) methods. Our recently reported work has modified existing MC codes resulting in improved performance when simulating x-ray imaging. The aim of this work is to validate the transmission of x-ray photons in grids from the recently reported new MC codes against experimental results and results previously reported in other literature. The results of this work show that the scatter-to-primary ratio (SPR), the transmissions of primary ( T p ), scatter ( T s ), and total ( T t ) radiation determined using this new MC code system have strong agreement with the experimental results and the results reported in the literature. T p , T s , T t , and SPR determined in thi...

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Reply to Comment on ‘egs_brachy: a versatile and fast Monte Carlo code for brachytherapy’

We respond to the comments by Dr Yegin by identifying the source of an error in a fit in our original paper but arguing that the lack of a fit does not affect the conclusion based on the raw data that ##IMG## [http://ift.tt/2Ev9nBz] {$ \newcommand{\eb}{\texttt{egs_brachy}} \newcommand{\e} \eb$} is an accurate code and we provide further benchmarking data to demonstrate this point.

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Motion vector field phase-to-amplitude resampling for 4D motion-compensated cone-beam CT

We propose a phase-to-amplitude resampling (PTAR) method to reduce motion blurring in motion-compensated (MoCo) 4D cone-beam CT (CBCT) image reconstruction, without increasing the computational complexity of the motion vector field (MVF) estimation approach. PTAR is able to improve the image quality in reconstructed 4D volumes, including both regular and irregular respiration patterns. The PTAR approach starts with a robust phase-gating procedure for the initial MVF estimation and then switches to a phase-adapted amplitude gating method. The switch implies an MVF-resampling, which makes them amplitude-specific. PTAR ensures that the MVFs, which have been estimated on phase-gated reconstructions, are still valid for all amplitude-gated reconstructions. To validate the method, we use an artificially deformed clinical CT scan with a realistic breathing pattern and several patient data sets acquired with a TrueBeam TM integrated imaging system (Varian Medical Systems, Palo...

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Improved proton CT imaging using a bismuth germanium oxide scintillator

Range uncertainty is among the most formidable challenges associated with the treatment planning of proton therapy. Proton imaging, which includes proton radiography and proton computed tomography (pCT), is a useful verification tool. We have developed a pCT detection system that uses a thick bismuth germanium oxide (BGO) scintillator and a CCD camera. The current method is based on a previous detection system that used a plastic scintillator, and implements improved image processing techniques. In the new system, the scintillation light intensity is integrated along the proton beam path by the BGO scintillator, and acquired as a two-dimensional distribution with the CCD camera. The range of a penetrating proton is derived from the integrated light intensity using a light-to-range conversion table, and a pCT image can be reconstructed. The proton range in the BGO scintillator is shorter than in the plastic scintillator, so errors due to extended proton ranges can be reduced. To ...

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Comment on ‘egs_brachy: a versatile and fast Monte Carlo code for brachytherapy’

In a recent paper (Chamberland et al 2016 Phys. Med. Biol . 61 8214) develop a new Monte Carlo code called egs_brachy for brachytherapy treatments. It is based on EGSnrc, and written in the C++ programming language. In order to benchmark the egs_brachy code, the authors use it in various test case scenarios in which complex geometry conditions exist. Another EGSnrc based brachytherapy dose calculation engine, BrachyDose, is used for dose comparisons. The authors fail to prove that egs_brachy can produce reasonable dose values for brachytherapy sources in a given medium. The dose comparisons in the paper are erroneous and misleading. egs_brachy should not be used in any further research studies unless and until all the potential bugs are fixed in the code.

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A treatment planning comparison between a novel rotating gamma system and robotic linear accelerator based intracranial stereotactic radiosurgery/radiotherapy

To compare the dosimetric parameters of a novel rotating gamma ray system (RGS) with well-established CyberKnife system (CK) for treating malignant brain lesions. RGS has a treatment head of 16 cobalt-60 sources focused to the isocenter, which can rotate 360° on the ring gantry and swing 35° in the superior direction. We compared several dosimetric parameters in 10 patients undergoing brain stereotactic radiosurgery including plan normalization, number of beams and nodes for CK and shots for RGS, collimators used, estimated treatment time, D 2 cm and conformity index (CI) among two modalities. The median plan normalization for RGS was 56.7% versus 68.5% ( p   =  0.002) for CK plans. The median number of shots from RGS was 7.5 whereas the median number of beams and nodes for CK was 79.5 and 46. The median collimator’s diameter used was 3.5 mm for RGS as compared to 5 mm for CK ( p   =  0.26). Mean D 2 cm was 5.57 Gy for CyberKnife whereas it was 3.11 Gy fo...

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Automatic T1 bladder tumor detection by using wavelet analysis in cystoscopy images

Correct classification of cystoscopy images depends on the interpreter’s experience. Bladder cancer is a common lesion that can only be confirmed by biopsying the tissue, therefore, the automatic identification of tumors plays a significant role in early stage diagnosis and its accuracy. To our best knowledge, the use of white light cystoscopy images for bladder tumor diagnosis has not been reported so far. In this paper, a texture analysis based approach is proposed for bladder tumor diagnosis presuming that tumors change in tissue texture. As is well accepted by the scientific community, texture information is more present in the medium to high frequency range which can be selected by using a discrete wavelet transform (DWT). Tumor enhancement can be improved by using automatic segmentation, since a mixing with normal tissue is avoided under ideal conditions. The segmentation module proposed in this paper takes advantage of the wavelet decomposition tree to discard poor textur...

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Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation.

Advanced Recurrent Hepatocellular Carcinoma: Treatment with Sorafenib Alone or in Combination with Transarterial Chemoembolization and Radiofrequency Ablation.

Radiology. 2018 Feb 01;:171541

Authors: Peng Z, Chen S, Wei M, Lin M, Jiang C, Mei J, Li B, Wang Y, Li J, Xie X, Chen M, Qian G, Kuang M

Abstract
Purpose To retrospectively investigate the safety and efficacy of sorafenib combined with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) (hereafter, TACE-RFA) in the treatment of recurrent hepatocellular carcinoma (rHCC) with portal vein tumor thrombosis, extrahepatic metastases (advanced hepatocellular carcinoma), or both after initial hepatectomy. Materials and Methods The study was centrally approved by the ethics committee of three tertiary medical centers in China. From January 2010 to January 2015, 207 consecutive patients with advanced rHCC after initial hepatectomy received sorafenib combined with TACE-RFA (combination group, n = 106) or sorafenib alone (sorafenib group, n = 101) at the three medical centers. Overall survival (OS) and time to progression (TTP) were compared between the two groups. Complications were assessed. Survival curves were constructed with the Kaplan-Meier method and were compared with the log-rank test. Results Baseline characteristics were balanced between the two groups. No treatment-related death occurred in either group. The toxicity profile in the combination group was similar to that in the sorafenib group. After treatment, median OS (14.0 vs 9.0 months, respectively; P < .001) and TTP (7.0 vs 4.0 months, respectively; P < .001) were significantly longer in the combination group than in the sorafenib group. Multivariate analysis showed that treatment allocation was a significant predictor of OS and TTP, while the number of intrahepatic tumors was another prognostic factor of OS. Conclusion Sorafenib combined with TACE-RFA was well tolerated and safe and was superior to sorafenib alone in improving survival outcomes in patients with advanced rHCC after initial hepatectomy. © RSNA, 2018 Online supplemental material is available for this article.

PMID: 29390197 [PubMed - as supplied by publisher]



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Diagnostic Performance and Interreader Agreement of a Standardized MR Imaging Approach in the Prediction of Small Renal Mass Histology.

Diagnostic Performance and Interreader Agreement of a Standardized MR Imaging Approach in the Prediction of Small Renal Mass Histology.

Radiology. 2018 Feb 01;:171557

Authors: Kay FU, Canvasser NE, Xi Y, Pinho DF, Costa DN, Diaz de Leon A, Khatri G, Leyendecker JR, Yokoo T, Lay AH, Kavoussi N, Koseoglu E, Cadeddu JA, Pedrosa I

Abstract
Purpose To assess the diagnostic performance and interreader agreement of a standardized diagnostic algorithm in determining the histologic type of small (≤4 cm) renal masses (SRMs) with multiparametric magnetic resonance (MR) imaging. Materials and Methods This single-center retrospective HIPAA-compliant institutional review board-approved study included 103 patients with 109 SRMs resected between December 2011 and July 2015. The requirement for informed consent was waived. Presurgical renal MR images were reviewed by seven radiologists with diverse experience. Eleven MR imaging features were assessed, and a standardized diagnostic algorithm was used to determine the most likely histologic diagnosis, which was compared with histopathology results after surgery. Interreader variability was tested with the Cohen κ statistic. Regression models using MR imaging features were used to predict the histopathologic diagnosis with 5% significance level. Results Clear cell renal cell carcinoma (RCC) and papillary RCC were diagnosed, with sensitivities of 85% (47 of 55) and 80% (20 of 25), respectively, and specificities of 76% (41 of 54) and 94% (79 of 84), respectively. Interreader agreement was moderate to substantial (clear cell RCC, κ = 0.58; papillary RCC, κ = 0.73). Signal intensity (SI) of the lesion on T2-weighted MR images and degree of contrast enhancement (CE) during the corticomedullary phase were independent predictors of clear cell RCC (SI odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.4, 7.1; P = .003; CE OR, 4.45; 95% CI: 1.8, 10.8; P < .001) and papillary RCC (CE OR, 0.053; 95% CI: 0.02, 0.2; P < .001), and both had substantial interreader agreement (SI, κ = 0.69; CE, κ = 0.71). Poorer performance was observed for chromophobe histology, oncocytomas, and minimal fat angiomyolipomas, (sensitivity range, 14%-67%; specificity range, 97%-99%), with fair to moderate interreader agreement (κ range = 0.23-0.43). Segmental enhancement inversion was an independent predictor of oncocytomas (OR, 16.21; 95% CI: 1.0, 275.4; P = .049), with moderate interreader agreement (κ = 0.49). Conclusion The proposed standardized MR imaging-based diagnostic algorithm had diagnostic accuracy of 81% (88 of 109) and 91% (99 of 109) in the diagnosis of clear cell RCC and papillary RCC, respectively, while achieving moderate to substantial interreader agreement among seven radiologists. © RSNA, 2018 Online supplemental material is available for this article.

PMID: 29390196 [PubMed - as supplied by publisher]



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A U.S. Multicenter Study of Recorded Occupational Radiation Badge Doses in Nuclear Medicine.

A U.S. Multicenter Study of Recorded Occupational Radiation Badge Doses in Nuclear Medicine.

Radiology. 2018 Feb 01;:171138

Authors: Villoing D, Yoder RC, Passmore C, Bernier MO, Kitahara CM

Abstract
Purpose To summarize occupational badge doses recorded for a sample of U.S. nuclear medicine technologists. Materials and Methods Nine large U.S. medical institutions identified 208 former and current nuclear medicine technologists certified after 1979 and linked these individuals to historic badge dose records maintained by a commercial dosimetry company (Landauer), yielding a total of 2618 annual dose records. The distributions of annual and cumulative occupational doses were described by using summary statistics. Results Between 1992 and 2015, the median annual personal dose equivalent per nuclear medicine technologist was 2.18 mSv (interquartile range [IQR], 1.25-3.47 mSv; mean, 2.69 mSv). Median annual personal dose equivalents remained relatively constant over this period (range, 1.40-3.30 mSv), while maximum values generally increased over time (from 8.00 mSv in 1992 to 13.9 mSv in 2015). The median cumulative personal dose equivalent was 32.9 mSv (IQR, 18.1-65.5 mSv; mean, 51.4 mSv) for 45 technologists who had complete information and remained employed through 2015. Conclusion Occupational radiation doses were well below the established occupational limits and were consistent with those observed for nuclear medicine technologists worldwide and were greater than those observed for nuclear and general medical workers in the United States These results should be informative for radiation monitoring and safety efforts in nuclear medicine departments. © RSNA, 2018 Online supplemental material is available for this article.

PMID: 29390195 [PubMed - as supplied by publisher]



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Breast MR Imaging before Surgery: Outcomes in Patients with Invasive Lobular Carcinoma by Using Propensity Score Matching.

Breast MR Imaging before Surgery: Outcomes in Patients with Invasive Lobular Carcinoma by Using Propensity Score Matching.

Radiology. 2018 Jan 31;:171472

Authors: Ha SM, Chae EY, Cha JH, Kim HH, Shin HJ, Choi WJ

Abstract
Purpose To investigate the association between preoperative breast magnetic resonance (MR) imaging and surgical outcomes in patients with invasive lobular carcinoma (ILC) by using propensity score matching to decide whether MR examination is beneficial in the ILC subtype of breast cancer. Materials and Methods The authors identified 603 patients with ILC who underwent surgery between January 2005 and December 2016. Of the 603 patients, 369 (61.2%) underwent MR imaging. The authors calculated the MR detection rate of additional lesions that were occult at mammography and ultrasonography and analyzed any alterations in surgical management. After propensity score matching, 196 pairs of patients were allocated to the groups, and the 17 possible confounding variables regarding patient and tumor characteristics and various clinical features were well balanced between the patients who underwent MR imaging and those who did not. Surgical outcomes were compared. Results Of the 369 patients who underwent MR imaging, additional lesions were detected in 145 (39.3%); 95 of the 145 patients (65.5%) had malignant lesions. A change in surgical management occurred because of MR findings in 94 of the 369 patients (25.5%). According to pathologic findings, this change was appropriate for 84 of the 94 patients (89.4%). In the propensity score-matched analysis, breast MR imaging was associated with lower odds of repeat surgery (odds ratio, 0.140; P < .001) and similar likelihood of initial mastectomy (odds ratio, 0.876; P = .528) and final mastectomy (odds ratio, 0.744; P = .151) compared with patients without breast MR imaging. Conclusion Preoperative MR imaging is useful for detecting additional synchronous malignancy and significantly reducing the likelihood of repeat surgery without increasing the rate of mastectomy in patients with ILC. © RSNA, 2018.

PMID: 29388904 [PubMed - as supplied by publisher]



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In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R )-4-Fluoroglutamine.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R )-4-Fluoroglutamine.

Radiology. 2018 Jan 31;:162610

Authors: Dunphy MPS, Harding JJ, Venneti S, Zhang H, Burnazi EM, Bromberg J, Omuro AM, Hsieh JJ, Mellinghoff IK, Staton K, Pressl C, Beattie BJ, Zanzonico PB, Gerecitano JF, Kelsen DP, Weber W, Lyashchenko SK, Kung HF, Lewis JS

Abstract
Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 μg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

PMID: 29388903 [PubMed - as supplied by publisher]



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A New Diagnostic Approach to the Adult Patient with Acute Dizziness

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Jonathan A. Edlow, Kiersten L. Gurley, David E. Newman-Toker
BackgroundDizziness, a common chief complaint, has an extensive differential diagnosis that includes both benign and serious conditions. Emergency physicians must distinguish the majority of patients with self-limiting conditions from those with serious illnesses that require acute treatment.Objective of the ReviewThis article presents a new approach to diagnosis of the acutely dizzy patient that emphasizes different aspects of the history to guide a focused physical examination with the goal of differentiating benign peripheral vestibular conditions from dangerous posterior circulation strokes in the emergency department.DiscussionCurrently, misdiagnoses are frequent and diagnostic testing costs are high. This relates in part to use of an outdated, prevalent, diagnostic paradigm. The traditional approach, which relies on dizziness symptom quality or type (i.e., vertigo, presyncope, or disequilibrium) to guide inquiry, does not distinguish benign from dangerous causes, and is inconsistent with current best evidence. A new approach divides patients into three key categories using timing and triggers, guiding a differential diagnosis and targeted bedside examination protocol: 1) acute vestibular syndrome, where bedside physical examination differentiates vestibular neuritis from stroke; 2) spontaneous episodic vestibular syndrome, where associated symptoms help differentiate vestibular migraine from transient ischemic attack; and 3) triggered episodic vestibular syndrome, where the Dix-Hallpike and supine roll test help differentiate benign paroxysmal positional vertigo from posterior fossa structural lesions.ConclusionsThe timing and triggers diagnostic approach for the acutely dizzy patient derives from current best evidence and offers the potential to reduce misdiagnosis while simultaneously decreases diagnostic test overuse, unnecessary hospitalization, and incorrect treatments.



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Evidence-based Review of Pharmacotherapy for Acute Agitation. part 1: Onset of Efficacy

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Leslie S. Zun
BackgroundThe main goal of antipsychotic medication in the management of acute agitation in the emergency department is to rapidly induce calm without oversedation, enabling patients to participate in their own care. However, there is a paucity of comparative studies, particularly with newer fast-acting second-generation antipsychotic agents.Objective of the ReviewThis structured evidence-based review compared the onset of efficacy of antipsychotic treatments for acute agitation using data from randomized controlled trials identified by a literature search of the PubMed database.ResultsBased on findings from 28 blinded randomized controlled trials, onset of efficacy was rapid and generally observed at the first time point after intramuscular administration of ziprasidone (15−30 min) or olanzapine (15−30 min), but was more likely to be delayed with intramuscular haloperidol, even when combined with lorazepam (30−60 min), and intramuscular aripiprazole (45−90 min). When administered orally, rapid onset of efficacy was also consistently observed at the first assessment time point with olanzapine (15−120 min), risperidone (30−120 min), and sublingual asenapine (15 min). Significant effects were apparent for inhaled loxapine within 10−20 min. Effects were apparent within approximately 5−10 min with i.v. droperidol. Onset of efficacy was typically more rapid with second-generation antipsychotic agents than benzodiazepines, but data are limited.ConclusionsAlthough the patient populations of trials included in this review do not truly reflect that of the emergency department, the results provide useful information to emergency physicians on the rapid efficacy of certain newer-generation antipsychotic agents for the treatment of acutely agitated patients.



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Approach to the Agitated Emergency Department Patient

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Michael Gottlieb, Brit Long, Alex Koyfman
BackgroundAcute agitation is a common occurrence in the emergency department (ED) that requires rapid assessment and management.ObjectiveThis review provides an evidence-based summary of the current ED evaluation and management of acute agitation.DiscussionAcute agitation is an increasingly common presentation to the ED and has a broad differential diagnosis including metabolic, neurologic, infectious, toxicologic, and psychiatric etiologies. Missed diagnosis of a dangerous etiology of the patient's agitation may result in severe morbidity and mortality. Assessment and management of the agitated patient should occur concurrently. Focused history and physical examination are recommended, though control of the patient's agitation may be required. All patients should receive a point-of-care glucose test, with additional testing depending upon the specific patient presentation. Initial management should involve verbal de-escalation techniques, followed by pharmacologic interventions, with physical restraints reserved as a last resort. Pharmacologic options include first-generation antipsychotics, second-generation antipsychotics, benzodiazepines, and ketamine. Finally, the management of pediatric, pregnant, and elderly patients warrants special consideration.ConclusionAcute agitation is an important presentation that requires prompt recognition and treatment. A focused and thorough examination coupled with appropriate management strategies can assist emergency clinicians to safely and effectively manage these patients.



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Colic Ischemia Precipitated by Gastrocolic Ligament Hematoma Onset after Gastroscopy

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Nicolas Pichon, Florence Pichon-Lefièvre, Muriel Mathonnet




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Benign Headache Management in the Emergency Department

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Brit J. Long, Alex Koyfman
BackgroundHeadache is a common complaint managed in the emergency department (ED), with emergency physicians focusing on evaluation for life-threatening conditions while treating pain and nausea.ObjectiveThis review evaluates the treatment of benign, primary headaches in the ED, with recommendations provided based on the literature.DiscussionHeadaches are a major cause of disability in the United States and a common condition managed in the ED. The primary objectives of emergency evaluation of these patients include evaluation for a life-threatening, secondary cause of headache, with treatment of primary headaches. Close evaluation for a secondary cause of headache include consideration of red flags and focused neurologic examination. The diagnosis of primary headaches is clinical. Literature has evaluated medication efficacy in headache treatment, with antidopaminergic medications demonstrating high rates of efficacy when used in combination with nonsteroidal inflammatory drugs or acetaminophen. Dexamethasone can be used for the reduction of headache recurrence. If dehydration is present, intravenous fluids should be provided. Diphenhydramine is not recommended for analgesia but may reduce akathisia associated with prochlorperazine. Ketamine, propofol, and nerve blocks demonstrate promise. Triptan agents are also efficacious, provided absence of contraindications. Most patients are appropriate for discharge with pain improvement.ConclusionsA variety of medications is available for the treatment of primary headaches in the ED. Antidopaminergic agents demonstrate the highest efficacy and should be provided with acetaminophen and nonsteroidal inflammatory drugs. Dexamethasone may reduce headache recurrence. Other treatments include ketamine, propofol, and nerve blocks.



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Suffering in Silence: Medical Error and its Impact on Health Care Providers

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Jennifer J. Robertson, Brit Long
BackgroundAll humans are fallible. Because physicians are human, unintentional errors unfortunately occur. While unintentional medical errors have an impact on patients and their families, they may also contribute to adverse mental and emotional effects on the involved provider(s). These may include burnout, lack of concentration, poor work performance, posttraumatic stress disorder, depression, and even suicidality.ObjectivesThe objectives of this article are to 1) discuss the impact medical error has on involved provider(s), 2) provide potential reasons why medical error can have a negative impact on provider mental health, and 3) suggest solutions for providers and health care organizations to recognize and mitigate the adverse effects medical error has on providers.DiscussionPhysicians and other providers may feel a variety of adverse emotions after medical error, including guilt, shame, anxiety, fear, and depression. It is thought that the pervasive culture of perfectionism and individual blame in medicine plays a considerable role toward these negative effects. In addition, studies have found that despite physicians’ desire for support after medical error, many physicians feel a lack of personal and administrative support. This may further contribute to poor emotional well-being. Potential solutions in the literature are proposed, including provider counseling, learning from mistakes without fear of punishment, discussing mistakes with others, focusing on the system versus the individual, and emphasizing provider wellness. Much of the reviewed literature is limited in terms of an emergency medicine focus or even regarding physicians in general. In addition, most studies are survey- or interview-based, which limits objectivity. While additional, more objective research is needed in terms of mitigating the effects of error on physicians, this review may help provide insight and support for those who feel alone in their attempt to heal after being involved in an adverse medical event.ConclusionsUnintentional medical error will likely always be a part of the medical system. However, by focusing on provider as well as patient health, we may be able to foster resilience in providers and improve care for patients in healthy, safe, and constructive environments.



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A Rare Case of Acute Right-Sided Colonic Diverticulitis Presenting as Pancreatitis

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Maria de Lourdes Ladino Sturchler, Evan A. Rusoja, Arun Nagdev, Barry C. Simon
BackgroundThis case report highlights the clinical presentation, radiologic findings, and medical management of a case of right colonic diverticulitis (RCD) with concomitant pancreatitis, a rare and easily missed entity in the emergency department (ED) of Western hemisphere countries. In our report, we present and discuss a case of RCD that led to pancreatitis in a female Asian patient. We review the epidemiology, diagnosis, and management of this disorder, and also discuss some complications associated with RCD. The importance of considering this pathologic entity within the ED differential even in those patients presumed to be at low risk for this condition is also explained, as this can prevent inappropriate surgical intervention for this presentation.Case ReportWe describe a 40-year-old Asian woman presenting for evaluation of epigastric pain and vomiting. She was initially thought to have cholecystitis or food poisoning, but had a normal ultrasound evaluation and ultimately had co-presenting RCD and pancreatitis diagnosed after computed tomography scanning. The patient was admitted and made a full recovery after receiving medical therapy and maintaining bowel rest. This is, to our knowledge, the first reported case of RCD and concomitant pancreatitis found in the modern literature.Why Should an Emergency Physician Be Aware of This?Severe epigastric pain in young Asian patients with minimal risk factors may be RCD. This condition presents much like appendicitis, cholecystitis, or food poisoning, but must be considered among early differential diagnoses and evaluated appropriately in order to prevent unnecessary interventions.



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Pott's Disease in a Patient with Subtle Red Flags

Publication date: Available online 1 February 2018
Source:The Journal of Emergency Medicine
Author(s): Lauren M. Cantwell, John C. Perkins, David C.V. Keyes
BackgroundTuberculosis (TB) is now rare in developed countries; however, it is an important diagnosis for the Emergency Physician to be able to make. Classically thought of as a respiratory disease, TB can present in other ways, making it more challenging to recognize.Case ReportWe report the case of a 41-year-old woman who presented to the Emergency Department with a 4-week history of back pain. A diagnosis of T12 osteomyelitis and right psoas muscle abscess was made after magnetic resonance imaging. The concurrent finding raised concern for TB as psoas muscle abscess is usually found along with spinal TB. A computed tomography-guided fine-needle aspiration confirmed the diagnosis. This patient's social history was negative for many of the classic predisposing factors associated with TB: immunosuppression, personal travel, crowded living conditions. Repeated investigation into the patient's history revealed a visit several months prior from a family member from Vietnam who had been treated for TB.Why Should an Emergency Physician Be Aware of This?It is important for Emergency Physicians to be aware of the relatively high incidence of TB as a cause for concurrent psoas abscess and vertebral osteomyelitis.



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Highlights from the Current Issue: February 2018.

Highlights from the Current Issue: February 2018.

Otolaryngol Head Neck Surg. 2018 Feb;158(2):201-202

Authors: Krouse JH

PMID: 29389308 [PubMed - in process]



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Commentary on: "Endoscopic Lateral Cartilage Graft Tympanoplasty".

Commentary on: "Endoscopic Lateral Cartilage Graft Tympanoplasty".

Otolaryngol Head Neck Surg. 2018 Feb;158(2):397

Authors: Lou ZC

PMID: 29389307 [PubMed - in process]



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Response to "Commentary on: 'Endoscopic Lateral Cartilage Graft Tympanoplasty'".

Response to "Commentary on: 'Endoscopic Lateral Cartilage Graft Tympanoplasty'".

Otolaryngol Head Neck Surg. 2018 Feb;158(2):398

Authors: Isaacson B

PMID: 29389306 [PubMed - in process]



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An Analysis of the Open Payment Database in Neurotology.

An Analysis of the Open Payment Database in Neurotology.

Otolaryngol Head Neck Surg. 2018 Feb;158(2):319-322

Authors: Ziai K, Sahyouni R, Moshtaghi O, Vu K, Goshtasbi K, Ghavami Y, Lee L, Lin HW, Djalilian HR

Abstract
Since the introduction of the Sunshine Act in 2010 and Open Payments Database (OPD) in 2013, a significant amount of data has been collected on physicians and the payments received through ties with pharmaceutical and medical device companies. To date, a study within the field of otology and neurotology using data from the 2015 OPD has not been conducted. As such, we assessed the validity and accuracy of OPD information for otologists and neurotologists (O&Ns). Of the 126 physicians listed as O&Ns in the OPD, 25 were actually general otolaryngologists, and 1 was a cardiologist. In addition, 88 O&Ns were misclassified by the OPD as general otolaryngologists. A total of 1156 payments, summing $1,966,204, were made to O&Ns as a whole, with 646, 507, and 3 payments classified as general, research, and ownership/investment interests, respectively. Analysis of OPD data for O&Ns demonstrates a significant financial relationship between O&N physicians and industry, as well as noteworthy inaccuracies in the OPD that likely affect other subspecialties.

PMID: 29389305 [PubMed - in process]



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Is the Program-Specific Paragraph Responsible for Declining Application Numbers? A Commentary.

Is the Program-Specific Paragraph Responsible for Declining Application Numbers? A Commentary.

Otolaryngol Head Neck Surg. 2018 Feb;158(2):215-216

Authors: Kramer S

Abstract
An alarming trend of declining applications to otolaryngology-head and neck surgery has surfaced over the past 3 years. There are many possible explanations for this decline, and a recent publication has implicated "impossible" qualifications as the reason for this decline. While these qualifications may deter a significant number of potential applicants, they have not changed significantly in the past 5 years and do not seem to explain a sudden decline. This commentary argues that the program-specific paragraph, which was introduced in 2015, may be at least in part responsible.

PMID: 29389304 [PubMed - in process]



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Clinical Consensus Statement: Balloon Dilation of the Sinuses.

Clinical Consensus Statement: Balloon Dilation of the Sinuses.

Otolaryngol Head Neck Surg. 2018 Feb;158(2):203-214

Authors: Piccirillo JF, Payne SC, Rosenfeld RM, Baroody FM, Batra PS, DelGaudio JM, Edelstein DR, Lane AP, Luong AU, Manes RP, McCoul ED, Platt MP, Reh DD, Corrigan MD

Abstract
Objective To develop a clinical consensus statement on the use of sinus ostial dilation (SOD) of the paranasal sinuses. Methods An expert panel of otolaryngologists was assembled to represent general otolaryngology and relevant subspecialty societies. The target population is adults 18 years or older with chronic or recurrent rhinosinusitis (with or without nasal polyps, with or without prior sinus surgery) for whom SOD is being recommended, defined as endoscopic use of a balloon device to enlarge or open the outflow tracts of the maxillary, frontal, or sphenoid sinuses, as a standalone procedure or with endoscopic surgery. A modified Delphi method was used to distill expert opinion into clinical statements that met a standardized definition of consensus. Results After 3 iterative Delphi method surveys, 13 statements met the standardized definition of consensus while 45 statements did not. The clinical statements were grouped into 3 categories for presentation and discussion: (1) patient criteria, (2) perioperative considerations, and (3) outcomes. Strong consensus was obtained for not performing SOD in patients without sinonasal symptoms or positive findings on computed tomography (CT) in patients with symptoms only of headache or sleep apnea without criteria for sinusitis. In addition, strong consensus was met that CT scan of the sinuses was necessary before performing SOD and that surgeons need to understand and abide by regulations set forth by the US Food and Drug Administration if they choose to reuse/reprocess devices. Conclusion Expert panel consensus may provide helpful information for the otolaryngologist considering the use of SOD for the management of patients with a diagnosis of rhinosinusitis. This panel reached consensus on a number of statements that defined the use of SOD as inappropriate in the management of a variety of symptoms or diseases in the absence of underlying sinusitis. When patients meet the definition of chronic sinusitis as confirmed by CT scan, SOD of the sinuses can be indicated and/or effective in certain scenarios. Additional consensus statements regarding proper setting and safeguards for performing the procedure are described.

PMID: 29389303 [PubMed - in process]



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Commentary on Bowe et al, "The State of the Otolaryngology Match: A Review of Applicant Trends, 'Impossible' Qualifications, and Implications".

Commentary on Bowe et al, "The State of the Otolaryngology Match: A Review of Applicant Trends, 'Impossible' Qualifications, and Implications".

Otolaryngol Head Neck Surg. 2018 Feb;158(2):217-218

Authors: Bhalla V, Sykes KJ, Kraft SM, Chiu AG

Abstract
An objective evidence-based review of the metrics used to evaluate applicants entering our field ultimately found these figures to have upward trends without any major correlation to performance in residency. The rise of these metrics coincides with a yearly drop in senior applicants, and in 2017, nearly 10% of programs did not match their contingent. The causes of unmatched spots must be examined to ensure that the field of otolaryngology can continue to grow and attract medical students who will excel in our field. Considerations into revising the applicant selection process, early introduction and mentorship within the otolaryngology field, and changes to the current otolaryngology interview process are discussed.

PMID: 29389302 [PubMed - in process]



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JFB, Vol. 9, Pages 15: Towards Additive Manufacture of Functional, Spline-Based Morphometric Models of Healthy and Diseased Coronary Arteries: In Vitro Proof-of-Concept Using a Porcine Template

JFB, Vol. 9, Pages 15: Towards Additive Manufacture of Functional, Spline-Based Morphometric Models of Healthy and Diseased Coronary Arteries: In Vitro Proof-of-Concept Using a Porcine Template

Journal of Functional Biomaterials doi: 10.3390/jfb9010015

Authors: Rachel Jewkes Hanna Burton Daniel Espino

The aim of this study is to assess the additive manufacture of morphometric models of healthy and diseased coronary arteries. Using a dissected porcine coronary artery, a model was developed with the use of computer aided engineering, with splines used to design arteries in health and disease. The model was altered to demonstrate four cases of stenosis displaying varying severity, based on published morphometric data available. Both an Objet Eden 250 printer and a Solidscape 3Z Pro printer were used in this analysis. A wax printed model was set into a flexible thermoplastic and was valuable for experimental testing with helical flow patterns observed in healthy models, dominating the distal LAD (left anterior descending) and left circumflex arteries. Recirculation zones were detected in all models, but were visibly larger in the stenosed cases. Resin models provide useful analytical tools for understanding the spatial relationships of blood vessels, and could be applied to preoperative planning techniques, but were not suitable for physical testing. In conclusion, it is feasible to develop blood vessel models enabling experimental work; further, through additive manufacture of bio-compatible materials, there is the possibility of manufacturing customized replacement arteries.



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Demonstration of simulated annealing optimization for permanent breast seed implant treatment planning

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Publication date: Available online 1 February 2018
Source:Brachytherapy
Author(s): Michael Roumeliotis, Brock Yates, Elizabeth Watt, Amy Frederick, Tyler Meyer
PurposePermanent breast seed implant (PBSI) is a developing brachytherapy technique for the treatment of early-stage breast cancer. In current practice, PBSI uses manual planning strategies to generate clinical treatment plans. In this work, a simulated annealing-based algorithm is developed to demonstrate the first application of inverse optimization for PBSI.Methods and MaterialsTarget, skin, and chest wall muscle contours, exported from a treatment planning system in digital imaging and communications in medicine format, are used as inputs. To optimize, the user defines the dose–volume histogram objectives for the target and specifies a relative weighting for target and skin constraints. A 10-patient cohort of previously treated patients was planned by using the inverse optimization algorithm. Plan quality was compared to the clinically treated manually generated plans using the V90%, V100%, V150%, and V200% for the planning target volume (PTV), V90% and D0.2 cc for skin dose, and PTV conformity indices.ResultsFor each of the 10 patients, patient-wise paired differences between inverse and manual plans were analyzed and presented in box plots. Comparing inverse and manual planning techniques, a statistical difference was not observed (p > 0.05) in PTV coverage criteria (V90%, V100%) and dose to skin2mm. A statistical difference was observed in the inverse plans as a reduction of the V150% (mean of 6.2%) and increase in conformity index of the 20%, 50%, 90%, and 100% isodose lines.ConclusionsThis work presents the first application of inverse optimization used to generate PBSI treatment plans. A 10-patient cohort previously treated with PBSI was retrospectively planned for comparison with the clinically treated manually generated plans.



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A buzz in the ear!

A buzz in the ear!

N Z Med J. 2018 Feb 02;131(1469):64-65

Authors: Bakshi SS

PMID: 29389931 [PubMed - in process]



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Intestinal-type adenocarcinoma of the sinonasal tract: an update.

Intestinal-type adenocarcinoma of the sinonasal tract: an update.

Curr Opin Otolaryngol Head Neck Surg. 2018 Jan 30;:

Authors: Rampinelli V, Ferrari M, Nicolai P

Abstract
PURPOSE OF REVIEW: Intestinal-type adenocarcinoma (ITAC) is one of the most frequent sinonasal tumors, especially in European countries. The purpose of this article is to review the most recent literature, with special emphasis on biological and genetic profile and treatment guidelines.
RECENT FINDINGS: Results on large series support transnasal endoscopic surgery as the technique of choice in the large majority of patients with ITAC. Adjuvant radiotherapy is recommended in advanced-stage and high-grade lesions. More robust data are required to confirm that early-stage, low-grade lesions can be treated with exclusive surgery. The efficacy of new chemotherapy and biotherapy regimens and the added value of heavy particle radiotherapy are currently under evaluation. With a 5-year overall survival ranging between 53 and 83%, which is mainly impacted by local recurrences, ITAC requires a more detailed understanding of its biology. Genetic and biological studies have identified alterations in the molecular pathways of EGFR, MET, and H-RAS which might be considered as potential targets for biotherapy.
SUMMARY: Surgery still plays a key role in the treatment of ITAC, but multidisciplinary management is mandatory. Although further validation is needed, the role of nonsurgical treatment strategies is rising, in agreement with the progresses made in the biological profiling of the disease.

PMID: 29389737 [PubMed - as supplied by publisher]



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A systematic review on Chinese herbal treatment for radiotherapy-induced xerostomia in head and neck cancer patients.

A systematic review on Chinese herbal treatment for radiotherapy-induced xerostomia in head and neck cancer patients.

Complement Ther Clin Pract. 2018 Feb;30:6-13

Authors: Nik Nabil WN, Lim RJ, Chan SY, Lai NM, Liew AC

Abstract
BACKGROUND: Over 80% of head and neck cancer patients suffer from radiotherapy-induced xerostomia (dry mouth). Xerostomia affects cancer patients' quality of life, and xerostomia sometimes persists throughout the patients' lifetime. This review aimed to evaluate the effectiveness and safety of Chinese herbs in relieving radiotherapy induced xerostomia.
METHODS: Systematic searches were conducted on 6 databases (English and Chinese). Studies published up till May 2017 were considered for inclusion.
RESULTS: A final 14 RCTs (total 994 head and neck cancer patients undergoing radiotherapy) compared Chinese herbs with no herbs, were included in analysis. Very low to moderate quality of evidence found Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications (such as oral mucositis and loss of appetite) in head and neck cancer patients.
CONCLUSION: There is limited evidence that Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications in head and neck cancer patients.

PMID: 29389481 [PubMed - in process]



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Bioreducible nanocapsules for folic acid-assisted targeting and effective tumor-specific chemotherapy

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Biofunctional Sr- and Si-loaded titania nanotube coating of Ti surfaces by anodization-hydrothermal process

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A novel therapeutic strategy for cartilage diseases based on lipid nanoparticle-RNAi delivery system

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pH-responsive charge-reversal polymer-functionalized boron nitride nanospheres for intracellular doxorubicin delivery

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Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Prakash P. Praharaj, Sujit K. Bhutia, Sunitha Nagrath, Rhonda L. Bitting, Gagan Deep
Traditional 2D cell cultures do not accurately recapitulate tumor heterogeneity, and insufficient human cell lines are available. Patient-derived xenograft (PDX) models more closely mimic clinical tumor heterogeneity, but are not useful for high-throughput drug screening. Recently, patient-derived organoid cultures have emerged as a novel technique to fill this critical need. Organoids maintain tumor tissue heterogeneity and drug-resistance responses, and thus are useful for high-throughput drug screening. Among various biological tissues used to produce organoid cultures, circulating tumor cells (CTCs) are promising, due to relative ease of ascertainment. CTC-derived organoids could help to acquire relevant genetic and epigenetic information about tumors in real time, and screen and test promising drugs. This could reduce the need for tissue biopsies, which are painful and may be difficult depending on the tumor location. In this review, we have focused on advances in CTC isolation and organoid culture methods, and their potential applications in disease modeling and precision medicine.



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Fusion genes: A promising tool combating against cancer

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Xiaofeng Dai, Rutaganda Theobard, Hongye Cheng, Mengtao Xing, Jianying Zhang
The driving roles of fusion genes during tumorigenesis have been recognized for decades, with efficacies demonstrated in clinical diagnosis and targeted therapy. With advances in sequencing technologies and computational biology, a surge in the identification of fusion genes has been witnessed during the past decade. The discovery and presence of splicing based fusions in normal tissues have challenged our canonical conceptions on fusion genes and offered us novel medical opportunities. The specificity of fusion genes to neoplastic tissues and their diverse functionalities during carcinogenesis foster them as promising tools in the battle against cancer. It is time to re-visit and comb through our cutting-edge knowledge on fusion genes to accelerate clinical translation of these internal markers. Urged as such, we are encouraged to categorize fusion events according to mechanisms leading to their generation, oncological consequences and clinical implications, offer insights on fusion occurrence across tumors from the system level, highlight feasible practices in fusion-related pharmaceutical development, and identify understudied yet important niches that may lead future research trend in this field.



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Colorectal cancer prevention: Immune modulation taking the stage

Publication date: Available online 31 January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Rochelle Fletcher, Yi-Jun Wang, Robert E. Schoen, Olivera J. Finn, Jian Yu, Lin Zhang
Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.



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